Michael Bogenschutz, MD. April 2023

Transcript

• 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.