Shariful Syed, MD & Deepak Cyril D’Souza, MD. March 2022

January 18, 2023

Title: Dose-Related Safety, Tolerability, and Efficacy of Dimethyltryptamine (DMT) In Healthy Volunteers and Individuals with Major Depressive Disorder – preliminary findings

Description: Dimethyltryptamine (DMT) is a potent, rapid-onset and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individuals with major depressive disorder (MDD) and healthy controls (HC) in an open-label, fixed-order, dose-escalation (0.1 mg/kg followed by 0.3 mg/kg) study that was conducted in a typical hospital setting with strategic psychoeducation/support, but minimal psychotherapy. Tolerability, safety, cardiovascular function, abuse liability, psychedelic and psychotomimetic effects, mood, and anxiety were assessed at each dosing session. In addition, depression was measured in MDD participants 1 day after each dosing session. Preliminary findings (n=10) were discussed.

Information

ID: 9384
To Cite: DCA Citation Guide

Download Transcript

00:22Hi everyone, good to see so many people.
01:00It's a minute or two after Cyril.
01:01You're ready to go.
01:05Yeah, I I am. Thanks.
01:07Thanks everyone for for coming.
01:11Actually, I'm going to.
01:12Have most of the talking done
01:15by Shariful Syed Sharif is a.
01:20The research fellow.
01:22In our lab. And he has been.
01:27He has really worked closely with me.
01:30In doing this study and so I'm
01:33going to hand it over to him and
01:36I may interject every now and
01:38then just add a few details.
01:40So should we take it away?
01:51Hi everyone. My screen.
01:57Can you share your screen?
02:01Yes.
02:05OK,
02:07OK. Can we see this? Looks good.
02:10OK. All right, I'll begin.
02:14Hello everyone. So I'm sheriff.
02:16Nice to thank you all for coming
02:19and listening to me today.
02:21So today I'm going to present to
02:24you the results from our exploratory
02:26study of the dose related safety,
02:29tolerability and efficacy of
02:32Dimethyltryptamine DMT in healthy
02:34volunteers and major depressive disorder.
02:41So, so why DMT so to start
02:45with context? Because I.
02:48Does the time
02:49to get in and get away sign
02:51and tribe and all, I think.
02:55So circumstances being right now,
02:58silybin LSD more so.
03:00Psilocybin is the main psychedelic
03:04drug being used and to treat
03:08neuropsychiatric diseases.
03:10It raises some concerns in terms of
03:14implementation and sustainability as a
03:16potential treatment option if the goal
03:20is to expand treatments and provide
03:22them to as many people as possible.
03:25And and so you know what it has to do
03:28with that is first the administration
03:31psilocybin is usually given orally.
03:33I did help with the our SILYBIN trial
03:36with the doctor slower doctor Desouza.
03:39So is able to kind of experience you
03:41know first hand what the silybin
03:43effects were like and you know
03:45it's a very slow onset takes an
03:47hour to get to peak and you know
03:50affects Slash report 6 hours.
03:52Absorption is naturally variable.
03:54And in terms of pharmacodynamics,
03:57you know, the psychedelic effects,
03:58you know they're very potent
04:00and and and they,
04:01they sustained for quite some time.
04:04And and it's these effects that impart,
04:06you know require the need of you know
04:10the current FDA guidelines requires 2
04:14clinicians to be supporting a patient
04:17if they're receiving a psychedelic.
04:19And so that's actually kind of a
04:22large use of resources in terms of
04:25you know 6 to 8 hours to clinicians
04:28for one session for for a patient.
04:31And so the other aspect is that
04:34you know the the use of therapy to
04:37scaffold you know the psychedelic
04:40treatment encounter is also quite a
04:43large endeavor in terms of many trials
04:46include eight weeks of twice a week sessions.
04:49And so all these things
04:51taken together you know it,
04:52it certainly raises some concerns
04:54in terms of scalability and
04:56accessibility and as it pertains
04:59to financial high cost insurance.
05:01Coverage being certainly something
05:03that's influenced by that.
05:06So I so for all those reasons I I
05:08think it it does actually make DMT
05:11seem like an interesting option
05:14and so so and part of that another
05:18dimension of why DMT we would argue
05:21is that something that's kind of
05:23assumed about psychedelics is that
05:25you know the effects are necessary
05:28to their therapeutic effects that's
05:30not proven yet but that's.
05:31By and large what a lot of people
05:34think and you know the magnitude
05:36of psychedelic effects that's you
05:38know seems to be you know part
05:40of just the process.
05:42People kind of lose themselves.
05:43They experience you like oceanic
05:45boundlessness and you know that's again
05:48you know these effects are part of
05:50what requires close medical monitoring
05:52and you know for our study we always
05:54have to have rescue medication.
05:55We were taking blood pressures
05:57and likely those things would
05:59be required and and practice.
06:01So you know it.
06:03It begs the question actually.
06:04So you know how much psychedelic
06:06effect is needed if they are indeed,
06:09you know,
06:10necessary in terms of duration
06:11and as well as the magnitude.
06:13Because in theory.
06:16If there was a minimum threshold
06:18that was needed,
06:19well then it would make sense
06:21to try and you
06:22know reach that and so that we could
06:26potentially optimize administration.
06:28So again, DMT, it's a tryptamine,
06:32serotonergic, psychedelic.
06:33We have psilocybin here and DMT and LSD,
06:39which you know as a molecule
06:40is a little bit different.
06:42But notice that psilocybin is actually.
06:45You know, and then Dimethyltryptamine
06:48with just that phosphorus
06:50phosphoryl group on the 4th carbon.
06:52OK, so concretely,
06:55DMT is normally administered either
06:59intravenously or smoked intranasal intra.
07:04Inhalation only and so it
07:05has a very rapid onset,
07:07you know within minutes and it's
07:09duration of effects is short.
07:11It's effect usually resolved
07:12by about 30 minutes.
07:14Now some of it's in in the.
07:18Informally,
07:18it's been called the businessman's trip.
07:21And so the reason it has to be given
07:25IV or intra intranasally is because the
07:28oral bioavailability is quite poor.
07:31And that's related to the fact that if
07:33it's if it reaches the peripheral metabolism,
07:36it gets metabolized very quickly by money,
07:38by monoamine oxidase and by by those enzymes.
07:45And so actually the DMT is not able to
07:47reach brain and so that's that limit
07:49its ability to be given that way.
07:52And so iasca is, you know,
07:54it's a ceremonial brew,
07:56it's a tea that you know,
07:59DMT is known to be,
08:01you know,
08:01a very active constituent in
08:03and it's used in the Amazonian
08:06regions of South America.
08:08There's a long tradition and
08:09history associated with it in
08:11terms of some of these cultures,
08:12Brazil in particular I think is 1.
08:15And, you know, looking at iasca,
08:17you know, having DMT in it,
08:19it also has other, you know,
08:21serotonergic potentiating
08:23compounds including,
08:24you know harmaline and other other
08:28SSRI acting components and ayahuasca.
08:33You know,
08:34when ingested orally it's associated
08:36with pretty profound hallucinations,
08:38perceptual alteration,
08:40spiritual insights, euphoria, anxiety.
08:42It also it's relatively.
08:45Associated with often nausea,
08:48vomiting, diarrhea.
08:51So, so then the question is,
08:53well, does DMT, you know,
08:55maybe in the form of ayahuasca,
08:56does that have antidepressant effects?
08:59And you know, interestingly,
09:00you know, I was trying to look at the
09:02history and to see what, you know,
09:03if if that was something on anyone's radar.
09:05And you know there was this psychiatrist
09:09Raymond Prince who wrote this article about,
09:13you know,
09:13his observations of iowaska and how,
09:15you know, shamans used it as you know,
09:18for a therapeutic like purposes
09:20and I thought.
09:21This was interesting because,
09:23you know, I actually want you to
09:25read this part and so referring to,
09:27you know, ayahuasca,
09:28it is a fearsome thing.
09:30I was very much afraid.
09:32And Tarner,
09:33reporting his own initiation into shamanism,
09:36describes the terrifying images he
09:38experienced after taking a species of Natura.
09:41There are two types of terror
09:43involved in psychedelic youth,
09:44specific hallucinatory images
09:45such as giant snakes or Jaguars,
09:49and the general terror of
09:51impending ego dissolution.
09:52Both could conceivably related
09:53to endorphin response as part
09:55of their therapeutic efficacy.
09:57So already there is some observation
09:59or thinking about you know
10:02these psychedelic effects as you
10:04know having some potential
10:06efficacy and curiously in terms
10:08of the you know the distressing
10:10elements seem to be actually
10:12important for that effect in in this.
10:15And in that perspective and so
10:17there are some, there are some
10:20clinical trials that looked at.
10:22Iasca, you know, in a rigorous way
10:25relatively speaking the left we have
10:27here is an open label trial that was,
10:29you know just done in a sample
10:31of three individuals.
10:32We have here on the X axis time and the
10:35Y axis is their Madras score, which is,
10:38you know, depression rating scale.
10:40And so you see here you know
10:43the peak effects, this is our,
10:46our minutes and this is days.
10:48So you have baseline before administration,
10:50you have relatively higher.
10:52Depression score and you know,
10:54it, it comes down,
10:56but it goes through an interesting
10:58kind of ups and downs and to remember
11:00the peak effects around 2 hours.
11:02And so curiously, you know,
11:05you see this actually uptick
11:07in depressive symptoms.
11:08So that you know,
11:09actually lends itself towards well
11:11what does the psychedelic experience
11:13need to be for it to be therapeutic.
11:16So I mean that's a question that
11:19certainly will need to be answered
11:21and probably will be looked at.
11:23In the in the future,
11:25the right is a a clinical trial,
11:27randomized clinical trial where
11:29you know we had a placebo control
11:31and so again this is using the AMD
11:33we see at by seven days after one
11:36administration of ayahuasca you see
11:38a change of from 25 to about 10
11:41that's a quite a large effect size.
11:44I'd say that's comparable to you
11:46know what some of the psilocybin
11:48studies have shown in terms of
11:50their impressive effects but and
11:52so while ayahuasca. Contains DMT.
11:54It contains all the other things as
11:56we mentioned, and so as a result,
11:59you know we can't really extrapolate
12:02about DMT itself because it has
12:05not been studied in isolation.
12:07So. You know it. It really does.
12:10You know,
12:11the question really arises for all
12:13these psychedelics of, you know,
12:15are these effects long lasting?
12:17And you know there is some suggestion
12:19that you know psilocybin does have
12:22effects that seem to last for
12:24maybe one month or even longer.
12:26And then the so the natural
12:27question is well how do we,
12:29how is that happening now?
12:31Depression to be associated
12:33with dendritic spine loss,
12:35decrease number inside the glial cells.
12:38These things have ramifications
12:40for brain regions such as
12:42hippocampus and prefrontal cortex.
12:44And as a result, you know,
12:45you get ultimately impaired.
12:47Activity.
12:48And these things correlate with,
12:49you know,
12:51depressive symptomatology.
12:53And so in terms of the basis of how
12:56these psychedelics work and this,
12:59it seems to be that they are impacting
13:02neuroplasticity insofar as we define
13:04it to refer to the connectivity between
13:08neurons and their actual, you know,
13:12their, their neurotransmission,
13:13you know, looking at the, at the.
13:17Post synaptic numbering.
13:20OK, so all taken together,
13:23these things guided our study designing to.
13:27In terms of any specific aims
13:28and hypothesis where we wanted to
13:30test the safety, tolerability,
13:32efficacy and potential mechanisms
13:34involved with DMT and major
13:38depression and healthy controls.
13:40So our initial study design
13:43was a double-blind randomized
13:45placebo control trial.
13:47And you know.
13:49But we actually ran into
13:52a roadblock of sorts.
13:54The IRB told us that we had to
13:59first do a fixed order open label
14:02dose escalation study to determine
14:05the safety of the highest dose
14:07of DMT that was tolerable and
14:10safe in depressed subjects as
14:12well as health healthy controls.
14:17And those are the results of this study,
14:20is what we shall be going over today.
14:23The doses, as I mentioned up to .3,
14:26so we had two doses that was our .1
14:29milligram per kilogram and then the .3.
14:31These doses are based off of the work
14:34done by Rick Strassman who actually was
14:37someone that was cited in the literature.
14:40And some of this, you know from the previous,
14:43you know, old article I showed you.
14:44There was others like that
14:46where he was actually, you know,
14:48co-author, but he has specifically
14:51studied intravenous DMT.
14:53Looking to understand more about
14:55human consciousness and so the and
14:57with healthy controls which were you
14:59know experienced psychedelic users.
15:00He has a few clinical trials where you
15:03know he established a paradigm and you
15:05know proof of concept of the safety and
15:08and psychedelic effects of these doses
15:10to .1 being a sub psychedelic dose.
15:13Meaning that .1 make per cake dose is
15:17not associated with over perceptual
15:19changes while the .3 you know is.
15:23Quite so robustly.
15:24One of the words that captures,
15:27you know,
15:28how people describe the intensity
15:29of it because it's known to be
15:31quite intense as you know, knowing,
15:33knowing its pharmacokinetics
15:34being very rapid and onset.
15:37You know that also suggestive,
15:39but one of the words that uses,
15:41you know,
15:41it feels like a breakthrough of sorts and
15:43that that initial induction of effects is,
15:46you know, referred to with words like
15:48that and the actual administration
15:50of the drug is done intravenously.
15:53And over 30 to 60 seconds as a bolus.
15:57And so that was doctor Dsouza,
15:59you know,
16:00administering those to our subjects.
16:03OK.
16:03So in terms of how we measured all
16:07these things that we discussed is
16:09very was our aims in terms of safety.
16:13Physiologically we had we measure
16:15blood pressures, heart rates,
16:18oxygen saturation and you know,
16:21heart rate oxygen being continuous
16:22blood pressure, you know,
16:24we measured at numerous time
16:26points adverse events.
16:29You know we were very careful you know
16:31this being you know the first clinical
16:33trial using DMT and depressed individuals.
16:35You know we really wanted to make
16:37sure we captured any and all potential
16:39adverse events that to any of the the
16:41subject experience and in terms of.
16:44Rescue medications based off the work
16:46done in healthy controls, you know,
16:49temporal increases in heart rate,
16:51blood pressure, anxiety, confusion.
16:53We selected a rescue medications
16:57to serve those needs,
16:59but we actually didn't need
17:00to use any in our study.
17:02And of course the need for the study
17:04to be aborted or if subjects dropping
17:07out after receiving the the .1 dose,
17:10those things also certainly would
17:12inform how we understood safety.
17:14OK.
17:15As for tolerability,
17:16so we use what's called a which I'm
17:19sure many of you know a visual analog
17:22scale measure which is basically a
17:25horizontal line anchored with vertical
17:27lines that's you know prompt the,
17:31the,
17:31the,
17:32the individual to answer on that spectrum and
17:35you know make a dash to indicate where.
17:39So you know for example tolerability was you
17:41know was one of those things and actually.
17:44You know something about.
17:47Just nomenclature or maybe semantics,
17:49safety. Tolerability.
17:51Those words seem to often.
17:53They seem to have a lot of overlap,
17:54but it seems to be this.
17:57There are some important distinctions between
18:00the two that I wanted to raise, and that's.
18:06You know, go away based off.
18:09Now the FDA looks at these things, so.
18:14I'm sorry.
18:19So do you at the FDA defines tolerability
18:22as the degree to which overt adverse
18:25effects can be tolerated by a patient
18:28while safety is defined as the risk
18:30to the subject or patient from a drug
18:33or biologic assist by laboratory test
18:35vital signs clinical adverse events
18:37and other special safety tests.
18:39So you know we keeping that in mind we
18:41we try to distinguish between safety
18:44and how we interpreted safety and.
18:46Capability so a psychedelic effects.
18:50We also used AVAS visual analog
18:53scale version of the altered states
18:56of consciousness. This was 23 items.
18:59We also use the psycho psychotomimetic
19:02effects scale.
19:04And then we measured anxiety and
19:07drug reinforcing effects.
19:09You know, being a schedule one substance,
19:12the psychedelic compounds
19:14necessarily have been, you know,
19:16viewed by the federal government
19:19as highly addictive compounds.
19:21That's part of the definition
19:22of a schedule one substance.
19:23So, you know,
19:24naturally it's very important to assess,
19:26you know, potential drug reinforcement.
19:30And in terms of efficacy being
19:32a clinical trial for depression,
19:34we utilize the grid AMD which is you
19:36know a well validated scale that's
19:39used in clinical trials for depression,
19:41our cutoff score being 17.
19:46All right.
19:47And so just to go over some of our,
19:51our pertinent inclusion exclusion
19:54criteria for the and overall it's
19:57very consistent with the psychedelic
19:59trials to date.
20:00You know in our depressed group we we
20:04define treatment refractory as you
20:06know having at least one failed SSRI
20:09treatment in the current episode.
20:11You know we also appropriately and
20:13that's really kind of required
20:15patients not be taking it.
20:16Depressants because of the
20:19potential concerns of, you know,
20:21an excess of serotonin such as,
20:23you know,
20:24leading to something like serotonin syndrome.
20:25So, you know,
20:26no one could be on a medication that
20:29was potentiating their serotonin.
20:32Likewise for supplements,
20:34everyone had to begin treatment.
20:36We excluded anyone with psychotic disorders,
20:38history,
20:38mania and in terms of suicide risk because,
20:42you know a lot of these patients being
20:44treated or resistant, you know, I had a.
20:46Appreciable risk of suicide if not previous.
20:51So we we've been really based it off
20:53if we temporarily had recent elevated risk,
20:56you know we excluded those
20:59individuals for healthy controls.
21:00We just wanted to be careful to minimize
21:04their psychedelic use as a specific point.
21:08OK, so here we have our consort chart
21:13and you'll see that we we assessed 52.
21:17People that called in a lot of
21:19them you know found this online,
21:21people looking for DMT to help themselves
21:24with their with their mental health.
21:27Many were deemed ineligible for
21:30a variety of the normal reasons,
21:33not meeting criteria,
21:35having excluding diagnosis,
21:37living too far away,
21:38not being in treatments.
21:39So we ultimately brought in 14 people,
21:42two failed screening,
21:44one didn't meet the minimum
21:46depression severity.
21:47Which was 17 and another head
21:50ongoing substance use disorder.
21:52So we enrolled 12 and we technically
21:54had two dropouts and these were
21:57individuals that did not you know even
22:00really start the any of our testing
22:02those sessions because you know one
22:04didn't complete the paper so they
22:06couldn't proceed and then the other
22:08you know schedule wise wasn't able
22:10to to connect and you know make
22:12it make it in for the test days.
22:14And so we had 1010 subjects complete.
22:18The first Test day,
22:19remember everyone got and at
22:21first the .1 make per cake and
22:24then the .3 make per kig dose.
22:26And usually the time between those
22:28two doses was usually a few days,
22:30at least 72 hours overall.
22:33And so out of these 10 subjects,
22:35we had three healthy controls and 7th press.
22:39This here is yes.
22:42Do you want to say how we?
22:44Decided whether someone would go from.
22:47Oh yes, yes to another.
22:49Right, right. So. You know we were
22:52as I was kind of saying before being
22:55very careful you wanted and this
22:57being you know opponent substance.
22:59We you know we asked every every
23:02subject if you know they if they
23:05were willing to come back for
23:07a second dose after the first.
23:10You know there was no there
23:12was no pressure whatsoever.
23:13You know just naturally them
23:15being here voluntary but also this
23:18independent to their their willingness
23:20to return we also looked at.
23:22Of a variety of things and assessing
23:25whether we felt it was appropriate
23:27for subjects to come back.
23:28So we would look at together all their
23:31readings of their blood pressures or
23:33heart rate, their subjective effects.
23:35You know,
23:36during the acute session and you know,
23:39during the entire session, you know,
23:41there was three or four of us,
23:42doctor Dsouza, myself,
23:44a research nurse in RA, you know,
23:46observing, writing down notes, etcetera.
23:48So taken together, you know,
23:51we we, we came to a consensus.
23:53As a team for each subject and you
23:56know whether to ultimately deem
23:59appropriate to proceed and yes question.
24:02So
24:03in the most places
24:04that are doing therapeutic psilocybin
24:06or following the protocol that Johns
24:08Hopkins developed 20 years ago where
24:10you got the two people sitting and
24:12providing her and sounds like you're
24:14setting is sort of more just straight
24:16observational and kind of more medicalized
24:18and not providing that kind of.
24:20Psychological support? What?
24:22What? How do you, how do you,
24:24how did you think about that?
24:26Yeah. So that's exactly what
24:27I was going to say here.
24:29So perfect timing.
24:32That's actually quite nice.
24:34So, so this is our test day,
24:36the test days happened in the
24:38you know in the bio studies unit
24:40BA which is on the 9th floor.
24:43We we ran these and in terms of
24:46the concept that was driving us,
24:48we wanted, we you know we really
24:51wanted to see you know what?
24:54What effects? Are due to the medication,
24:57the biology of what they're doing.
25:00And so unlike philosophy, which, you know,
25:03does, which are soliciting trial.
25:05We had a very we had a dedicated
25:07dosing room for just silybin.
25:10It had it had nice artwork on the walls.
25:12It had, you know, nice lighting plants.
25:17No no lava lamp.
25:19Are
25:19we allowed to have those I'm not
25:20even sure but but we had we had nice
25:24lighting but no love the land and
25:27and and background music you know we
25:29had a very actually a very doctor
25:31Sunshower had a very specific playlist
25:34that he designed for the trial which
25:36was well received by everyone but
25:38you know so that was silybin for DMT
25:40being that we wanted to really try
25:42and start to get at well you know if
25:44you don't have that those all those.
25:46Setting dimensions present what happened.
25:48So we specifically and intentionally
25:51wanted to make it as very, you know,
25:54not these words sterile but very simple,
25:56very hospitalized. You know,
25:58similar to how ketamine treatments are done.
26:01And I can make some comparison because
26:03I work in the the TRD service at the VA
26:06we're giving ketamine to our veterans.
26:08So you know, it was we did this and
26:11then one of our EEG booths,
26:13which is a square enclosed space,
26:15you know, that's soundproof.
26:17There was a hospital grade
26:19reclining chair in it, you know,
26:21kind of dim overhead fluorescent lighting
26:24and no art on the walls, no music, you know,
26:27just doctor D'souza and myself and you know,
26:29the IV lines and you know,
26:32and that that was the entire setup and,
26:35you know, and so we stayed with them,
26:36you know,
26:37to be a source of support if needed.
26:41But, you know, our, our, our,
26:43our focus was to let subjects,
26:46you know, experience the effects.
26:48You know entirely.
26:49On their own and not really guide.
26:52So it was a very it was a very non
26:55directed approach by design and
26:58that and that's how we.
27:00When about conducting the doses,
27:03we decided. That he would not speak
27:07to the subjects for the first five.
27:11Minutes, because we were concerned that.
27:15Interacting them with them
27:18might disrupt the experience.
27:20So unless the subject reached out to us.
27:24And wanted to engage us.
27:26We kind of remain.
27:28Silent in the background,
27:29we were standing a few feet away from them.
27:31Even the instruction we gave the
27:34subject was to indicate to us,
27:36either by raising their hand,
27:37the first change that they noticed
27:40after the administration of PM.
27:42But otherwise we we we didn't say anything.
27:45I I guess the first interruption would
27:48have been the the blood pressure cuff
27:51being inflated at about 5 minutes.
27:53But otherwise we kept quiet
27:54because we can see anything.
27:56So there was just to be clear,
27:57no psychotherapy the way that
27:59psychotherapy is done for psychic studies.
28:02Yeah it it is worth I mean this is of
28:05course a super active issue in the
28:07in the field in which about which I
28:09don't have strong opinions but but
28:11it's with sure even what you just
28:12noticed they're two different things
28:13that you're trying to keep neutral.
28:14There's the environment and
28:16there's the guidance, right.
28:18So you could have an unmet actualized
28:21environment with no guidance.
28:22Have a medicalized environment with guidance.
28:24And so it's just you know,
28:26in think trying to wrap our heads
28:28around what matters and what doesn't
28:30and I have no idea and I'm just,
28:32I'm trying to keep these
28:33things straight in my head,
28:34but thank you for that,
28:36for that clarification.
28:36That's really helpful.
28:38Yes, I continue to struggle
28:40to keep them in my head too.
28:43And so just at 30 minutes we we gave them
28:46scales to you know assess the effects.
28:48So remember by about 30 minutes
28:50they basically resolved but you
28:52know they they were able to kind
28:54of capture what they felt were
28:56the peak effects and then again 2
28:58hour at the two hour mark and this
29:01is where we assess tolerability 2
29:04hours after receiving drug. OK.
29:06So we just just one other
29:08thing I wanted to mention.
29:09We chose to administer all those scales.
29:13When we were confident that the
29:16acute effects of BMD would be.
29:19Would have faded away because we were
29:21concerned that while under the influence,
29:23people may not be able to accurately
29:25describe or report what they were feeling.
29:27So we waited to yeah.
29:30Yes. OK, so let's start
29:34to present the results.
29:36Here's our demographic table.
29:38Notice that our our first three.
29:41Rows are healthy control subjects
29:43and then the remaining seven
29:45are are depressed individuals.
29:48Overall, there are subjects had about
29:53an illness burden of at least 20
29:57years and most of them were educated,
30:00quite educated graduate degrees.
30:03Previous academic use was,
30:04you know, very limited.
30:06You know, there was one or
30:08two discrete at the uses for
30:10for maybe half of subjects.
30:14And notably in terms of, you know,
30:16what makes them treatment resistant,
30:18looking at the, you know,
30:19past past antidepressant trials failed,
30:22you know, we had quite a few
30:23subjects that you know did not have,
30:25you know, relief with ketamine,
30:27ECT, RTMS and you know,
30:31really the most robust
30:33treatments that are offered.
30:36So you know, so these are pretty,
30:38these were pretty ill patients.
30:42And in terms of our healthy controls and
30:45to also note no one had used DMT before
30:49that that we were also made certain of.
30:52OK. So next we'll be going through
30:54the results in the order of the
30:56outcome measures, as I said.
30:58So say in terms of safety, looking at our,
31:01our cardiac parameters going from
31:03left to right just to Orient everyone,
31:06the red lines are going to represent
31:09the blue lines represent the .1 dose,
31:11so the the the first session and
31:14then the red lines present.
31:16The .3 dose the second session and
31:19so going and the green arrows here,
31:21they represent the time point at which
31:24the DMT I bolus was given over 30 to 60
31:29seconds just just so everyone is clear.
31:31And so going from left to right we see,
31:34we see an expected increase in all three
31:38measures, systolic blood pressure,
31:40diastolic blood pressure and heart rates,
31:43the magnitude of the increase.
31:47I would say,
31:47and you know I know there are many experts
31:49here in the audience and know better.
31:51You know,
31:52comparing to ketamine,
31:53it's also associated with a
31:55transient increase in blood pressure.
31:57It seems about similar from what
31:59I get from my understanding.
32:04But, you know, one of the one thing I
32:06think that is different is the heart rate.
32:08That was pretty impressively increased
32:12acutely after administering DMT.
32:15Not of that being more.
32:18That being dose.
32:21Difference between doses for
32:23the other for blood pressure,
32:25they were fairly similar.
32:27Heart rate still wasn't
32:29statistically significant overall
32:30given all these time points,
32:32but you know at at this one time point
32:35certainly that was significantly different.
32:37OK, so next here we have a
32:40graphic illustration of our
32:42psychedelic affect ratings.
32:44So this this is our modified AC scale.
32:48These are the 23 items that query
32:51that the psychedelic effects.
32:53And you'll notice, you know,
32:54the red is quite long and so right
32:58there more intense the .3 dose.
33:00The the bars here represent
33:02standard errors of the mean.
33:04And I guess I'd like to bring
33:06your attention to a few of the.
33:07Items here.
33:09You know the last item here,
33:11how intense was the drug
33:13experience on average?
33:15You know, people found the .3
33:17dose to be about 95 out of 100.
33:19So that that does seem to be quite telling
33:22of just how intense the the experience was.
33:25Also subjects found that the
33:28experience was much more challenging,
33:31but the .3 dose,
33:33you know about 65 versus.
33:36You know 25.
33:39But they also,
33:40you see they found the those the
33:43experience being much more meaningful
33:46and so the ones with the asterisks here,
33:49these are all significantly
33:51different between those the the two
33:54stars means you know it's greater
33:57smaller P value and this was
33:59corrected for false discovery rates.
34:03And, you know,
34:04there's only so much that, you know,
34:06these, the graphic illustrations
34:08and scales can tell us.
34:09So included here we have one of
34:11our healthy control subjects.
34:13Now that, you know, went,
34:15I was able to draw for us what
34:17what their experience was like.
34:20So I'll show you a few drawings so,
34:23you know, it's written here, you know,
34:26this turns into a cavernous room
34:28that's depicted in the drawing.
34:30It was domed,
34:31and the ceiling and walls had the
34:32same sort of look as the mucks.
34:34Filling in the attached picture,
34:36the main difference is that
34:38everything was made out of light and
34:40was moving quite quickly and so.
34:43So yeah.
34:46It's smooth solids, tiled shapes,
34:49tiled shapes, interesting puzzle like.
34:53Things. Looks like a double Helix there.
34:58And so this was the mosque picture
35:01that they're referring to.
35:02So apparently, you know,
35:04their experience was a light. You know,
35:08complex that looks something like this.
35:11Seems pretty impressive to me.
35:15Then more more details.
35:17So this then gave way
35:20depicted in the entity space,
35:23drawing what felt like a different
35:25a temporal realm with its own order.
35:28Here all surfaces were smooth and uniform in
35:31color as as as if they were enamel painted.
35:34The two flying beings pictured had
35:36round bodies that were smooth but Matt
35:38gun metal Gray as per the back wings.
35:41Their color and texture were like that of
35:43those glossy dark red KitchenAid mixers.
35:45I don't remember the color of
35:47their front winglets or appendages,
35:49but I do remember that they were vague,
35:50being vaguely there.
35:51They had no eyes or faces,
35:53but were somehow looking at me.
35:56So I mean that's what these are referring to.
35:59One of the reasons we thought we
36:01would share this with you is because.
36:04Anecdotally, at least.
36:07There are a number of reports of people.
36:09To claim. To see entities or
36:13feel the presence of entities.
36:16After the CPMT.
36:20And so I think this was the
36:22only subject in our entire
36:23subject list of 10 subjects who
36:25reported anything like this,
36:27but what it highlighted for me is.
36:31What you bring to the occasion
36:33is likely what's going to.
36:37Influence your experience.
36:38So this is a subject
36:40from the Divinity school.
36:41So no, no surprise that he saw
36:45the inside of a mosque and that's
36:47how he described it and and many
36:50of many of his interpretations
36:52of these perceptual alterations.
36:55Had religious connotations.
37:00Yeah, it it was remarkable just to mention
37:03anecdotally that a lot of the perceptual.
37:06Changes that subject experience did have,
37:08you know, temporal relation
37:10to things they had seen and.
37:12Recent like the day before the experience
37:14or you know something actually,
37:16you know, long standing and you know
37:17maybe in their subconscious so to speak,
37:19but that's, you know,
37:21for another sort of talk. OK.
37:23So move back to our results.
37:26So these are the the assessments of
37:30using the psychotomimetic effects scale.
37:34So as you can see there was an
37:36acute elevation much that in the
37:39with both doses the difference
37:41being more significant than the .3.
37:45Notably you see at baseline they're
37:47being you know it's it wasn't a
37:49negligible you know baseline and the
37:51next slide look if we break it down into
37:54its six subscales we can understand.
37:56A little bit better you know what
37:59what what the PSI was picking up
38:01and so the only two scales that
38:03were significant were the perceptual
38:06distortion and cognitive disorganization.
38:08The other four were not and you know
38:12I guess this here tells us what you
38:15saw before which was that baseline
38:17our depressed subjects reported more
38:20Antonia makes sense but that also
38:22you know brings really important
38:23point to stand that now it's really
38:25important to look at the.
38:27Change in the effects because if
38:29one just looks at the objective one
38:32time point that may miss something,
38:34especially when we're talking about you know,
38:37depressed individuals who are
38:39experiencing symptoms that are affecting,
38:42you know,
38:43their experiences including you
38:45know their perception etcetera.
38:47Sharif.
38:48Yes.
38:48So
38:49that what you have is the 30 minute
38:51time point that's the scale is
38:53administered at 30 minutes after
38:55the acute effects have dissipated.
38:57Yes. And are they asked to rate
39:00their memory of the maximum effect
39:02within the last 30 minutes? Yes. OK.
39:06And then at the 120 minute time point
39:07and at the -, 60 minute time point,
39:09I presume they're asked to rate how
39:11they're feeling right now. Yes.
39:13So just to clarification,
39:15so at mine, at baseline,
39:17they asked about how they're
39:18feeling at that moment at
39:2030 minutes, they're asking,
39:22they're asked to integrate.
39:26At the time from from the time
39:28they received the injection and
39:30then at the 120 minute time point
39:32they asked about what happened
39:35between plus 30 and plus 1/20.
39:37To report the maximal effects.
39:41So, OK. And and at at the
39:4230 minutes they're at,
39:43they're not asking for the peak,
39:44to report the peak,
39:45they're asked to integrate,
39:47integrate, but report the highest.
39:51Which is. And if you do ask
39:52people to integrate, they
39:53usually report the peak anyways.
39:56So that that missed that, yeah,
39:59that's important point. Thanks.
40:02And that is that
40:04increase in anhedonia 30 minutes
40:06that was not significant.
40:08No, it was not OK,
40:10but it's kind of. It's if
40:12it's real, it's odd, but
40:15it is. Yes, it is odd. Yes.
40:17And that's going to show up again
40:18actually in another scale. Good.
40:20Good catch, doctor fenninger.
40:23OK, so next we have our last,
40:26our second to last result related to safety.
40:29And this is our AE or adverse event table.
40:32So again, here we have all 10 subjects.
40:36You know. Grossly speaking,
40:39overall the effect the adverse events
40:43that are subject experience were mild
40:46and they most often occurred during the
40:49onset of effects being in that zero to 10,
40:53zero to 20 time point.
40:56Qualitatively, the actual effects that
40:59they experienced were relatively varied.
41:02There wasn't really any specific thing
41:04that seemed to really ring true for
41:07for the most more subjects than not.
41:09So we had not anxiety,
41:12hypertension, nausea,
41:16those were the main things.
41:17Some Lightheadedness kind of goes a
41:19little bit with the nausea and anxiety,
41:21but very important to emphasize
41:24now is that we did have.
41:27One serious adverse event.
41:29And that was related to subject #5 here.
41:35So this is one of our depressed
41:37subjects and we're actually going to go
41:39through that in some detail right now.
41:42So this this table here is the
41:44is the time points and the the
41:47details of exactly what happened
41:50for this serious adverse event.
41:52So, you know,
41:54basically this at from the five minute
41:58time point after administering the DMT,
42:02we noticed the the blood pressure
42:06and pulse in tandem start to drop.
42:10And so we see here at the zero time point,
42:14their baseline is their blood
42:15pressure is on the lower side,
42:17108 / 60 heart rate,
42:2054 individual is someone that
42:22does exercise a lot is very fit.
42:24So those things you know seemed
42:26you know within normal limits for
42:28them and as per history as well.
42:30But you know at at the plus 5
42:33minute time point it dropped quite
42:35precipitously to about 70 / 40,
42:38the pulse went to 42.
42:41And actually, you know,
42:42still went down further at the a
42:45minute later and another minute later.
42:47And so this, you know,
42:49when we saw this change,
42:50which was not expected.
42:53Because all the literature to date of
42:57DMT remember being in healthy control
42:59showed very consistently increase in
43:02blood pressure and increase in heart rate,
43:05not decrease.
43:06So this was you know quite surprising
43:09but you know we we adapted accordingly we
43:12were prepared but so you know we see by.
43:16The plus 10 time .5 minutes later,
43:19the blood pressure and pulse
43:22starts to trend back or get back
43:25to their normal baseline.
43:27And so while that was,
43:29you know quite scary in real time,
43:31I still remember that I guess relatively
43:33well-being quite junior in my experience
43:36as a clinician and researcher.
43:39It was very,
43:40it was very interesting that
43:42the subject in terms of their,
43:45their subjective experience of what was
43:47going on and remember this is the .3 dose.
43:51You know they didn't report any
43:54distress actually they were
43:56coherent, they were they were actually
43:58kind of puzzled by us you know because
44:00the interventions we made where we we,
44:03we placed her in a closer
44:05to Trendelenburg position.
44:07We increased the fluids which
44:09were already running.
44:10At baseline at a drip rate we
44:12increased it to the Max normal flow.
44:15So as you were doing those things
44:17the subject actually asked us
44:18like you know what's going on.
44:20Why are you like doing doing all
44:22this because you know we were we were
44:25responding to these numbers because
44:27they were were were concerning but
44:29luckily you know again after after
44:31the effects had resolved you know we
44:34we asked again and they said you know
44:36they didn't experience any discomfort,
44:38distress, anxiety,
44:40Lightheadedness.
44:40Loss of consciousness,
44:43they remember they were verbal the
44:45entire time and what was really
44:47important that came out after was this
44:50subject told us that they had a history of,
44:52you know of fainting many times in the past,
44:55of syncope basically.
44:56And they've had maybe 30 to 50 lifetime
44:59events to the point that you know,
45:01they have adapted their lifestyle around it.
45:03And so this was not something that
45:06was revealed to us until until
45:08this and so that you know,
45:09that helped us under make sense of.
45:11Why this may have happened,
45:13but you know, that being said,
45:14it was still quite concerning and something
45:18to adapt all future protocols for.
45:21And obviously do very rigorous screening.
45:26So.
45:26Then you know in terms of desirability,
45:30in terms of the drug reinforcement
45:33aspect of of safety.
45:35With people basically if they asked how
45:37much they would pay for it from 0 to $100,
45:39they said about $2425 for both
45:42doses and in terms of how likely
45:45they were to use the drug if they
45:47could of from zero to 100,
45:49again about the similar in the 20s.
45:52So it didn't really seem like people enjoy,
45:56really enjoyed or took pleasure out
46:00of the the actual dose experience.
46:05This figure is this is the measure
46:08of tolerability as we assessed
46:11it 2 hours after the dose.
46:13Was given after they were completely
46:16back to baseline on the we'll see
46:19here it goes from zero to 100.
46:21We have each subjects scores for each
46:24of those we have the 1st 3 being
46:27the healthy controls and then the
46:29remaining seven are depressed subjects.
46:32And you see here at the end the
46:35aggregate means and so unsurprisingly
46:38we see the the tolerability for
46:42the higher dose was lower.
46:44The average approximately was 90
46:46out of 100 for tolerability of the
46:50low dose and then 70 out of 100
46:53for the high dose.
46:54But something that is also worth
46:56noting here is just kind of looking
46:59at the the variability in the
47:02tolerability for the low dose where
47:04we actually had a few subjects that
47:07rated the tolerability as low as 30,
47:10so which is sounds quite difficult
47:14to tolerate.
47:15But overall, you know,
47:1670 was what it came out
47:18to be.
47:21So again it it's clearly not something
47:24that you know is 1 size fits all
47:27the dose even the effects et cetera.
47:29OK and so Doctor Pittinger your point
47:32about the depression curious finding
47:34well it came up again here as we
47:38we measured both anxiety depression
47:40separately on top of everything else
47:43to assess for the acute impact on
47:46by the by DMT and so we we asked.
47:51About anxiety for both groups.
47:53The only depression in our
47:56depressed subjects.
47:57So in all ten we asked for anxiety
48:00and they did report elevated
48:02anxiety and the higher dose.
48:05But again notice that on on objectively
48:08speaking 50 out of 100, you know,
48:11that's not 100 being you know,
48:13the very anxious or the most anxious or
48:17more more anxious than usual is what the
48:20100 anchor stood for more anxious than usual?
48:23Much more.
48:24So they rated at 50 for the high dose and
48:27then similarly the wording for depression,
48:30we saw that you know the
48:33.3 dose subjects felt,
48:34you know,
48:35more more depressed during during
48:38the peak effects.
48:39So that and this this was statistically
48:43significant in terms of the effects.
48:46And so our main finding which
48:48again is curious given you know we
48:51see this increase in depression.
48:54Depression endorsement acutely.
48:55You know the day after,
48:58you know we do see reduction and
49:01So what we have here is a the graph
49:06showing the change in Hamilton
49:08depression scores starting at
49:11baseline and showing the trend for
49:14each subject being a different color.
49:17The black line represents the
49:19mean for the group.
49:21And so we we put,
49:23we show here one day after the low dose when
49:27we measured the Hamilton, the change was.
49:33Not too much.
49:34One day after the .3 dose,
49:37you know, we see,
49:38we see an interesting spread.
49:39We see some subjects report
49:42significant improvement,
49:44you know change of nine points
49:46on their Hamilton and then
49:49some may not maybe one point.
49:51So you know so some people seem to
49:56experience reduction of in their
49:59depression symptoms while some did not.
50:01This is also somewhat contrasting,
50:04or at least, you know,
50:05juxtaposed against silybin where you
50:07know you get a much more homogeneous,
50:11you know,
50:12positive response.
50:13I haven't seen these sort of
50:15spreads in terms of the depression
50:17scores when they looked at their
50:19acute antidepressant effects.
50:20Most subjects tend to respond,
50:22but that may be because of our small sample.
50:25Right, right, right. Of course.
50:26Sorry. And so our effect size is .75
50:30reported that is, is G and and Oh yeah,
50:34of course to mention that the the
50:37analysis we did was comparing the
50:40change from baseline to each test day.
50:43So the change between baseline and one day
50:46after the low dose was not significant,
50:49but the change between the day
50:52after the .3 dose and baseline was.
50:55And so that affects size was .75.
50:58We use hedges G that's calculated
51:01as the the change in the mean over
51:05the standard deviation pooled and
51:08so that is how we arrived at that.
51:10This is the table that just shows
51:13our means for the depression scores
51:16and the differences.
51:17So you see here our average is near 24
51:21baseline Hamilton score and you know.
51:25One day after.
51:26The low dose you know about point
51:30difference and one day after the
51:33higher dose about a 4.5 difference
51:36and so this this was statistically
51:38significant for what for what it for
51:41whatever it means which is limited
51:43by a variety of things which you know
51:45will comment on now and then kind of
51:49open up to you know thoughts and questions.
51:52So this study is the the
51:55first to demonstrate no.
51:57Safety, tolerability and DMT are most novel.
52:01Finding is that we did see a reduction,
52:05a significant reduction in depressive
52:09depressive symptomatology after
52:11subject received .3 milligram per
52:15kilogram of DMT intravenously.
52:17Of notes.
52:20Confounding this potential effect,
52:22you know,
52:22besides being open label and you
52:25know fixed dose etcetera,
52:26I mean there we cannot say that
52:29the .1 dose was non contributory
52:33to that potential effect, you know,
52:36as a carryover.
52:37And that's you know,
52:38again one of the other challenges with doing,
52:40you know multiple dose studies with
52:43the psychedelics because you know
52:45it's very difficult to separate,
52:47you know what what they're doing
52:49and how they.
52:50Interact or accumulatively act in general.
52:54So in the study we did not provide
52:57any psychotherapy.
52:58There was no special setting and so
53:01taken together I think this study
53:04raises a lot of interesting questions.
53:07Naturally the next step is you know
53:10we have the approval to proceed
53:12with our randomized clinical trial
53:15which is which is what our plan is.
53:18You know there are still very much
53:20questions about what is you know
53:22an optimal dose,
53:23you know in terms of reducing
53:26depression severity. What duration?
53:29And, you know,
53:31by having IV administration we
53:33do have the ability to, you know,
53:37exquisitely control the the level,
53:39the concentration and the duration
53:41of effects.
53:44And you know something that's intrinsically
53:47a challenge to these clinical trials is to
53:51how to control for expectancy given that
53:54you know many placebo effect etcetera.
53:57These things you know really do seem to
54:00impact you know the changes associated with
54:03with these with these drugs and there's no,
54:07there's no easy answers at the there was
54:09a site there was the first psychedelic
54:11NIH workshop in January and these
54:13were some of the things that.
54:15You know, they were also contemplating
54:17and kind of discussing and that,
54:19you know there really aren't any
54:22easy solutions but you know certainly
54:25there seems to be some interesting
54:27potential that needs to be explored.
54:30Something I'm very curious
54:31about to you know ask,
54:33you know the experts in the audience
54:36that have much more robotic experience
54:38with you know the depression
54:40treatments as you know where are
54:41people think how we should move from
54:43here in terms of study design if the.
54:45People have thoughts or recommendations.
54:47I'm I'm quite curious and trying to you
54:51know isolate and you know question,
54:53you know the five HT 2A component
54:56of you know the mechanism.
54:58You know to see if we can actually
55:00kind of prove that because it doesn't
55:02seem to be that study today really have
55:05discerned that you know very definitively.
55:10So, so yeah, I mean. Thoughts.
55:13Comments. Feel free to.
55:16Umm. London. Thank you.
55:21Thank you sheriff. This is really
55:23cool work and I do know how much.
55:24Well maybe, I probably don't.
55:26I probably still underestimate how much
55:27work goes into getting this off the
55:29ground and doing the first DMT study and.
55:31So it's really impressive to
55:33have gotten to this point.
55:35With the the controlled study,
55:36are you going to stick with the
55:38three group Saline point 1.3 or do
55:40these pilot results make you think
55:41that maybe you could go straight
55:43to a two group just say Linden .3?
55:47If between the two, more likely the latter,
55:50I think we're also really curious about
55:53the idea of potentially a constant
55:57infusion to maybe prolong the effects.
56:00Maybe a lower dose because the .3
56:03seems to be right as we saw kind
56:06of varied in its tolerability.
56:08It's you know, we we thought the .3 for
56:11depressed subjects seem to be less tolerable.
56:14I mean it will be really important
56:16to see differences if there are any
56:18between controls and depressed objects.
56:20I mean if there may be that
56:22wouldn't be too surprising.
56:23So I'm thinking we may need
56:25to adapt for things like that.
56:26But I think, you know we'll have to
56:29do more studies to get get at it.
56:32The other reason we are thinking about.
56:34Ways of doing a. Both this and
56:37constant confusion which would.
56:39Produce effects that are not
56:41as intense as the .3 milligram.
56:44Still is if psychotherapy is
56:47supposed to be a key component in in.
56:53In this approach. In half an hour.
56:58Of such intense effects.
56:59I don't think people can actually
57:01engage in meaningful psychotherapy,
57:03at least in our hands,
57:05what we saw at this point 3 milligram dose,
57:07but it's conceivable that at a lower dose.
57:11People might be able to
57:13engage in psychotherapy,
57:14again based on the if we make the assumption
57:17that psychotherapy is an essential
57:19ingredient to people getting better.
57:21I don't think that's been
57:23clearly demonstrated,
57:24though that is how most groups
57:27are actually approaching.
57:29Use of psychedelic drugs.
57:30So.
57:31So we are looking at ways of
57:33of extending the infusion but
57:35at but with the idea of having
57:39less intense effects.
57:42Makes sense?
57:44May I ask a question?
57:48Thank you so much Terry for the presentation.
57:50Speaking of dosing, I noticed that in
57:53the table that you had or it was a graph
57:57that about the effects of .1 and .3,
58:00a good number of individuals also
58:03reported intense experience with .1.
58:05I don't remember what was the number,
58:09but that was interesting to me
58:11that what was the intensity of
58:12the experience they had with .1.
58:16Yeah, yeah, they scored it as well.
58:2045 out of 100 right for
58:23the intensity for the .1.
58:26I I think what people?
58:31What what many subjects may be
58:34reporting is the initial rush.
58:38That you get when it's administered
58:40intravenously as a bolus that
58:42rushes like being launched,
58:44you know, into space,
58:46kind of that initial joke.
58:48And whereas with the .3 milligram dose,
58:52that effects may last a little
58:54longer and be more intense,
58:56at .1 it kind of tapers off pretty quickly.
58:59So does it mean that .1 also
59:02has some psychedelic effects?
59:04Like do they have altered
59:06perception and some type of like
59:08those feelings that people really
59:10experience with psychedelics?
59:13As you can see on this graph
59:15itself there was some, you know,
59:17obviously this is not placebo-controlled.
59:19But some subjects reported.
59:23You know, I felt unusual bodily sensations.
59:27I saw geometric pattern, so so for example,
59:30some of the effects that subjects
59:32reported on the .1 milligram doses.
59:34I don't know if you've seen
59:36the inside of the EEG boot,
59:37but it's it's covered with copper mesh.
59:41And it's the the the IT has a
59:44geometric pattern that's there,
59:46but it's almost you're oblivious to it
59:48most of the time because it's really trap.
59:50But what subjects reported was that
59:53geometric pattern came to the fore?
59:56And the lines start shimmering,
59:59uh, and assuming different colors.
01:00:01And they were previously unaware of
01:00:03those kinds of, but it wasn't disturbing.
01:00:05It was just that.
01:00:06Yeah, so those are the kinds of
01:00:08things that people with other subjects
01:00:10reported feeling like they were.
01:00:12The entire chair was kind of floating in,
01:00:15you know,
01:00:16those were the kinds of experiences.
01:00:20OK. Thank you.
01:00:24I was hoping to comment on the on the
01:00:28mention of the of of the worsening.
01:00:33Worsening depression measures
01:00:35acutely and the anhedonia.
01:00:38So in the in the headache studies that
01:00:41I've been doing in the in the same lab,
01:00:45a lot of patients get headaches.
01:00:49Not necessarily on the test day but
01:00:51maybe later on that evening or the
01:00:53following day and these are headache
01:00:55patients so they're they're getting
01:00:57headaches anyways but some people but
01:00:59we we let patients know that these
01:01:01drugs are known to cause headaches.
01:01:03So just you know be be ready for
01:01:05that and it's not official because
01:01:07I haven't done like this like the
01:01:09the analysis but it almost seemed
01:01:11like the patients who had more
01:01:13had worsening headaches did did
01:01:15better ultimately and I tell them
01:01:17you know in my non scientific way.
01:01:19So it's probably just shaking up
01:01:21the system to help turn it off.
01:01:22So it needs to generate the headache
01:01:25for it to to turn off the the system.
01:01:28So I tell patients don't worry about
01:01:30an extra headache or two because
01:01:31it actually probably means that
01:01:32it's it's going to work.
01:01:34So I probably shouldn't do that because
01:01:36then I guess their expectations
01:01:38out if they're having headaches.
01:01:41But so I actually wonder if there's
01:01:43something similar going on here where
01:01:45the system is being activated so
01:01:48that it can be it can be suppressed.
01:01:51And that's that's a non
01:01:53scientific hypothesis.
01:01:55No, it is aligned with, you know,
01:01:58the 1972 article from Doctor Francis
01:02:02Raymond who's who seems to again
01:02:05suggest as well that some of this
01:02:08intensity of this negative affective.
01:02:10Experience seems to be relevant,
01:02:13but you know, so I think it is
01:02:15very interesting, it's very,
01:02:17it's very interesting in terms of
01:02:19predicting response and hopefully
01:02:21that's something we're going to try and
01:02:23do moving forward with some level of.
01:02:25Record.
01:02:27Yeah. And and and another note is
01:02:30that in our headache studies we
01:02:33there is also no psychotherapy,
01:02:35we're not treating an underlying
01:02:38underlying depression or anxiety.
01:02:39So it's a similar the we the patients
01:02:42are are given the capsule and the nurses
01:02:45are there to check vitals and such,
01:02:48but we don't sit with the patients either.
01:02:49And this this is also supportive of
01:02:53decades of patients self medicating with
01:02:56these compounds in their living rooms.
01:02:58Without, without psychiatry or
01:03:01medical professionals there.
01:03:03So there certainly is there
01:03:06there separating out the,
01:03:08the effects of the drug versus the
01:03:10effect of the of of the setting and
01:03:13of any other procedures like like
01:03:15therapy have to be separated out.
01:03:19Agreed.
01:03:23I just, um, I guys, can you hear me? Yes,
01:03:27I had a quick question about the concept
01:03:30of individuals like seeing the grading
01:03:32on the wall even though ordinarily
01:03:34wouldn't wouldn't attend to it and that
01:03:36kind of being the underlying basis
01:03:37for some of the things they perceive.
01:03:39I'm wondering if you have any knowledge.
01:03:42And literature on attention
01:03:45work using these substances,
01:03:48because a lot of the theories
01:03:50of attention postulate that the
01:03:51attention spotlight is not actually an
01:03:53enhancement of attention on one thing,
01:03:55but it's the ability to inhibit
01:03:57things you're not attending to.
01:03:59And if that is kind of if these
01:04:02preferences are kind of impairing that
01:04:04normal capability and if has there been,
01:04:06you know, attempts to do like Posner
01:04:08cueing tasks or other attention based
01:04:10tasks while they're using these substances?
01:04:14So I'm not aware of anyone
01:04:15has actually done that.
01:04:16But I, I, I, I think I agree with
01:04:18your hypothesis that what these drugs
01:04:20may be doing is basically impairing
01:04:22our normal filtering capacity of
01:04:25filtering out irrelevant stimuli.
01:04:28And so the kinds of things that would
01:04:32support that hypothesis is the air
01:04:34conditioner that I was previously unaware of.
01:04:37I'm now aware of the noise it's making.
01:04:40Or I was previously unaware of
01:04:42the IV line dripping and now I can
01:04:44hear the dripping of the IV line.
01:04:46And and so that extends to
01:04:50also visual stimuli.
01:04:51I think I I saw a lot of that
01:04:53with some of the early ketamine
01:04:55studies where we were using much
01:04:57higher doses of ketamine that's
01:04:59current than what's currently used
01:05:01in the treatment of depression.
01:05:03And we would often notice that
01:05:06subjects would would notice seemingly
01:05:08irrelevant stimuli in the environment
01:05:11that they were previously unaware of.
01:05:14So you may be on onto something
01:05:16and I'm sure it can be tested.
01:05:18In this kind in these kinds
01:05:20of laboratory experiments,
01:05:21yeah. And I'm a quick adding
01:05:23adding to that they experienced.
01:05:25So I was curious in this case.
01:05:27Part of that would be if they're more
01:05:29aware of like they're interoceptive
01:05:30processes like body position or met by
01:05:32explain the body sensations they report.
01:05:34But in that case you would
01:05:36think that they would.
01:05:37Report on like the sudden versus event.
01:05:39They would report on feeling odd
01:05:41if they had low blood pressure or,
01:05:43you know, feeling. More tense.
01:05:45If they have the physical,
01:05:47you know the heartbeat going up.
01:05:48And maybe that could explain the
01:05:5030 minute sudden anxiety and the
01:05:5230 minute sudden ledonia if they're
01:05:54like more aware of potentially
01:05:56negative body sensations.
01:05:57But that's
01:05:57just a thought.
01:05:59I think that's a really
01:06:00good thought, yeah. Yeah. I
01:06:05mean we clearly saw some subjects who were
01:06:09had significant anticipatory anxiety.
01:06:11Hmm, which which really influenced the.
01:06:16Their experience of the first dose,
01:06:20but then they were able to get over
01:06:22it and and come back for the 2nd dose.
01:06:27Yeah, thanks. This is fascinating.
01:06:30Yeah. Remind me how long
01:06:32was the the the gap between the 1st and
01:06:342nd dose? Was that fixed or variable?
01:06:37It was variable? It was,
01:06:38I think it was three to seven day
01:06:41window closer to three days. Thanks.
01:06:49OK.
01:06:53OK. Well, thank you so
01:06:55much both Sharif and Cyril.
01:06:57This is exciting and exciting new area.
01:07:00And serial, the point you make
01:07:01about you know the the rapid
01:07:03action and short half life mean
01:07:05that you can adjust the timing.
01:07:06You know the if you can adjust both
01:07:08the intensity and the duration,
01:07:09that opens the door to a lot of
01:07:11really interesting manipulations.
01:07:12This is exciting.
01:07:14Thank you. Alright,
01:07:17thank you all for coming.
01:07:18We'll have another meeting
01:07:19at the seminar in April.
01:07:20I'm not sure who who
01:07:21will line up for that.
01:07:23I'm open to suggestions.
01:07:26It's a great doctor.
01:07:27Schindler has a number of ongoing studies.
01:07:30Yes, it was syben and and you know.
01:07:33Headache disorders. Yep.
01:07:35And then I think Patrick
01:07:37has Patrick and Jordan.
01:07:40We just looked over some of our.
01:07:43Our EEG findings. Typing.
01:07:47And one of them could
01:07:49present to wonderful. OK.
01:07:52Thank you. I'll be in touch.
01:07:55All right. Take care, everyone.
01:07:57Thanks again. Have a good weekend.