David Erritzoe, MD, PhD. May 2023

June 13, 2023

Title: Psychedelic Therapy for Depression - Clinical and Neuromechanistic Data

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00:06Hello everyone and thanks for coming
00:09to our May Psychedelic Seminar,
00:11our last for this academic year.
00:14We have a treat today.
00:15David Oritzo from Imperial College
00:17in London will be presenting.
00:19He was invited by Mark Patanza.
00:21Thank you Mark for making this connection.
00:25So David is a.
00:29Senior Clinical Senior Lecturer in
00:30General Psychiatry at the Centers
00:32for Neuropsychopharmacology and
00:33Psychedelic Research at Imperial.
00:35He's a consultant psychiatrist at Saint
00:38Charles Hospital and he's very active
00:40in research using PET MRI and other
00:43techniques to investigate neurotransmitter
00:45abnormalities in the brain, modulations,
00:48modulation of neural circuitry,
00:50and in particular and of
00:51interest to this audience,
00:53psychedelics in which he is so he is the
00:55clinical director and the deputy head.
00:57Of the Center for Psychedelic
00:59Research at Imperial,
00:59which has been one of the real
01:01Trail Blazers in the in the modern
01:05era of psychedelic research.
01:08So David's talk today is psychedelic
01:11therapy for depression clinical
01:13and neuromechanistic data.
01:15We've actually seen compasses data
01:17recently and had a discussion there
01:20about psychological mechanisms.
01:22And we've done a little bit of neuro imaging.
01:23Actually Lucy Berkovich is here gave
01:25us a beautiful overview of neuro
01:26imaging earlier in the year.
01:27So we have that the audience
01:29is primed for this,
01:30for this material.
01:31And we very much look
01:32forward to seeing your work.
01:34Thank
01:34you so much for, for having me.
01:38Let me share my screen.
01:40Can you see this? Yeah,
01:45it's perfect. Good.
01:48OK. So, yeah, so thanks a lot for for
01:51the invite and for the kind introduction
01:54the obviously probably you know you know
01:57there will be a a great deal that is,
02:01is that probably familiar we can discuss
02:04some of it probably some here will be more
02:08MRI expertise than than I am I come more.
02:11From PIT originally and also as mentioned
02:15you know from clinical psychiatry,
02:18but in the center we we use
02:20different imaging modalities, MRI,
02:22G and and and also some PIT although
02:24you in the instruction you made
02:26it sound like I do a lot of PIT,
02:28It's difficult to fund some of that.
02:30So it's it's limited but we do
02:33some quite exciting stuff often
02:35quite small samples unfortunately.
02:37And the the nature of of of
02:39doing pet in academia I think
02:43as also you you in terms of Imperial College,
02:46I've been involved there since 2009.
02:50So for quite a long time.
02:51Obviously as a lot of you will
02:53know alongside both David Knott
02:54and and Robin Cart and a lot of
02:56other fantastic colleagues and in
02:58the last couple of years Robin has.
03:02Migrated over to your part of the world
03:04although on the other coast to San Francisco.
03:06So he's over there still quite involved
03:09in and we have very regular meetings he's
03:12involved in supervision into some of the
03:14trials that he initiated but that we
03:16are still carrying out and then there's
03:19some some new stuff where that he has
03:22less in in involvement is but he's he's
03:25in he's he's very involved still just to
03:27to to make that clear okay so let me.
03:31Go to the first slide,
03:32this is just sort of a little overview of
03:38the compounds that we're talking about,
03:40phenothylamines, tretamines all together
03:46being the group of of psychedelics and.
03:49The classic cell genetic ones are
03:52the ones mainly in in focus of the
03:55work we're doing and but actually not
03:58particularly masculine and no longer
04:01much LSD work in our lab specifically.
04:04But these compounds together
04:06are typically the one referred
04:08to as the classic cell genetic,
04:10sometimes also including five Emile DMT.
04:13As we can see they are quite similar
04:16in structure to serotonin itself.
04:19Structure, which also informs some
04:22of the pharmacology mimicking to some
04:25degree effects of serotonin by agonizing
04:28range of receptors in the system.
04:31This is probably so familiar that I won't,
04:34you know spend too much time on this.
04:37Just mention obviously we have these
04:40associated compounds that sometimes
04:42are referred to psychedelics sometimes
04:45is atypical psychedelics MTMA that's.
04:48Is very progressed in the development
04:51maps finished have finished their phase
04:54three trials for PTSD and then Katz,
04:57Amin and and Ivocaine that could be
05:01described as dissociative psychedelics
05:03with overlapping phenomenology.
05:06But still.
05:07Also with some significant
05:10pharmacological differences in case,
05:12I mean already being repurposed
05:14and licensed and nasal spray
05:16for for for depression as well.
05:18So into mental health from
05:22medicine in terms of
05:27let me see here. Just a little
05:31bit more about the pharmacology.
05:32They stimulate these receptors.
05:34As I mentioned,
05:35one of them is a two way receptor
05:38abundant in high function regions,
05:43evolutionaryly preserved, pronounced
05:46into the high function cortical areas,
05:51whereas SSRI&amp;MDMA to the XG.
05:55Extreme degree work presynaptically on
05:57this sort of production side of things
05:59and releases and inhibits reuptake.
06:04Their the psychedelics more directly
06:07work on receptors including the
06:10two A and we can see that the
06:12more offensive they have for the
06:142A the the more potent they are.
06:17As psychedelics. We can see the
06:19mapping the 2A receptor using PET.
06:22That they are distributed
06:23mainly cortical regions.
06:25They are difficult to quantify with
06:27PET in subcortical regions due
06:32to sort of poor signal to noise.
06:35We can use PET as well to establish
06:38the relationship between binding
06:41to this specific to a receptor
06:44and the intensity and also related
06:46for that matter to plasma levels.
06:48All that done.
06:49That Copenhagen group that I'm
06:51originally coming from where I did
06:52my PSD now I don't know starting
06:55that almost 20 years ago back in
06:57Copenhagen would get the most
06:59close and then people there.
07:01So they have done that and they're
07:03currently actually doing pet occupancy
07:05work with LSD as well at the moment.
07:10What what is a little bit interesting
07:12on on on the occupancy slide,
07:16pick it to the right.
07:18Is that if you look in the sort of
07:21low dose range with the that those
07:25doses that you can't see on the slide
07:28on the low part of the the the curve,
07:31they are in the range of what people
07:34use for micro dosing and that shows
07:37us that there's actually significant
07:40occupancy 3040% of doses that people.
07:45Use for micro dosing.
07:47So that means the pharmacologically
07:49on the two way could be some effects
07:51which I think is sort of a nice extra
07:53information from the occupancy work there.
07:56You can also see that if we say
07:58Lexing block the two way receptor
08:00then take the mute the static
08:02effect and also some mood improving
08:04effects shown in in some studies.
08:07So just this is now years back,
08:11six years, seven years back we did.
08:13At in period the first depression trial
08:16for for many years with a psychedelic
08:19intervention that was after we have
08:21been doing work in healthy people
08:23in order to establish some of the
08:26brain imaging effects and the neuro
08:28correlates to psychological effects
08:30of psychedelics and also safety and
08:32and getting familiar with using the
08:35combats and study them before we
08:37we took it back into a clinical.
08:40Indication and and that was depression
08:42some of the reasons why we did it
08:44in depression was that the effects
08:46that we saw in the healthy in a way
08:50counter at what was in the opposite
08:52direction of some of the moist.
08:55That list and and reproduced findings
08:59in depression with MRI including
09:03we saw reduction in in prefrontal
09:08activations areas that.
09:10In meta analysis come out as hyper
09:14activity with with the MRI and also
09:17BE and also a range of treatment
09:22with antidepressant effects have
09:24reduced those regions.
09:25So that was a part of the sort of
09:27imaging tick list things that we
09:30checked before we we moved it into.
09:33To patients obviously we also
09:35reviewed the existing at that point
09:38safety data and looked at
09:40reviewing of data from the first area in
09:42the 50 sixties before we did this trial.
09:46So this trial was an open
09:48label in 20 patients with.
09:50Treatment resistance or fulfilling
09:52criteria for treatment resistant
09:55depression and most of them severely
09:57depressed that baseline as you
09:59can see at at baseline on this
10:02graph where the patient depression
10:04scores with quits are plotted.
10:06So we did a test dose of 10 milligram and
10:09then the real dose a week later was 25.
10:11The 10 milligram was also due
10:13to Caution and Ethics Committee
10:15at that point back in 2000 and.
10:1815 or something like that.
10:21So we did this open label,
10:22single arm proof of concept,
10:24so no, no control condition.
10:26We had to pray MRI at baseline and then
10:29the day after the the 25 milligram dose.
10:32So that was basically that trial and
10:35and what we saw there was was good and
10:38response overall obviously again open
10:41label important to mention to to to
10:44to mention again and as we get the bold bar.
10:48Nice and sustained effects overall
10:50for the group and that obviously
10:53induced a lot of yeah interest
10:56and optimism in the space.
10:58And I wouldn't say just that
11:00trial did the whole thing,
11:01it didn't but it it was part of what
11:04inspired some of the more commercial
11:07industry activities in the space to
11:10scale this up into larger scale files
11:12and as as as we know Compass have
11:15have done a multi set up phase two.
11:17Free trial,
11:18more recently we we we also saw
11:21in this trial and that has been
11:24seen in a lot of different studies
11:26and different indications that the
11:29treatment outcome is associated
11:30with the subjective experience.
11:32And more specifically when that is
11:35sort of zoomed in a bit on aspects of
11:38the acute experience meshes typically
11:40things related to the psychological
11:43peak or mystical type experiences here.
11:46The construct ocnic boundlessness from
11:48the altered state of consciousness scale
11:51and we can see relationships between
11:54the score there and the outcomes.
11:56So single intervention with this,
12:01you know, lasting effect, not forever,
12:04but in this trial good sustained
12:07effects and then that the experience
12:09was related to the outcome.
12:11So all that obviously.
12:14Suggesting a new and different
12:16and interesting paradigm,
12:18Obviously not new new,
12:19but very different and new in
12:22conventional psychiatry in modern times
12:24because because that's not what what
12:27we're used to in in mental health.
12:29Then COMPASS did a larger version
12:35of it than logical next step which
12:38was to instead of just having 25
12:40milligram have different doses
12:42of 1/10/25 and for that reason.
12:45At that point that was in a way what
12:47we would have done as our next study
12:48sort of kind of logical next step,
12:50but because that was what they ended
12:53up doing endorsed and supported by
12:55you know conversations also with
12:57the FDA and so on,
12:59we thought okay then then what,
13:00what other questions that are
13:02relevant for us to try
13:05and address could be possible
13:07different mechanisms of how the
13:09psychedelics work in their in
13:12the treatment of depression.
13:14And therefore we so,
13:17so here is a bit theoretical
13:19background that you with SSRIA lot
13:21of the action there is the steps to
13:24to work through the 1A whereas the
13:26psychedelics are agonizing the 2A
13:29as I mentioned and and the 1A effect
13:33can then reduce stress and also
13:36emotional responsivity, impulsivity,
13:38aggression, anxiety and so on.
13:40But that also for some patients.
13:43Come out.
13:44Particularly the reduction of emotional
13:47responsivity to some degree of of
13:50blunting as a side effect for some
13:52people with that treatment and with
13:54the psychedelics more in in work,
13:57suggesting that it reduces rigidity and
14:01flexibility and perseveration and yeah,
14:06so an increasing.
14:07Both cognitive,
14:08psychological,
14:08flexibility in emotional ability and so on.
14:11So two different magnetism through
14:13two different receptors.
14:15Although it's not that there's not
14:17also some other actions of both
14:20compounds and some psychedelics
14:22also work a lot on the 1A.
14:24So it's a bit of a simplified model,
14:27but nevertheless it then opens up for us.
14:31Yeah.
14:31Can I ask why so so that.
14:33I mean, it's an interesting conceptual
14:35model to divide the two aspects of.
14:37Of depression up in this way,
14:39but why would you say that that SSR
14:42I's for example act primarily on
14:44the 1A when really they're going to
14:47increase the half life of serotonin
14:50that it's released the the two a
14:52focus for psychedelics makes sense,
14:54although of course they also
14:55have one affinity.
14:56The 1A focus for the SSRI don't
14:59understand as opposed to for example,
15:00Buspirone which is A1A agonist and that
15:02would be a cleaner dissociation but
15:04also doesn't work very well clinically.
15:07No,
15:08absolutely. So it's a bit of,
15:11yeah, so, so this is right.
15:14Absolutely. They work by, as you say,
15:16by sort of increasing levels of serotonin.
15:20But it is established that in different,
15:22yeah models that the 1A play a
15:26significant role for the effects of.
15:28S s arise. So it it doesn't
15:30mean that there's not also some,
15:32there are some studies that also
15:33suggest some action through the 2A,
15:35but much, much more more through the 1A.
15:38And I think in in different studies and
15:42also preclinical models that action is
15:45associated with some of those effects
15:47there that are sort of different
15:50from what the 2A mechanism induces.
15:53But it yeah there's some degree
15:56of arbitrary separation by.
15:57Showing it in in this model,
15:59but you're right,
16:00if it was just about showing 1A versus
16:022A then it is not particularly logical
16:04to do an SSRI. So it's it's yeah.
16:07So it was also just to also to see
16:09whether there was any different
16:11obviously in clinical outcomes between
16:14SSRI conventional pharmaco gold
16:16standard pharmacological therapy for
16:19depression and a psychedelic treatment.
16:22But when it came to brain mechanism,
16:23we were sort of thinking a bit in this model.
16:27If that makes sense,
16:28that does actually something that
16:29occurred to me as you were speaking.
16:30There is some literature mostly from
16:32animals that chronic SSR I treatment
16:34leads to down regulation of the two A.
16:36So it you could imagine that the SSR I
16:39leads to increase serotonin everywhere
16:42activates both 1A and 1-2 and two A.
16:45But 2A becomes down regulated by the chronic
16:48treatment and so the net enhancement in
16:502A is limited by that down regulation.
16:52Isn't it that so that there may
16:54in fact that that may be a source
16:56of the specificity. Yeah.
16:58So, so you're saying that chronic
16:59gas is a right lead to down
17:01regulation of 2A and then there will
17:03be less mediate through the 2A and
17:05so. So that's SSRI is causing there
17:06to be more serotonin everywhere,
17:08but there's less 2A receptor.
17:10And so maybe it's awash on the 2A receptor,
17:13but an enhancement of signaling in the 1A,
17:15yeah, that's that's another
17:16way of of thinking about it,
17:18but that they are studies,
17:19but maybe they are not chronic
17:22in some animal literature.
17:23Blocking to A and with
17:27SSRI and seeing effects,
17:28but that's probably more acute
17:29studies in I think that's acute.
17:32Yeah, I think you're right.
17:34That's a good point.
17:35So yeah, so we then designed this trial.
17:42Where the people received 2 doses,
17:442 sessions with with three weeks
17:47between of of psilocybin and
17:49then in the other arm they were
17:52they were they were randomized
17:54to either 259 patients total to
17:57either of these two conditions.
17:58So if they were in the red
18:01psilocybin I'm here with the we use
18:03compasses 25 milligram compound.
18:07If they were in that arm,
18:07then they would receive daily
18:10placebo version of the is a
18:12telegram and they would in both
18:14arm get exactly the sort of.
18:16Not exactly,
18:17because there might have been
18:19a bit more time with therapists
18:21due to the integration part
18:23of it after the psilocybin,
18:25but they received overall similar
18:28preparation support during the experience
18:31and integration session afterwards.
18:34The same room,
18:35same therapist same.
18:37Music and so on.
18:38And they got two placebo sessions
18:41in in when they were in the blue
18:43arm with the active acetalgram,
18:46first three weeks they got 10
18:48and then they were upped up to
18:5020 milligram afterwards for
18:51acetalgram which is pretty standard
18:54clinically with acetalgram.
18:55And obviously As for all studies
18:59and also for our first study it
19:01was done in in in in this sort
19:04of setting environment with.
19:06Some sort of pleasant,
19:07often a bit nature inspired
19:09decoration and dim light and music
19:10and eye mask and and and guides
19:12in the room and they were sort of
19:14prepared through a few I think
19:163 preparation sessions with the
19:19same therapist that then followed
19:21them through the trial and also
19:24through integration afterwards.
19:25And okay.
19:27I actually had this slide,
19:29sorry the way that is explained.
19:31So you see the two arms to the left,
19:33the full dose.
19:342/2 times with three weeks between
19:37and then in mirrored in the other
19:39arm by two one milligrams of the
19:41placebo levels in those item
19:43sessions and then either placebo if
19:45they got to the side and placebo
19:47instead of as a telephone and so on.
19:50And then they the the primary
19:51outcome was at six weeks.
19:53So that means after six weeks of
19:56is a terrible treatment and that
19:57would then be after the three
19:59weeks after the last of the two.
20:02Pull those psilocybin session or
20:05psilocybin session and then there
20:07was imaging sitting at that time
20:09point and also at baseline and then
20:12we followed them up for six months.
20:13So this is just to to show that like
20:17another other places we are building,
20:20not building but decorating spaces that
20:23are in a way a bit more specifically.
20:29Designed for for,
20:30for holding these spaces and
20:32providing this therapy.
20:34And now we have,
20:35and I don't know why I
20:36show this, but that's because we're
20:38a little bit proud that now we
20:40have our own clinic space within
20:42the health system, within the NHS
20:44National Health System in London,
20:46where we have been allowed to use the
20:49space it was previous in ECT clinics.
20:51That means we don't have to
20:52decorate and take it all down,
20:53which we have to do for years,
20:55which was quite exhausting.
20:56And now we have the rooms decorating.
20:59So yeah, any questions?
21:01I think the
21:01I just chuckling because we have
21:03to do that set up the decoration.
21:05I was just chuckling because we
21:07have to do that in our dosing room.
21:08We have to set everything up
21:09and then take it all down and
21:10then set it all up and then
21:12take. It's so irritating isn't it?
21:14So, so yeah. So we we we also
21:16do that actually for some now.
21:17I think now we're using the room and
21:19the other side so frequently that
21:21I think we are allowed to keep it
21:23actually most of the time at least.
21:25But this one is now sort of.
21:26Permanent I don't know how permanent
21:28until they kick us out but we we
21:30have been allowed to do it and
21:32obviously not obviously but in
21:34collaboration with some some nice
21:36designers that have given us some
21:37tables that are in sort of stone.
21:39So using sort of net bringing some
21:42nature materials in which are not really
21:44open there in a hospital setting and
21:46and some art and some plant plants
21:48and some very scanty me being Danish
21:53mushroom lamps and so on okay so.
21:56And then the results from from this
22:00trial where we compared to esoteric,
22:02if you look to the right you see this
22:04is sort of the main findings there and
22:06and that the primary outcome measure
22:08which was quits this self rated depression,
22:11it didn't separate the two condition at
22:14this primary time points of six weeks.
22:17But actually all the other measures
22:19that we had,
22:20including three other measures of depression,
22:22the two clinician rates at
22:241 Hamilton mattress.
22:26They did separate and so did BDI
22:29and also avoidance and Adonia,
22:31working social function flourishing
22:33and Spielberg anxiety, wellbeing,
22:35suicidality favored this,
22:37the psilocybin condition in this data set.
22:43And you have the,
22:45the well-being on the bottom left and
22:47and you can also see a quick onset.
22:49Also when we look at response
22:51and remission rates,
22:52they were quite a lot stronger for the
22:56psilocybin condition as well in this trial,
22:59looking at some of the cycle,
23:01sorry. What do you make of the
23:02fact that you got such a rapid response
23:04in your Lexapro group like the kinetics
23:06of the two curves don't look different.
23:08No, I I think it's it's.
23:12Because so why you have such a
23:15quick response to esoteric that's
23:17because I think that's because of the
23:20psychological support in both arms so
23:23and and the first session will with
23:25a 1 milligram with all the music,
23:28the therapies, the guiding and all that.
23:30So so that obviously was also
23:32present in the in the esoteric arm.
23:34So I think that's the reason because
23:36you're right if it has just been an.
23:38You know just SSRI with nothing else.
23:41Then it probably would have been a a
23:43slower slope that might not have even
23:45gone that far because I think the
23:47psychological support of all those
23:50many hours accumulated over the time
23:52of the study has has also mixed into
23:55the response to in the SSL from.
23:58Yeah, and when it comes to why quits
24:02is actually acting a bit differently
24:04from the others.
24:05We have a great postdoc researcher,
24:10Brandon Weiss, who has recently.
24:13I don't think it's out yet,
24:15but it has been accepted.
24:17A nice paper where he actually really
24:20dissects the quits versus the others and.
24:23Discusses differences in these meshes
24:25and and and and analyzes it and also
24:28constructs a factor from all the
24:30different 4 measures at at sort of
24:33single depression factor from them
24:35and that also clearly separates.
24:38I don't have it here on these slides
24:40but that's coming out very soon.
24:42It's not to try to sort of speak quits
24:45down is trying to understand why that
24:48actually might be the case that we
24:50saw that difference in this in the meshes.
24:52So in terms of rumination
24:54and thought suppression,
24:55they too sort of kind of defense mechanisms.
25:02Rumination sort of a maladaptive one.
25:05Thought suppression I think can both
25:06be sort of a good and a bad thing.
25:08But nevertheless we saw a decrease in
25:11measures of that following psilocybin
25:13and we didn't see that following as a
25:17telegram experiential avoidance we also saw.
25:24Reductions in in the psilocybin
25:27arm and we could see that those
25:32effects of experiential avoidance
25:35via increases in connectedness
25:37was associated with improvement
25:39in in the in different outcomes,
25:42well-being depression and so
25:43on in in this in this study.
25:46And also other things that again
25:49maybe show some degree of and this is
25:52again little bit sort of simplified.
25:54But if you think about the what a
25:56lot of patients described with some
25:58degree of blunting and in a way putting
26:00the lid on in terms of of of their
26:03symptoms and and their presentations,
26:04their ability to sort of.
26:07Emotionality and so on then it seems
26:11like the the psychedelics psychological,
26:14psychologically,
26:14mechanistically,
26:15if anything possibly does be the opposite.
26:18Sort of taking that lid off and
26:21and another example of that is
26:22you can see here ability to cry,
26:24ability to feel compassion and in
26:26particular I guess the ability to
26:28feel intensive motion increases
26:30in the psilocybin condition much
26:33more than than for as a teleprom.
26:36And so suggesting a bit of the same thing.
26:41So I'm focusing a bit on depression in
26:43this talk, but as you probably all know,
26:45there's a lot of different trials
26:48being done and already some pilots.
26:50Gone for all the conditions and
26:52indications OCD we are currently
26:54doing more OCD work at Imperial.
26:56There's a wonderful work over on
26:58your side of the pond with end of
27:00life distress at NYU and and James
27:03Hopkins anxiety studies showing
27:05reductions their addiction namely so
27:09far alcohol and nicotine dependence
27:13positive outcomes and so on.
27:15But the depression one there are more
27:18and more studies coming including the.
27:20Relatively recent COMPASS trial
27:22that I understand you guys have
27:24already heard about in detail and
27:26discussed the previous meetings
27:28that also showed a good and.
27:30Sustained effect at at at at three
27:33months with the 25 milligram.
27:36Also when we sort of look across studies,
27:38this is actually it can be updated soon.
27:41So there will be even more
27:43studies represented on the slide.
27:45But overall it's not just our initial trial,
27:49both COMPASS and a range of
27:51other trials that have measured.
27:53Depression severity see see long
27:56lasting effect for months in average
28:00in these trials and when we look at
28:04effect sizes within condition so pre to
28:08post and look at coins D effect sizes.
28:11They are in in the range listed
28:13there 1.1 to 2.9 and when we
28:16look at between condition,
28:17when there is some kind of control condition,
28:19they are in the range of 0.4 to 1.49 and
28:24all these effect sizes are sort of larger.
28:26So then what is conventionally seen with
28:31antidepressant pharmaco therapy and
28:34talking therapies which is of course part
28:37of the reason why it's it's a bit of a.
28:40A popular topic and is being
28:43explored massively.
28:44So more recently we were involved
28:46at Imperial with a company called
28:48small Pharma that is sort of that's
28:51london-based that use intravenous DMT.
28:54So their own compound is below 26
28:57which is a DMT molecule that they
29:00used in patient with depression.
29:03So in that trial.
29:05There were 34 patients randomized to
29:07either to two one of two conditions
29:10so either they got a DMT and infusion
29:13over 10 minutes in total so a short
29:1720 minutes experience and because
29:19DMT is is is short and particularly
29:24when done intravenously and but
29:26also if it's smoked and then.
29:30And the other half of the patients
29:32they were allocated to placebo and
29:34then they will follow for two weeks
29:36and then the two weeks the blind was
29:38broken and then the people who got
29:41placebo then got a DNT experience and
29:44the other got a second DNT experience.
29:46And there's also in this trial sustained
29:49antidepressant effect at at 12 weeks at
29:53even there is a treatment response after.
29:57Six months of of 40% in in the data
30:01that we we we are currently working on
30:06in this study and also other measures
30:09of depression including B&amp;RPDI but also
30:11anxiety measures and wellbeing measures.
30:14All I would say kind of mimic what has
30:17been seen with oral psilocybin and
30:19remember oral psilocybin is a 4-5 hour
30:22session and here it was just 20 minutes.
30:25IV DMT experiences and at Yale there
30:29has been also a pilot study also
30:33showing antidepressant response with
30:36with DMT and a little bit about some
30:40of the work done by us and others in
30:43the space of trying to understand
30:45mechanisms using brain imaging.
30:48We have this sort of up in the
30:50top right corner we have the.
30:54The MRI functional network and
30:56connectivity that the different colors
30:59are along the periphery represented by
31:01functional networks with MRI and on the
31:05placebo these networks are sort of developed,
31:10are segregated,
31:12separated,
31:12so mainly connected within regions,
31:15mainly connected within the networks
31:18and then under psilocybin and
31:20also other classic psychedelics.
31:22Then that is broken down,
31:24so there is
31:28less separation of these function
31:31networks and also breaking down of
31:33some of the connectivity within
31:35the networks and that has been now
31:38quite consistently found with these
31:40compounds and also we can see higher
31:43signal diversity in ET brain signal
31:46and for that matter MRI signal.
31:50We also that's not us but
31:54people doing preclinical work.
31:57Olson's lab and and several other
32:00labs focusing on brain plasticity
32:03neuroplasticity can see that happening
32:06in tissue after psychedelics including
32:09also ketamine and and and MTMA in the
32:14tissue and I also know at Yale have.
32:17Looked at ketamine so far with
32:20a tracer called UCPJ which is a
32:23synaptic basically 2A receptor.
32:25So marker that is that can be used
32:32as a measure of synaptic density,
32:35at least interpreted in that
32:37way and we also doing work with
32:39that with ketamine and TMT.
32:41Currently we also have other in vivo human.
32:45Paradigms with e.g.,
32:47visual long term protentiation in
32:49particular that we are sort of having
32:52in a lot of our studies these days.
32:55Psychologically increasing connectedness
32:56is one of the current themes,
33:00not currently,
33:01but consistent themes in narratives from
33:03patients undergoing psychedelics and
33:06psychedelic therapy and also avoidance
33:08turning into acceptance as I showed before.
33:11Trade openness increasing in
33:14some studies with psychedelics,
33:16cognitive flexibility and
33:19psychological insight increases.
33:21Negative cognitive biases
33:23decreases rumination,
33:24thought,
33:25the president experience and as I
33:28mentioned for decreasing in terms
33:30of of sort of a model of of that is.
33:36Considered of of how these compounds
33:38work is sort of in the framework
33:42of prediction error and top down
33:46regulation that that Robin Carhartt has
33:49and others as well have been describing.
33:53Robin named this his specific model,
33:57the Rebus model and the idea.
34:02I guess is that instead of having this
34:05sort of top down in interpretation
34:07and framing of how we see and
34:10experience the world and ourselves,
34:12then under the psychedelics there's
34:14more at bottom up and possibly a
34:17reshaping of these priors of these
34:20models and there's some some evidence.
34:25Of some of this bottom up effects
34:28following psychedelics and then if
34:30we look at the top right again that
34:32I started describing on this slide
34:35the the functional network model,
34:40then that is in the acute
34:42state with psychedelics.
34:43So we and also others are looking
34:45into sort of instead of in the
34:47acute psychedelic state because
34:48that is now quite consistently
34:50showing some of these effects.
34:52What about?
34:53Pre to post, so as you saw on the
34:58some of the first slides and now
35:00two separate depression trials,
35:01we had MRI and what we see there,
35:05OK, before I mentioned that in our
35:09Healthy Psychedelic Naive trial
35:11that data are on their way out.
35:14So it's not published yet.
35:15In Psychedelic Need Healthy,
35:17we saw a measure of modularity.
35:21Being associated with well-being.
35:23So the more that modularity is being reduced,
35:26the more will be increases.
35:27And modularity is sort of a bit an
35:30inverse measure of global connectivity.
35:32So modularity being reduced is sort
35:35of increased in global connectivity
35:38with the global measure of that.
35:40And when we then looked at our
35:43two separate depression samples,
35:45we could see that modularity went down in.
35:50The the the patients from before the
35:53psilocybin intervention to after in
35:55two separate samples and that the
35:58degree to which the modularity was
36:01decreased also here was associated
36:04with psychological effects,
36:06in this case improvements in in depression.
36:10And we didn't see such relationships in
36:14the esoteric condition in the in that trial.
36:17So we didn't see changes modularity or in
36:20the relationship with depression measures.
36:23We also did emotional faces in the
36:27trial and could see that whereas we
36:31see reduction in amygdala response
36:34to fearful faces and a sort of
36:38global overall reduction in in.
36:40Brain responsivity to emotional
36:43faces that is not seen in in
36:47the psilocybin face condition.
36:50So again a little bit the same thing
36:54about this lid on lid off that at
36:58least there's no lid on coming from.
37:01The psilocybin in this comparison as well,
37:03so pointing in the same direction and
37:05then I just want to talk a little bit
37:07of a couple of minutes about micro dosing.
37:10Let me see the time.
37:13So in terms of micro dosing,
37:16it's a bit of a troubled child that that
37:18people tend to disagree quite a lot.
37:20What is the evidence for micro dosing?
37:22Is it having any proper effects,
37:24Is it promising or not for effects,
37:27affective disorders, mood, anxiety and so on?
37:31Or is it not?
37:32People really disagree I would say
37:34and I think that one of the reasons
37:36is it depends on what chunks of
37:39evidence people are referring to
37:40and thinking of and and looking at.
37:43So therefore what we did was to try
37:47to look at all the data evidence for
37:50micro dosing and sort of arrange
37:52it based on where it sort of sits
37:55in the hierarchy of evidence from
37:57anecdotes up to proper control
37:59with a placebo condition
38:01and blinding and so on.
38:02And and to basically separate all
38:05the different micro dosing evidence
38:07into four different categories,
38:09so into effective as one.
38:12And then cognitive and other psychological
38:17and and somatic symptoms and try to
38:21look at all the different trials.
38:23So when we do that,
38:24you can see that if we are in the
38:26bottom of the hierarchy which we are
38:28here and when it says Christmas tree,
38:30it will appear in a second.
38:31Why we have so far called
38:33it a Christmas tree plot.
38:34It's basically a pyramid of of evidence.
38:37So you see here up in the
38:38top you have randomized,
38:39you would have meta analysis
38:40sitting up in that.
38:41At top of the pyramid,
38:43but there are no meter analysis yet and
38:45then you go down perspective and then
38:48case control retrospective qualitative.
38:50So if you look at the evidence and
38:52if you stay in maybe the left side
38:55of the Christmas tree here you can
38:57see that the effective symptoms,
39:00so the green in the pies or
39:02the Christmas decoration bowl
39:04or whatever we can call them,
39:06they are made in a way that
39:09everything that is proper green so.
39:11Bold green or dark green that
39:14is sort of reported
39:18support in the positive beneficial direction
39:21with these symptoms for micro dosing
39:25condition and you can see when you go up,
39:27when you actually have control conditions
39:29on then the bold green overall
39:32disappears quite a lot from the the plot
39:34and that means that there might be.
39:37Something in that green direction,
39:39There's also things in the red direction
39:41and the green doesn't become bold because
39:43it's not statistically significant.
39:45So if you look at that part, you might
39:48conclude that microtosing is is very,
39:51very promising and interesting
39:53and showing evidence for effects.
39:55But if you move up,
39:57the more control that the studies become,
40:01the the more it sort of dies out and.
40:05And the same for for the other
40:08categories overall.
40:09So it doesn't mean that I'm trying
40:10to say the micro does not work.
40:12I'm just saying that it's about being
40:14a little bit cautious and critical
40:16towards the data and think about what
40:18kind of data we are talking about
40:20and what kind of level of rigidity
40:23and stringency we want to put to the
40:26kind of evidence we conclude on and.
40:29And it's still early days and it
40:31could be that Michael doesn't work
40:32but so far it's not super convincing
40:34beyond the effects of placebo apart
40:36from very few outcomes.
40:40So and and what does that mean?
40:43So obviously we need to
40:45sort of be you know have.
40:50To basically you know exploit the
40:52privilege of micro dosing where we
40:54actually have an ability to placebo
40:56control because these low doses are
40:58much easier to please control is just
41:00quite unpractical and expensive to do
41:04repeated dosing over a long time with
41:06scheduled drugs that are difficult to
41:07give people to take at home and so on.
41:10And and that's why we at some point
41:12did this sort of self blinded
41:14citizen science approach where.
41:16We allow people to follow a manual
41:20written manual so a video they could
41:23follow where they could sort of
41:26blind themselves by by using their
41:28own drug on their own initiative
41:30for their plant micro dosing.
41:32But then the following the manual
41:34would allow them to replace their.
41:38Micro doses with placebo at least for some
41:41of the people if they followed this manual.
41:43So people would then randomly end up
41:45in one of three groups here either
41:48placebo every week for four weeks or
41:50micro dosing every week four weeks Or
41:52a mixed group where they micro dose
41:54one week then placebo for one week.
41:56Micro dose volume.
41:57And then we could see what they were
41:59doing by a QR code in the envelopes that
42:02they constructed with the with the dosing.
42:04For one micro envelope for each
42:06week and we could then through the
42:09QR code that they could scan on lab
42:11see what they were doing and and and
42:14the reason why I'm saying this is
42:16that this study in a way explains
42:19some of the issues and the reason
42:21why I think people disagree a bit
42:24about the evidence for micro dozing.
42:25Because when we look at our data it
42:27in a way confirms all those parts
42:29of the lower part of the Christmas
42:31tree or the hierarchy of evidence.
42:33Because it does show here as an
42:37example mindfulness that that
42:42my computer is not charging and I
42:44don't know why it is plugged in.
42:47Just hopefully this works.
42:50I don't know. We can't charge.
42:52Uh oh, I hope I'm not going to fall out.
42:54It is plugged in.
42:55I don't know why it's not charging.
42:57Anyway, I might disappear if it dies.
42:59I'm sorry about that.
43:02So we can see that mindfulness is
43:05increasing in in in this study.
43:09The issue is that when we look
43:10at the placebo condition,
43:11it also increases.
43:12So in a way if we ignore that we had a
43:16placebo or if we didn't have receive,
43:18we confirmed the anecdotes and actually
43:21quite a solid response for most measures.
43:23It's also then worth to remember
43:25that you have all the recipe from
43:27placebo because it's a very high
43:29popular phenomenon with a lot of
43:31attention to and you belong to a
43:33specific group when you do this,
43:35in particular a few years ago and so on.
43:37So we also see improvements in the
43:39placebo condition and not only
43:41do we see that,
43:42but if you look here it's a
43:44bit difficult to navigate in,
43:46but look at the one to the top left here,
43:48take the first one that is.
43:52The higher you are on the Y axis,
43:56the more of a positive outcome.
43:59So if you take placebo,
44:01guess it's placebo, you're on this level.
44:03If you actually take micro dose but
44:05you wrongly guess it's placebo,
44:07then you don't improve much.
44:10But if you take placebo and that's
44:12actually what you take what you
44:14thought you took micro dose.
44:15Wrongly.
44:15Then you really see a response to the
44:18same level as you do from taking micro
44:20dose and guessing that's micro dose.
44:22So that shows you here that
44:24for a lot of these outcomes,
44:26for most of them not so much for the
44:28more objective task measures here,
44:31acute cognitive performance and then
44:33you don't really see that effect.
44:35Because probably because it's
44:36a much more objective measure,
44:38but these self rated measures if the
44:42expectation placebo effect plays a
44:44big role and we can see that there's
44:4710 times bit more predictive value
44:49of think guessing that you took
44:51micro dose than actually taking a
44:53micro dose And that explains the
44:56discrepancy probably and the reason to
44:59be cautious when evaluating evidence for.
45:01Micro dosing and then just this
45:03one just a little bit of over
45:06approximate what we're doing.
45:07We're doing some gambling
45:08work without psychedelics.
45:09We're doing the plasticity work as
45:11I mentioned both with ketamine also
45:14with DMT and then we're doing some
45:20OCD work, fibromyalgia work
45:22and erection of also work and.
45:24This small farmer trial now is
45:26entering Phase 2B where we have less
45:28involvement but we're sitting with
45:30the Phase 2A data you saw some of it,
45:32it will be published hopefully not
45:34in the near to to distant future and
45:37doing different work with DMT and
45:39setting up and starting five meal
45:40DMT and so on and hopefully setting
45:43up an opiate trial with psilocybin
45:45and also looking at noninvasive brain
45:47stimulation combined with with psychedelics.
45:50We are we are planning and setting
45:51up some pilot work there so.
45:53I will stop here and and thank you
45:56for your attention and thank obviously
45:59all the colleagues involved and so on
46:01and the people have supported work.
46:03Thank you very much and I'll stop sharing.
46:09Thank you David for that great overview of
46:10what I know has been many years of work.
46:12I'm particularly struck by the self
46:14blinding micro dose study that's very,
46:16very clever. Thank you and
46:19I'm glad to say it because then I.
46:23I don't have to brag about how smart
46:25that is and also but I I sometimes brag
46:27about it because it was balances balance.
46:30She gets his idea so I can do it without
46:32being too much of A of a of a ****.
46:35Saying that because I also think it's a
46:38very smart and novel idea to to to do that.
46:41Now I didn't go into crazy details and
46:43it required quite a lot of wonderful
46:46smart bio statistician to help
46:48interpret the data because in that.
46:52A bit wack wacko design we did,
46:54we both obviously we had acute data you
46:57know from day-to-day we had placebo
47:00mixed in to even the micro dosing
47:03addition to make it better blinded and
47:06we also we had a cumulative effect
47:08we had within and between group
47:10and all that same science.
47:12So it was required quite a lot of of good
47:16statistical help to to make sure we got it.
47:19Right.
47:19As well as we could when we,
47:22when we worked on the dates afterwards,
47:25that was a sort of general population
47:27of those who are micro dosing or
47:29interested in micro dosing sample,
47:30not a depressed sample. Is that right?
47:32Exactly. So yeah,
47:33so that means that it was overall
47:36a group of healthy people.
47:38But what we did was we then
47:41zoomed in in sort of retrospect,
47:43so post hoc on the people who were sort of.
47:48Lowest on well-being highest on
47:50neuroticism and and had some scores
47:52on depressive measure to sort of sue
47:55in and just look at that subgroup of
47:57the trial because of all they were.
48:00Yeah and when we did that the
48:01patents were the same but
48:04and one thing that this work does is
48:06really focuses on the placebo effect
48:08because as physicians if we could find
48:10a way to harness the placebo effect that
48:13would be beautiful if that's one of.
48:15If that's one of the outcomes of the
48:18obviously people have been working on
48:19trying to understand the mechanisms
48:21of the placebo effect since before
48:22the recent psychedelic work. But.
48:23And that was one of the outcomes of this,
48:27this line of work that would be
48:29brilliant even if it in the long run
48:31didn't entail any 5HT2A agonist.
48:35Yeah, no, absolutely. And not.
48:37I did ask in the seminar,
48:38as in the other day I asked what if
48:40the what if the outcome from all this
48:41work is that the best way to get our
48:43patients better is to lie to them.
48:47That would be awkward.
48:48It would be very awkward wouldn't
48:50it And and and I I don't know what
48:53you guys feel about micro dozing but
48:55I think it's it's a bit of a weird
48:58and awkward one because I mean the
49:00effects are really quite good right?
49:02But if we and some others are showing
49:05up here that's true but but if placebo
49:08control is kind of the same and.
49:10And and that the people really plays
49:12a big role and then we often are met
49:14by but who cares and it's a good point
49:17but I would say in order to to keep
49:20it out of alternative medicine space
49:22and convince regulators be able to
49:24prescribe it and and have investors
49:26going into it and scale it up and
49:28getting it out as a real treatment,
49:30then obviously it matters quite a
49:32lot And also the more work done to
49:34show that it's placebo if it keeps
49:36on looking like that then.
49:38Then the placebo effect might also go down,
49:40right. So yeah, yeah,
49:42it's a bit of an in terms of this
49:45thing about the blinding because of all
49:48that stat work that was done on this trial.
49:50And then the data also by Ballast
49:53himself is coming out with quite an
49:55interesting paper of actually suggesting
49:57to more thoroughly and more consequently
50:00collecting information in normal trials,
50:03let's say.
50:04And this is the right trial
50:05about blinding integrity.
50:07And he's he's
50:11suggesting A mathematical statistical
50:14method to actually correct for the
50:18lack of blinding integrity down
50:21to randomness which the level of
50:23of completely random guessing.
50:25So in a way perfect blinding and and
50:29we found out when we looked into all
50:31that over the last couple of years
50:33that when you look into the SSRI.
50:35Literature and even going into
50:37archives or studies and trying
50:39to find out whether they exist,
50:40how much it that data is collected
50:42of how well people are blinded.
50:44It's 10% of something.
50:45It's very, very few studies that
50:48report anything on it and obviously
50:49they are not fully blinded either.
50:51That's not a big surprise,
50:52but but it I think there's some
50:55not necessarily learning but at
50:57least a bit maybe refocused.
50:59On that aspect,
51:00because if we are very stringent
51:02of applying that thinking and
51:04analysis to this kind of data,
51:06you should in a way also do
51:08it to SSRI and yeah,
51:10and in a way that RCT model that has
51:13been gold standards in the early 60s,
51:15it hasn't really changed, right.
51:17It's the same model.
51:18Maybe that thing is a bit lacking.
51:20It's not that there's any perfect perfect
51:22solution for how to deal with that,
51:24but.
51:24At least ballast,
51:25we are together with ballast,
51:27we are sort of suggesting a possible
51:30starting point for a statistical
51:32way of of correcting data from it.
51:34That's obviously really conservative,
51:35A cautious way of looking at the data.
51:37But it's an interesting suggestion, I think.
51:40Sorry, there's a question.
51:42Yeah.
51:42Anita.
51:44Yeah. Hi. Thank you for a great time.
51:48So I have a question about
51:50the micro dosing study.
51:51When did you ask them if they could guess
51:54what arm they were like if they get they
51:58got placebo or the study medication.
52:01And the reason I'm asking is that if
52:03you ask that at the end of the study
52:05then those who didn't feel better might
52:07think that okay it was placebo. Yeah,
52:10it's and and and that in a way is
52:13exactly the the the hammer on the nail.
52:16If that's a expression in English
52:17that that is exactly an issue.
52:19And that because you're right if you
52:22are asking and we asked, by the way,
52:24we asked on every day they took a
52:26dose of something we asked them,
52:28but we asked them obviously in
52:29the end of the day what they
52:30thought they had been on that day.
52:32So if they had an effect that was
52:35a real effect on whatever they
52:37would like to have an effect on.
52:40If that was the reason why
52:42they guessed correctly,
52:43then you have a catch 22 issue.
52:47But The thing is we then asked
52:49them what was the basis for what
52:51why they guessed and that was
52:53sort of more physical sensations
52:55that that was the dominant.
52:57A reason of them being
52:59able to break the blind.
53:00We could also look at the data because
53:02it was a naturalistic study where
53:04people were using their own doses,
53:06then they obviously used a range of
53:08doses in the micro dosing range and
53:11then we could then plot all these
53:13self reported doses and figure out.
53:16When were P,
53:16when was the threshold as a group
53:18of where they started breaking
53:19the blind so we could actually
53:21use the data for a lot of things.
53:22And that was then around I think 13
53:26equivalent of 13 micro MLSD level and
53:28the equivalent in psilocybin which is
53:31exactly the same as they find in in lab,
53:33in in in lab studies.
53:34Which is kind of neat that it seems to
53:36be an average around there that you can
53:38that's where you start detecting it.
53:40But a lot of it is the physical sensations.
53:44And and and there didn't seem to
53:47be that much due to the actual
53:49mental health beneficial effects,
53:51but it's a really good point and that's
53:53very difficult to get fully around.
53:55Yeah. Cool. Thank you.
53:59That's. Yeah. Hi. Hi.
54:03Also to follow up on the,
54:06on the micro dosing, so first,
54:08did you say it was at
54:11around 30 or 13 micrograms?
54:1413 micrograms of LSD or
54:17equivalent. Yeah, yeah.
54:18OK. OK. But the question I had was do
54:21you think that there are other measures
54:24that are not sort of typically measured
54:27by micro dosing studies that can have
54:30a more sort of objective effect beyond
54:35the expectations because in, in.
54:38Current studies it's heavily
54:40focused on mental health outcomes,
54:43so wellbeing and effective outcomes
54:46and also creativity and sometimes on
54:50cognitive performance but a lot less
54:54of the time and also other things
54:56are not taken into consideration.
54:58So essentially I guess what I'm
55:00asking is do you think that it has
55:03placebo effects across the board
55:05or there are some things that it?
55:09Objectively affects and other things
55:10that are driven driven by expectation.
55:13Yeah it's a really good question
55:14and I would hope the latter.
55:16I would I would hope that there are
55:18real effects but and and because
55:20obviously it would be fantastic
55:22if it can be used for something in
55:25with proper effects beyond placebo
55:27for any kind of health benefits.
55:30There are ADHD studies.
55:31We can't say anything from our data
55:34whether it could be that LSD micro dosing.
55:37NSD has some dopamine actions,
55:40could it be that in the right dose that
55:42could be actual beneficial effects for that.
55:44There's a lot to explore and a lot
55:47being explored and I think jury is out,
55:50it's not and even with this we can't
55:52rule out because they haven't yet been
55:54at the pressure study will repeated
55:57micro dosing with the in the blinded
55:59that's not out yet that is being
56:01conducted a couple of places but
56:03and we are now doing another micro
56:05dosing trial as well in our lab.
56:07Still self blinded with their own
56:08dose but where we are zooming in and
56:11and including people who are treating
56:13mood mood mood symptoms so so to to
56:16try to understand more whether there
56:18could be some effects if we we try
56:21to sort of enrich this sample for
56:23for people like that so so I think
56:25jury's out it could be it would be
56:27stupid for me to say I think it's
56:29definitely will keep on bleeding just.
56:32As not better than placebo for
56:35for everything.
56:35I don't know and I hope it could.
56:37There's some data in humans
56:40about increases BDNF.
56:41What if it increases plasticity?
56:43What if it was combined with something?
56:45If they if it does sort of lift
56:48the level of of of plasticity.
56:50Could it be that if you combine it
56:53with talking therapy or you know maybe
56:55it's other kind of healthy practice
56:58that you will get an additive effect.
57:00Or an extra effect of of those
57:02practices because of that
57:04plasticity effect maybe maybe.
57:06And also to to follow up,
57:09have you explore maybe if you know
57:12the studies that have explored the as
57:17a potential mechanism the increasing
57:19of internal locus of control so
57:23you you take psychedelics or.
57:27Micro dosing or placebo and have those
57:31effects and they are driven by expectation,
57:33but they're also driven potentially
57:36by more internal locus of control
57:39versus more external locus of control.
57:42So yeah. I
57:44I mean it's not something we
57:46have specifically looked at.
57:47I don't know if it's potentially
57:49somewhat integrated into some of
57:52the Robin studies. I'm not sure.
57:54Is it something you or you know
57:56that others are looking at?
57:58No, I'm I'm just curious because in in
58:02the placebo science there's an idea
58:06that placebos work because they may
58:09increase the self sense of agency so.
58:14Essentially there is open label
58:17placebos where you have nondeceptive
58:20placebo administration and off there
58:23was a qualitative study that suggested
58:25that it was effective through that
58:28increase of attention towards oneself,
58:31increase of selfefficacy and and agency
58:33over one's actions and so kind of
58:37transporting that onto psychedelics maybe.
58:41Micro dosing also works through that
58:44increase of self efficacy and more
58:47internal locus of control rather than
58:49sort of externalizing it to to something
58:53that's a good point. I know it's the same.
58:55Brandon is not here because whether he
58:58has put that into our volume two of our
59:01micro dosing work is a bit interesting
59:03and if he hasn't maybe we should.
59:05So yeah, so it might be.
59:08Maybe he should reach out to
59:10you and I'll look into that and
59:12think about incorporating last
59:13minute into our next study. Yeah,
59:15definitely. I have a couple of papers
59:17I could I could write send them.
59:19Amazing. Thank you. Thanks a lot. Thank you.
59:25One last question if I may.
59:27When you were talking to presenting
59:28the original open label 2016 paper,
59:30you emphasized the correlation which
59:32we've of course seen before about oceanic
59:34boundlessness during dosing and subsequent.
59:36Antidepressant response which which seen
59:38in a couple other studies and spurred a
59:41lot of theorizing about the psychological
59:43or psychospiritual effects of these drugs.
59:46My read of the literature is that
59:48that hasn't been uniformly replicated.
59:49I know it wasn't in the Hopkins
59:51blinded study.
59:52They didn't see that correlation
59:53in the follow up study,
59:55My follow up analysis,
59:56it may have been in the New York in the NYU
59:59alcoholism study that that correlation.
01:00:00So it seems to be a mixed bag.
01:00:03Did
01:00:03you look in the.
01:00:05Lexapro controlled study in the
01:00:07Essetaloprem comparison study,
01:00:09if there was a correlation in the
01:00:11psilocybin group with the experience
01:00:13of oceanic boundlessness during dosing,
01:00:17yeah, so we looked. It's
01:00:20been a really interesting
01:00:21thing to see evolve.
01:00:22Some people are latched on
01:00:23to that finding as being.
01:00:25Profound importance but the data are
01:00:27getting muddier so that that's but
01:00:28I'm sorry corrupted your answer.
01:00:30It's not in all studies but actually I
01:00:32would say it's in a lot of the studies
01:00:35also some of the Johns Hopkins work
01:00:38as as seeing seeing the relationship.
01:00:41So a lot of trials are seeing such a related.
01:00:43We also do see it in the psilocybin.
01:00:48With the SL prime arm in this design
01:00:49and I would do see a relationship there,
01:00:52we are looking at Meqs and mystical
01:00:54experience questionnaire scores and
01:00:56also emotional breakthrough inventory.
01:00:58So a A a newer construct that actually
01:01:02we also I think suggested for compass
01:01:05to use in the compass trial and they're
01:01:08also seeing it in the compass data with
01:01:10the emotional breakthrough which was
01:01:12developed by Leo Roseman from our lab who.
01:01:15Who was the one doing that
01:01:17finding that relationship with,
01:01:18with the oceanic boundaries And
01:01:20interestingly in that in that first trial,
01:01:22small trial of 20 he he also
01:01:25looked at the other constructs.
01:01:27So small perceptual changes, visual,
01:01:29blah, blah, and didn't really see it.
01:01:30But yeah,
01:01:31right. Which argues that it's not just
01:01:33a surrogate marker for effective dose.
01:01:34Yeah. Yeah, yeah, yeah, exactly. Exactly.
01:01:39OK over at time and I know it's
01:01:42getting a bit late there. Yeah.
01:01:46Thank you so much.
01:01:47You can see I'm sitting in dark
01:01:48because I had to plug out to get the
01:01:50the charter to work in another block.
01:01:52So I was like multitasking a bit so
01:01:54I apologize for that. So I'm sorry.
01:01:56Thank you so much for spending this
01:01:57time with us and we'll I know people
01:01:59I know there are a number of people
01:02:00who wanted to be here and couldn't
01:02:02but we'll we'll put the recording
01:02:03up and and and send that out.
01:02:04So your audience will be several
01:02:06fold what you see here and it's
01:02:08been it's been really great to see
01:02:09this work reviewed. Thank you.
01:02:11It has been a pleasure.
01:02:12Thanks a lot for having me.
01:02:13Have a good weekend and thank you,
01:02:15David. Take care.
01:02:16Thank you. Bye, bye, bye.