Michael Bogenschutz, MD. April 2023

April 24, 2023

Information

Title: Exploring mechanisms of psilocybin-assisted treatment for alcohol use disorder.

Description: We will describe the historical and scientific context of current research on psychedelics and review the efficacy data for classic psychedelics in the treatment of substance use disorders. We will discuss what recent preclinical and mechanistic clinical research can tell us about how classic psychedelics may work in the treatment of AUD, and consider possible future directions for research to answer the “burning questions” in the field.

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00:00Thank you,
00:05Okay.
00:07So thanks for waiting.
00:09And so I'll you know shorten this a
00:13bit and focus on the more interesting,
00:16probably more interesting
00:17newer material that I have and
00:19shorten the introductory parts.
00:21But we'll try to get through
00:24the get to the to the meat of
00:26it pretty quickly here and have
00:27a little time for questions so.
00:35Let's see. No,
00:37you have to do it on the
00:38laptop. Does it not work?
00:45That's right. It goes
00:47okay, okay. So yeah,
00:49so we're gonna blaze through the historical.
00:54Context and the old efficacy data
00:56and then I will really spend the
00:59majority of the time then presenting
01:02some hopefully interesting secondary
01:05analyses we've done with the data
01:08from the completed randomized trial.
01:12So just this is the sort of kube
01:17bolkoff model of alcohol use disorder
01:20and I think it's a useful model.
01:23It's, you know,
01:26we can argue about whether these
01:28are really separate domains,
01:29but they really capture the functional
01:32aspects of addiction in incentive salience,
01:37negative negative emotionality,
01:40and executive function problems.
01:44And we'll come back to this later looking
01:49at the data I was going to for for.
01:52Based on a conversation I had recently
01:55with with the Jerry Sanacora here,
01:57I was going to say a little
01:59bit about the how the
02:03ideal paradigm of translational science
02:04is not really what we've been doing here.
02:08We've been working with things that
02:10were serendipitously discovered and kind
02:12of trying to figure out how they work,
02:15but I don't think that's
02:16worth spending much time on.
02:17And I think everybody probably also
02:20knows what classic psychedelics are.
02:21And you know that there are other
02:23kinds of psychedelics and so forth.
02:25But we're really talking about
02:27mostly psilocybin,
02:28but other relatively similar,
02:33mostly 5HT2A agonist or partial
02:36agonist type drugs in the in this talk
02:42the yeah, this is the history
02:44that will kind of blaze through.
02:47You know, there was a lot of research and
02:50a lot of interest in classic psychedelics,
02:53both as a model of psychosis and
02:56then quickly people who became
02:58interested in the potential therapeutic
03:02uses of classic psychedelics.
03:05And then that really shot
03:08shut down around 1970.
03:11For a variety of reasons but there was
03:15a fair amount of work done on alcohol
03:19use disorder and six randomized trials
03:23which was which I'll I'll get back to
03:26it in a moment showing you some the
03:28meta analysis that was done of those.
03:30But so now we're in the second wave
03:34and this is this goes up to 2020,
03:37we'd probably be up to the ceiling.
03:40Of this room by now if we included 2021
03:44and 22 but in any case there's a big
03:47renewal of interest and relatively a
03:51relative paucity of real useful data
03:55their clinical or mechanistic although
03:57that is that is starting to change.
03:59So so quickly reviewing the
04:02efficacy data of for psychedelics,
04:05classic psychedelics for alcohol use
04:07disorder and other addictions to some extent.
04:11This is the meta analysis that was
04:13done by Krebs and Johansen in published
04:15in 2012 looking at the six randomized
04:18control trials that had been done with
04:21LSD in the treatment of alcohol use disorder.
04:24And these were they were all
04:28double-blind up to Drug Administration.
04:30And then sometimes people were knew that
04:35they were getting no drugs for example, but.
04:40There were some similarities are
04:42among all of these studies,
04:44almost all males, almost all inpatients,
04:46high doses of LSD,
04:48up to 800 micrograms,
04:49which is really quite an enormous dose,
04:53just some different active and
04:55inactive control conditions.
04:57And the psychotherapeutic models range
05:00from really pretty much nonexistent
05:03to extensive preparation and and and
05:07psychotherapy afterwards as well.
05:09So the the main finding of this
05:12was that there was a,
05:15you know a robust and very consistent
05:19effect across these trials.
05:21It was really very little evidence
05:23of heterogeneity and it was a you
05:26know a good moderate sized effect in
05:28spite of all the variability and the
05:31overall odds ratio of close to two for.
05:35Abstinence or near abstinence at the
05:38first available follow up time point.
05:41And those effects appeared to
05:43persist for six months at least.
05:47It's interesting,
05:48I had noticed this before
05:49but every single one of those
05:50trials technically failed.
05:51Yes one of them was like on
05:53the border, but that's right.
05:55And they were all under powered and they all,
05:58but they all look exactly the same.
05:59But they all look exactly the same.
06:00So. So it's yeah, it's interesting.
06:03It's just. This is a good lesson
06:07in not doing underpowered trials
06:09unless you want to convince people
06:11of something that isn't true.
06:13So there was one controlled trial
06:15that maybe is less well known of
06:18LSD for opioid use disorder and this
06:21one was it was randomized but it
06:24was not double-blind 74 patients.
06:27So you know, not tiny but not
06:30very large and these people,
06:32these were all.
06:34People who were on,
06:38they were, they were getting out of
06:40of jail and they were on parole and
06:42they would either go out and be on
06:45parole and or they would stay in the
06:47hospital and they'd get this preparation
06:49and then a high dose LSD session
06:52and then go to the aftercare clinic.
06:54And then both groups were followed for a year
06:57and part of their parole was daily urine.
07:01Drug monitoring.
07:03So if the outcome data is is
07:05is certainly of high quality.
07:07And so the the very kind of low
07:13tech figure on the right there from
07:16Archives to General Psychiatry shows
07:19the cumulative total abstinence
07:23rates at 369 and 12 months and you
07:26can see there's a a real pretty.
07:29Robust separation starting as early
07:31as three months and then for the
07:33treatment group it really kind of
07:35flattens out around 25% between 9
07:38and 12 months versus about 5% in the
07:41in the other group which is you know
07:42probably what you would have expected.
07:44The 5% that is in people with you
07:47know this was they weren't getting
07:50methadone and they were just out in the
07:52community and the 30 you know 25% is.
07:57You know,
07:58I mean it doesn't sound like the
08:00greatest outcome, but it it's it,
08:01it's much better than than what
08:02you otherwise would have seen.
08:04So this was actually,
08:05I mean I think an interesting study
08:07that also should be followed up.
08:09So now jumping forward to the the
08:13first study that was published
08:15of Psychedelic for Addiction in
08:20the 21st century,
08:22this was Matt Johnson's pilot study,
08:25open label study, 15 participants.
08:28And this was two sessions of psilocybin,
08:34can't
08:37remember exactly the dose,
08:38but it was a high dose,
08:4025 milligrams or so. And the people,
08:46in fact some of them got a third dose.
08:48And So what you see here
08:50is cigarettes per day.
08:51So this is a continuous outcome, very large.
08:55Effect at the six months and the
08:59majority of the participants,
09:0180% of them in fact were
09:03abstinent at that point.
09:06They did some longer term follow-ups up
09:09to 12 months and a follow up paper owning
09:12people for anywhere from 16 to 57 months.
09:16And found that nine out of 15 of them
09:19still at 60% were still abstinent.
09:22So pretty remarkable compared
09:23to any available treatment,
09:25small open label study.
09:27So there's an ongoing nearly finished
09:31open label RCT with I think supposed
09:35to have 80 participants that they're
09:38getting pretty close to completing,
09:40which is psilocybin.
09:43Versus nicotine replacement,
09:46open label RCT and the results look
09:50not quite as striking as this,
09:52but still highly significant in the
09:55interim analyses that they've done.
09:57And we're that's that's at Johns Hopkins,
10:02yeah at Matt Johnson and we're also with
10:09with University of Alabama Peter Hendricks.
10:13Matt Johnson and NYU are doing a
10:16three site night of funded study now,
10:18which is a placebo control for
10:23cigarettes for for cigarette addiction.
10:25Yeah,
10:25so that'll be the first double-blind money.
10:31So that's that. So alcohol now.
10:34So this was published a year later.
10:36This is the pilot study that.
10:38My group completed University of
10:40New Mexico before I came to NYU,
10:43so very similar,
10:44kind of designed to the the smoking study.
10:46We just looked at 10 participants and
10:51it was really a feasibility study,
10:53but we did look at the drinking
10:56outcomes and this is percent.
10:58Heavy drinking days.
11:00So for anybody that's not
11:02in the alcohol field,
11:03that's heavy drinking day is for
11:05a man it's five or more drinks,
11:07and for a woman it's four or more drinks.
11:09Standard drinks that is,
11:11which is, you know,
11:13roughly it's .6 of an ounce of
11:15absolute ethanol and it's about
11:17a beer or a glass of wine or a
11:20shot of of hard liquor and so.
11:23This is heavy drinking days and
11:26you can see the two psilocybin
11:29sessions happened at weeks four
11:31and eight after the second and
11:34third time point on the graph.
11:37So you can see there's some
11:39improvement between baseline with
11:41the first time point in week four.
11:44That's while people were
11:46receiving some psychotherapy,
11:47which was, part of which was.
11:51Motivational interviewing and and
11:53cognitive behavioral skills training.
11:55And so they were getting
11:57some active treatment.
11:58There was some improvement,
11:59not surprisingly,
12:00but after week four,
12:03the second month after the
12:05first psilocybin session,
12:06there was a marked reduction in
12:09heavy drinking days and the second
12:12psilocybin session at week eight.
12:13And those games were basically
12:16maintained out to week 36, which was.
12:2028 weeks after the second psilocybin session.
12:24And so we computed the effect
12:27sizes versus both the the
12:29baseline and the the week four,
12:31which is sort of the real baseline because
12:35that's the immediate pre psilocybin
12:39baseline and the effect sizes are
12:44you know on the range of .8 to.
12:46To 1.0 or a little bit more.
12:48So they're, they're good size effect
12:50sizes, large effect. The second
12:51dose was after that third data point.
12:53So there's no further, there is no further
12:55improvement after the second one. Yeah.
12:59Intent patients labeled
13:00yeah. And you know and it might have,
13:02you know the effect might have not
13:04persisted as long or it might have.
13:05So we. Yeah. So we don't know,
13:08but that's a big question
13:09too is how many sessions.
13:11So this is the design of the completed
13:12trial and this has been published.
13:14I don't want to spend a lot of time.
13:15On this, but just as an example
13:18of sort of a typical design,
13:20the way a lot of these
13:21studies have been done,
13:22there are two hydro psilocybin
13:24sessions and there's
13:28manualized psychotherapy before the first
13:30one in between the two and afterwards.
13:33And these are a combination of content
13:38that's intended to help people
13:41get prepared for the sessions and.
13:45Be able to manage the intense subjective
13:48effects and to hopefully figure out
13:53how to make use of the experience.
13:56And so that's the sort of psychedelic
13:59part of the treatment and the other
14:02part is evidence based treatment for
14:05alcohol use disorder to help them.
14:08Actually make some behavior changes.
14:10So in this case again it was combination
14:13of of motivational enhancement therapy
14:16and some very brief cognitive behavioral
14:21skills based therapy and so the.
14:25We followed them in the double-blind
14:29out to week 36.
14:30There was an open label extension phase
14:32that I'm not going to talk about,
14:34but here's the primary outcome from the
14:36papers which was percent heavy drinking day.
14:39So same thing we were looking at in the
14:41pilot and you can see very similar curves.
14:45The psilocybin is going to be in red and
14:48the control in blue and all of these slides.
14:51So the again there's a big.
14:54Decrease during those first
14:55four weeks of therapy,
14:56but then another large increase in the well,
15:00decrease in drinking in the psilocybin
15:03group after the first medication session,
15:06which then is for the most part maintained.
15:09I mean we can you know it looks just that,
15:13you know,
15:13there may be some attenuation of the effect.
15:16There really wasn't a time effect.
15:21You know once you take the baseline
15:22out of this that that was significant
15:25but or a group by time interaction.
15:28So they weren't the the separation wasn't
15:32diminishing to a significant extent.
15:35But if you look at it, it looks like,
15:37you know maybe the treatment effects
15:39wearing off a little bit but maybe not.
15:41Yeah, Hedges G for this outcome was .52.
15:45So it's a solid medium sized effect
15:47which is much better than you would
15:50ever see with you know something
15:53like naltrexone or a camper say so.
15:55So that was encouraging.
15:57Drinks per day is another.
15:59This is just total quantity of
16:02alcohol divided by the number of
16:05days and so it looks very similar.
16:09And you know and that was also significant
16:12over the entire follow up period
16:16and these are some of the dichotomous
16:18outcomes we looked at and I don't
16:20want to spend too much time on this,
16:22but again psilocybins in red and the
16:24ones that I put in bold there are the,
16:26this is the last week of follow up.
16:28So that would be
16:317 to 8. Well, seven months after
16:36the second psilocybin session.
16:38And so at that .48 of the psilocybin percent
16:42of the psilocybin patients versus 24% of
16:45the control participants were abstinent,
16:48completely abstinent for that month.
16:50And 62 1/2 versus 40% were
16:54having no heavy drinking days,
16:55which is you know, it doesn't doesn't
16:59mean they're in full remission,
17:00but it's you know they're they're not having.
17:03They're not doing binge drinking at least.
17:05So so those effects were all pretty
17:09consistent and fairly compelling
17:12and problems related to alcohol.
17:14This is the SIP short inventory
17:15of problems that you know covers
17:17a number of different areas.
17:18So that was just showing that there
17:20was functional significance to
17:21these changes as well much larger
17:24decrease in the psilocybin group so.
17:28Here's one thing that is not in the
17:30paper that I wanted to show you before
17:32I talk about mechanisms a little bit.
17:35It's just in terms of outcomes.
17:37This is a little bit complicated to look at,
17:41but we were interested in seeing,
17:45did it matter whether people had already
17:47stopped or cut down on their drinking
17:50before they received the sill assignment?
17:52Did you know in terms of what
17:53the size of the effect is?
17:55And so?
17:57I divided the sample into people who were
18:01still drinking at a problematic level,
18:04so that would be WHO risk level
18:07of two or greater.
18:09So that's at least moderate risk,
18:13moderate, severe or very severe
18:16or less than that which would be,
18:18you know,
18:19basically within relatively safe
18:21guidelines which are comparable,
18:22not exactly the same,
18:24but they're comparable to the NI AAA.
18:26Guidelines for for safe drinking.
18:28And so the ones in this with the
18:32solid lines are the ones who have
18:35who are still drinking at a,
18:39you know at a clinically significant
18:41level and the ones with the dotted
18:45lines were abstinent or just low low
18:48intensity drinking and so obviously the.
18:50People who are not drinking as much
18:53have fewer heavy drinking days less
18:56than 10% at baseline and they do
19:01both groups maintain that almost it's
19:04it's just a flatline for both groups
19:07there's it's really no evidence that
19:09the psilocybin or the treatment is
19:11doing anything further after that
19:14that that where the therapy I mean
19:16but the it's a different story with
19:18the people who are still symptomatic.
19:21There's a, you know,
19:22a much bigger drop in the psilocybin group
19:25and it, you know, even looks in this,
19:27this is, you know,
19:28not a huge sample now if you're
19:29dividing it in half, right?
19:30But.
19:3342 total in the in the higher risk
19:36group but still the you know it's
19:38a bigger effect and if anything it
19:40looks like the groups are diverging
19:42over time that the psilocybin
19:43people continue to do do better.
19:45So it didn't look exactly like that for
19:47all the outcomes for total abstinence,
19:49there was some of the people who were
19:51abstinent, you know or close to abstinent,
19:53they still they benefited some
19:56but for these continuous measures
19:59it it looks like they're it.
20:01You really get a larger effect for the
20:03people who are still symptomatic and so non.
20:06So that has implications both for
20:08treatment and for study design in terms
20:10of who you want to have in the trial.
20:15So okay, how does this work?
20:18If it does work, so they're just in
20:22real most of this in the last few years.
20:25There are quite a few studies now looking
20:27at the effects of classic psychedelics in.
20:29Animal models of of alcohol use
20:31disorder and it's really only three
20:34of those actually are with psilocybin.
20:36There's a number of other compounds
20:40including psilocybin and variety of
20:45different animal models including
20:48just alcohol consumption,
20:50voluntary consumption preference,
20:53selfadministration,
20:54behavioral sensitization and
20:56conditions place preference, so.
20:59Different variety of different models
21:01and 15 out of 18 of these that I I
21:05was able to find had at least some
21:09one of the psychedelic conditions
21:12had had a larger effect than control
21:16and there are a few negative studies.
21:20One of them was by the same group
21:22that published this the second study
21:24that that that I that's in the
21:26bottom of the slide here.
21:28They using a different model in this study,
21:32they were able to demonstrate that
21:34psilocybin did significantly reduce
21:38alcohol self self administration
21:41and it also restored the M blue
21:472 receptor gene expression in the
21:50rats that were alcohol dependent.
21:52And so what's the significance of that?
21:55They also demonstrated in a different
21:58cohort of animals that knocked down
22:00of this of the M blue tube receptor
22:04was associated with executive
22:06function impairments and increased
22:08Q induced reinstatement and so.
22:11So the story is that this
22:14is a plausible model.
22:16They haven't connected the dots,
22:18assume they're working on that
22:19right now probably.
22:20But they haven't you know shown that this
22:22is what happens when psilocybin treated.
22:25Rats.
22:26But it's a,
22:27it's a hypothesis and a testable 1.
22:29So we'll see how that pans out.
22:31But
22:34that's, you know, one of the more
22:37sophisticated efforts to really come up
22:39with an explanation on a molecular level.
22:41Do you know where that knockdown was?
22:43Was that medial Pfc or was it global or was I
22:49think it was global?
22:49I think it was. I think it were.
22:53Yeah, I think I think so.
23:01Okay. There's been more done in
23:04animal models of depression and
23:07anxiety and stress related disorders
23:09and there have been, you know,
23:12persisting effects demonstrated
23:14with classic psychedelics and
23:16in a number of different models,
23:18including for swim test,
23:22aversive foot shock
23:25another study looked at.
23:28Male preference for sucrose and female urine,
23:31which is a sort of an hedonic well,
23:34it's the, it's it's a hedonic response.
23:36So it's they recover their interest in
23:39things that they should be interested in.
23:42There's studies with DMT demonstrating
23:47anxiolytic and antidepressant effects and
23:51also the facilitation of fear extinction.
23:56So, so this all looks promising and
24:00and fairly consistent across you know
24:02a number of of of different systems
24:06neuroplastogenic effects you know
24:09been clearly demonstrated including
24:12spinogenesis and eptogenesis and
24:14and some extent neurogenesis that's
24:17you know the significance of that.
24:19Well the significance of all of
24:20this is you know less than clear,
24:22I mean cocaine will.
24:24Cause neuroplastic changes, I mean,
24:27so it doesn't mean that this is all
24:29great and causing anything but it you
24:32know this does this is something that
24:35reliably happens and it you know that's
24:37the case with ketamine as well so.
24:41But we'll see and there's also
24:44these antiinflammatory effects
24:45of classic psychedelics which you
24:48know really it's not clear what
24:49the significance is at this point,
24:51but they're pretty,
24:52they're quite pronounced and some
24:53of them occur at very, very low doses,
24:56sub sub experiential doses that.
24:59So it's whole other possible mechanism
25:04of action at least for some,
25:06you know some conditions perhaps.
25:10And then, you know, we always talk
25:12about these drugs AS5HD2A agonists or
25:15partial agonists that that is true.
25:17And a lot of the effects definitely
25:19seem to be mediated by that receptor
25:23and you know, we can attenuate
25:26those effectors by by blocking it
25:30or knocking it out.
25:32But there are a couple of studies
25:35demonstrating that in animal models
25:37that you can get the neurotrophic
25:40and antidepressant effects
25:44at a while blocking the 5H T to A receptor,
25:50at least to the extent that you don't
25:52get the head twitch which is considered
25:55to be a that's a I don't know if it's,
25:59I wouldn't say it's the
26:00animal equivalent, but it's.
26:01If it's the kind of dose that would,
26:05it's the animal counterpart to the to
26:07the subjective effects and and so it's
26:09a good you know an animal models if
26:11there's a head twitch then that drug
26:13if you give a comparable dose to a
26:14human it's going to be a psychedelic.
26:16So that's so the point of this is
26:19you know not that to a agonism isn't
26:22important but that it may be possible
26:24to get some of these therapeutic
26:26benefits without.
26:30The mind altering effects or at least
26:32without you know the same extent of them.
26:35So that remains to be demonstrated in people,
26:37but that's that's a possibility Okay.
26:41So now I'm going to show you what
26:45we can say about it again that you
26:47know the trial that we completed
26:48wasn't wasn't a mechanistic study,
26:50but we had a lot of self report
26:53measures and we did a small pilot.
26:58FM, RI study that,
26:59I'll show you some of the results
27:01of which are you know.
27:02Again,
27:03it's very small but it's you know somewhat
27:09interesting I think.
27:12So starting with some of the
27:16obvious self report measures,
27:18craving was significantly attenuated with.
27:24Psilocybin and it happened
27:26right away at week four,
27:28I mean following week four.
27:30So it'd be week five and was maintained
27:33pretty much over the the entire period.
27:35So these just quick or quickly Orient you to
27:39these slides because I'll show four of them.
27:42I think the where it says week four,
27:46that's really the baseline in this MMRM.
27:49So that's not.
27:50Part of the repeated measure that's that's a,
27:52that's the baseline covariate
27:54and where it says baseline,
27:56that's the beginning of the
27:57study and that's in there just to
27:59kind of show you what they were,
28:00where they were at the beginning.
28:01But that's not actually part of the model.
28:03So maybe you shouldn't have
28:05connected the dots, but
28:08so then all of the points after
28:10that five weeks 5 through 36,
28:12those are the repeated measure.
28:15And So what you're interested in here
28:17in terms of the treatment effect is
28:19called the treatment effect and it
28:21was highly significant and the time
28:23effect is called assessment and that's
28:26also highly significant is they're,
28:28they're both groups are going
28:30downhill and the time by treatment
28:32assessment is you know whether the
28:34slopes are the same after people
28:37after receiving the psilocybin.
28:39And so they weren't
28:40significantly different here,
28:41but you know maybe close.
28:44It is interesting that the cravings
28:46continues to angle down throughout most
28:47of the followup as opposed to your other
28:49outcome measures where you got your
28:51your strongest effect at week five,
28:53the five to eight time point and then
28:55if anything flat or a ramp adrift
28:57up well may not be significant.
29:00Well, I mean I think it's a real effect,
29:02it's the, the best way to decrease craving
29:04is to get people to stop drinking.
29:07So you know it always goes
29:09down if people were asked.
29:11So you know downstream this, you know this.
29:13You know, like we will maybe try to spend,
29:16those people are not drinking
29:17because we decreased their craving.
29:19But after week five,
29:20if they stop drinking,
29:21then their craving is also going
29:23down because they stop drinking.
29:24So it it's it's not a very strong causal
29:29even suggestion that we can make here,
29:30but it's, you know,
29:31it's a possibility, right?
29:32If we don't know the
29:34direction of the causality,
29:37this is something kind of like.
29:41Craving it's temptation from the Alcohol
29:45Abstinent Selfefficacy questionnaire.
29:46So this is hypothetical craving really.
29:49If you were you know in a walking
29:51down the street and you passed
29:53your favorite bar and your buddy
29:55said come on in don't be a square,
29:58how tempted would you be to drink
30:01and and you rate a bunch of 20
30:03different things like that and so.
30:07We see in this case the separation
30:09didn't really happen until after
30:11the second psilocybin session,
30:12which is you know,
30:13so that we saw that in a couple of these
30:16measures and then it is maintained.
30:19So in this case we we do have a treatment
30:23by assessment interaction and yeah,
30:25I don't know about that.
30:27Delay, but it it does look different
30:29from some of the other curves.
30:31How much does this measure correlate
30:33with other clinical outcomes?
30:35Just it seems like a much more cognitive,
30:37you know, measure than the behavioral or I
30:43think it's, I mean people often
30:44call it a craving measure.
30:46I mean I think and you know,
30:47craving is a reasonable
30:49predictor of of outcome.
30:51I mean it's fairly consistent,
30:54you know, moderately predictive.
30:57Okay selfefficacy is also
30:58a pretty good predictor.
31:00I mean in general if you're doing
31:01just treatment outcome studies,
31:03if people say I'm, I am confident
31:05I can stop that it means something.
31:08And so you can see here there was yeah,
31:14this is 1 where there's a there
31:17isn't a treatment by assessment
31:18interaction that's going to sound
31:19surprising if you look at the.
31:23But you're not, well you're not
31:24including the very baseline,
31:25yeah, but it's it still looks like
31:27the slopes would be different
31:28but apparently they're not.
31:29But there is this you know pretty
31:31strong treatment effect and it's
31:33it's persists overtime and so
31:36that's that's good and that is
31:39something that tends to predict good
31:41outcomes and then self compassion
31:44is kind of a complicated construct,
31:46but I think it's it's highly relevant.
31:49I mean, for one thing,
31:49the effects are really this is I
31:51think the largest effect that we
31:52saw in any of the questionnaires.
31:56And there are two subscales to this,
31:59and one of them is sort of the
32:03opposite of self compassion.
32:04It's it's self criticism.
32:05It's the extent to which you, you know,
32:08are always like beating up on yourself.
32:09Or if you make a mistake you say
32:11I'm stupid, I always mess up.
32:12I'll never do right.
32:16You know that kind of negative
32:17self talk is a big part of it.
32:20And the other half is self compassion,
32:22which is kind of the opposite.
32:23It's like saying, you know,
32:24well put it in perspective,
32:27you know you're you're not so bad and
32:29you're doing your best or whatever.
32:31You know you have good qualities or
32:33you know it's okay to make a mistake
32:35or what those those sorts of things.
32:36So it's it's cognitive and effective.
32:40You know I don't know you know
32:42so if we want to you know in
32:43terms of the the three domains,
32:45is this executive control or or you
32:48know negative or you know less negative
32:50affect it's probably both but I it
32:52doesn't really map on to those that well.
32:54But I think it is it is interesting
32:56in in capturing something that
32:58changes you know both cognitively
33:00and effectively for people.
33:04So that's interesting and we you know
33:06we're working on a paper where I mean it
33:08looks like they're you know there is some.
33:10It it does predict some amount of the
33:13the the drinking outcome variance
33:16that is the biggest factor.
33:18The self compassion is the
33:19biggest of the individual.
33:20Well that's the biggest
33:21effect just in between group.
33:22Yeah group effect in terms
33:24of like the self report,
33:25the effects of psilocybin on
33:27the self report itself. Have
33:29you done any multivariate analysis
33:32across these like you could do a?
33:38I'm blanking on the analysis
33:39I thought you could do,
33:40but something that looks at the relationship
33:42between these two measures over time,
33:44because the curves as you've pointed as
33:48we've gone through the curves and the
33:50point at which they separate are the tank.
33:52They're not identical,
33:53which could be noise in the data,
33:54but you might wonder if you could
33:57make some inferences across about the.
33:59You know, the unfolding of
34:00different phases of the effect of
34:02no, I would love to and I mean that
34:04is something we can do and you know
34:06the drinking outcomes we have in
34:07these one month, one month bins.
34:09So we can we can tease that out and we could
34:12do cross like kind of analysis like that.
34:14I mean the problem is there's
34:16just so many we could do,
34:17you know so you don't want to take
34:19too many bites of the apple here but.
34:22And it's not a huge sample,
34:23so I don't want to over analyze this,
34:25but I think you know those
34:27are really good questions.
34:28And another thing that we will do
34:32is try to do some machine learning
34:36approach to try to identify likely
34:39responders and we can do that
34:41based on baseline characteristics.
34:43We could also do that based on the
34:46subjective effects or or you know week 5.
34:49Outcomes you know week five values of of
34:51some of these self-reports or you know,
34:53so you can include you look at the
34:55pretreatment things but then you could
34:57also see you know if there's something
34:58that something in the immediate
35:00response to treatment that will predict
35:02the longer term drinking outcomes.
35:07So how about how about the nature of the.
35:12Intoxication effect. Yeah.
35:14So we'll get to that.
35:15That's So that's the other that's the
35:16new piece that I want to show you too.
35:18We have taken some look at that.
35:20So this is, you know it's well
35:24known that psilocybin tends to
35:27produce some personality changes.
35:29That increase in openness is the one
35:31that's been demonstrated the most times
35:33decrease in neuroticism was that it was
35:36had been demonstrated before as well.
35:38So we saw.
35:40Yeah between group differences in
35:42and in change in that neuroticism
35:44extraversion and openness and
35:46and within the psilocybin group,
35:49conscientiousness also increased but you
35:51can see it did in the control group as well.
35:54And you know I think I,
35:57I don't want to over reify these personality
36:00dimensions either because you know,
36:02I mean we we like to think about
36:04them as fixed characteristics
36:05but if you stop drinking,
36:07you know you're going to act
36:09different and you're going to.
36:10You know,
36:11I was taught in in my clinical training,
36:13you know,
36:14don't ever try to make a personality
36:16disorder diagnosis somebody who's
36:18actively addicted to something
36:19because they're going to act like
36:20somebody with a personality disorder.
36:22And I think, you know, there's some,
36:24there is some truth to that.
36:26But but you know,
36:27these were pretty robust differences
36:29and it's particularly interesting
36:32if you look at the facets that
36:35actually changed because there's
36:36a lot inside of neuroticism.
36:38And what actually changed significantly
36:41within the psilocybin group,
36:43less depression,
36:44less impulsiveness and less
36:47emotional vulnerability.
36:48And the extraversion,
36:49it wasn't that they wanted to
36:51go out and party but not drink.
36:54It was actually increase in positive emotion.
36:56So, you know,
36:57I don't know why that doesn't end up in
36:59neuroticism, but it's it's, you know,
37:00it's more of a positive affect thing.
37:04And in openness,
37:05it was increased openness to,
37:08you know, fantasies,
37:10internal thoughts and and feelings.
37:13So, you know, I didn't, you know,
37:15when we talk about cognitive flexibility,
37:17this could be one.
37:17I mean that can mean a lot
37:19of different things.
37:20But this is one kind of flexibility perhaps
37:22that that we're saying that could be useful.
37:25And then increased deliberation.
37:27So, you know,
37:28decreased impulsiveness and
37:30increased deliberation, you know,
37:31does this mean they've they had,
37:33they have better?
37:35Inhibitory control perhaps at
37:37least that's what they think.
37:39So,
37:42so that's suggestive but don't
37:44want to take it too far but they
37:47are you know good size changes.
37:49So, so here's the really the
37:50really new part that these next
37:52two things I have not presented
37:53before and be interested to see
37:55what people think about them.
37:56So we had four, how are we doing for time.
38:00All right,
38:01time is at the time is. It's a construct.
38:04I don't want to over reapply the
38:07construct and I shouldn't take it instead
38:09of the Uber, but
38:13so we used four questionnaires
38:17after each of the psilocybin or.
38:21Diphen Hydramine sessions.
38:22And I'll tell you more about
38:24what those were shortly.
38:25There are other questionnaires that are
38:27now available that we didn't have when
38:29I wrote this protocol and you know,
38:31I kind of wish we did.
38:32Like the, there's one called the
38:36Emotional Breakthrough Inventory.
38:37There's one called the that specifically
38:40gets at the challenging experiences.
38:44And you know,
38:45I think there's even a couple more now, but.
38:49And I decided that it it's a
38:53little bit complicated because not
38:54everyone gets the second session.
38:56Most people did,
38:57but there are people who didn't
38:59and because they didn't want to.
39:03I mean, a couple people dropped out, man.
39:06Actually nobody really dropped out.
39:07They continued
39:08psychotherapy, but they
39:09declined psychotherapy
39:10in the follow up, but just just said,
39:12you know, that was too much
39:14for me or boring for me.
39:15So and we we we wanted to be
39:17able to let people do that. So
39:20and the rent of course people
39:22getting the same drug diphenhydromin
39:23or 07 in both sessions.
39:25So if they are pretty sure they
39:28got placebo the first time they're
39:29going to then they know yeah so
39:34so there wasn't a significantly different
39:36number of of dropouts in the in the but
39:39there were more people who declined
39:41the second diphenhydromin session.
39:45And you can imagine they declined
39:46for different reasons and
39:47they pouring versus too much,
39:49right. So, you know, so you can
39:51either look just at the first session,
39:54but then I think you know, you might
39:56be missing the boat because it just,
39:58you know, clinically people
40:00could have a terrible, you know,
40:01a miserable experience one time in a.
40:03Be a tivic experience the next time and and
40:05and we you know we definitely saw that.
40:07So I, you know I think we'd lose a
40:09lot of information if we did that.
40:10So what I ended up doing was just
40:13to add consider it sort of a dose,
40:16you know dose effect,
40:17how much so how much of A particular
40:21kind of subjective experience did
40:22you get and I mean I don't know
40:25if it's really additive or what
40:26but that's what I did.
40:28So if they didn't have a second
40:30session they just get 0 for that one.
40:32And if they and and if they
40:33did have a second session,
40:35then the two are added together
40:36and then there's a lot of different
40:39drinking outcomes you could
40:40look at and a lot of you know,
40:41other outcomes you could look at.
40:44So to keep it simple,
40:47what we're going to look at here is
40:49the correlations between you know,
40:51all these different Christira,
40:54sorry.
40:57So we're going to look at the
40:59correlation between these these
41:00subjective effects scores.
41:02And they're drinking outcomes
41:05for the whole subsequent seven
41:10months to two months to month.
41:14Yeah, well, second month of follow up
41:16after it's the first month after the
41:18second psilocybin session all the way
41:20out to to the end of the double-blind.
41:23And we're going to look at
41:25this for the whole sample.
41:26I don't think the whole sample is
41:28necessarily all that informative
41:29because I don't know what it mean.
41:31If you know,
41:32if we looked at blood pressure
41:34as a mediator or you know this,
41:36we're not a mediation yet.
41:37But let's just say you know,
41:39well, what do you know,
41:40the psilocybin people have much higher blood
41:42pressure increase in and what do you know,
41:44they they drank less.
41:46Let's see if there's a mediation,
41:48if there's a relationship there.
41:50And we could demonstrate that
41:51and that would be dumb, right?
41:53So.
41:54So I don't know what you know
41:56the whole sample really means.
41:57It's a lot more convincing if we can
42:00demonstrate a relationship within
42:01the psilocybin group that like when
42:03they got this particular kind of experience,
42:06they did better.
42:07And based on what I showed you,
42:09with the effect being larger and
42:11the people here were still drinking,
42:16I then removed sequentially
42:19the people who were.
42:23At a level of base of 0,
42:24meaning abstinent people who were
42:26abstinent before they got the
42:28psilocybin or or diagonidro mean,
42:31and then people who were at the
42:35low level And then so I remember
42:38first the abstinent people,
42:39then the the low level drinkers
42:40and then the moderate drinkers.
42:42So you get smaller and smaller groups
42:45so you know less and less power,
42:47but you can still look at what the
42:50correlations are and if they're.
42:52The same or different so so these people
42:57may unless you're doing this work,
43:00you may not know these scales
43:02so I'll describe them briefly.
43:04This is the the five D5 dimensional
43:07altered states of consciousness scale.
43:10It's the one from the the Zurich
43:12group front full inviters group.
43:15And it is you know it's a well you
43:21know it's constructed psychometrically
43:24and and well validated on some
43:28you know medium size samples.
43:30And so it has these factors as
43:32five but these are the the first
43:34three here are the main ones that
43:36people generally care about.
43:37First one is is what they call
43:40oceanic boundlessness because they
43:42think mystical experiences is.
43:44Hocus pocus.
43:44So, so this is much more scientific sounding,
43:47right?
43:49It probably sounds better in German, but
43:54it's anyway it's really this this you know,
43:57oneness, bliss, connectedness.
44:00Meaning it's it's basically it maps
44:03pretty tightly on to what the other
44:06groups have called mystical experience.
44:08So I heard George Goldsmith also,
44:11you know, talking down the
44:13mystical experience questionnaires,
44:14and we use the scientific one it's
44:15and they're measuring the same thing,
44:16but they've got a a,
44:18a better name for it I think so And
44:21then visionary restructuralization
44:24that means really the the perceptual
44:28effects you know alters altered
44:32perception and then dread of ego.
44:36The solution is sort of the bad trick factor,
44:40anxiety, sense of impending doom
44:44or annihilation or whatever.
44:47And then the general scores
44:49is the sum of those three.
44:51So and then looking across the the columns,
44:54the 1st is the whole sample.
44:57Then we have the whole psilocybin group,
44:5944 people who were not abstinent before
45:02they got the the the psilocybin now.
45:0621 people who were drinking at least at the
45:12medium risk level and then 14
45:14who are at least were who were
45:16high or very high after they've
45:18gotten the four weeks of therapy.
45:20So because people had improved quite
45:22a bit and So what you see is that the
45:25oceanic boundlessness does seem to
45:27be pulling most of the weight here.
45:30So that the the.
45:31The the correlate you know the
45:34the significant, you know,
45:36I don't know what significance
45:36means in this context,
45:37but the the P values that are you
45:41know under point O five are are
45:43bold and red and the ones that
45:45are trend level or or not bold and
45:47red just so you can kind of see
45:49them but you could look at the the
45:51correlations just as well and they're
45:54probably more interesting actually,
45:57but what you see is.
45:59Yeah,
46:00the oceanic boundlessness factor
46:02is correlated with drinks per day
46:08at each at each level,
46:11and the correlation gets higher
46:12as you get to the people who
46:14are drinking more and more.
46:16So whether you experience this
46:19oceanic boundlessness had a
46:22stronger effect on whether you
46:24drank less if you were drinking
46:26more before you got the psilocybin.
46:28So that's so
46:29there is just a I mean there's
46:31a floor effect thing there that
46:34people who aren't drinking much
46:35don't have far to go that's true.
46:38So you would expect increased
46:40but they could but they couldn't
46:41go the I mean they could they
46:42could have gone the other right.
46:43But I would expect larger I would
46:45expect larger correlations with a
46:48higher baseline for this analysis
46:50more room to more room to improve.
46:51Yeah no that that you have to
46:53do is I don't know how you.
46:55Well, if it's working, you would if it's
46:57something you would expect that. But
47:00yeah, no, this supports that.
47:01It's working.
47:01I'm not sure it supports.
47:03It's working better in the people who
47:04are drinking more as opposed to just.
47:06It's working right.
47:07Pretty well across the board.
47:08And you see it more in the people
47:10that are drinking, right.
47:11That's all.
47:11Well, it's, yeah, they're just more to do.
47:14I mean, there's more benefit
47:15to be had, I guess. So, yeah.
47:18And then, you know, the other.
47:21It is interesting that the oceanic
47:22boundless just jumps out as carrying.
47:24Yeah. And the other ones,
47:27the correlations don't really even
47:28go up except for the general which
47:31includes and that's it's oceanic
47:33boundless as it's pulling that one.
47:34So, so that's so that's interesting.
47:39This is the mystical
47:40experience questionnaire.
47:41So this one there are you know
47:43there's there's been factor
47:45analyses demonstrating this.
47:47This four factor,
47:48it's been done a couple of different
47:50ways but the sort of most standard
47:52one now is these four factors
47:5411 is what they which they call
47:56mystical which has to do with
47:59the unity and and meaning and
48:03and then they've.
48:05Taken out that the positive moods
48:07tends to go there's some questions
48:10that go separately transcendence
48:11of space and time and ineffability.
48:14So those I think ineffability
48:15only has three items.
48:17So they the the mystical has about
48:18half of the items and then they're
48:20smaller numbers after that but
48:22so here you know in the whole
48:25sample you know all of them had
48:28you know modest but statistically
48:31significant correlations and
48:33then as you go across. The
48:38they tend to increase to some extent.
48:42And so even you know that so that the MEQ 43,
48:46that's the old that the old version of
48:49the scale where they had and there's
48:51a total score that you get from that.
48:52So if you put put it,
48:54put those all together, it's all the
48:58aspects of the mystical experience.
49:00Yeah, you can see those correlations
49:02going you know all the way up to.
49:06Over .5 in the in this smallest
49:09group and it's it's so it's a
49:11nice kind of consistent effect
49:16here and this is another mysticism
49:20scale that hood mysticism scale.
49:22And these are I think you know some of
49:26the largest correlations of all with
49:28introvertive Introvertive mysticism
49:30means being kind of being one with.
49:34With nothing, being one with
49:37nothingness or kind of going inside
49:39and just being being one with non.
49:43Being extrovertive means being one
49:46with the universe and the plants
49:48and the animals and everything.
49:50And interpretation means that it's
49:52sort of their religious meaning
49:54that people give to it.
49:55So really all three were pretty
49:58strongly correlated and yeah,
50:02the more you drank.
50:03The higher the correlation again and
50:07then this last one the hallucinogen
50:09rating scale this is this one is really
50:11coming from a different perspective
50:13and trying to so it's made by Rick
50:16Strassman and he actually based it
50:18on the the five what are called
50:21skandas in in Buddhist psychology
50:24that they're just different aspects
50:27of subjectivity of mind and.
50:31Or I guess a human being,
50:33because somatic is one of them.
50:34So that's not even mind really.
50:36But so we're made-up of these
50:37things they say.
50:38So somatic is,
50:39you know,
50:39physical experience of your body
50:41that didn't seem to be very strongly
50:44related to anything affective experience.
50:48Emotions strongly correlated
50:50in this case and none of those
50:52other skills really get at that
50:54particularly except for positive mood.
50:57So that's so that one shows some
51:01strong correlations of perceptual,
51:03just as this is pretty much what's
51:05measured in the five DASC under the
51:09the visionary restructuralization,
51:12nothing there.
51:14And then changes in cognition,
51:17there's, you know,
51:18moderate sized correlations
51:20there and volition.
51:22Is, is, is in the smaller group.
51:25So it actually was, was,
51:26was quite strongly correlated,
51:28but this, you know,
51:30not so much in the larger group.
51:31So I'm not sure that I'd be
51:34quite as confident in that.
51:35One is intensity a combination
51:36of the rest is a separate,
51:37it's a separate thing.
51:39And it's actually very simple.
51:40It's like how strong is your experience,
51:42What dose do you think you got?
51:43And I think it's, it's like 3 items.
51:45So it's, it's,
51:46it's interesting and it's and it's not
51:49any that's really about all it is.
51:52So I think you know.
51:55So anyway the conclusion from this I
51:57think is that it does seem to make it.
51:59You know they higher,
52:02higher,
52:02stronger experiences seem to do seem
52:06to make a difference to people.
52:07But
52:09I always wonder what these
52:10correlations if if the like,
52:12if some of these are simply
52:14surrogate markers for how much
52:15the drug affected the neurons.
52:17Yeah right.
52:18But the so the specificity if you
52:20have this you know more specificity
52:22to the mysticism than the other
52:23components starts target that they're
52:24maybe not but something like intensity.
52:26I wonder if it's just you know
52:28how got in there and how tightly
52:29did it bind the receptors and how
52:30much did it affect the neurons
52:33and how are the preparatory sessions
52:35how are they how are they introduced
52:39to it they so we we tried to be very.
52:46Non directive and as far as what kind
52:49of an experience is a good experience
52:53but we did we we were willing to
52:56suggest that you know you you whatever
52:58experience you have you know that that
53:00might be the one you need to that
53:02that's the one for you and it's it's
53:05you know you may do do with it what
53:07you can and see if see if you can but
53:09do you think they fidelity actually
53:11that was true because that's what is my
53:13concern is you know if if if it's an if then.
53:16Type situation where you're told
53:19that if you have this experience,
53:20you're going to get better.
53:21And then therefore if I didn't
53:23have that experience,
53:24I'm not going to get better.
53:26Well, so like I said, we, we, you know,
53:30I don't know what people believe.
53:31Yeah.
53:32I mean because we also said it,
53:33it it's also possible that you know that
53:36this is going to do something in your brain
53:38and it may have nothing to do with that.
53:40So that equipoise,
53:41I mean so that was so that was
53:43so that was put out there too.
53:46I but I think you know I think
53:51people have expected expectations
53:53sure and and therapist due to so
53:56but we we we you know definitely
53:58we're not privileging mystical
53:59type experience per se for example
54:06we probably should wrap up because
54:09it's getting but but MRI so
54:11I'm going to show you this
54:12really quickly these are.
54:15Really just hot off the press.
54:18And you know, I don't want to make too much
54:20of it because this is only 11 subjects,
54:22but I think it's it's interesting pilot data.
54:26We had a task that evaluated a
54:31response to visual alcohol cues
54:34and negative emotional pictures.
54:36I have pictures and we scanned
54:39people three days before and two
54:42days after first dose of the drug.
54:45And we were you know interested
54:47in the alcohol versus neutral and
54:50and the negative emotion versus
54:52neutral change in those and and and
54:54the difference in change of those
54:56between the two groups and we looked
54:59at regions that we thought were most
55:03likely to be involved in you know.
55:09Craving response and reward processing
55:12and and negative emotional processing.
55:14So lateral medial Pfc and singular
55:20and ventral indoors will stray
55:22them and when we found significant
55:28effects we then only for those.
55:32Roi's we looked at functional connectivity
55:35between groups to see if there are
55:37any differences in between Roi's,
55:39between no between the groups. So if
55:43functional connectivity compared between
55:45groups, yeah, yeah, for the
55:46for the ROI that was that was
55:49different between the groups.
55:54And then we also looked at whether
55:56these the differences that we found.
55:59Had any relationship to the
56:01change in drinks per day,
56:03so this is a just a summary
56:06in terms of the bold contrast.
56:08There were some, you know, fairly small
56:15clusters in right ventrilateral
56:18prefrontal cortex,
56:19left dorsolateral prefrontal cortex,
56:22and left caudate.
56:24That were different and it was
56:27all more more activation in the
56:29psilocybin group and for negative
56:31effective stimuli they were
56:34areas in left medial prefrontal
56:37and that were also left odd eight.
56:40I'm sorry, is this these task
56:42data from the before psilocybin
56:44or the after psilocybin?
56:45It's where the after minus before.
56:49So it's task dependent
56:51activation after minus.
56:53Identical task, dependent activation,
56:55yeah between groups and then relative
56:57to neutral stimulus
57:01and then yeah, so they the ones that we
57:04looked at those in terms of functional
57:07connectivity and there were two of the
57:13alcohol Q responding.
57:16Areas that that did have
57:18some connectivity changes,
57:19so I'll show you the pictures
57:21really quickly and I, you know,
57:22again let's not get too carried
57:24away here, but this is this
57:29right intralateral Pfc area
57:30and using that as a seed then
57:33there was increased functional
57:35connectivity with this area in the
57:40IFS lateral pre central gyrus there.
57:46This is the area in the left dorsal
57:50lateral Pfc and this is the left caudate,
57:55which yeah, this was,
57:57this was a bit of a surprise and
57:59you know we didn't really expect to
58:01see greater reactivity in dorsal
58:04strayatum as being associated
58:06with therapeutic response.
58:08So you know, I'm not sure what to make of it.
58:12It also showed greater
58:14connectivity with a CC,
58:18though I don't know but
58:21there was for that one.
58:23There was a significant relationship
58:25between that that effect and the the
58:30functional connectivity now and decreased
58:34in drinks per day and then for the
58:39negative effective stimuli this is.
58:42Yeah, the the left medial prefrontal area
58:46and which this increase in activation
58:49there was associated with decreased
58:54drinking and then this is the left
58:58caudate again, which was no functional
59:02connectivity changes in this case,
59:04but it was associated also with
59:07the decrease in drinking, so.
59:10So that's so that's that.
59:12So you know, So what was the time
59:14from the dosing to the scanning,
59:17it was one to two days after,
59:20two days after Okay. Yeah.
59:22And so you know these,
59:24these are pretty large effects given
59:26you know that we see that we're seeing
59:28anything with with samples of this
59:29size and they kind of make sense.
59:31I mean they're in regions that make sense,
59:33they weren't in you know just
59:35kind of bunch of random spots.
59:37Some of them were accompanied by
59:39functional connectivity changes
59:40and some of them were correlated
59:42with changes in drinking.
59:46You know,
59:47obviously you know we have a
59:51replication problem in in FM RI
59:53work and this study is you know
59:57a a prime candidate for that being
60:00very small and you know the the
01:00:02directionality was not exactly.
01:00:04Entirely in some cases it was with
01:00:08the the OR dorsal prefrontal areas
01:00:12but with with the medial prefrontal
01:00:15and the and the dorsal straight
01:00:17and we didn't really expect to see
01:00:20increases in the in this especially
01:00:22for the alcohol accused so,
01:00:24so we'll see but you know executive
01:00:28functioning is not all about.
01:00:30Just you know inhibition there might be
01:00:32other things going on and more complicated.
01:00:34So I think it's it's interesting and
01:00:36we'll we'll follow up on it and we're
01:00:39really hoping very soon to be able to
01:00:44do a much more you know much larger
01:00:47and more sophisticated version of this
01:00:50with Regina's help and NA AAA funding
01:00:53if we can get get the grant funded so.
01:00:57So that's that.
01:00:59So overall you know I think looking good
01:01:03for efficacy we need to do more there
01:01:07obviously and there's some evidence
01:01:09that these drugs are acting across all
01:01:12three of the core domains of addiction.
01:01:14And you know I think it's,
01:01:18it's complicated, right.
01:01:19And this is, this is,
01:01:20this is really why I like it is because.
01:01:23I mean you know we do want to
01:01:25be able to reduce things to you
01:01:27know the level of the receptor.
01:01:28But for a lot of things that's,
01:01:32you know, it's like you know,
01:01:33we don't do biology,
01:01:34we using quantum mechanics.
01:01:36You know,
01:01:36we you need to use higher levels
01:01:38of it's you know,
01:01:40and it still should be scientific
01:01:42and it still should need to
01:01:44be rigorous and makes sense.
01:01:45But we need to find ways to you know
01:01:47looking at at at these higher level
01:01:50phenomena including subjective experience
01:01:51to really make sense of this so.
01:01:53So that's that thank you wonderful.
01:01:58It's really nice to see the new,
01:01:59the new stuff.
01:02:00So
01:02:01worth worth worth staying
01:02:03later enough today afternoon.
01:02:07Anybody still there? Well that's what I
01:02:10was checking out and the answer was yes.
01:02:16So do we have you know question or
01:02:18two or any comments for for Michael
01:02:20before we we call that tonight?
01:02:24Hello. Hi, I have
01:02:25two quick questions.
01:02:29Thank you so much for the
01:02:31presentation and the great work.
01:02:33I have two quick questions. One is that
01:02:35do you have did you collect any data
01:02:37after the like between those one and
01:02:40two after the sign in and like how
01:02:43long can you comment on how long after
01:02:45the first dose you could see any
01:02:48changes in the outcome measures and?
01:02:51If like how long do they last after
01:02:55the first psilocybin administration?
01:02:57And the second question is that why
01:03:00the second dose of the psilocybin has
01:03:02higher dose compared to first one.
01:03:04OK, yeah. So that's a good question.
01:03:07So for the first,
01:03:08as far as the first question, we there's a,
01:03:12there was a follow up at one week
01:03:15after the first psilocybin dose,
01:03:17we didn't do anything you know the same day.
01:03:20You know, I guess I just,
01:03:23I'm not that interested if people,
01:03:25you know, I mean,
01:03:26I know that like in the ketamine studies,
01:03:28you know, it's like right afterwards you go,
01:03:29you're less depressed.
01:03:30That's great and it is great.
01:03:31But I mean, especially an addiction,
01:03:33you know, I don't really care if
01:03:35somebody's got less craving 8
01:03:37hours after they took psilocybin.
01:03:39So maybe we should have done it the next
01:03:41day and then I am going to do that in
01:03:43the next study and just just just to see,
01:03:45you know,
01:03:46if there are some changes that are.
01:03:49Detectable that early but but you
01:03:51know most of these self report things
01:03:54were were showing changes after a
01:03:57week the craving you know it it it
01:04:00does seem to the effects are a little
01:04:02larger far a little farther out it
01:04:05seems like there's you know these
01:04:10but right it could just it could
01:04:11be more related to the fact that
01:04:12they're not drinking as much so I
01:04:14don't know so the second question
01:04:15is why do we go up on the dose.
01:04:18Because we could.
01:04:20I think clinically it makes,
01:04:23I mean it's it's it's a little
01:04:25complicated because people got to get
01:04:27different doses in the second session, right.
01:04:29But clinically you know you would want
01:04:31to be able to titrate people especially
01:04:34if you think you know they need to have.
01:04:37A really strong experience
01:04:38or a maximal receptor,
01:04:40you know occupancy or whatever,
01:04:42whatever it is,
01:04:43you know if you think it's dose related,
01:04:44you want to maximize the dose
01:04:46without you know hurting people
01:04:47but you can't give them,
01:04:49you can't.
01:04:49So with the doses were 25 milligrams
01:04:52and then it was 30 or 40 depending
01:04:54on how robust their response was.
01:04:56And so we gave about 15 people
01:04:59I think the 40 milligram dose.
01:05:02You know
01:05:03and those were by weight 25%.
01:05:05That's right. So it was,
01:05:06it was actually, I mean the biggest
01:05:08dose was about 65 milligrams.
01:05:10So you you would not give
01:05:12somebody who walked in off the
01:05:13street that dose to begin with.
01:05:15You know you just because some people,
01:05:17some people are really
01:05:18challenged by the 25 milligrams.
01:05:20Is there any thought that you,
01:05:21I mean there could be an inverted
01:05:23I mean for ketamine it seems pretty
01:05:24clear there is an inverted at least
01:05:26in rodents probably in units that you
01:05:29can bypass that sort of sweet spot.
01:05:31Yeah.
01:05:31I have not seen any evidence of that at all.
01:05:34I and yeah I couldn't but I've gone
01:05:37higher than most people but we've gone
01:05:40pretty high and you know in the in the 60s,
01:05:45you know they they you know
01:05:47they this is in the in America.
01:05:49I mean it was different in Europe where
01:05:50people are more sophisticated than subtle.
01:05:52But it was like you know we're going
01:05:54to just blow them out of the water.
01:05:56And it was like so one,
01:05:57one time get it you know one time
01:05:59get them ready and then just.
01:06:01You know the whole point is ego death right.
01:06:03So you want them just to completely you know,
01:06:07it's like you know,
01:06:08psychic ECT.
01:06:09It's like you're just completely
01:06:11flatlined your your brain activity if,
01:06:13I mean that's not really true
01:06:16but you're you're conscious your
01:06:18consciousness is going to be obliterated.
01:06:22So but they just made that up so we don't
01:06:26know if that's necessary or not and so the.
01:06:29But that was the prevailing wisdom
01:06:31and you know, most drugs more is
01:06:33better until you start hurting, right.
01:06:36So that's to maximize the dose
01:06:38is the short answer.
01:06:40Yeah.
01:06:47Thank you, Michael.
01:06:48This is Emmanuel Schindler.
01:06:50Thank you for coming and and for
01:06:53braving the Southern Connecticut
01:06:54traffic on a Friday afternoon.
01:06:57I had a question about
01:06:58and I may have missed it,
01:07:00When you talked about the study
01:07:02the the with the mouse model where
01:07:06they blocked with with Catanzeran.
01:07:08Did they do a dose response
01:07:10with the Catanzeran?
01:07:11Was it just a single dose they they
01:07:15found a dose I think I mean they they
01:07:18might have done some pilot work but
01:07:20they used a dose which was reliably.
01:07:24Blocking the head twitch and in at
01:07:28least one of the studies that also
01:07:31blocked the characteristic EE G
01:07:35changes which is you know decreased
01:07:39power and gamma that goes that
01:07:44that's that particularly goes down so
01:07:46they're in in humans and in animals
01:07:48that you can that it correlates
01:07:50with the subjective effect so but.
01:07:54You know we we know that people you know
01:08:02it's it's it's tough because I don't
01:08:04think you know we we can't assume that
01:08:06you know all of the 582 A receptors
01:08:09were were blocked obviously and people
01:08:14the serotonin receptors are
01:08:16almost saturated at at you know
01:08:18fairly low doses like I don't
01:08:20know like 10 milligrams right so.
01:08:24So what is it about these
01:08:26higher doses that you know,
01:08:28Are there some other you know,
01:08:31noncanonical signaling
01:08:34pathways that are that require
01:08:39higher activation or is there
01:08:41a subset of receptors that are
01:08:44less sensitive or is you know,
01:08:46I don't, I don't know what it, no,
01:08:47I don't think anybody knows what it is.
01:08:49But so the point is that
01:08:51it's it's it's not like.
01:08:53The receptors weren't seeing any psilocybin.
01:08:55I mean I'm sure they were just if
01:08:57they were blocked enough blocked
01:09:00enough of them that they didn't
01:09:02get the head twitch and they
01:09:03didn't get that the EEG. So it's
01:09:07yeah, the reason I asked I'm I'm I'm
01:09:09very interested in trying to identify
01:09:10what you know what's this when I know
01:09:12it's not just going to be 1 receptor
01:09:14it's going to be very complex mix
01:09:16but from from some work I did back.
01:09:21Back in grad school and I
01:09:22didn't do the mouse head twitch,
01:09:23but I did the rabbit head Bob
01:09:25which is somewhat analogous.
01:09:27There are differences and how
01:09:29much of the antagonist you
01:09:31needed for the head Bob versus.
01:09:33I also looked at different
01:09:35behavioral outcome,
01:09:36also Pi hydrolysis,
01:09:37but it was different for
01:09:39the different outcomes.
01:09:39So I just wonder whether yes,
01:09:41it makes sense to like pick a dose
01:09:43that you'd think it's going to
01:09:44be big enough because otherwise
01:09:45your place can be just way too
01:09:46big and take much too long.
01:09:48But I wonder whether you know whether
01:09:51it just needed a higher dose or I
01:09:54mean there's also all these off,
01:09:56off, not off target because the
01:10:00transfer is not all that clean either
01:10:03maybe some other targets.
01:10:04But but but also this, you know raises
01:10:08the idea that even if it's going
01:10:10for the same receptor, they could be
01:10:12different on downstream pathways that
01:10:13are being activated or that are being
01:10:14blocked by by certain antagonists.
01:10:17And so that the therapeutic
01:10:19effects may still be coming from
01:10:21the same receptor, but maybe
01:10:22not not the same bonds genius
01:10:25signal or maybe there's also
01:10:27collo colloquialization
01:10:28of the perceptor. So it's
01:10:30obviously highly complex and you can't tell
01:10:32this from one now study,
01:10:35but I wouldn't be discouraged by that,
01:10:37you know, negative,
01:10:38you know, by that finding.
01:10:39But I still think that it's it is possible
01:10:41that the QA is something involved.
01:10:45Yeah, no, I I I I think. It.
01:10:47I would guess that it that it is.
01:10:51Yeah. And at least in some of
01:10:53these at least in you know some
01:10:55of these potential indications
01:10:56and you know headache may be
01:10:57something completely different.
01:10:59I mean don't don't really
01:11:01know but and I mean we do know
01:11:04that different to a agonists
01:11:09activate different.
01:11:12Signaling cascades to
01:11:13different to varying degrees.
01:11:15So I mean can be biased in One
01:11:17Direction or or in another direction
01:11:20and so that's you know a big,
01:11:23so you know maybe the pathways that
01:11:25treat depression don't involve you know,
01:11:30having mystical experiences or
01:11:31maybe they do it, but you know,
01:11:32there there really could be,
01:11:34I mean principle these things
01:11:36might be separable or.
01:11:38But they might not break.
01:11:39So but it's definitely something
01:11:41to work on and you know just a
01:11:44question of dose we you know we
01:11:46just haven't had the money to
01:11:48do good dose response studies.
01:11:49I mean you know MAPS is about to
01:11:52get you know maybe I mean they
01:11:54finished two phase three studies.
01:11:57You know they picked a dose based
01:12:00on these phase two studies that
01:12:02they did with you know they gave.
01:12:05A few patients a middle medium
01:12:07dose and few patients a low dose.
01:12:09They decide the low dose was was
01:12:12not good but the the one study
01:12:13that used the 75 or 80 milligram
01:12:15dose had it had better outcomes
01:12:17than the than the higher dose.
01:12:19So we don't know,
01:12:20I mean this is a drug that's you
01:12:22know may be approved and nobody's
01:12:25really determined what the optimal
01:12:28dose is and we might be able to
01:12:30expensive or not it's really
01:12:33yeah. I think it's it's 5:30 on a Friday.
01:12:37So I want to thank everyone who stuck it
01:12:38out for your patience. Thank you, Michael.
01:12:41Yeah. Well, I, I, you know apologize again.
01:12:43I've learned my nest lesson.
01:12:44Next time I'll come the night before
01:12:47and but no this just
01:12:49that Glad you stuck it.
01:12:50Glad you stuck it out.
01:12:51And thank you for sharing the data.
01:12:53Yeah. My pleasure.
01:12:53Thanks for thank you everyone.
01:12:55Have a good weekend in there
01:12:56and have a good weekend.
01:12:57Thank you.