Gerard Sanacora, MD, PhD & Ben Kelmendi, MD. December 2023

December 21, 2023

Title: Psilocybin’s Role in Depression: Usona Phase 2 Study Analysis

Description: Drs. Kelmendi and Sanacora briefly reviewed the findings from previous studies exploring the potential antidepressant properties of psilocybin and reviewed in detail, the findings of the recently published randomized single dose trial comparing the antidepressant effects of Psilocybin and Niacin sponsored by the Usona Institute.

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00:00And and they were both OK.
00:03All right. Hello everyone. Thank
00:05you for coming to our
00:07psychedelic seminar for December.
00:08We have our own Jerry Sanacora and
00:11Ben Kilmendi here today who ran our
00:15sites Yale sites contribution to
00:17the bona funded study of multi site
00:21study of psilocybin in the treatment
00:24of depression which was published in
00:26JAMA Psychiatry earlier this year.
00:28And so I I thought it'd be great to have
00:31Jerry and Ben tell us about that study,
00:33the design, the results and some
00:35of the the issues that come up in
00:37next steps from that program of
00:39research which is one of the sort of
00:41one of the leading programs that's
00:42moving towards the potential for
00:44approval of psychedelic treatments.
00:46So very current, very important.
00:48Thank you for being here.
00:50All right, thank you. Thanks Chris. Well,
00:52thank you all. Let me just make sure
00:54we can share our screen. Jessica,
00:56I don't know if there's a there we
00:59go should be able to
01:02looks good now and.
01:10OK, all right. That should be a Ben.
01:12OK yeah. I'm going to start up.
01:14So we're going to do something
01:17differently in a sense that Jerry
01:19and I are going to split the talk.
01:21I'm going to go over the first half
01:23of the talk, which is going to,
01:25it's going to cover more or
01:26less the same things that are
01:30no longer unfamiliar to this group.
01:32And so I'm going to cruise through
01:35so we can get to sort of the data.
01:37And the more interesting part of this, we
01:41have time for discussion
01:42and then Oh yeah,
01:43we want to leave as much time
01:44as possible for discussion.
01:45Let me just see how this works.
01:48OK, so disclosures,
01:51all of these above are Jerry's
01:53and I have this measly one liner
01:59skip. So psilocybin as as I said,
02:02I'm not going to go into detail about what
02:05psilocybin is and where it comes from.
02:07It's a natural occurring compound found
02:11in psilocybin mushrooms. It's found in.
02:17The particular extract comes
02:19from psilocybin kubensis,
02:21that the number of psychoactive
02:25species of mushrooms,
02:26at least in the United States,
02:27is in the range of 60.
02:30Briefly here I thought would
02:32be really useful to review the
02:35metabolism of psilocybin.
02:36As you can see psilocybin in its
02:39natural form it's not it's not active,
02:43it actually is.
02:45Once it's ingested that it is
02:52mute and turn off your your speaker
02:54it's so it
02:57GI once it actually hits the stomach
03:01it's dephospholarated as you can see
03:03here and it becomes silos silosin or
03:06silosin is the active ingredient and
03:09the capsules that we use in our study
03:13actually contain silosin rather than silos.
03:16Cyben the much of the metabolism is actually
03:21in the IT undergoes hepatic metabolism.
03:26So it's glucurini,
03:28Glucurini needed that it's broken
03:31down into four hydroxy indole acetyl
03:34hydrate and then the four HDP and four
03:39HAIAAR excreted urinary and it's
03:45the half life Typically this is out
03:48of your system within 24 hours.
03:50The half life is 4 to 6 hours.
03:54So just a little, I guess this is more
03:57what I said earlier that sell us you
03:59know the use of psilocybin in various
04:04cultures throughout the world goes
04:07back to a couple of 1000 years.
04:10But it's most prominent use that at
04:14least in the United States that's
04:16had an influence really comes from
04:18the indigenous use in Central
04:22America and Sierra Mastic region,
04:25particularly the Sierra Mastic
04:27region in Mexico. It came.
04:29It was first introduced to the States
04:34in 1950s and shortly thereafter
04:37studies with psilocybin were underway,
04:40particularly late 1950s and 1960s
04:44Psilocybin became a scheduled
04:46one compound in 1974.
04:50Here is just a quick Since recently with,
04:56you know, what's been dubbed as
04:59the Renaissance of psychedelics,
05:01there's been an interest in doing
05:05some more work with psilocybin.
05:07And this table summarizes the recent,
05:11most recent studies looking at the
05:13effect of psilocybin and depression.
05:15So there's been quite a few studies.
05:17This is actually not a comprehensive table.
05:20There's some studies that actually
05:21go back to 2016 that were done in
05:25patients with anxiety and depressive
05:28symptoms in palliative care setting,
05:31but those patients did not
05:33necessarily meet criteria for MD.
05:35These studies are,
05:36this one does not actually include the
05:38study that we're going to talk about,
05:40but these are the studies that have
05:42looked at psilocybin and MDD or and
05:46as well as PRD though this table
05:51doesn't differentiate between the two.
05:53And here in this I think we're going
05:56to spend most of the talk looking at
06:00the talking about the study at hand
06:03which is a single dose of 25 milligram
06:06of psilocybin in major depressive disorder.
06:09And as Chris mentioned earlier
06:11that we were Doctor Senecora and I,
06:13we were one of the sites here
06:16at Yale and ran the study.
06:18And with that any further ado,
06:19I'm going to hand this over
06:21to Doctor Senecora,
06:22He will review the details of the study.
06:25Great. Thanks Ben.
06:27So just to go through the
06:31the purpose of the study,
06:33as as Ben said there have been
06:35several studies prior to when
06:37this study was initiated.
06:38But many of the problems with
06:41those studies surrounded the
06:43small sample sizes that we use,
06:45the relatively short term
06:47follow up that was used,
06:50the the comparative that was used
06:54and and the frequent unblinding
06:56of the assessors or the raters.
07:00So this study aimed to try to
07:03address many of those concerns
07:06with the original studies when
07:07when it was originally initiated.
07:10So we'll take quite a bit of time
07:13just going through I'm there.
07:15I'm getting a message saying
07:17it's hard to hear.
07:18So I don't know if anything
07:19we can do about the volume,
07:21but so I wanted to just take
07:24some time going through this,
07:25sorry. We can turn off the room
07:27mics and you can turn on your
07:29computer mic and then it'll make it.
07:57OK. I don't know
08:02if that's that that
08:12that you were getting. I don't know.
08:16We didn't get any complaints from others, so.
08:18OK. So I I'm assuming people can hear.
08:20So I'm going to move forward.
08:22It sounds good. OK.
08:24Thanks, Jess. Thank you. Good.
08:25So we're going to spend a little
08:27bit of time going through.
08:28This was actually the study
08:31design and this was a randomized
08:352 group which was psilocybin 25
08:38milligrams or niacin 100 milligrams.
08:41Phase two clinical trial designed
08:43to evaluate both the efficacy of
08:46psilocybin as compared to niacin
08:48what it's administered with
08:50psychological support in patients
08:53with major depressive disorder.
08:55It was run at 11 US sites between
08:59December 2019 and June 2022 and we'll
09:02get a chance to talk a little bit later.
09:05That's kind of a interesting
09:07period of of history.
09:09So we'll get a chance to talk about how
09:12that could have had impact on the study.
09:15The inclusion criteria for the study,
09:19the main the key inclusion criteria was
09:21patients had to be medically healthy or
09:24participants had to be medically healthy.
09:26It was for adults between the
09:28ages of 21 and 65 with,
09:30as I said,
09:31a diagnosis of MDD with the current
09:34major depressive episode lasting
09:36of two months or or 60 days.
09:39They had to have a rating of over
09:4328 but equal to or above 28 on the
09:47Madras by the Central Rater and
09:50they couldn't have more than a 30%
09:52drop from the screening to baseline.
09:55So that's the inclusion criteria.
09:56Key exclusion criteria which are
09:57going to be important to remember is
10:02the patients had to be
10:03able to be medication free.
10:05So either not on a medication
10:07at the time of screening,
10:09or being able to tolerate a taper
10:12and a washout during the screening
10:15period and remain off antidepressant
10:17medications during that period of time.
10:20They also needed to be able to go
10:22without seeing an outpatient therapist.
10:25So if they have not had an
10:27outpatient therapist, that was OK,
10:28but if they were seeing one,
10:29they would have to be able to
10:31at least take a hiatus or a
10:33pause in their treatment with
10:34their outpatient therapist.
10:37The other part that was important to
10:39think about is the family history.
10:42So there was no personal history
10:44of either psychosis or mania,
10:46but also no first degree relative
10:48with psychosis or mania.
10:51And then the other major important two
10:56exclusion criterias was having psychedelic
10:59drug use in the past five years,
11:02or more than 10 lifetime
11:04uses of a psychedelic.
11:06And then finally the last one,
11:07was anybody with active suicidal
11:10ideation with intent or a plan within
11:13the past six months or or self,
11:15I'm sorry, or suicidal behavior in
11:17the past 12 months were excluded.
11:19So just to give you a general sense that
11:22this was a generally healthy population,
11:25really screened pretty carefully
11:27not to have psychosis,
11:28not even a family history
11:30of psychosis or mania.
11:32So well this is the population
11:33that it was geared towards.
11:35As you can see here,
11:36the original plan was to run 80
11:40participants that was actually updated
11:45see if I can. So it was updated to
11:48100 in the beginning of the study.
11:49The the there was a reanalysis and the and
11:53the idea to run 100 patients was was changed.
11:57So patients were screened and
11:59then after a screening period of
12:01lasting either 7 to 35 days,
12:03largely depending on if they needed
12:05to do a medication washout or not,
12:07they would then go into a baseline period.
12:11And during that baseline period
12:13they would be reassessed.
12:14And as I said,
12:15if they had more than a 30 point drop,
12:17a 30% drop in their ratings,
12:19that would be an exclusion,
12:20but otherwise they can move on and that would
12:23be their baseline ratings moving forward.
12:25And then before actual treatment
12:27or randomization was a preparatory
12:29session and these preparatory sessions
12:31were designed to last 6 to 8 hours,
12:34usually two sessions prior to the.
12:37Originally in this design it was meant to
12:40be the person with the two facilitators.
12:43The two,
12:43the two people in the room in these
12:45studies were called facilitators.
12:47But again if we go back and look at
12:50the timing starting in December 2019,
12:53the pandemic hit.
12:54So the prep sessions were altered
12:56where many of these prep sessions,
12:58at least one of them was done virtually.
13:02So that little bit different
13:04than the original study design.
13:06And then then there was day one
13:08and that was actually the dosing
13:10day and that's where patients
13:12or participants were randomized
13:14either receive the psilocybin 25
13:17milligrams or niacin 100 milligrams.
13:19And I'll just say briefly that the
13:21idea of using niacin was to have
13:24an attempt of at an active placebo,
13:27meaning that there may be some sensation
13:30from taking 100 milligrams of niacin,
13:33there's some flushing.
13:35It also offered us the opportunity
13:37to provide some equipoise by saying
13:39'cause there were there are some
13:41studies suggesting niacin may
13:42have an antidepressant effect.
13:44So you could legitimately tell patients
13:45that there is some evidence that they
13:48both may have antidepressant effects,
13:50but it was still was listed as a a placebo,
13:54what would be called an active placebo.
13:58So dosing was provided on that day
14:01and dosing typically lasted 6 hours.
14:04And then patients were seen again
14:06the day after, which was day two.
14:08And on day two,
14:09they had their first integration session
14:12along with the ratings that were
14:13performed And in the integration session,
14:15typically lasting about an hour,
14:17then I think an hour to two hours depending,
14:21they were seen again.
14:23And then day five was a telephone interview.
14:26The day eight was one of
14:29the secondary measures,
14:30an outcome at day eight.
14:31And again they had their rating
14:33scales and you can see all the
14:35individual rating skills listed there.
14:37Day nine,
14:37they came back for another
14:39integration session.
14:40So this is again a meeting with
14:43the two facilitators lasting
14:45about an hour to to two hours.
14:47And then day 15 were more assessments.
14:50And then on day 16 was the
14:523rd integration session
14:53meeting with the facilitators again
14:55and then there was another exploratory
14:57endpoint at the end of the month.
14:58And then the primary endpoint,
15:00the, the main goal of the study
15:03was the look at the response.
15:05There were the change in the Madras score on
15:08day 43 that was really look at six weeks out.
15:11That's the primary endpoint for the study.
15:14So let's just look a little bit.
15:17The idea of using this, as I said,
15:20along with psychological support goes
15:22back to the set and setting principles.
15:24And then I don't know if you want
15:25to talk a little bit about this or.
15:26Sure, yeah, yeah. The idea
15:29behind set and setting is something that
15:31was taken very seriously in this study.
15:34And set is defined as mindset sort of the
15:40your sort of baseline thinking process,
15:44your mood at the time of dosing and the
15:47setting typically referred to the environment
15:49where the dosing occurred in this.
15:52What's a typical though this
15:55becoming familiar to this group
15:57is that these dosing sessions are
15:59administered in a slightly unusual
16:02environmental setting where you know,
16:04as you can see in the picture here,
16:06there is actually a couch.
16:10The room is set up to actually
16:12looks to look like a ordinary room.
16:17It's typically a little bit
16:18more aesthetically appealing
16:20than a typical Med room.
16:22The other idea behind the setting
16:25that it would facilitate A
16:28therapeutic alliance and between
16:30the facilitators and participants.
16:32So you know this is what was
16:35taken into account during both the
16:38preparation as well as integration.
16:41This idea of using Satis setting
16:44as a foundation for where a lot
16:47of the conversations took place.
16:49So treatment sessions,
16:52so, so as Ben described this,
16:55the idea of using the the integration,
17:00I'm sorry, the preparatory sessions to help
17:03work on the set and the actual physical
17:06setting was was very tightly controlled.
17:09During dosing sessions participants were
17:11encouraged to wear eye shades and to listen
17:14to a curated playlist with headphones.
17:16So this is again very tightly controlled.
17:18The setting the leaf facilitators
17:21were all doctoral level,
17:22either psychologists or physicians with
17:27treatment with depression treatment
17:29experience and the Co facilitators
17:31held a minimum of a bachelor's degree
17:33in a mental health related field.
17:35All facilitators completed
17:36a study specific training.
17:38So this is clearly a case where
17:40there was great effort taken to
17:42make sure that the facilitating
17:47study members were were providing
17:50as much of the uniformed experience
17:52as possible in the study.
17:55Here if we go through looking
17:57at the consort diagram.
17:58So this is one of the first interesting
18:01things to see is that there were
18:0515129 people assessed by phone
18:10screen with 1425 excluded.
18:13So this is one of these studies
18:15where there was a lot of interest
18:16and a lot of people that wanted to
18:18take part in a study and we can
18:20talk about the pros and cons of
18:21that that that that could either
18:22work in your favour or that could
18:24work against you in some ways.
18:25But for this study,
18:26you can see that's a pretty large
18:28number that was whittled down
18:33to to a number.
18:35As you said, 11182 were excluded
18:38just on the telephone screen.
18:39So just on those initial telephone screens,
18:42it was either the patient didn't meet
18:44the depression or some of the patients
18:46would call and didn't have depression at all.
18:49They just wanted to try study,
18:52but others had other clear reasons
18:54where they may have had psychosis
18:56or a family member had psychosis
18:57or for a variety of reasons.
18:59But then it got down to the point where
19:01240 were actually screened in person.
19:03And then there were additional
19:05exclusions down to 104
19:07participants that were randomized,
19:1051 randomized to receive the psilocybin
19:13and 53 randomized to receive niacin.
19:17In fact, if we,
19:18if you read the paper
19:19real quick real closely,
19:21it actually ended up that 50 people
19:23actually received the psilocybin and 54
19:26received niacin because one patient was
19:30by mistake given the wrong treatment.
19:34So, so really ended up 50 to to 54
19:38which is actually not that uncommon
19:40in in these studies that there's
19:42one mistake in there somewhere.
19:45And then you can see the number
19:48that completed at the day 8
19:50assessment you had 51 of the of the
19:5351 patients completing the day at
19:55and actually 50 of the psilocybin.
19:58Of the 51 psilocybin patients completing
20:00the six week evaluation where for the
20:03niacin you had 48 of the 53 make it
20:06to day eight and only 42 of the 53
20:09make it to the six week assessment.
20:12So you had nine people that
20:14did not make it on?
20:15And then on the right,
20:16you can actually see by the
20:19individual sites how many people
20:21were recruited at what percent.
20:23This is the number of participants
20:25that each site had and the percent
20:27of the total that they shared.
20:29You can see although there was 11 sites,
20:32really the top five or six accounted for
20:34the large majority of the patients run
20:39Kathleen. At the patient characteristics
20:42we can see that there was a
20:44pretty much an equal distribution
20:46of men and women in this study.
20:49The average age was about 41.
20:52Ethnicity was something
20:55we'll talk about later.
20:58There was about 94%
21:04white patients participants in the study
21:09and only less than 3% or about 3% black or
21:15African American participating in this study.
21:18The other things of real interest is only
21:23about 12% had treatment resistant depression.
21:27So this was primarily and the large majority
21:30of these patients were not meeting criteria
21:33for treatment resistant depression,
21:34although there was no cap on the
21:36number of treatment failures.
21:38So, so there were people that could have
21:41had any number of treatment failures.
21:43It was really about 12,
21:441/2% that would have met the criteria
21:46for treatment resistant depression.
21:48And you can see the number that
21:50actually went through a medication taper
21:52both for psilocybin and for niacin.
21:54But in general it was about one out of
21:56five people required a medication taper,
21:58meaning that about 80% of the patients or
22:0375% of the patients didn't require a taper.
22:05They were not on an antidepressant
22:08at the time of entering the study.
22:11Baseline mattress,
22:12as I said the cut off was was actually
22:15pretty high for the study of 28.
22:17So the the baseline mattress of 35
22:20is is a pretty high average level
22:25of severity for a study.
22:27The SDS scores of,
22:29you know somewhere around seven was actually
22:32a little bit lower then you would expect.
22:35So a lower level that's the
22:37Sheehan disability scale,
22:38a little bit lower level of disability than
22:41you see in most other depression studies.
22:44And then you can see the average length of
22:46depression and number of previous episodes.
22:50Jerry,
22:51what do you make of that observation
22:52that the the Madras is on the high
22:54side but the SDS is on the low side?
22:56Is that because so many other possible
22:58sources of disability are screened out?
23:00I I think that's a a large possibility.
23:02The way the way the Sheen is collected
23:05may give you some artificial
23:06ratings with that too a little bit.
23:08But I also think and we'll talk about
23:10when we talk about the generalizability,
23:12this is kind of a unique population,
23:13very highly educated,
23:14more so than you would see in a lot of
23:18other typical antidepressant trials.
23:20And that I think probably
23:21attributes to some of that. There
23:23is buffer. There are various
23:25characteristics that buffer
23:26disability in this population.
23:28Yeah, they have a lot of other
23:31buffers to to prevent it.
23:33All right. So here's the data.
23:35I mean, there's the data is the
23:37real easy thing to present here.
23:39This is pretty, pretty clear.
23:42So that, yeah, that there was no doubt in
23:45the significance there with AP of 001.001.
23:49The mean difference was the 12.3 points
23:52on a mattress which is quite large,
23:55you know very large.
23:58So this is really standing out in
24:00in many ways as a very strong.
24:02Remember the the primary end
24:04point here is day 43,
24:05so it's this last time point.
24:07If you look look at it other ways,
24:09this is actually my new favorite
24:11way to present data.
24:13It's called the waterfall
24:14plot where you actually,
24:16you can see the the mattress
24:18score that the patients start
24:20with or the participants and
24:24then how far they drop or rise.
24:26For the few people that actually got worse,
24:28you can see here that there's an increase.
24:31So you can see the group,
24:33the orange represents the psilocybin and
24:36the blue representing the the niacin.
24:39You can see that the large majority
24:40of people getting psilocybin
24:42had significant drops,
24:44very few that did a little
24:45bit worse and in fact no,
24:47no more doing worse than
24:49the people getting niacin.
24:50So it's really nice way of looking
24:54at individual patient data here.
24:56And then you can see the change
24:58in Madras from baseline to day 43,
25:00which was the primary outcome
25:03measure very clearly hitting
25:04statistical significance.
25:06So this data for the primary outcome
25:08I don't think could be more promising.
25:11I don't think you could have
25:13asked for much more.
25:15Also for secondary measures,
25:17the data were very strong.
25:19So here's looking at the Madras
25:20scores throughout the different days.
25:22You can see pretty much
25:24significance all the way through.
25:25Even the the Sheehan,
25:26even though I said the the the
25:28baseline levels of disability
25:29weren't maybe as high as you may
25:31expect in some other studies,
25:32they still showed high levels of change
25:36significance compared to niacin.
25:39And if you looked at the sustained
25:43depressive response at the six week point,
25:45highly statistically significant remission
25:47didn't quite hit statistical significance,
25:50but pretty darn close.
25:52And you can actually see here sometimes
25:54visually it's just a little bit better.
25:56This is looking at the response rates.
25:58So we had 20 of 48 in psilocybin 5
26:01and 44 in Niacin meeting response,
26:03which was a 50% improvement on
26:06the Madras and an odds ratio
26:08of response of about 5.6.
26:11If you look at sustained remission,
26:13there was 12 of 48 meaning that
26:16they had a Madras less than 10 for
26:19psilocybin and only about I think it
26:22was about 11 percent or so for for
26:26Niacin with an odd ratio of over three.
26:29So again very strong data and remember
26:32this is different than some of the
26:34other studies that you may have seen
26:36where there's been repeated dosing.
26:38This is just that one single
26:40dose and then these
26:41measures are made day 43 out other
26:46secondary measures pretty much
26:47across the board you you can look at
26:50and see how they were carried out.
26:52I did forget to say early on that these
26:55ratings are all done by central Raiders.
26:57So in order to address the
27:00the unblinding of the Raider,
27:03all these ratings were done by
27:05somebody off site calling in.
27:07And it was very rigorous that the
27:11the person doing the raid and
27:13did not even know at what point
27:15the person was in the study.
27:17So they didn't know if this was a
27:19baseline rating this is the end of
27:21study rating if this was a week,
27:23Week 2 rating, a week 1 rating.
27:25So they really didn't know
27:27everybody was treated the same.
27:28So these these data are pretty
27:30strong from that perspective.
27:31So
27:32it wasn't the same rater consistent,
27:34it was not the same rater
27:36consistently which is you know
27:37when you design studies that's
27:39something you usually do want to have.
27:42But in this case to try to prevent
27:45the functional on blinding of
27:48the of the rater that was a
27:50precaution that was put in place was
27:52there any formal assessment of blind
27:54for either the subject or the rater.
27:55So that we'll we'll talk
27:57about that's one of the major
27:59limitations of the study.
28:00So there there was not
28:04the other I I I think the the flip
28:06side the real important data from
28:08the study of the safety data.
28:10So here you can see that 88% or
28:1444 or 50 other participants in
28:17psilocybin and 33 or out of 54 or
28:2061% receiving niacin reported at
28:22least one AE through throughout the
28:25end of the the 43 day follow up.
28:29But I think a little bit more important
28:32is what would be considered drug related.
28:35So the investigator at least said it's
28:37possible that that these side effects
28:39were related to the drug and you can
28:41say here that it was 41 of the 50 or
28:4482% of the patients in the psilocybin group.
28:48And you can see it was 24 of the
28:5154 or 44% in the niacin group
28:55experienced at least an AE that was
28:57thought to be drug related.
28:59And then even bumping it up a
29:02little bit more in importance is
29:04more of the severe related AES.
29:06And this is through the first week really.
29:09I reported four out of the 50
29:12participants receiving psilocybin or 8%
29:14of those that consisted of migraines,
29:17headaches, illusions, panic attacks,
29:21paranoia.
29:22There were none in the Niacin group,
29:26but I I'm bumping it up one more
29:28in level of importance and this
29:30is obviously the most important
29:31all of these there were no serious
29:33treatment emergent adverse events.
29:35So for those of you that aren't
29:36familiar with clinical trials,
29:37a serious adverse event basically
29:40means hospitalization,
29:41risk of death or some other long
29:47term impairment that results from it.
29:50So nothing along those lines occurred,
29:53Jerry. Yeah, that difference
29:55between in in severe aids.
29:57Well, in both categories,
29:59I guess you're lumping
30:00together days one through 9,
30:01but we expect a lot of
30:04psychological effects during dosing.
30:05So I'd be interested in the differences
30:07on days two through 9 because like
30:09how much of that difference was,
30:10you know, panic attack on day one during
30:12dosing means something very different.
30:14So many attacks four days later,
30:16so many were here we can go through.
30:18We'll talk a little bit about some of
30:19the more persistent ones or outside
30:21ones because those are obviously the
30:22ones that everybody's worried about.
30:24Yeah, good question.
30:27Yeah, they'll come up a little bit.
30:29I'm also, I'm a little surprised it's
30:31reported as day one through 9, yeah.
30:32Yeah, As opposed to day one, yeah.
30:34And then day two through nine. Well,
30:36I think that people were worried about that,
30:38that total time frame,
30:40people meeting the regulatory agencies, OK,
30:46when it came to solicited adverse events.
30:48So ones that were adverse events of
30:50interest that was specifically asked
30:52about the most common were headache,
30:55nausea and visual perceptual effects,
31:00which was not so surprising I think and
31:03you can see the relative ratios of them.
31:06The one that may be a little bit more
31:09concerning with the visual and perceptual
31:11effects is 3 of the 50 patients
31:13receiving psilocybin or 6% actually
31:16reported some visual or perceptual
31:20effects occurring after that first day.
31:22So this is getting a little bit more of what
31:25you're talking about S 6% smaller number,
31:27but still a number that I I think
31:30it's important to pay attention to.
31:33And and they all did resolve
31:34by the end of this.
31:35Well
31:35what was the severity of those Because
31:37if that's a little flickering on day
31:392 versus well formed hallucinations
31:41of pink elephants on day 20,
31:43those are very different.
31:44You know, so remember there were
31:45no SAES, so nothing reaching the level
31:47of an SAE and I don't think any of them,
31:49I I I can't say for sure,
31:51but I don't think any of them even met
31:52the level of severe adverse event.
31:55I I I would have to look at
31:57the details but I don't recall.
31:59I would have to agree.
32:02And these out of those three,
32:05I think it it's possible we worked
32:07with one of them and you're right,
32:10it was more flickering and it was,
32:12but it was not sustained or
32:14there was no overt hallucinate,
32:17frank hallucinations,
32:19no more kind of illusions.
32:22And I think other good news is in terms
32:26of any suicidal ideation or behavior,
32:29they're really the main
32:31thing is right on the bottom,
32:32there was no real clinically significant
32:35increases in suicidal ideation or behavior
32:38associated with the study, if any.
32:40If you look at any patients that
32:42even had some level of increase
32:44throughout the main part of the study,
32:46there were numerically more
32:48in the niacin group,
32:50about 10% compared to about 2%.
32:52There are just five people versus
32:55one person that showed some increase
32:58in suicidality or suicidal ideation.
33:01This I I think is becoming more
33:04important as we realize how to
33:06move forward with these studies.
33:07At least for me running these studies,
33:09I worry less about the people
33:10getting the active drug than the
33:12people being randomized,
33:13especially if there's functional
33:15on blinding for the patient that
33:17you really have to worry about
33:19how they're going to react to
33:20feeling they didn't get treatment.
33:22So now if we just talk about the
33:24limitations of the study quickly and then
33:25we'll be able to go into discussions
33:27because I think that's the main thing.
33:29So one of the biggest limitations and we
33:31mentioned it one or two times already,
33:33was this study was conducted between
33:35December of 2019 and June of 2022.
33:38Here is just the death rate
33:41due to COVID during that time.
33:42I mean this was smack, we started it.
33:45I think we were ready to run
33:47our first patient in like March
33:50just as everything was hidden.
33:53So this study was thrown on its head.
33:56That being said,
33:57it's a limitation because the
33:59study was run during COVID.
34:01Almost most studies run during
34:03this time has had major problems
34:07because the placebo response rates
34:08have been astronomical and most of
34:10these studies run during COVID.
34:12And we're not quite sure why that is.
34:13But many of the studies run in
34:16depression during the summer has
34:17had very abnormal elevated and
34:19it may be the people.
34:21Some of the hypothesis that's been put
34:23out is that people are really more
34:25starved for socialization and just
34:28the fact of getting out was actually
34:30working a lot you know in their favor
34:32but against the study drugs favor.
34:35And in this case if anything
34:36this would be something.
34:38The fact that we did see
34:40such a big effect is,
34:41is probably not a major limitation
34:43that we would use that we would
34:46worry about going forward.
34:47But there are some other limitations and
34:50and I think maybe the the biggest one
34:53moving forward is the generalizability.
34:56So as I mentioned this,
34:57you know ways that this differs than
34:59many of the other depression trials
35:00is that the male to female ratio
35:02is different than we typically see.
35:04We typically see a one to two
35:06male to female ratio.
35:08This was pretty much a one to one.
35:10The age was a little bit younger in
35:12this group and typically in trials
35:14of antidepressants the age is about
35:1645 and here it was about 41.
35:18I don't know if that's going
35:20to make any major difference,
35:22but there really was a failure to
35:26have adequate representation of the US
35:29population in general in this study,
35:31mainly in terms of race
35:33and even in ethnicity.
35:3589% were white,
35:37with only 3% black in the study.
35:41And even if you broke it down during
35:44other things like other demographic
35:46and social demographic factors in
35:49terms of income, education level,
35:52this probably wasn't as representative
35:54of the population as we'd like to see.
35:57And and I think ultimately regulators
35:59would like to say that this,
36:01this is a treatment if approved
36:03would work in the large majority
36:05or would the data they would have
36:08would be representative of the large
36:11majority of of people in the US.
36:13The other point was that the
36:15majority of these people were not
36:17taking antidepressants at the time.
36:18So you're really looking at a group of
36:21either antidepressant naive patients
36:23or at least patients that weren't at
36:26the level of severity that they were
36:28seeking treatment in some of the way.
36:30And
36:33then there were also patients are able
36:35to remain free of both medication and
36:37free of contact with the therapist.
36:39So these are all issues that in the
36:41future we're going to have to either
36:42determine if we're going to limit it
36:44to that or we're going to broaden the
36:47categories and and figure out other ways
36:49of managing the risk associated with that.
36:51As I said, the baseline SES was
36:53slightly lower and that that could
36:55be for a variety of reasons.
36:56I wouldn't worry too much about that.
36:58And the other main limitation is this
37:00was probably over represented for the
37:02age group and the number of people that
37:05have had previous psychedelic experiences.
37:08And as we know this can have a major impact.
37:10I've been a major impact on the validity
37:13of some of these measures that those
37:16first things I said were more related
37:18to the ecological validity of the
37:20study which we can fix by study design.
37:23And some of these future ones I'll
37:25talk about is related to really the
37:28the interpretive validity of study
37:30is you know is this due to the drug
37:32or some of the other effects.
37:34And one of the major ones that
37:36continues to the
37:39be dealt with or or the to be
37:42difficult to deal with is the struggle
37:45around blinding or or unmasking
37:48of allocation, group allocation.
37:51You know it's really hard when you
37:53have a drug that has very prominent
37:57and acute psychoactive effects
37:59in comparing it to something.
38:01So Niacin was used as an attempt.
38:03But as Chris mentioned,
38:04you know if you really ask somebody,
38:06I don't know I I can say now
38:08the study's over at our site.
38:10I think we may have had one person
38:12in each group that I think it's fair
38:15to say that we had one person that I
38:17think the staff would have guessed,
38:19got it and didn't get it.
38:20And I think there was one person who
38:21got it and staff would have guessed,
38:23didn't get
38:23it. It was only one exactly.
38:26So probably many one on
38:27each time. What, I don't
38:28know how many time I need to deal with 15.
38:30Yeah, I think 1350, I can't remember.
38:33Yeah. So I mean there are,
38:35there are cases of it,
38:36but I think the large majority of people,
38:39both participants and site members,
38:43staff members would would guess
38:45for the majority of the point
38:46And just an idea of how important
38:48some of this unmasking can be.
38:50There was a recent paper that
38:52some of you may have seen that
38:54came out of Stanford Boris Boris
38:56Heifetz paper where he was getting
38:58ketamine under adequate blinding
39:00because they're under anaesthesia.
39:02So he actually these are people
39:04going for surgical procedures
39:06where they were getting general
39:08anaesthesia during their anaesthesia
39:09given .5 milligrams per kilogram
39:11ketamine over 40 minutes during
39:13that time with the idea of seeing
39:15one of the questions is how much
39:17does that psychological experience,
39:18how necessary is that for ketamine but
39:21also if it's blinded will it still work.
39:24And I think that the results were
39:26actually shocking to to some people
39:29was and this is like a rush of
39:31test on itself what people see
39:33here and the date is small,
39:35so you may not see anything here.
39:36But I can tell you,
39:38I can tell you what is here is you know
39:42there was over 50% response at day
39:46one to the group that got ketamine,
39:48but there was nearly 50% to
39:50the group that got placebo.
39:51So there was just a huge placebo
39:54response rate in this in in in
39:56terms of their depression ratings.
39:58We we published sort of the commentary
40:00on this and there are a lot of
40:02problems with the interpretation
40:03of this study and we can go through
40:05that from the mechanistic side,
40:07but that's not the main point of it.
40:09I think the main point of it is to
40:11realize how important expectations
40:13and especially if you have unmasking
40:15going on can be.
40:17So if you look at the HEIFET study,
40:19if you look at the 19 patients that
40:22got ketamine and 19 patients that got
40:24the placebo during their surgical procedure.
40:27Really no difference in their
40:29their Madras score at two weeks.
40:31But if you add,
40:31but when they went back and asked the
40:33people what they thought they got,
40:35then you can see dramatic.
40:36So the people that thought they got
40:38it on average had a remission and the
40:40people that thought they didn't get
40:41it or didn't know didn't do so well.
40:43So this idea of you know what you
40:45think you got an expectancy really
40:47plays a big role although that
40:50it could work either way.
40:51It could be that they thought
40:53they didn't get ketamine because
40:54they didn't stay better.
40:55So one, one of the big problems with
40:57this study and several of the other
41:00studies including the next one I'll
41:02show you is the asking post hoc
41:04asking you really have to ask these.
41:06And that's some of the questions
41:09moving forward that we're trying
41:10to really do is to assess both
41:13expectations and and preference.
41:15And also what you think you got much
41:17closer to the time because this is
41:20this is very flawed doing it this way.
41:22Was there any
41:24Cyril asked this question in the chat
41:26earlier, was there any assessment
41:28of expectation in the Usona study?
41:31No, no, no, no.
41:35So and this is another, this is actually
41:37a study that we recently completed.
41:39This was the study funded by Pecorie
41:42which was ECT versus IV Ketamine,
41:46a 400 person study,
41:47actually a little bit more than 400 people,
41:49200 approximately 200 randomized C CHARM.
41:52You can see where there's really not
41:56the dramatic difference between the two.
41:58Actually. Numerically ketamine looked
42:00like it did a little bit better than ECT,
42:04but this was a non inferiority study.
42:06So all we can say with confidence
42:08is that ketamine was non inferior
42:10to ECT in this study.
42:12But the main point here was when we
42:14went back to look at how preference.
42:17So the idea of what they wanted
42:19and impacted how they did.
42:20And again, this is limited by the fact
42:22that we asked the preference after,
42:24not before. But if you look here,
42:29you know the the percent, I'm sorry,
42:33the percent of responders who preferred
42:37ECT but got ketamine was only about 20%.
42:40But the ones that preferred ketamine
42:42and got ketamine was nearly 60%.
42:44So the how,
42:45how the impact of preference may play
42:47on how well somebody actually does.
42:49So these are all things when
42:51we're designing these studies we
42:53just can't be blind to it.
42:54And again these are very flawed analysis
42:57because they were done post doc as it is.
42:59So the first thing is to make sure
43:01you're doing it earlier on and
43:03it's not just how it complicates,
43:06well maybe they wanted it
43:07and they got better.
43:08It's really important if you have
43:10differential drop out and in this
43:11case I did mention there was some
43:13differential drop out the people
43:14that really yeah they these people
43:16came in my guess is the majority
43:18really one and we didn't ask but I
43:21think the probably very likely they
43:23were very much looking forward to
43:26getting psilocybin when they didn't.
43:27There was some evidence of a little
43:30bit of a differential dropout
43:31because when you do look at day 48,
43:33there was only one of the psilocybin
43:35patients at day 43 that didn't
43:37make it that far,
43:38but nine of the niacin and that remember
43:39that was the primary outcome measure.
43:41So now you have to impute their data.
43:44So it really makes these trials
43:46complicated that when when you don't have
43:48data on everybody starting at the end.
43:51So yeah,
43:51to manage those preferences is
43:52going to be really important.
43:54There was no opportunity for
43:57open label follow up and
43:57there was no open label. Yeah, I
43:59know the answer to that. Yeah,
44:00there was, there was no.
44:01So that's why these things are so
44:03important in the clinical trial design
44:04is to do what you can to make sure you're
44:07not getting this differential drop out.
44:09And then lastly there there was
44:12some questions or concerns about
44:15the onset of antidepressant action.
44:17So I don't know if you, I can flip back,
44:19but take my word for it on day one,
44:22day two, one day after,
44:24there really wasn't a big
44:26antidepressant response to either
44:27the niacin or the psilocybin.
44:29And people were questioning how come
44:31most of these other studies showed
44:33a more rapid onset of benefit.
44:36And it's difficult.
44:36We don't know 100% why that happened here.
44:40But I think it's quite likely that
44:42one of the main contributors to that
44:44finding was the way that study was designed.
44:47I I mentioned in in order to try
44:48to preserve the blinding of the
44:50Raiders as much as possible.
44:51These were remote Raiders done off site.
44:54They didn't know at what point
44:56in their assessments they were.
44:58They were at one point in their
44:59treatment they were assessing them.
45:01So they asked very carefully and very
45:06rigorous about saying tell me how
45:08you've been doing for the last seven days.
45:12But so if they only received
45:13the drug one day before,
45:15you know six of those seven days
45:16were before they got the drug.
45:17So that may account for part of it.
45:20So it's so when but when was
45:21the integration session,
45:24the integration session was right,
45:25was after this right after.
45:27Yeah.
45:28Question the 1st
45:30in your, I mean in my experience when you
45:32ask patients about seven days they use
45:34pecan heuristic but you know they talk
45:36about how they are now and yeah so I I
45:38don't get incredibly powerful
45:40effect made accurately across the week.
45:42Yeah no that I mean that's why
45:45these type of measures like the
45:47mattress says serious limitations.
45:50So I think this contributes part to it.
45:53I I'm not sure what some some of
45:55the other reason could just be that
45:57by really blinding the Raiders
45:59you do have some effect that way.
46:02We don't know that,
46:03but it's one of the things moving
46:05forward that we have to look at.
46:07And then the last thing that I I just
46:09put in here is to put it in perspective
46:12a way or or to give some context to it,
46:16'cause these results are pretty amazing.
46:19I mean there's there's you would be hard
46:21pressed to say these aren't impressive.
46:23These are they're they're
46:25pretty big findings.
46:26But I I did want to put them in
46:28perspective to some of the others.
46:29So this is to one of the ASPIRE studies
46:32done with S ketamine looking at treatment,
46:34the green line here I have
46:36it faded out so you can,
46:37I can superimpose them over.
46:40But you can see that the response
46:42to ketamine over S ketamine
46:44sporvato over that time and going
46:47out over the same time period,
46:48that's on the graph here
46:52with with the extra going on for
46:55for the psilocybin in the study.
46:57But you can see, you know,
46:58really on par with what we're seeing.
47:00And remember this is just a single
47:02dose of psilocybin witnesses
47:058 doses of esketamine here.
47:09But you know, one of the caveats is look
47:12at where the standard of care treatment is.
47:15Yeah, which was another,
47:16which was anti standard of
47:19antidepressant treatments, big gap.
47:21The biggest,
47:21the thing that stands alone here
47:23is the psilocybin is the niacin,
47:25not the psilocybin.
47:26So it's it's a lesson that for
47:30many trials in antidepressants
47:32what determines if a drug works
47:35or not is the placebo.
47:37If you if if you get a large placebo
47:40response it's very difficult what
47:41is the there are two lines there
47:43is one of those placebo and one of
47:44those. So one of these is the
47:46actual esketamine is the green
47:48line and the blue line is actually
47:50the standard of care treatment.
47:53We what it mean well in
47:54in those esketamine studies they
47:56were allowed to have regulated.
47:57So a new antidepressant was
47:59started, OK, so that that's
48:01and they had intensive interventions
48:04and they had very intensive interventions.
48:08And this is just comparing it to one of the
48:12TRANSFORM studies with S ketamine seeing
48:14here you don't see that rapid effects These
48:17those other patients were hospitalized,
48:19these patients weren't hospitalized.
48:22But again, you can see looking
48:24at that endpoint of four weeks,
48:26you you can see where where it is overall
48:30compared to the effect with S ketamine.
48:32And again these are
48:33comparing apples and oranges.
48:34You have to be really careful
48:36comparing across studies.
48:37This is just to give some level of context,
48:40but again really to show where the big
48:42difference lies is with the Niacin.
48:43So we really have to be careful you
48:46know and moving forward not to get so
48:48confident that these effects sizes are
48:50going to hold up as you move forward.
48:53There's there's a real trend in all
48:56clinical trials work that going from
48:58phase two studies to phase three studies
49:01that delta between the active and and
49:03sham or placebo treatment narrows down.
49:06So you really want to make sure
49:08that's managed as much as possible.
49:10And then finally, Curtis,
49:10how would you interpret that the
49:12fact that there's such a such a low,
49:14is that because of a nocebo effect,
49:16because of functional unblinding? Well
49:18I I mean I don't it's hard for
49:20me to know for sure. I think
49:25I I think functional unblinding
49:27probably plays a a large role in it.
49:33So we don't really know but I think we
49:35have to be careful as we move forward.
49:38I think expectations, functional
49:40unblinding play a large role and
49:42lack of open labels.
49:43So patients had really fun to
49:45because of functional unblinding,
49:47that's going to increase the
49:48nocebo effect because there's
49:49going to be a sense of despair
49:50and betrayal. Yeah. So the questions yeah,
49:54I was going to ask you,
49:55how do you feel as well about the psycho,
49:57like the control psychotherapy?
49:59Because there's recently being an editorial.
50:02Right. Unless psychiatry on this.
50:04And I think it's really valuable because
50:06what the control condition is
50:07given the patients is this form
50:09of psychotherapy that has never
50:11been tested for anything. So
50:14it's it is truly nocebo
50:16in no way because it's not like
50:18we're giving them let's say
50:19CBT active behavioral therapy you know
50:22behavioral activation story and then
50:24giving them you know you
50:25know silos happened or not.
50:26I I wonder how you think you can
50:28we can address that in the future if
50:30there is room for that even because
50:32I assume that user institute is
50:33pushing forward that we test silo
50:35cyber under that specific model.
50:38So I've been maybe you want to answer
50:40too I mean I'll stop by saying this
50:42is a very complicated issue because
50:44it actually comes to what's in your
50:46label when when you do get approved.
50:48So it it gets very complicated and has a
50:52lot of legal and regulatory meanings to it.
50:55This study was really with
50:57psychological assistance.
50:58It it was not and very clearly not
51:02done to augment a psychotherapy.
51:05And Ben I
51:05don't know if they used a model
51:07that's called non directive
51:08supportive therapy which really does
51:10not necessarily meet criteria of
51:12structured targeted psychotherapy
51:14that we would see conventionally.
51:16It still is a form of supportive
51:19therapy which really includes
51:20checking in during preparation,
51:23building report and getting to become
51:28familiar with the facilitators.
51:31So it that's what non directive supportive
51:36therapy is as opposed to in some other
51:39studies where it's psilocybin assisted
51:41psychotherapy which is much more
51:45with kind of a conventional therapy
51:48heavy as opposed to what was it here.
51:50So they try to actually use the
51:52the reason they use this non
51:54directive approach is to minimize
51:56the psychotherapy as a variable to
52:00whatever as much as it's feasible.
52:02But it remains to be seen what
52:07eventually how this will be packaged
52:09in the label and how this what
52:11sort of training will be required
52:14to say that you are certified to
52:16actually deliver this treatment with
52:18a non directive supported therapy.
52:20I that that remains to be seen
52:25there there. I mean the first thing is
52:28let's just demonstrate that there is
52:30efficacy in general safety and then
52:32I think decomposing the treatments.
52:35But as you see right down at the bottom
52:37just very quickly things moving forward.
52:39I think the field needs to address
52:41this to address the generalizability.
52:42And I can tell you future studies
52:44are working hard to make sure it's
52:46a more representative sample of
52:48participants address the safety.
52:51And longer term,
52:51you know if these are going to
52:53move forward to approval,
52:57the clinicians and the regulators are
52:58going to want to have some more information
53:01about what if the person relapses,
53:03can you do this again, how,
53:04how do you manage this?
53:06So that's more data that's
53:08going to need to be collected,
53:09a better understanding of the
53:11dose response relationship,
53:11that's only just one dose.
53:14We're going to have to have
53:15a better understanding is,
53:15is that dose necessary.
53:19And then as I said,
53:21we're going to have to figure out
53:22how to manage some of the trial
53:24design issues a little bit better,
53:25asking about expectations,
53:27asking about preference,
53:29that guess of a study assignment,
53:33those will all be studies.
53:34And then really moving forward,
53:36getting more to your question
53:38is you know how are we going to
53:41address the cost effectiveness?
53:41You know how,
53:42how are we going to do this in a
53:44way that would increase access
53:46and and reduce the overall cost.
53:49And then a better understanding of
53:51the mechanism, mechanistic actions.
53:52And then a quick review of
53:54everything just here.
53:55This is the main point.
53:56It's a huge, that's a huge effect size.
53:59I mean it the this is is encouraging.
54:05Those of you that know me,
54:06I'm quite sceptical coming into
54:08this and my scepticism share is
54:11across the board for everything.
54:13I think that's the way you should
54:15be running these clinical trials.
54:16But I have to say this is quite
54:18encouraging that you know it's it's there.
54:20I think there's very little doubt
54:22that in this study design this,
54:24it's a very large effect and then
54:27really the support of so many people
54:29that just at this yell site just
54:31to give you a sense of how many
54:33people contribute to these studies.
54:35So this is 11 sites doing this
54:38and this is just an oversight.
54:39So and really the patients participating
54:42in this especially during the pandemic
54:45were were really troopers and and
54:47they all needed support systems that
54:48would bring them back and forth.
54:50So really required a lot of
54:52work both from the participants
54:53and all the staff and faculty.
54:55So I'll stop with that.
54:57All right, thanks.
55:00Any question?
55:01Oh,
55:01I should probably go
55:10kind of are there any questions,
55:13Terry, why don't you stop
55:14the share so we can see it?
55:15Yeah, let me stop share
55:31the questions about the blinding and
55:33expectancy that I think we've addressed
55:35a question about modifying the Madras,
55:38the time frame of the Madras in order to
55:40try to avoid that day two point but that
55:45So I I think honestly if for these clinical
55:49trials that are going through FDA,
55:52the FDA doesn't care about day two,
55:55right. It's just not it.
55:56You know they're much more
55:58interested in this endpoint.
55:59So you can modify it if you want,
56:01but it's always going to be a
56:03secondary or an exploratory aim here
56:06because the I don't think the FDA
56:09is interested in giving approval
56:11for rapid acting specifically
56:12that's they're they're much more
56:14interested in the longer term.
56:17It was an early question I don't
56:18think we talked about about the music.
56:20I think you everyone listens to the
56:22same playlist in the same order. Yes.
56:24And sequence which is an interesting,
56:26I mean that's going to be more that's going
56:28to be a perfect fit for some people and
56:30kind of weird for other people, right.
56:31So that's some participants and that may
56:35interact with ethnicity or cultural.
56:37Absolutely. Yep.
56:40And I think this is,
56:40this is the general idea,
56:42the whole idea of generalizability.
56:44And and I think
56:45one of the comments in the bottom,
56:47Chris, if you don't mind scrolling,
56:49Steve made a really good
56:52point which ties into, yeah,
56:56that's the one, ties into the
57:01functional unblinding potential
57:03NASEBO effect is that because of the
57:07uniqueness of the study designed
57:10patients who knew that they did not
57:12receive psilocybin and they had to stay
57:14in the study for a total of 6 weeks.
57:16That was very challenging also on the staff,
57:18both on the facilitators as well
57:22as research assistants who work
57:25more closely with participants.
57:27It was just a shared heartfelt
57:30experience. And
57:31when it's easy to imagine there being
57:33a feedback process that's right,
57:34the distress and the staff and the distress
57:36and the patient over that time period,
57:38well that's the importance of
57:39the of the raters being blinded.
57:41But that's that's that could have been.
57:44So thank you Steve for bringing that up.
57:49Any other questions or hi,
57:51I have a question.
57:53So in the paper there's mention of three
57:58people in both groups that started
58:00an antidepressant during the study.
58:03To clarify, for any of the participants
58:06that were on a medication,
58:08did they restart or was it only patients
58:12that had not been on a medication
58:15prior to the study?
58:18So I I I can only I think we
58:20had one at our site and I think
58:23that patient was a restart.
58:25I the other ones, I don't know
58:26for sure, I can't answer.
58:28But these are people that you know
58:31the the way the protocol was written
58:33was patients were supposed to
58:36remain off all oral antidepressant
58:38medications or all types of medication
58:41antidepressant treatments from
58:45baseline through or at least be
58:48at least five half lives prior to
58:51dosing until the end of day 4243.
58:55So that meant they were supposed
58:58to not have any contact with
59:00their therapist or to have
59:04any antidepressant used during that time.
59:07And some people just said
59:08they couldn't stay that long.
59:09It's going six weeks without any treatment.
59:12So I I don't know to answer your
59:15question specifically if these
59:16are people that were restarting
59:18or starting new ones offhand.
59:20And do you, did
59:22you account for
59:23how starting or restarting a
59:26medication affected their outcomes
59:30in terms of how the Mitras was affected
59:33with those medications? We we do not,
59:36I I'm sure we can get that data.
59:38We don't have that data offhand,
59:40but it's it's probably going to be difficult.
59:42I mean it's a small number of people and
59:44they, I think all of these people started the
59:47medication 'cause they weren't feeling well.
59:49So you're going to have a lot of
59:51regression to the mean going on things
59:53that I don't think such a small number.
59:55It's probably not going
59:56to be that informative.
59:57All right, thank you.
60:00Thank you.
01:00:01Hey, Jerry, thanks.
01:00:02Thanks for the talk question
01:00:04about the 22% who had previous
01:00:08experience with psychedelics.
01:00:09Was it sensitivity analysis conducted
01:00:11where if you took out those 22%, was there
01:00:15any change in the responses?
01:00:18Great question.
01:00:19I don't remember seeing that,
01:00:23Ben. I don't think so, no.
01:00:24But that's a really good
01:00:26question to what because that's a
01:00:28disproportionately high number.
01:00:29It's something it's above
01:00:31general population as well. So,
01:00:36and one would imagine that that
01:00:38those 22% would have the highest
01:00:41expectancies and that's why they've
01:00:44taken part in the study and it would be
01:00:46interesting to look at that. So go ahead.
01:00:48No, I'll let you go first. Yeah.
01:00:50No, I think there's actually a bit of a
01:00:55paradox when it comes to think how we
01:00:57think about the participant participants
01:01:00who had prior exposure to psilocybin
01:01:03and psychedelics for that matter.
01:01:05Specifically what I'm getting at is those
01:01:08who actually had prior exposure and ended
01:01:13up getting either psilocybin or niacin,
01:01:17they had less of AI should say it
01:01:20called a disappointment or a let
01:01:22down and they were less likely.
01:01:25Again, this is just based on my
01:01:27general impression in the from the
01:01:30participants that we worked with to have
01:01:33an exaggerated response because they
01:01:36knew sort of they were already familiar
01:01:39with the the effect of psilocybin.
01:01:42So they actually based in this conversation,
01:01:45they were much more realistic about what
01:01:47to expect that they did not come into
01:01:49the study thinking that this was going
01:01:51to be a Tennessee unlike participants
01:01:53with no prior exposure to psilocybin,
01:01:55their sense of expectancy was really
01:01:58through the roof and we struggled
01:02:00to really bring down that sense of
01:02:03expectancy which was really being
01:02:05enforced by you know as it's become
01:02:08dubbed as the pollen effect.
01:02:11Michael Pollan that is.
01:02:14And so it's I think prior exposure
01:02:18to psilocybin actually is going to
01:02:22give participants a more realistic
01:02:24expectation rather than the ones who
01:02:27have not had any prior exposure who are
01:02:29coming in really expecting a silver bullet.
01:02:32Like there really are just it's spelled
01:02:34silver bullet when they're coming in.
01:02:36Yeah perhaps it perhaps it contributes
01:02:39to lower side effects profile
01:02:43because they've had some experience
01:02:44with it before it's
01:02:46that's very likely. Yes I I absolutely.
01:02:50Yeah. So I I actually we've been
01:02:53I hadn't really talked about this
01:02:54before but I I I agree with Ben.
01:02:55I think in general people came in with
01:02:58such a high level of expectation that
01:03:00I'm not sure there was a big difference
01:03:03between the previous exposed and the audit.
01:03:05And if anything, they may have had
01:03:07a more realistic expectation. So,
01:03:12hey, Jerry, I have a question for you.
01:03:15You or Ben, You know,
01:03:17talking about the issues of
01:03:19generalizability and the fact that
01:03:21most of your population was Caucasian,
01:03:24what strategies you think may need to
01:03:28be done to actually improve on that?
01:03:30I mean is, are these like echoes of Tuskegee
01:03:33or what are your thoughts about that?
01:03:37Hey Gerard, first of all great great hearing.
01:03:41I I I think it's you know
01:03:44it's a multi fold issue.
01:03:46I mean it's always difficult getting
01:03:50adequate representation from all
01:03:52aspects of the you know the population.
01:03:54I think this study was
01:03:56unique in some ways that
01:03:59among certain groups this psychedelics
01:04:03is much more talked about and and much
01:04:07more seen in a favourable light than
01:04:09than in other groups in the population.
01:04:11And I think that contributes
01:04:14specifically to this.
01:04:15But I think, you know,
01:04:16obviously having adequate representation
01:04:18is a struggle in in all of medicine.
01:04:22How to how to improve that I I
01:04:24think is really to make sure
01:04:29the sites are chosen well that that
01:04:31there's really adequate representation
01:04:32at each site and and I don't mean that's
01:04:35going in and just going into an area
01:04:37that has an over represented group of
01:04:39anywhere but trying to go into groups
01:04:42that have adequate broad representation.
01:04:47And I and I think you know getting
01:04:49realistic information out and getting
01:04:51real patience I mean that that I think
01:04:53is going to be that's the thing I've
01:04:55said over and over is you know we're
01:04:57we're going to really need to get
01:04:58active treatment seeking patients.
01:05:00So people that are responding
01:05:03specifically for a research study
01:05:04already are quite a unique group.
01:05:06So you're going to really want
01:05:07to get people that are much more
01:05:09coming out of clinical settings.
01:05:10So Ben, I don't know.
01:05:11Yeah, no I I think Jerry you that covers it.
01:05:15I don't think I have anything to add.
01:05:17There is actually in our group and I do not
01:05:20want to single out that tan single amount.
01:05:24I'm going to single him up.
01:05:26But who has done a lot of work in
01:05:29this area and to explore different
01:05:31strategies and how is it that we can
01:05:34actually improve our recruitment,
01:05:38diversify our recruitment and what sort
01:05:40of outreach programs that have been
01:05:43more successful in achieving this goal
01:05:46versus some that have been tried and
01:05:48have proven not to be as successful.
01:05:51And but you can most definitely look
01:05:54up some of his work on Pub Med and
01:05:59and I think I'll leave it at that,
01:06:01but I do not have anything else to add.
01:06:04What Jerry said,
01:06:07Jared, do you want to speak to
01:06:08that at all briefly or not today?
01:06:12Thank you for singling me out just really
01:06:16briefly. I think it is really it's
01:06:20already so hard to run a clinical
01:06:23trial navigating all of the regulatory
01:06:26demands and everything on top of what
01:06:28needs to be done in the study itself
01:06:30that it requires tremendous effort.
01:06:33On top of all of that to conduct
01:06:36really intensive outreach
01:06:37efforts to communities of color,
01:06:41particularly the black and
01:06:42brown population in New Haven.
01:06:47You know, just really pointing to
01:06:48the cultural ambassadors program.
01:06:50We've been in touch with them,
01:06:54Jordan, Jordan Slowshower is also
01:06:56on this call and we've had a
01:06:58couple of conversations with them.
01:07:00They've never done anything
01:07:01psychedelic related.
01:07:03So it's all just going to
01:07:04be new frontiers for us.
01:07:06It's worth the effort,
01:07:08but have haven't worked on an
01:07:11MDMA trial looking to exclusively
01:07:14recruit by POC participants.
01:07:17I can say that
01:07:19it it really is a very
01:07:22tremendous effort that is
01:07:23required to to
01:07:25even bring people into the consent
01:07:28call to run through screening
01:07:29procedures with them because
01:07:31there's just so many considerations
01:07:32that people have
01:07:34about completing the trial.
01:07:37So all of these are worthwhile issues
01:07:39to think about that I think you know
01:07:42it. If the team is aligned
01:07:45in making this
01:07:46work, I think we can move the needle
01:07:49on making sure that we have more
01:07:50diverse samples moving forward.
01:07:54Jerry, I had a Jerry and Ben I had
01:07:57a question about generalizability.
01:07:59So all these patients
01:08:00were off antidepressants.
01:08:02How compelling is the data that
01:08:05antidepressants would interfere
01:08:06with the effects of these drugs?
01:08:08And in future trials is the
01:08:11FDA going to, you know,
01:08:13allow patients who are taking antidepressants
01:08:18participate in studies with with the
01:08:20serotoninergic psych psychedelics?
01:08:23It's a really
01:08:24good question and I think there is some
01:08:27work being done in this area to explore
01:08:31the extent to which the presence of
01:08:35antidepressants at the time of dosing
01:08:38versus a six week follow up versus 5
01:08:43half life paper is impacting outcome.
01:08:46I think in this particular study
01:08:50Particip I many participants did not.
01:08:54We're not an antidepressants.
01:08:55And the ones that were on antidepressants,
01:08:57they were actually tapered and they had
01:09:01to have been off of antidepressants,
01:09:04fully tapered for six weeks prior to
01:09:11baseline rating.
01:09:12I believe it's five half lives.
01:09:15Five half lives, five half lives.
01:09:16So, yeah, so there's basic and
01:09:20recently there's been a paper
01:09:22that has and more specifically,
01:09:25there is a a company that's received,
01:09:29I believe mind Mendapatent,
01:09:30where they actually are used
01:09:32using psilocybin with Lexapro to
01:09:37enhance the effect of psilocybin
01:09:39by minimizing its side effects.
01:09:42And so there is some preliminary
01:09:44data showing that the presence
01:09:45of SSRI in fact might actually
01:09:49enhance the effect of psilocybin by
01:09:52mitigating some of the side effects.
01:09:55But that is just very clear.
01:09:57But it does go back to your question,
01:09:59Doctor Sousa and that is we do
01:10:02not to say that actually patients
01:10:04should be off of SSR is to
01:10:06participate in these studies.
01:10:07I think that is not any more supported.
01:10:13And it's also the COMPASS
01:10:15and the COMPASS open label.
01:10:17That's right.
01:10:18So there's been a couple of studies and
01:10:20there are two different.
01:10:21I mean you said that that having Lexapro
01:10:23on board at the time may not interfere,
01:10:25may actually enhance, but that's a
01:10:27very different question from chronic.
01:10:29There's evidence from animal studies
01:10:30and I think this is where some of the
01:10:32thinking came from that you need to
01:10:33be off is edited from animal studies.
01:10:35The chronic SSRI use leads to a down
01:10:37regulation of the two a receptor.
01:10:39That's right. And so it may,
01:10:42which is a different question from
01:10:43what's the effect of having an SSRI
01:10:45on board at the time of dosing.
01:10:46Yeah. So the five half lives is
01:10:48calculated to make sure it's out of
01:10:50the system so that there's no SSRI
01:10:52on board at the time of dosing.
01:10:53But that may not be enough time to reverse
01:10:55the down regulation of the two A receptors.
01:10:57So two different.
01:10:57And then the third mechanistic concern
01:10:59I've heard is serotonin syndrome
01:11:00as a risk of serotonin syndrome
01:11:02that I think is overblown and I've
01:11:04seen that's right to suggest that,
01:11:06that's a realistic concern.
01:11:07But those are kind of the three different.
01:11:09Yeah, I I mean, I
01:11:11think this is a major,
01:11:13I mean this is going to be a big issue
01:11:15moving forward in implementation.
01:11:16This is going to be a big deal exactly
01:11:19in generalizability too. Yeah.
01:11:22Yeah, yeah, You know, I think this,
01:11:24I mean my take on it is, you know,
01:11:28it's really the lore in the fields.
01:11:30I I think the studies will
01:11:31have to be done to test it.
01:11:32There is the preclinical data that
01:11:35suggests that maybe but and now there's
01:11:38exactly companies are in an open label
01:11:39city where it didn't seem to make and
01:11:41if it is a 2A down regulation issue,
01:11:42it may just be an issue of dose, maybe you
01:11:44need a slightly higher dose and that's
01:11:47so the pre the preclinical date on down
01:11:51regulation of 2A receptors preclinically
01:11:53is actually really quite spotty.
01:11:55There's really and is down regulation
01:11:59really meaningful or are there alter
01:12:01other alterations in 2A receptor function?
01:12:04I looked at, I looked at it once in a
01:12:07very small population of that's and
01:12:09I saw absolutely nothing with them
01:12:11getting reasonable exposures of an SSRI.
01:12:14So it's, it's questionable I think.
01:12:17Yeah. Thank you, Jerry.
01:12:17It's like it's like 2 papers
01:12:19from 20 years ago. Yeah, that's
01:12:21right. I mean this is something I think
01:12:23that feels it's like all of all of,
01:12:26you know, biomedical science,
01:12:27but especially in this area,
01:12:29there's a lot of war that's hard to overcome.
01:12:31I mean this is things, you know,
01:12:33people have been doing this since
01:12:36the 1950s and to try to to try to
01:12:39change that with data requires data.
01:12:41So, and I I do respect that companies
01:12:44being nervous about jumping right into
01:12:47those studies first, first prove,
01:12:50you know, proof of concept under those
01:12:52conditions and then going forward.
01:12:54But I agree with you.
01:12:56Yeah, I think and
01:12:59not too dissimilar from the REMS that
01:13:03was eventually was attached to the label.
01:13:06As for Avada, where if patients
01:13:08did not at the time of dosing with
01:13:11Astravada were not on antidepressants,
01:13:14they had to start an antidepressant.
01:13:17And I would not be surprised to that if
01:13:21the data begins to show that the Pres
01:13:24adding an antidepressant before dosing,
01:13:26whether it is for treatment issues
01:13:30or to have something on board when
01:13:34psilocybin wears off or to really
01:13:37just minimize some of the adverse
01:13:39events associated with psilocybin.
01:13:42I would not be surprised that we will
01:13:44be seeing more of those studies in
01:13:46the next couple of years to really
01:13:49either optimize the treatment or
01:13:51sort of provide an antidepressant
01:13:54on board as a safety mechanism.
01:14:01I do want to put in a plug to the
01:14:02issue of the regulatory framework
01:14:03and what this is going to look like.
01:14:05Will there be a Rams and so forth
01:14:07has come up several times at
01:14:08this seminar time in February.
01:14:10We're going to have a panel of folks
01:14:12discussing precisely that issue including
01:14:14two folks whose names I don't remember
01:14:16off the top of my head, Sean Bulan.
01:14:18But leaders from the Department
01:14:20of Health and Human Services,
01:14:22who are the people who are going to be
01:14:24running the process of developing this,
01:14:26as well as Jerry and a couple other
01:14:28discussions from from a couple
01:14:30universities across the country who are
01:14:33thinking deeply about these issues.
01:14:35There's a call for commentary open
01:14:37right now from the Department of Health
01:14:39and Human Services asking for people
01:14:41in the field to put in information,
01:14:43questions and concerns on these issues.
01:14:46And we've timed that round
01:14:47table discussion in February.
01:14:48So it'll be shortly before
01:14:49the close of that call.
01:14:51So there will be discussion of the,
01:14:53you know the the in the early.
01:14:55I think it's the first public
01:14:57synthesis of the information that
01:14:58has come in over the next two months.
01:15:00And then after that there will be still
01:15:03another week I think to where one can can,
01:15:06where where folks can after hearing
01:15:07that discussion continue to put
01:15:09in information on that call.
01:15:10So I think it'll be and we're going
01:15:12to advertise this nationally.
01:15:13I think it's going to be an important event.
01:15:15So I just want to put in the plug for that.
01:15:17It'll be at the usual time the,
01:15:18you know, the the third Friday in
01:15:22February publicity going out soon.
01:15:24OK, That's right.
01:15:25Well,
01:15:27OK, just all right.
01:15:29Any other any other questions?
01:15:35What's on the horizon for the
01:15:37Yasona program? So. So I think
01:15:45clearly it is a plan for a phase
01:15:47three study that hopefully will
01:15:48be underway in the near future.
01:15:54So the the goal is to move forward. Yeah.
01:15:59OK. Chris, anything else?
01:16:02Anything else? Yeah.
01:16:03Thank you both. Thank
01:16:03you all. Thank you. Bye.