Jordan Sloshower, MD & Patrick D. Skosnik, PhD. February 2023

February 20, 2023

Information

Title: Psilocybin-Induced Neuroplasticity in the Treatment of Major Depressive Disorder: An Exploratory Placebo-controlled, Fixed-order Trial

Description: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature and mechanisms of action remain unclear. This talk presented the methods and results of an exploratory placebo-controlled, fixed order study of psilocybin-assisted therapy among individuals with moderate to severe major depression (n=19). The study aimed primarily to investigate the role of neuroplasticity and psychological flexibility as mechanisms of change.

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00:00In person and on video.
00:03Recording his progress.
00:06And so we have a treat
00:08today. We're going to hear from both
00:11Jordan Slusher and Pat spouse Nick.
00:13We're going to tell us about
00:14different aspects of the study
00:16that they did together with Cyril
00:18D'souza and others on psilocybin,
00:20the treatment of depression.
00:21This may well have been the first
00:24silybin study that was started
00:25at Yale annuals, Emmanuelle.
00:27Yes, on this one.
00:29That was the the trailblazing. Hey.
00:34So we're going to hear
00:35some some clinical results from
00:37EEG and some background and it's
00:38great to have you guys here.
00:40Thanks Chris for inviting us.
00:42Great to be here and thank
00:44you all for being here.
00:45It's really fun to be finally
00:49presenting this work. Doctor,
00:51this is a smiling it's been a long road
00:53to get here 7 about seven years or so.
00:57And so just great to finally be at
01:00a place of presenting the results,
01:02having had at least one of our
01:05papers accepted for publication.
01:08So let's dive in here.
01:12And I should, I should thank Jordan and
01:14Cyril too, because they did the hard work.
01:17I just put EEG electrodes on people.
01:22Definitely A-Team science approach and
01:24was a been a labor of love for sure.
01:29So Steve in this study was called suicide
01:34and induced neuroplasticity and the
01:37treatment of major depressive disorder.
01:39And happy representing Patrick today.
01:43As far as disclosures for myself,
01:45really nothing relevant to the talk.
01:47The research we're presenting was funded by
01:50the Hefter Research Institute and I serve
01:53as a consultant with you Sona and ZYBAN,
01:55which both are involved
01:57in solar sybian research,
01:58but not with this study.
02:00And as far as where we're going to go today,
02:02I'm going to just give a lightning
02:04fast overview of suicide.
02:05Ben Pression talked about the study
02:08design and methods of this study and
02:11I'll share the clinical results of the
02:13study and then I'll pass it to Patrick to
02:16talk about the EEG methods and results.
02:18If there's time at the end,
02:19I'll touch briefly on psychological
02:22flexibility and we'll have a
02:25little time for discussion.
02:27So just real quick,
02:28have you guys had talked specifically
02:30on suicide then?
02:32Yeah, but the attendance varies.
02:33Yeah, fluctuates. I think it's worth the
02:35really briefly, Sivan is is a member
02:38of the classical psychedelic family.
02:40It's a serotonin 2A agonist.
02:44Particular. Chemical occurs naturally
02:48in silicide mushroom species which
02:49are widespread around the globe,
02:51and psilocybin mushrooms have
02:53been used for millennia.
02:56Actually, at the bottom right you can
02:58see mushroom statues from Meso America,
03:01Middle America, Guatemala specifically
03:03that date back about 2500 years.
03:06As far As for Western science,
03:08it is first isolated from the
03:11mushrooms by Albert Hoffman in
03:131957 and there was research with.
03:16The side then back in the early
03:19phase of psychedelic research
03:21in the West in the 50s and 60s.
03:24Not going to talk about that.
03:26More recently it has been the preferred
03:29psychedelic for most of the clinical studies,
03:32of which there is increasing many
03:35increasing numbers across different
03:37mental disorders as well as neurological
03:40disorders and increasing risk,
03:42potentially psychosomatic illness for sure.
03:45Depression, addictions,
03:48OCD increasingly and.
03:52Was headache disorders,
03:53you're Yale are getting more
03:55attention with the Sobin, please,
03:58as far As for the mental health conditions?
04:02The studies with suicide, then?
04:04Have used some sort of inside
04:06that assisted therapy model,
04:07which is which.
04:08There are many flavors,
04:10but the common elements generally include
04:13some attention to set and setting,
04:16meaning that mindset of the
04:17individual going in setting in which
04:20the medication is administered.
04:22And then the drug.
04:23So seeing that those are all important
04:25elements in determining the outcome and
04:28they followed essentially this three,
04:31three stage kind of model of using
04:34preparation support and integration,
04:36meaning preparation sessions leading
04:38up to the medication session,
04:40a supportive approach during medication
04:43administration and then follow up
04:45appointments sometimes called we call
04:48debriefing or integration sessions
04:50and of course there's been a lot of.
04:52Variety in what those sessions
04:54would look like,
04:56but have generally followed
04:58that three-part structure.
05:00As far as philosophy studies for depression,
05:03only going to mention do this very briefly,
05:06but this was really the state of
05:08the research when we were designing
05:10this study like 6-6 seven years ago.
05:12There was two trials that were
05:15published in 2016 looking at suicide
05:17and therapy in cancer patients
05:19who had depression and anxiety.
05:21And those were medium sized studies,
05:24about 100 participants and there was a
05:27lot of publicity generated from those.
05:30That is because the main finding sort
05:33of indicated these rapid acting and
05:35long lasting results from a single dose
05:38of psilocybin that were persisting
05:40up to about six months out and then
05:42later in follow up even longer.
05:44And so kind of generated
05:46this narrative around wow,
05:47you know,
05:49lasting effects from single
05:51doses of solar cylin.
05:53We talked about how the
05:54media picked up on that,
05:55but that was sort of the state of of that.
05:59And then right as we were
06:00really submitting this study,
06:02Robin card Harris published in 2016,
06:04this first Open label study of
06:07suicide then therapy in TRD or
06:10treatment refractory depression,
06:11very small open label study.
06:14And those were the individual
06:15patient results in the graph
06:17below. But just briefly you
06:19know showed robust effect that
06:22one week and that persisted to
06:24some degree for about 3 months.
06:26So again kind of.
06:28Providing some preliminary excitement
06:30around the potential of this therapy.
06:33Since then there's been a number of
06:35better studies that have gone on
06:38at Hopkins in back in London and
06:41increasingly now we have phase two
06:44level studies from Zona that will
06:47be published soon and one that was
06:50published from Compass Pathways in
06:51New England Journal just recently.
06:52I don't have time to dive into those
06:54because I want to spend time on our study,
06:57but you know.
06:58One of the.
06:59The brief summary that led into
07:00the design of this study was
07:02that there was intriguing data
07:04supporting suicidal therapy as a
07:06promising approach for depression,
07:08rapid acting, and sustained effects
07:10from limited numbers of doses of doses.
07:13There were very significant
07:14limitations to those studies,
07:15including small sample sizes,
07:17lack of placebo controls,
07:19or for blinding, functional,
07:21unblinding,
07:22suspected and significant expectancy
07:24effects increasingly as the
07:26media also continued to hide.
07:29Couples therapy and the big one,
07:32you know,
07:33the big question is also if we're seeing
07:35these long lasting effects from single doses,
07:37how is this working?
07:38What are the mechanisms of action those are?
07:41Were and still are to a large degree,
07:43still unclear.
07:45So that led into US cooking
07:47up this this study.
07:48So Sabin induced neuroplasticity.
07:51And just to introduce the study aims,
07:55it was primarily a mechanistic study.
07:57This is a exploratory and
07:59relatively small study.
08:01The things we were interested
08:03in looking at were neuropathy,
08:05effects of could neuroplasticity be
08:07an explanatory mechanism and Patrick
08:10will share about the EEG paradigm
08:12that we used to look at that possibility.
08:15And I was interested in this idea
08:17about psychological flexibility,
08:19which is baked into acceptance
08:20and commitment.
08:21RP as another more psychological
08:23mechanism of action and we
08:25collected some data on that.
08:27And of course as secondary measures
08:30we did collect efficacy measures
08:32for depression and being quite so
08:35a clinician administered and self
08:37rated measure looked at anxiety
08:38and quality of life as well as well
08:42as some basic safety outcomes.
08:45As far as our methods,
08:46this was we recruited adults with
08:48moderate to severe depression
08:50and they had to have had one or
08:52more treatment failures,
08:53so not technically TRD,
08:54although most of them had
08:57probably met criteria for TRD,
08:59they had to be offered antidepressants
09:01at the time of inclusion and
09:04study and major exclusion.
09:07Pretty typical for most of
09:08the studies in the field.
09:09Personal family history of psychotic
09:11or bipolar disorders or uncontrolled
09:13medical issues and we excluded.
09:15Anyone who had a past year use
09:18of psychedelics.
09:19And we aim to enroll 18 subjects or targets.
09:24And as far as the design,
09:25which I'll show you on the next slide,
09:27this was a placebo control within
09:29subject fixed order design with enhanced
09:32blinding procedures and it's a mouthful,
09:35I'll show you what that looked like.
09:37So our participants
09:39enrolled in the study here.
09:42At screening, they underwent an
09:44initial psychotherapy session and
09:46then all the participants received
09:49an initial placebo session.
09:51And then four weeks later,
09:53was there still a cybin session.
09:55However, they were not aware of the fact
09:57that it would be in that fixed order.
09:59They were told that there were
10:01three possible study conditions.
10:03A placebo in lower dose of Zoloft,
10:06cybin at .1 milligrams per kilogram and a
10:09higher dose of .3 milligrams per kilogram.
10:12And so the the middle,
10:13the low dose was actually never administered
10:16although participants received the placebo.
10:17And then the higher .3 milligram dose
10:21of soliciting 4 weeks later and the
10:23blue heads there indicate where we did
10:26EG which is was one day and two weeks
10:29after each of the dosing sessions and
10:31then the yellow and yellow you can see.
10:34We collected our depression
10:35measures all the way out to 16
10:38weeks after that initial session,
10:40or three-week three months after Silybin.
10:43And there was psychotherapy
10:46throughout the intervention as well.
10:49All right.
10:52Keep on moving unless there's any
10:54burning questions about the design.
10:59So I'm going to jump in and share some
11:02of the clinical study results first here
11:06and just really briefly show you our
11:08consort diagram and just make the point
11:10that we assess a lot of individuals
11:13for this study recruitment is a big
11:16deal and these studies assessed in
11:19a 949 patients to enroll 22 and had
11:24fifteen complete two both test days,
11:2619 completed the first Test day and so.
11:30For the purposes of our EEG and
11:32primary depression outcomes,
11:33we analyze all everyone who completed
11:35at least one of the tests says.
11:40Alright, I'm just going to share
11:41initially actually the blinding success.
11:43And I'm going to present this in
11:45part because I think it's really
11:47important when thinking about actually
11:48the rest of the efficacy results
11:50and also because this is just a
11:52glaring blind spot in the literature,
11:55not only the psychedelics,
11:57but really been looking even more
11:59recently just across amical trials
12:02that say they're blinded but actually
12:04do not present any data related to how
12:08successive the blinding and this is.
12:10Even more of a heightened issue
12:11and psychedelic arena.
12:13So actually proud to show the data
12:17that we collected at least on that.
12:20So as far as you know,
12:21and we we asked the only the participants.
12:23We didn't ask the therapist,
12:24which would have been even
12:26another layer we could have done.
12:28But during the placebo session,
12:30about 80% of our participants
12:32correctly identified the placebo and
12:35the other four guests the low dose,
12:37there was some confusion there,
12:39but no one mistook the placebo for the
12:42higher dose and that was also true in
12:45the subsequent high dose silybin session.
12:4880% correctly guessed they had
12:51received that intervention.
12:52A few guests that they had
12:54received the lower dose silybin,
12:56but no one confused again but.
12:58Suicide, then for the placebo.
13:01So while it was not 100% failure,
13:04it also was not an overwhelming success
13:07as far as maintaining the blind.
13:10And so share a few thoughts of
13:13how that relates when you're yeah,
13:15I've just forgot about my question was
13:18were these subjects psychedelic, naive?
13:21No, actually about I have this
13:24at least over half were OK,
13:26but the criteria was passed.
13:28The year was an exclusion past year.
13:31Is there any suicide?
13:34Conclusion. Correct.
13:37And about half were naive and about
13:40the other half had a limited exposure,
13:43so it wasn't, we didn't need any
13:45one who I'd say was a psychonaut.
13:48But I think no one had
13:50more than seven lifetime,
13:53because whether or not they have,
13:54whether or not people have previous
13:56experience can influence their
13:57expectation and can influence blinding.
13:59And it's not going to make
14:00people think that saline is.
14:02You know a robust
14:03trip. And then my other question
14:05was do you can you speak for the
14:07Group A little bit about the
14:08dose .3 milligrams per kilogram,
14:10why weight dose instead of fixed
14:13and what is that dose mean?
14:15How do you like what is
14:16that a high dose of medium?
14:18Thanks. So .3 is I guess can often
14:22considered a medium to high dose?
14:25Um, so definitely a dose that is will
14:28produce generally pronounced subjective
14:31psychedelic effects .1 being a lower
14:35threshold dose like where maybe
14:37not quite a microdose where there,
14:39but definitely not like robust psychedelic
14:41effects .3 and weight based dosing.
14:44At the time we designed this was kind
14:46of the standard and there's been a
14:49shift more recently to use fixed dose
14:51wait. Those dosing is a
14:52pain in the **** it is,
14:54it requires compounding.
14:55So I think probably as these drugs
14:57are getting closer to phase two,
14:58phase three and they're seeing
15:00that writing, you know,
15:01the actual scale of the suit.
15:04Towards fixed dosing.
15:05And I think there's some data also
15:07that perhaps body size is not a
15:10huge predictor of the robustness
15:12of the psychedelic effects as
15:15much as other idiosyncratic,
15:17you know, brain chemistry factors.
15:21But that was .3 was the dose also
15:23generally the dose used in those cancer
15:25trials that showed those early effects.
15:27So we just kind of adopted that.
15:31I'm just curious,
15:32during screening it was like 900 out of the
15:36949 were ineligible for in person screening.
15:40Was that was there like a common reason?
15:43There was so many reasons that we did
15:46have it all in the paper,
15:48but so many you know speaks to the
15:50difficulty of recruitment and and
15:52also how restrictive the product.
15:54Most of these protocols actually
15:57are as far as you know having to
15:59have had one fit like at least one
16:01failed medication trial and then
16:02being able to come off of that.
16:04And we require people to be in active
16:07treatment at the time of enrollment
16:08and they have to be in the area and be
16:11able to come for all these sessions.
16:12So it's. So many logistical and
16:15just factors why people couldn't.
16:17Participate.
16:19I'm going to be able to come off of,
16:20especially having to be able
16:21to come off of antidepressants,
16:23but having to have had a recent trial
16:25in the current depressive episode?
16:27Very tricky.
16:29So it's a lot of factors.
16:34So let me having shared those binding
16:36results, I'll show you the results
16:38from the handy which is our is our
16:41primary depression outcome widely
16:43used clinician administered scale.
16:45So just let me just walk you through it here.
16:47So from the left, people came in
16:49with about a handy of about 23.
16:52Are you upper moderate depression and
16:54after the placebo they had a notable and
16:58significant statistically significant
16:59drop in their depression which actually
17:01persisted all the way out for four weeks.
17:06Drop was around five points on the handy
17:09and then have their silibin session
17:12and improved again with a significant
17:15drop a little bit larger in magnitude,
17:186 to 8 points.
17:20Roughly the difference however between.
17:23The magnitude of change here pre
17:26postal cybin and pre post placebo this
17:28it was not a significant difference
17:30from this change to this change.
17:33However,
17:33the effect size in this case would be
17:36crime looking at was larger postal cybin.
17:40Anything,
17:40just a couple of things that
17:42are interesting thinking about
17:43also the blinding results is,
17:45is that people came in,
17:46they had the placebo session most
17:49actually realized they got placebo and
17:52instead of you know maybe getting worse
17:54or having an osebo response actually
17:56continue to improve and so you might
17:59think what what was going on there.
18:01At least two ideas are we're one
18:04they were receiving therapy and
18:05so having some therapy effects but
18:08another big one I think related to.
18:10Expectancy was that they knew that
18:12they had this other session coming
18:14up and we're engaging in therapy.
18:16So there was and I think we encouraged
18:19the generally hopeful attitude and
18:21thinking of this as one big journey.
18:23So I think that's that is interesting
18:25because we'll see probably in a few
18:27weeks the results of the USONA study.
18:29That was a single dose study
18:31where if you didn't get it,
18:33you had no hope of another session.
18:35So you know be quite different
18:38effects from the placebo session.
18:40I would imagine and then just the
18:43other caveat here is that there
18:45was a carryover effect that we we
18:48had anticipated that four weeks
18:49would be enough to wash out,
18:51but we did have carryover effects
18:53into the second part of the study.
18:55They're getting weekly therapy throughout,
18:57not exactly weekly, but it was two.
19:00They would get therapy the day
19:02after and a week after the each
19:04of the sessions and then there
19:06was a few follow-up sessions after
19:08week six after that final. That
19:11may have helped may have
19:12contributed to carry over.
19:13But as you point out the anticipation
19:16of males that combination of and
19:19there's no therapy between the day
19:20before the W zero day before dosing
19:22and W 0 day after dose correct.
19:24The only thing that happens
19:26there is that correct
19:28session with two with the therapists
19:30anesthesiologists in the room
19:32that the therapy that happened to concurrent
19:34with the dosing session. Yes exactly.
19:38So, you know, I think someone's
19:41trying to say something.
19:44Was there someone? And it's just.
19:50Just said a lot of that contact,
19:52probably more than standard of character.
19:53Yeah. So, you know, I think it's,
19:56it's one thing I've.
19:58So of course suicide then at least
20:00for this primary outcome not not a
20:03statistically significant difference
20:04though if you look from a clinical
20:06standpoint from the beginning to end
20:08pretty significant drops with the
20:10combined the effect sizes as well as
20:13the overall intervention pretty large.
20:15And again this was not designed as an
20:18efficacy study with such a small and but
20:21just another piece on the clinical results.
20:24You know we also look at rates
20:26of response and remission for
20:28those who completed both sessions.
20:30And just also show here that after placebo
20:32you know a little bit of response,
20:34but 20% response rate which really
20:37jumps up after this whole sibin sessions
20:41with responses lasting up to that.
20:44This was our primary MDM point
20:46endpoint at Week 6.
20:49Was the response to that response rate is a
20:5150% improvement relative to what baseline?
20:56Actually, for this is actually
20:58relative to the day before. Each dose.
21:01OK. So the psilocybin response
21:03there is relative to a day before
21:05psilocybin, not three weeks a week.
21:09Yeah. Jordan, I know the
21:11numbers are really small,
21:12but the people that did not
21:17accurately guess their. Assignment.
21:19Was there any difference there?
21:21Were they? Were they the big
21:25responders and non responders?
21:27So we have numbers are so small,
21:29we just have to be a
21:30qualitative look at it. But
21:31yeah, the the the one that was the
21:33biggest outlier was actually it
21:35was our very first participant.
21:37He had a very robust he detected
21:41effects from the placebo session and
21:44had very significant antidepressant
21:46response from the placebo session
21:49as far as the other ones.
21:52Sort of less memorable.
21:53I think they were just unsure,
21:55you know, which.
21:57Because that was the participant
21:59that sticks out the most in my mind.
22:07All right.
22:11So as far as just you know the other thing
22:14that I mentioned at the beginning was this,
22:16this whole narrative around the duration
22:18of response from a single dose.
22:20And so that was something we were
22:21interested in looking at and we look,
22:23we look at that best looking at the quiz,
22:25the self rated measure of depression
22:27that we collected because unlike the
22:29hand D which was just out to week six,
22:31we did collect this all the way out
22:33to week sixteen or three months after
22:35the suicide then dosing session.
22:37And So what I'm just highlighting
22:39in this box here is that relative to
22:42the pre sobin baseline from one one
22:46day after the dose there was that
22:49a significant drop similar to what
22:51the Hamdy and that response remains
22:55statistically significant for two
22:57months and then at three months that
23:01difference was no longer significant.
23:03However, they were at this point they
23:05were still significantly better than their.
23:07Initial baseline prior to placebo,
23:09but you know again small numbers,
23:11but I to me this was both.
23:14And encouraging,
23:16but also maybe perhaps more realistic result
23:19of seeing a two-month about a two-month.
23:22Response and duration from the single
23:24dose of suicide then at least the
23:27combination of everything that came
23:29before it and then the solar sybian does.
23:31So perhaps that you know I I mentioned
23:34that because I'm a bit skeptical
23:36of the single dose is going to
23:38cure people who've had 20 years of
23:41depression narrative and perhaps
23:43this is what we might see a little
23:46more realistic moving forward.
23:48All right.
23:49Before I wrap up this section,
23:50I'll just show you also some interesting
23:53results from our quality of life measure,
23:55which was the Rand 36 it had
23:59contains 8 health related domains.
24:01And I think this is important in depression
24:03studies not just to look at symptoms,
24:04but also the collect some idea of how
24:07people are actually doing in their life.
24:09And we collected qualitative data as
24:11well that I'm not going to show here,
24:13I haven't analyzed yet,
24:14but as far as from these eight domains,
24:17so actually.
24:17Out of seven, out of the eight,
24:19we saw significant time effect,
24:21meaning people significantly improved
24:22from their initial baseline over
24:25the course of the whole study.
24:26And in these three, sorry,
24:284 domains on the left now in green,
24:31that we actually did see a
24:34statistically significant improvement
24:35post silybin compared to post SIBO.
24:38So unlike the depression measures,
24:40this was statistically significant.
24:42Still cybin and these are pretty
24:46relevant domains that role limitations.
24:48Due to emotional problems and emotional
24:50well-being, social functioning.
24:52And general Health,
24:53we didn't see it for energy and fatigue.
24:55And just to show you what those results
24:57for us look like with something like this,
25:00this is for role limitations
25:01due to emotional problems,
25:02increase in scores, improvements.
25:04And so we we did see pretty
25:08significant jumps after the
25:10suicide and actually and this is
25:122 weeks. After the Silybin session
25:14and then we collected it at the end
25:16of study and that improvement was
25:19still significant three months later.
25:21And that was true for these other
25:23domains and the emotional well-being
25:26and social functioning as well.
25:28So that is. And perhaps promising results.
25:31So just to sum up that before I
25:34pass it over to Patrick from this,
25:36we did see significant improvements in
25:39depression following both the placebo
25:41and the sobin without a statistically
25:43significant difference between the two.
25:45However, we did see larger effect
25:46sizes and higher rates of response
25:48and remission postal,
25:49cybin and after the SILIBIN dosing session,
25:53the decreases in depression remains
25:55significant for two months and we saw
25:58significant and lasting improvements.
26:00In several mood related quality
26:03of life domains.
26:04Again, the limitations that I touched
26:06on for this section against small
26:09sample size for for an efficacy study.
26:11Any study we did have carryover
26:14effects that may have limited
26:16detecting that that difference.
26:18We had limited success with blinding
26:20and clear expectancy effects
26:22at play and therapy effects,
26:25and you know we can't separate in
26:27this model the therapy effects
26:29from the actual drug effects.
26:31Discuss more in the discussion.
26:34So with that,
26:35I'm going to stop my share
26:37and pass it over to Patrick.
26:43All right. Thank you, Jordan.
26:55Can everyone see my
26:57opening slide? Looks good.
27:00Alright. Great pointer.
27:05So now we want to talk
27:06a little bit what are the potential
27:09neural mechanisms of the antidepressant
27:11effect that Jordan just outlined.
27:15And so we're really in the
27:16middle of a paradigm shift.
27:22In the sense that there's this idea that
27:26psychedelics are psychoplasm begins,
27:28so they induced a neuroplastic state,
27:31which might open a therapeutic
27:35window for therapy.
27:37And it's a paradigm shift because it
27:41goes beyond the standard, you know,
27:44trying to manipulate neurochemistry
27:47with via mono Amiens, Prozac and Zoloft.
27:51And whatnot and instead.
27:54Try to selectively modulate and change
27:57neural circuits that are implicated
27:59in depression and anxiety and OCD and
28:02other things as well in addiction.
28:08So I'll start with what's neuroplasticity.
28:10So neuroplasticity refers to the
28:13activity dependent modification
28:14of cement synaptic transmission,
28:17which is thought to be one of the neural
28:19substrates of learning and memory.
28:21In some sense,
28:22I think neuroplasticity plasticity is
28:24redundant because the brain is so dynamic.
28:27Our environments are constantly
28:29changing and relationships are changing.
28:31And so the brain is so dynamic,
28:33so it's always plastic,
28:35but we use the term neuroplasticity.
28:38And this idea goes back
28:41to Donald Hebb from 1949.
28:43And this quote of his is is so
28:48iconic and really I think prophetic.
28:51So Donald Hebb said in 1949 when an Axon
28:56of cell A is near enough to excite a cell B.
29:01And repeatedly or persistently
29:02takes part in firing,
29:04firing it.
29:05Some growth process for metabolic
29:08change takes place in one of both
29:11cells such that a efficiency as one
29:14of the cells firing B is increased.
29:17So a simply simple way to say that is
29:19sales or networks that fire together,
29:22wire together,
29:23that's these the essence of neuroplasticity.
29:27This is really important in the
29:29context of depression because
29:31enhancing neuroplasticity,
29:32for example through psychedelics,
29:34could up again open up this therapeutic
29:37window in which traditional
29:39therapies such as CBT and others
29:42could prove more efficacious,
29:44and indeed deficits and
29:47markers of neuroplasticity,
29:48for instance a peripheral BDNF,
29:50have been observed and depression.
29:55So this review paper just came out showing.
30:00Some of the work that's been done
30:03in the context of psychedelics on
30:06different measures of neuroplasticity.
30:09And there's several measures that.
30:12Have been used, including.
30:16Immediate early genes,
30:19upregulation of other plastic
30:22plasticity genes, spinal genesis,
30:25neurogenesis, density of synapses.
30:28One thing that to note here,
30:30which may come up in discussion later,
30:32is that each of these different
30:36measures of neuroplasticity looked
30:38to have a different time course.
30:40So of course the immediate early
30:42genes are early, you know,
30:44within an hour of administration of.
30:46Of the second relic,
30:47whereas some of the morphological
30:49changes tend to happen later.
30:55You asked in the chat if you
30:57get neuroplastic changes after
30:59conventional, like monoaminergic.
31:02Antidepressants, the answer is yes.
31:06And with ketamine and with ECT.
31:10Correct. In with TMS I believe as well.
31:14Umm, but you know the the change of
31:17psychedelics are pretty rapid and
31:18they they can be pretty long lasting.
31:21And for like the typical, you know,
31:24SSRI's, it may take months for
31:27these types of changes to occur.
31:30In a really elegant study for from
31:33some of our colleagues right here
31:35at Yale shall it all showed that a
31:39single dose of silybin increased spine
31:41density in the media prefrontal cortex.
31:44It immediately related stress related
31:46behavioral deficits using learned
31:48helplessness paradigm which is a standard
31:51animal model of depression and also
31:54also promoted excitatory neurotransmission.
31:57So it was really elegant in
31:59the sense that it showed.
32:00Silas Sylvan could induce
32:02morphological changes,
32:04structural changes,
32:05behavioral changes related to depression,
32:08and.
32:11Excitatory neurotransmission
32:14via electrophysiology.
32:17So going back to this plot I showed earlier,
32:21one thing to note is this, this,
32:23this middle row here is it's in yellow.
32:27These are the human studies.
32:28And what you can see is most of
32:31the human studies have really just
32:33looked at peripheral BDNF levels,
32:35which are thought to be
32:37related to neuroplasticity.
32:38And there have been several
32:40negative findings as well.
32:41But there's a question of,
32:42you know, do BDNF levels
32:44peripherally reflect being the be.
32:46Enough levels in the brain.
32:50Which is not highlighted here.
32:51There have been some F MRI studies
32:53look at functional connectivity
32:54in the context of psychedelics
32:57showing increased connectivity,
32:58but what this really does show
33:00is there's a possibility of data
33:02using sort of brain measures,
33:05especially electrophysiological,
33:06in the context of psychedelics
33:08and depression.
33:13So how can we non invasively
33:17assess neuroplasticity?
33:18In humans, and one way we could do
33:21it is with long term potentiation.
33:24So one form of synaptic plasticity
33:26is the ability of synapses,
33:28as I mentioned earlier,
33:29to strengthen overtime in response to
33:32increases or decreases in their activity.
33:36The type of synaptic plasticity
33:37that's typically measured is
33:39called long term potentiation,
33:41which is a persistent increase in
33:43synaptic strength followed flood following
33:46high frequency pre synaptic tetanic
33:49stimulation typically at about 100 Hertz.
33:52And it is really this is to be a neural
33:53substrate of learning and memory.
33:55So high frequency Titanic stimulation
33:57of the presynaptic cell will increase
34:00excitability in the postsynaptic cell.
34:03This has been one of the quintessential
34:05models of neuroplasticity going back.
34:06Decades,
34:08and while it's traditionally been
34:10studied in slice preparations,
34:11and it has been done in humans using
34:15exercise tissue some surgical patients,
34:18it's now possible to index LTP
34:21and humans non invasively using
34:24sensory stimulation and EG.
34:30So this, so this is what the,
34:33the, the typical paradigm that I'm
34:36Speaking of entails. And in fact
34:38this is the very paradigm we used.
34:40So it's good to pay attention to this.
34:42So, so we chose this paradigm adapted from
34:45clap at all 2005 and it's an auditory.
34:50Sensory LTP paradigm.
34:54Losing my point here.
34:55So the way it typically works is
34:58you have a pre tetanus period where
35:01you present roughly 120 tone pips.
35:04They're just 1000 Hertz tones,
35:0650 milliseconds each and what they
35:09do is they induce an auditory
35:12ERP or the way we have analyzed
35:15it an event related oscillation.
35:18So this is standard ERP stuff.
35:21You present a tone,
35:23you get an ERP or you get an
35:25event related oscillation.
35:27And then we do 2 minutes of
35:30a tetanus at 13 Hertz,
35:33which has been shown to be
35:35optimal for the authority cortex.
35:36And then we redo the the test
35:39phase with the same types of
35:41tone tips as in the pre tetanus.
35:43And what you can see here is an
35:46increase in event related oscillations
35:49particularly in the Theta range.
35:51And these are actually our data.
35:52These are about 9 control
35:55subjects that we used to.
35:57Deposit the paradigm.
35:58So this is what you should see
36:00in a normal individual.
36:02So is there any questions on,
36:03on the paradigm
36:05ERP is event related potential.
36:07So that's like the reliable EG squiggle
36:09that comes after a sense risk stimulus,
36:11right. And that's what's typically done with
36:13with this paradigm and we did that as well.
36:15I'm not going to show that,
36:17but I chose event related oscillations
36:19because you really get the same
36:21information but you get added
36:23information about the frequency
36:24characteristics of the response.
36:26Does that make sense? Yeah, yeah.
36:28When you look at an ERP,
36:29you, you really have no idea
36:31what frequency that ERP is.
36:34Once, but at the time it didn't.
36:38I'm sorry, I didn't catch that.
36:44Someone asking you a question if
36:45someone who had need wasn't muted.
36:51How long does it last this posted?
36:53And it's like this increase in
36:55the data band after the auditory.
36:59How long does the entire task take? How how
37:03long do you observe this this effect
37:05and and when does it come back?
37:07Does it come back to know to the
37:09President state after a while?
37:10And if yes, after how long?
37:13That's a really good question.
37:15So we did not test that.
37:16But in the original plat study,
37:19they observed it up to six
37:22hours after after the tetanus.
37:25So they observed this increase in,
37:27in their case they did ERP's,
37:29but they observed it six hours after.
37:31They didn't go beyond that.
37:33Um, probably just for logistical
37:35reasons and subject burden.
37:37So it could last longer than that.
37:39But they did observe it six
37:40hours after the tetanus.
37:43And maybe you can get in Vivo LP in the
37:45hippocampus that lasts a month or more.
37:46So in principle it can last a very
37:48long time whether that would happen
37:50in this paradigm, but in principle.
37:56So this is just a
37:58reiteration of Jordan slide.
38:00So just to remind everyone that
38:02we did EG 24 hours after placebo,
38:06the first placebo session.
38:07We did it two weeks after
38:10the placebo session,
38:11then we did a 24 hours after the
38:13style of seven session and then two
38:15weeks after the Salah seven session.
38:19General EEG methods pretty standard.
38:21We use the Compton medics and M6 to
38:24four channel nurse scan EEG system.
38:26Umm. This good to note that all
38:28stimuli presented at 80 decibels
38:30SPL which is standard and it's kind
38:33of the same decimal level as as
38:36you know conversation sample rate
38:38of 1000 Hertz, bandpass filter,
38:40notch filter to get rid of line noise,
38:43standard preprocessing,
38:44getting rid of bad trials and ocular
38:46correction and all data was analyzed using.
38:48Brain products and less for 2.0.
38:53OK. So this is the event related
38:57oscillations across all the conditions.
38:59So the first thing to pay
39:01attention to is the top left.
39:03So this is the day after placebo and
39:06what you can see is we observe no
39:10LTP pre tetanus versus post tetanus.
39:13So they related oscillations
39:15in the Theta band identical.
39:19Suggesting that perhaps in this depressed
39:22population they have impaired LTP.
39:24But that's speculative at this
39:27point because we did see it in our,
39:28at least our pilot control study.
39:32Likewise, 2 weeks after placebo, same thing.
39:35No, no LTP from pre tetanus to post tetanus.
39:41Moving on to Silo Sybian,
39:43so 24 hours after Silas Sibin.
39:45Again no change from pre
39:48tetanus to post tetanus.
39:50And the other thing to note is the amplitude
39:53or the power of the Theta responses
39:56were the same in all these conditions.
39:59The thing that was we weren't expecting,
40:01which is really the interesting thing
40:03of this study is we found we we
40:07didn't see pre tetanus versus post
40:09tetanus 2 weeks after silaban either,
40:12but we saw an almost doubling
40:15of data power just in general.
40:18And these are just the bar graphs
40:20showing what I just showed, so.
40:23The difference?
40:24Pre tetanus post tetanus 24
40:27hours after two weeks after,
40:30maybe a little bit two weeks after here.
40:33Not significant though.
40:35Nothing the day after Silas Syben.
40:38And then you see this doubling of data
40:41power two weeks after Silas Simon.
40:44And the really intriguing part of this
40:47study is that we found that change
40:50in AMD scores after Salas Livin.
40:53Negatively correlated with change
40:55in Theta power.
40:56So an easy way to to say this is those
40:59individuals that had the greatest
41:01decrease in their hand D scores had
41:04the greatest increase in their Theta power.
41:13Sorry, was it computed at the brain level
41:16or on specific clusters of electrodes?
41:20That's a good question.
41:22We used electrode FCZ umm because
41:25that's we typically we do that a lot.
41:28That's just where the signal was maximal,
41:30which is typical for auditory
41:32stimuli to have the front of central
41:35electrodes have Max responses.
41:36So we just competed this at FCZ.
41:42Patrick, the the because of the
41:45fixed order here, you can't.
41:47Am I right that you can't disambiguate
41:50whether the increase in power that you
41:53see pre tetanus at 2 weeks is related
41:56to the tetanus given at one day?
42:02Well, this correlation has changed.
42:04This I I should specify this
42:08correlation is change from.
42:1124 hours post silacci ibin
42:14to two weeks psilocybin.
42:16I'm sorry but I've been just in
42:18the EG if you go back one slide.
42:21So I don't know if this
42:22makes any sense or not,
42:23but this is just where my mind is going.
42:24So you're giving a tetanus one
42:26day after psilocybin, right?
42:28And you see no change in power one
42:31hour after that tetanus, right?
42:34It's shorter than that.
42:35It it it's it's about it's about
42:388 minutes of the tone pips,
42:402 minutes of tetanus and then
42:43another two another 8 minutes
42:45of the does it make sense?
42:49Only no enhancement of LTP immediately
42:51within minutes after the tenants, correct?
42:53But suppose you got an enhancement
42:56of LTP an hour after the tetanus.
43:01See that in your week four data?
43:03Because you're looking too soon.
43:06And that could be the cause.
43:09Of the increase that you see at 2 weeks,
43:11it could be long lasting LTP.
43:14Obviously enhanced could be long lasting LTP.
43:19From the Week 4 stimulus, right. You
43:22know that's a really interesting
43:24interpretation that I didn't
43:25think of. Yeah, so you don't
43:27that we didn't see any change
43:29from that initial week 02 weeks.
43:31I would clearly it would be 4 weeks
43:34and you have a silybin effect, right.
43:36So it could either be that psilocybin
43:38is enhancing Theta in a completely
43:40non contingent way that you know two
43:42weeks after psilocybin you have an
43:44increased in the Theta that's induced
43:46by these auditory pips full stop,
43:48has nothing to do with the tetanus.
43:50Or it could be that it is psilocybin
43:55increases plasticity it increases.
43:58Plasticity produce in a long lasting way,
44:00it's just that you don't see it at 8 minutes.
44:03You see it sometime hours or days
44:05after and it persists for two weeks.
44:07And because of the fixed story,
44:08you can't, you can't disambiguate
44:10those from this design.
44:11But it's it's just this may be
44:13a plasticity effect, right?
44:14This may be a result of your tetanus.
44:15It's just taking just manifesting much later.
44:18What it it's a great,
44:20it's a great point.
44:20I didn't think of that interpretation.
44:22I think either way it's a plasticity effect.
44:24It could be like you said the places
44:27plasticity effect from the tetanus
44:29just takes longer to kick in for back.
44:33Lack of a better phrase or.
44:36The way we've thought about it with
44:38this paper is in in revision.
44:40So the way we framed it is we
44:42think this increase in Theta in
44:44general is sort of a qualitatively
44:46different type of plasticity.
44:51But yeah, in the mechanisms of synaptic
44:53plasticity the they were qualitatively
44:55different mechanisms involved in
44:57short term plasticity lasting minutes.
44:59Then there are in plasticity that
45:01lasts hours or days they're completely
45:03and you can dissociate them.
45:05That's actually.
45:05This is actually what I did my PhD thesis
45:08on was blocking long lasting plasticity
45:10without affecting short term plasticity.
45:12You can also enhance long lasting plasticity
45:14without affecting short term plasticity.
45:17So depending on the mechanisms whereby.
45:20Hillside and is acting on plasticity.
45:22It it's it's very plausible that
45:23it could have not have a short term
45:26effect but have a long term effect.
45:28So I think that's an important your date.
45:31This is a discussion point is not
45:32something your data can speak to,
45:33but it's an important possibility
45:34to to think, to think about when
45:36looking at future studies.
45:38If this were a non contingent effect,
45:40meaning if this had nothing
45:42to do with the tetanus,
45:43it would be startling to me.
45:45If you do you do you see any
45:47effects in Theta in resting Theta?
45:49If you just look at your resting
45:52EEG if this were a non contingent.
45:55Change in brain wiring that
45:57causes enhanced Theta power.
45:59You should see something in your resting age.
46:03And if you only see it with your stimulation,
46:05then that makes it sound like
46:07it's a circuit specific effect,
46:09which makes it to my mind more likely to
46:11be a late effect of your of your tetanus.
46:14Yeah, we didn't see anything
46:16in the resting Theta.
46:17In fact if you did so this
46:20this dashed line here,
46:21that's stimulus onset.
46:22So if you saw differences in resting data,
46:25you would actually see it in this,
46:27in this window here,
46:28this pre stimulus window, so.
46:32But this is a great point.
46:33It goes back to that plot I showed
46:36earlier with the different time courses,
46:38from the early, immediate early
46:41genes to the synaptogenesis and the.
46:45Increase in dendritic spines.
46:48The one study from I think it's
46:50Ravel at all showed that in pig
46:52brain a single dose of Cialis
46:54Cybin you don't see increases in
46:57synaptic density until about.
46:58Seven days after.
47:00And that also makes sense because
47:03the way what EG is measuring
47:06is thousands of postsynaptic
47:08potentials from pyramidal cells.
47:11So if you have increased spine
47:14density and synaptogenesis,
47:15you're going to see increase
47:18ERP's and increase power.
47:19So that's sort of the way
47:21we're thinking about it.
47:26So just in summary,
47:27EG long interpretation was not observed
47:30in this sample depressed subjects,
47:32we did it observe increased Theta power which
47:36correlated with decreases in depression.
47:39This increased Theta power post Silas
47:42statement is objective evidence
47:43of sustained electrophysiological
47:44changes in the brain produced by
47:47Psylocybe bin and given the correlation
47:49with decreased depression,
47:51this may represent a biomarker response
47:53to Silas cyber couple limitations.
47:55We didn't have a control group to
47:58compare the EEG LTE LTP outcome.
48:00We do have pilot data,
48:01but we don't have the longitudinal 4
48:04test days with with control subjects,
48:07so it's unclear if if that lack of.
48:09LP was it because that these are depressed
48:12people and that's impaired in general.
48:14So that's an area of future study.
48:17We didn't have any baseline EEG measures,
48:20you know, before the.
48:22The sequence started,
48:23but I think because there's a placebo arm,
48:25I don't think that's a big limitation.
48:28I should mention that
48:29the effective data pile,
48:30we're actually at trend level at .07,
48:32so that's probably due
48:34to the small sample size.
48:35But we think these limitations
48:37notwithstanding these results complement
48:39the emerging notion that Silas Syben
48:41and perhaps other psychedelics,
48:43classical psychedelics can
48:45produce long-term alterations in
48:47neuroplasticity as assessed via
48:49electrophysiology or EEG in this case.
48:55All right. And that's what
48:56I ask from the EEG portion.
49:00Patrick, it's Jerry.
49:01So I understand your logic by not
49:03doing it before the placebo, but.
49:07The studies that I know and
49:09depression actually the best
49:11predictor is EG of placebo response.
49:13You know, the Lucia's data and others
49:16that that's a pretty powerful predictor.
49:18In fact, I think they're trying to
49:20develop whole methodologies of predicting
49:23predictor of what predictor of
49:25clinical response to antidepressant.
49:26Yeah, with with EG to to placebo.
49:33But so the the thought was you weren't,
49:35you weren't really interested in
49:37the placebo response that's why
49:38you didn't do it prior to placebo?
49:42But Jerry, EG what EEG measure and
49:46they they have, they're looking at alpha
49:48and gamma and a few other things in
49:50the resting part of it is proprietary,
49:52so you don't know exactly what.
49:54What the whole set of measures are,
49:58but and they're looking at resting and then
50:00they look at the change after placebo.
50:05Yeah, it's a fairpoint. I guess we
50:07were thinking about subject burden,
50:08but you know maybe in retrospect we we
50:10should have had a a baseline EEG before
50:14before placebo and the whole sequence.
50:16I can understand that that's
50:18a that's a pretty heavy
50:19burden on people right there.
50:20You want to minimize it,
50:21but that that was the reason
50:23we didn't do it subject burden.
50:29Yeah, these edges take, you know,
50:30these are very depressed people.
50:31They take about 3 hours.
50:34Our hour and a half set up hour
50:37of task and. No. Debriefing
50:41you're doing pre post stimulation.
50:43I think that's the lesson, the concerns.
50:49So do you have a couple more slides?
50:52But if there's that, I could show.
50:53But if there's other questions,
50:55you could do you now or I could wrap
50:58up my slides, but you would want to.
51:01Ask anything about the Lego piece.
51:06Can I ask you a quick question?
51:09Sure. Hi, this is Pasha. I'm MD,
51:13pH. D student in Alex Kwanzaa.
51:15So I actually did the ethers for
51:16the shall at all paper that you
51:17showed and I'm doing in vivo now.
51:19So we're trying to think of like more
51:22reverse translationally relevant.
51:24Did you look
51:25at any of the other bands?
51:26Because I know there's been
51:28some work in preclinical
51:30and clinical for like
51:31gamma bands and stuff, but
51:32and you said all of this was in the frontal
51:34cortical electrodes. Is that right?
51:38Yeah, but you know, these discrete
51:42auditory stimuli almost always.
51:45They they live in the Theta
51:47band between 4:00 and 8:00.
51:48You just, you just don't,
51:49you just don't say any evoked
51:52activity in the higher bands.
51:54Thank you. Had we done a more
51:58cognitive perceptual task,
51:59then certainly we would probably want
52:01to look at the other bands as well,
52:04but this is very simple sensory stimuli.
52:06Patrick, did you look at the
52:09the affected VLT EEG correlates?
52:15The AV Lt. yeah, yeah.
52:19That's in process, So what I didn't
52:21mention to everyone is when you
52:24take all the the time to get people
52:27set up with the EG in the booth.
52:30This this task is about 12 minutes
52:32this LTP task, so you don't want
52:34to do all that set up and get.
52:37Just 10 minutes of data,
52:3812 minutes of data.
52:39So we have several other tasks that we're
52:41going to be looking at and hopefully
52:43we can have some follow up papers on.
52:44One is and EG version of the Gray
52:48auditory verbal learning task and
52:50we also have gamma driving P300.
52:53So there's other things that we
52:55can look at that might inform.
52:58Potential mechanisms.
53:06Well, we have a couple of minutes.
53:08I'll just quickly show a little bit of
53:12data related to psychological mechanisms
53:14and this was relates to in some ways
53:18what could be a psychological correlate
53:20of what we're seeing in terms of
53:23neuroplasticity are to equate the two,
53:25one being cellular,
53:26but in this other concept much more
53:28in the psychological realm but.
53:30Still going with that same general
53:33notion that psychedelics might open
53:35up this period of critical plasticity
53:37in which there may be more potential
53:40for psychological flexibility and
53:42other changes in people's lives.
53:44So we did use this therapy model using
53:47acceptance and commitment therapy,
53:49which explicitly targets psychological
53:52flexibility. That's the main mechanism.
53:55We've written some papers and I could give
53:58a whole talk about just this this model.
54:02But the basic idea was was that we
54:05saw conceptual and phenomenological
54:07overlaps between the components of
54:10act and the effects of solar cybin.
54:13And we thought that these two might
54:15synergize well together and that this
54:17increases in psychological flexibility
54:19which there there are measures
54:21for could maybe a key mediator.
54:23So we wanted to look at that and
54:26increasingly actually other investigators
54:27have picked up on this idea and this
54:30is from now on Davis that did show it.
54:32This is from survey data,
54:34but did show that basic kind of model
54:36of the acute psychedelic effects
54:39feeding into increases in psychological
54:42flexibility that that mediated.
54:44Clinical improvements.
54:45This far just quickly to show you
54:47because I think it it was nice
54:49data that we we did see.
54:51So this is the AQ,
54:52it's one of the primary measures that
54:54was developed to look at the idea of
54:57psychological flexibility decreases are
54:59actually clinical improvements here.
55:01So we did see a statistically
55:04significant improvements in
55:05psychological flexibility following
55:07soybean but not after placebo and this
55:09was a significant difference here.
55:12We looked two weeks after Socmen
55:14and again it did persist.
55:16Three months later,
55:18I do have some other measures that we
55:21looked at that relate to this idea.
55:23Especially mindfulness and there
55:25were some significant changes
55:26there as well as in value living.
55:28And just to show,
55:29you know the other thing that was Nice is,
55:31is we also saw,
55:32did see a correlation here between those
55:36changes in psychological flexibility
55:38and the actual clinical improvements.
55:42So those things trending together
55:43of course can't see causation,
55:46but it was highly significant
55:48correlation between those those two.
55:51So, so just a promising direction here.
55:54And you know,
55:55it's interesting given the
55:56small sample that we did see a
55:58highly significant improvement,
55:59sorry,
55:59correlation here,
56:00but we actually did not see a
56:03statistically significant correlation,
56:06really any correlation here between the
56:08strength of the mystical experience and
56:11the clinical improvements postal cybin,
56:13which and that has,
56:14you know typically been one of the
56:17prominent explanatory mechanisms on the
56:19more psychological experiential level.
56:22So we didn't see that,
56:23but we did see the correlations.
56:25Both with the EEG measure
56:27that Patrick shared,
56:28as well as with psychological flexibility.
56:32So that's just what I said there.
56:33And so just to wrap up,
56:34you know I think the study was
56:36really a good demonstrator
56:38of with psychedelic studies,
56:40just how tricky these are from
56:42a methodological standpoint.
56:44And it's such a complex interplay
56:46between expectancy effects,
56:47therapy effects and drug and placebo
56:49effects that we need to be really
56:51mindful of as we design these trials.
56:53I I do think given the robustness of
56:55the clinical effects that we saw that
56:58it does again add to the promise of
57:00this overall treatment model both
57:02suicide and therapy and potentially
57:04with actions and psychological
57:06flexibility as being important
57:08potential ways of providing this
57:11treatment to patients with depression.
57:13And both of our these alterations
57:16in neuroplasticity and changes
57:18in psychological flexibility may
57:20be important potential mechanisms.
57:22Of course psychedelic therapy for depression,
57:25but potentially again we we're seeing
57:28effects across many other mental
57:30disorders and and both of these are
57:33potentially transdiagnostic mechanisms
57:35and so I think that adds to the
57:38intrigue around both of those so.
57:41Lot of questions remain on how to deliver
57:44this treatment most effectively and discuss,
57:47but I think I'm just going to
57:49wrap up so we can discuss here.
57:51Again, just really want to thank
57:54Doctor D'souza for sticking with me
57:56and the study for the duration and
57:59taking it to the finish line as well
58:01as everyone who's been involved from.
58:04Of the synergy lab at the VA there
58:06and our whole team of therapists
58:09and and our funders as well as the
58:12study participants who were our
58:14best teachers in this never so.
58:17Thank you all.
58:20See if there's any. Great for discussion.
58:24Thank you both.
58:25It's really great to see this
58:27come to fruition and there's
58:28some nice results, you know,
58:30small and limited study,
58:31but given those limitations
58:32have some nice stuff in there.
58:35So thank you.