YCSCAN2 February 2025 Webinar

Transcript

• 00:29Good afternoon, everyone. I hope
• 00:30you can hear me.
• 00:34Okay. So
• 00:36this is our second
• 00:39webinar,
• 00:40hosted by the Yale Center
• 00:41for the Science of Cannabis
• 00:43and Cannabinoids.
• 00:45Thank you all for for
• 00:46joining.
• 00:48I'd like to commemorate this
• 00:49month's webinar,
• 00:51to our late,
• 00:53colleague Patrick Skosnick,
• 00:55who passed away,
• 00:57about a year almost to
• 00:58the date.
• 01:00Patrick was our colleague for
• 01:02almost fifteen years.
• 01:04And for most of his
• 01:05academic life,
• 01:07he spent,
• 01:09investigating
• 01:10the acute and chronic effects
• 01:12of cannabis
• 01:13in humans
• 01:15using a number of complementary
• 01:17methodologies,
• 01:18including EEG,
• 01:20polysomnography,
• 01:21eye blink conditioning,
• 01:23positron emission tomography,
• 01:25fMRI,
• 01:26and MRI.
• 01:27He passed away,
• 01:29at the tender age of
• 01:30fifty after a tragic and
• 01:32freak accident.
• 01:35At the at this time
• 01:36last year, he had just
• 01:37started working
• 01:39at the at Northeastern University,
• 01:41as a professor,
• 01:44and, he maintained an adjunct
• 01:46appointment here at, at Yale.
• 01:48He's gonna be missed by
• 01:49many of us,
• 01:50and I'm proposing that every
• 01:52February,
• 01:53we will,
• 01:54commemorate his,
• 01:56his contributions,
• 01:58by dedicating this webinar to
• 02:00him.
• 02:01And I couldn't think of
• 02:02a better way,
• 02:03to commemorate him than with
• 02:05today's speaker,
• 02:07Romina Mizrahi.
• 02:09Romina is a professor of
• 02:11psychiatry at McGill University.
• 02:14She is the director of
• 02:15the clinical and translational
• 02:17sciences lab.
• 02:19She has done some wonderful
• 02:20work over the years
• 02:22using,
• 02:22positron emission tomography,
• 02:25to understand,
• 02:28clinically high risk psychosis,
• 02:30psychosis in general,
• 02:32and the relationship between cannabis,
• 02:34and psychosis.
• 02:36Romina's work has been published
• 02:37in the
• 02:38in top tier journals, including
• 02:40JAMA Psychiatry, Molecular Psychiatry, American
• 02:43Journal, and so on and
• 02:44so forth.
• 02:46Romina has been quite active
• 02:48also
• 02:48in engaging
• 02:50the public about
• 02:52about cannabis. She's, in fact,
• 02:54served as a expert witness,
• 02:57to the Canadian House of
• 02:58Commons,
• 02:59in regard to her expertise
• 03:01on cannabis. So without further
• 03:03ado,
• 03:05Romina,
• 03:06it's yours.
• 03:08Thank you for thank you
• 03:09for coming and speaking with
• 03:11us.
• 03:12Thank you very much. It's
• 03:14a pleasure to be here.
• 03:16I want to mention this,
• 03:18leak bomb is not real.
• 03:19It's, the com it's computer
• 03:20generated. It's my first time.
• 03:22I think it looks okay.
• 03:24This is the beginning of
• 03:25a world where
• 03:27part of us will be
• 03:28real and part of us
• 03:29will will not. So,
• 03:32so I hope that you
• 03:33enjoy,
• 03:34the talk I will be
• 03:35presenting today.
• 03:37I'm not sure how I,
• 03:39I share let's see. I
• 03:40I was I need to
• 03:41send a request to share
• 03:43my screen.
• 03:45No. I think you should
• 03:46be able
• 03:47I think Wendy set it
• 03:48up so that you can
• 03:49share a screen. You'll be
• 03:51able to share.
• 03:52Alright. Okay.
• 03:54So let's see. I'll open
• 03:56this here, and let's see
• 03:58whether that works.
• 04:19Okay. So,
• 04:21does it work now?
• 04:26Not yet.
• 04:28Okay.
• 04:31I do see it. I,
• 04:34Yep. Now we can.
• 04:36Okay. So let me just,
• 04:38You wanna go to tab.
• 04:39Yeah. Presenting mode. Presenter mode.
• 04:41Yeah. Yeah. Here. Okay. Alright.
• 04:43So, thank you very much
• 04:44for the intro. I'm going
• 04:45to start over.
• 04:48I'm going to be talking
• 04:49I selected the studies
• 04:51looking at, cannabis effects on
• 04:53microglia,
• 04:54astroglia,
• 04:55and,
• 04:57sorry, and,
• 04:59synaptic density.
• 05:03So I have really nothing
• 05:04to disclose other than I'm
• 05:06just presenting work from our
• 05:08own lab, but this is,
• 05:09of course, in the context
• 05:10of, great work from other
• 05:12labs
• 05:13around the world.
• 05:17There are three studies. All
• 05:18of them are published. And
• 05:19there's a fourth study also
• 05:20I will be presenting,
• 05:22which is Da Silva,
• 05:24looking at, c four a
• 05:26and,
• 05:27the effects on
• 05:29microglia activation, which I did
• 05:31not list here.
• 05:33So, microglia is critical for
• 05:35the immune response.
• 05:37It monitors,
• 05:38brain pathogens and and, it's
• 05:40critical for,
• 05:42monitoring,
• 05:43damage, brain damage, phagocytosis,
• 05:46debris, pathogens.
• 05:47It's involved in release of
• 05:49cytokines and regulates immune response.
• 05:52It's critically involved in synaptic
• 05:53pruning.
• 05:54It it eliminates weak and
• 05:57unnecessary synapses during development,
• 05:59maintains synaptic plasticity and circuit
• 06:02refinement,
• 06:03as well as it's involved
• 06:04in neuroprotection.
• 06:06And that means it's involved
• 06:08in programmed cell death and
• 06:09modulates inflammatory response to prevent
• 06:12excessive damage from stress or
• 06:14injury.
• 06:15Now
• 06:16there are several ways to,
• 06:18quantify
• 06:19microglia.
• 06:20And in this case, I'm
• 06:21going to be presenting the
• 06:23line of work we've done
• 06:24looking at translocator
• 06:25protein
• 06:26or TSPO.
• 06:29More recently, we started to
• 06:31look into astroglia as well.
• 06:33And, I like this slide
• 06:35because it really shows that
• 06:36while microglia and astroglia explode
• 06:39I'm sorry. I'm interrupting. I
• 06:40don't we don't see your
• 06:41slides.
• 06:43No?
• 06:44No. I'm sorry. And in
• 06:45the chat, it seems that
• 06:46others also cannot see it.
• 06:48Oh,
• 06:49okay. That's odd. Thanks for
• 06:51letting me know.
• 06:53I can see them. So,
• 06:56maybe do you want
• 06:57to reshare your screen?
• 06:59Sure.
• 07:00That's odd. Never happened. I'd
• 07:02have
• 07:03some people share an application,
• 07:05entire screen.
• 07:10We can see them now.
• 07:13Great.
• 07:14So, Romina, you can continue
• 07:16then. It looks like you
• 07:17you can.
• 07:18Alright. So I I briefly
• 07:20presented the work, or the
• 07:22summary of microglia
• 07:24does. I'm sure everyone knows.
• 07:25It can be quantified,
• 07:27using,
• 07:28PET radioligands targeting TSPO.
• 07:30And I was saying that
• 07:31astroglia has different functions in
• 07:33the brain.
• 07:35It's involved in a homeostasis.
• 07:38It balances extracellular
• 07:39iron, potassium, and calcium, regulates
• 07:42pH. It's involved in six-zero
• 07:44architecture,
• 07:45including neuroglia vascular interfaces, so
• 07:47it controls the blood brain
• 07:49barrier.
• 07:50It's also involved in metabolic
• 07:52support, supplies nutrients
• 07:54to neurons such as glucose
• 07:55and lactate, as well as
• 07:57regulating,
• 07:58energy metabolism.
• 07:59It creates it's involved in
• 08:00waste clearance, including, reactive oxygen
• 08:03species.
• 08:05It's also involved in neurotransmitter
• 08:06levels via clearance,
• 08:08and that's via,
• 08:09EAAT
• 08:10and, dopamine transporters, and that
• 08:12includes FEMA two as well
• 08:14as MAOB.
• 08:15And it's also involved in
• 08:17synaptic function,
• 08:18such as,
• 08:20its role involving
• 08:22strengthening,
• 08:23neural connectivity through myelination.
• 08:27Using PET radioligands, we can
• 08:29actually
• 08:31quantify astroglia. We believe we
• 08:33can
• 08:34quantify microglia,
• 08:36using a specific radioligand for
• 08:39MAOB or monooxidase
• 08:40b.
• 08:42So
• 08:43first, the studies on TSPO
• 08:45are looking at microglia,
• 08:46specifically
• 08:47microglia
• 08:48density
• 08:49in long term cannabis users.
• 08:51There are several reasons one
• 08:53why one would like to
• 08:55explore or investigate
• 08:56immune response and cannabis.
• 08:59Regular cannabis use has been
• 09:00associated with long long term
• 09:02changes in the brain, particularly,
• 09:05this is critical given its
• 09:06legalization across the world.
• 09:09It's also critical in the
• 09:10modulation of inflammatory
• 09:12responses.
• 09:14Preclinical studies have reported,
• 09:16anti inflammatory as well as
• 09:17immunosuppressant
• 09:18effects of cannabinoids
• 09:20by inhibiting microglial activation, inhibiting
• 09:23the release of ROS, decreasing
• 09:25proinflammatory cytokine secretion, and increasing
• 09:27anti inflammatory cytokine release from
• 09:29microglia.
• 09:31Now THC and cannabidiol
• 09:33are also currently being investigated
• 09:35as potential
• 09:36therapeutic targets,
• 09:38agents for several inflammatory
• 09:40and immune diseases, including schizophrenia
• 09:43and CHR participants.
• 09:46So based on this, back
• 09:48in the day, a few
• 09:49years back,
• 09:50we we decided to investigate,
• 09:53neuroimmune activation or TSPO in
• 09:55long term cannabis users. And
• 09:57here, we included twenty seven
• 09:59healthy controls
• 10:00and forty, sorry, and twenty
• 10:02four cannabis users.
• 10:05These were young people in
• 10:06the very young twenty three
• 10:08years old as a mini
• 10:09age
• 10:10who had started to use
• 10:12cannabis at the age of
• 10:13sixteen more or less, some
• 10:15some of them younger.
• 10:16This is the estimated lifetime
• 10:18cannabis use. And of these,
• 10:20twenty four participants, fifteen,
• 10:23had a cannabis use disorder
• 10:25diagnosis,
• 10:26and seven were using tobacco.
• 10:29And so we, showed,
• 10:31contrary to our hypothesis,
• 10:34higher TSPO,
• 10:36in long term cannabis users
• 10:37compared to controls.
• 10:39Here on the y axis,
• 10:40you have f eighteen FIPA,
• 10:42VTs.
• 10:43The higher the VT, the
• 10:45higher the microglia density.
• 10:47And in the x axis,
• 10:49you have the different brain
• 10:50regions, DLPFC,
• 10:52MPFC, temporal, ACC,
• 10:54cerebellum, and gray matter. And
• 10:56this is elevated across the
• 10:58board.
• 10:58And this is even higher
• 11:00when looking into cannabis use
• 11:02disorder individuals,
• 11:04which you can see here.
• 11:07To me, it was also
• 11:09interested,
• 11:10that higher TSPO was associated
• 11:12with higher behavioral measures
• 11:14of both stress and anxiety
• 11:16scores
• 11:17and which are critical for,
• 11:20the role of the endocannabinoid
• 11:22system as everyone knows. I'm
• 11:23not presenting any of that
• 11:24work today, but to me,
• 11:26that was important to see,
• 11:28as well as higher circulating
• 11:30CRP levels, per in the
• 11:31periphery for cannabis users. As
• 11:34you can see here, VT
• 11:35values, chronic stress measures.
• 11:38And in the x axis
• 11:39here, you have,
• 11:41the high sensitivity CRP levels,
• 11:43showing a direct relationship in
• 11:45both cases.
• 11:48So
• 11:48this is what we found
• 11:49for, for
• 11:52TSPO. And,
• 11:53then,
• 11:54we had
• 11:55somewhat preliminary data at the
• 11:57time,
• 11:58looking at monox monoxidase b
• 12:00or MAOB,
• 12:02which you may know is
• 12:03confined to the outer mitochondria,
• 12:05of astrocytes
• 12:06as well as as well
• 12:08as serotoninergic
• 12:09neurons and cell bodies.
• 12:11It catalyzes the oxidative
• 12:13deamination of monamine neurotransmitters,
• 12:15including dopamine, norepinephrine.
• 12:19Maub is also critically engaged
• 12:20in hydrogen peroxins synthesis
• 12:23that's involved in mitochondrial dysfunction
• 12:25and oxidative stress,
• 12:27as I've mentioned previously. And
• 12:29MAOB expression is significantly
• 12:31increased in reactive astrocytes, both
• 12:33in hippocampus and frontal cortex
• 12:35in Alzheimer's disease,
• 12:37as well as MAOB inhibitors
• 12:38can reduce astrogliosis.
• 12:41GFAP, a sensitive and reliable
• 12:43marker of astrogliosis,
• 12:45demonstrates
• 12:46very high correlation with, with
• 12:48MAOB.
• 12:49This is a study that
• 12:50we did back in Toronto.
• 12:52Carbon eleven c, SL twenty
• 12:55five one one eight eight,
• 12:57it's a radioligand we used
• 12:58back in Toronto and now
• 12:59we use here in in
• 13:01in McGill.
• 13:02It's a valid radioligand to
• 13:04quantify MAOB,
• 13:05increase MAOB,
• 13:07selectivity and sensitivity as compared
• 13:09to previous MAOB radioligands.
• 13:12This is a third generation,
• 13:13MAOB radioligand as compared to
• 13:15the previous two generations.
• 13:17Has very good reproducibility
• 13:20and identifiability.
• 13:22And MaOB can be used
• 13:23as a reliable reactive astroglia
• 13:25marker supported by significant increase
• 13:28in MAOB levels
• 13:30in out opposite striatum of
• 13:31patients with multiple system atrophy.
• 13:33This is characterized by marked
• 13:35increase in astrobleiosis.
• 13:37We also showed very high
• 13:39correlation between regional MAOB,
• 13:41total volume of distribution
• 13:43for SL twenty five,
• 13:45and MAOB density
• 13:47in autopsied brains.
• 13:50So
• 13:51at the time, it was
• 13:52really unclear what the evidence
• 13:54was for MAOB,
• 13:56and in particular in psychosis.
• 13:57And you'll see that this
• 13:58is a preliminary study. It's
• 14:00a combination of,
• 14:03participants
• 14:04who and which I will
• 14:05show you in a few
• 14:06minutes.
• 14:07Participants who had different diagnosis
• 14:10and, different levels of cannabis
• 14:12use, very low in this
• 14:14case. And I'm going to
• 14:15tell you a bit about
• 14:16the ongoing studies study which
• 14:18we are,
• 14:19close to, to an end
• 14:20here, in in in Montreal.
• 14:23So in terms of psychosis,
• 14:26postmortem studies, peripheral studies, and
• 14:28preclinical studies show complete variable
• 14:30results for MAOB,
• 14:32in in either animal models
• 14:34or postmortem,
• 14:36brain tissue of patients with
• 14:38schizophrenia.
• 14:40It is consistent,
• 14:42however, that in regular cigarette
• 14:44smokers, there is both a
• 14:46decrease in MAOB,
• 14:47both postmortem,
• 14:48many times,
• 14:50replicated,
• 14:51periphery,
• 14:52as well as many pet
• 14:53studies,
• 14:55going back all the way
• 14:56two thousand to two thousand
• 14:57and five.
• 14:58Now in terms of cannabis,
• 15:00it's really or it was
• 15:02it is really unclear.
• 15:04There were two studies we
• 15:05could find at the at
• 15:06the time only.
• 15:08One showing MAOB gene expression,
• 15:11being lower,
• 15:12after acute low dose of
• 15:14cannabis exposure,
• 15:16and one GVAP study expression,
• 15:19showing preclinically
• 15:20reductions
• 15:21as well.
• 15:23As I've mentioned,
• 15:24TSPO is lower in psychosis
• 15:27as well as in cannabis
• 15:28use.
• 15:29However, it's elevated in cannabis
• 15:31use suggesting that, astroglia
• 15:33may may be lower
• 15:35or higher. At the time,
• 15:36actually, we were not sure.
• 15:38We hypo we hypothesized
• 15:40lower based on our findings,
• 15:42in schizophrenia.
• 15:44No in vivo study investigated
• 15:46MAOB in the brain of
• 15:47psychosis pain patients or cannabis
• 15:49users.
• 15:51So at the time, we
• 15:53wanted to examine the effects
• 15:55of a study group. And
• 15:56in this case, as I've
• 15:57mentioned, we included healthy controls,
• 15:59those at clinical high risk
• 16:01for psychosis, as well as
• 16:02first episode psychosis patients.
• 16:05We use a center SL
• 16:06twenty five, total distribution volume
• 16:09to estimate,
• 16:10astroglia,
• 16:11function
• 16:12in this case.
• 16:13And, we examine the effect
• 16:15of cannabis,
• 16:16and we look at the
• 16:17the interaction,
• 16:19between both cannabis and group.
• 16:22This was a study which
• 16:23was meant to be a
• 16:24really large study,
• 16:26but that's when I moved
• 16:27from Toronto to Montreal. So,
• 16:29what I'm presenting here, which
• 16:31was published in Molecular Psychiatry,
• 16:33is all the samples that
• 16:34we have available to us,
• 16:36before,
• 16:37changing, location.
• 16:39So for this study,
• 16:41as we've done over the
• 16:42last few decades,
• 16:44first episode psychosis patients were
• 16:46diagnosed with the DSM five.
• 16:49Clinical high risk individuals with
• 16:51the seps. Kanavis users were
• 16:53carefully,
• 16:54studied, and,
• 16:56the presence of cannabis was
• 16:58quantified objectively with urine drug
• 17:00screens.
• 17:01We have the very deep,
• 17:03drug history questionnaires with record
• 17:05tobacco use. It's a small
• 17:07sample as you can see
• 17:08here. I'm going to show
• 17:09you a little bit more
• 17:10about the sample in the
• 17:11next slide.
• 17:12We obtained MRI,
• 17:15scan for each participant. We
• 17:17scanned participants in the HRT
• 17:19for ninety minutes.
• 17:20We obtained arterial blood sample
• 17:22with the automatic blood sampling
• 17:24system as well as manual
• 17:26samples,
• 17:27and we obtained, we used,
• 17:29the two tissue compartment model,
• 17:31and,
• 17:32the outcome measure was total
• 17:34volume of distribution or v
• 17:36t.
• 17:38As I've mentioned, the sample
• 17:39is not ideal,
• 17:41based on the move, but
• 17:42I just want to highlight
• 17:43a few things.
• 17:46It's relatively
• 17:47young cohort
• 17:48and,
• 17:50here you can see there
• 17:52were no tobacco smokers in
• 17:54the healthy controls. There was
• 17:55one tobacco smoker in the
• 17:57clinical high risk group and
• 17:59three in the first episode
• 18:01group.
• 18:02In terms of cannabis,
• 18:04two healthy controls
• 18:05were,
• 18:06cannabis users,
• 18:08two in the clinical high
• 18:10risk group, as well as
• 18:11one in the first, episode
• 18:13group.
• 18:14And then there were, of
• 18:15course, as you would expect,
• 18:17difference in differences in antipsychotic
• 18:19exposure,
• 18:20no difference in PET parameters,
• 18:22and these are the differences,
• 18:24in terms of,
• 18:26psychopathology
• 18:28for for the three groups.
• 18:31And what you can see
• 18:33is that there are significantly
• 18:34significant differences with, within, between
• 18:37groups.
• 18:40In the y axis, you
• 18:41see SL twenty five or
• 18:43a marker of astroglia function.
• 18:45In the top panel, you
• 18:47can see the striatum. In
• 18:48the lower panel, you can
• 18:50see cortical regions.
• 18:52It's divided, and you'll see
• 18:53the y axis. It's higher
• 18:55in the,
• 18:56estriatal regions,
• 18:57versus in the cortical regions.
• 18:59It's divided so as to
• 19:00make sure,
• 19:02you can see them clearly.
• 19:04And there is a very,
• 19:06to us, in bed at
• 19:07least, a very big effect
• 19:08size as you can see
• 19:10here,
• 19:11even with this very, very
• 19:13small sample.
• 19:15Of course, there is an
• 19:16effect of tobacco, as you
• 19:18can see here, as well
• 19:19as an effect of cannabis.
• 19:21So it's both significant for
• 19:23three, both it's not both.
• 19:25Significant for group for cannabis
• 19:27and tobacco.
• 19:29And this is present both
• 19:31in estriotic regions as well
• 19:33as in cortical regions.
• 19:36Just trying to summarize what
• 19:38we,
• 19:39have seen,
• 19:40the effects of cannabis
• 19:42or the very small sample
• 19:44that we have of cannabis
• 19:45users.
• 19:46And I I wanna show
• 19:47you these effect sizes because
• 19:49they're big,
• 19:50for us.
• 19:52You may remember there were
• 19:53very, very few people in
• 19:55this cohort, but there seems
• 19:56no effect in the healthy
• 19:58controls,
• 19:59of cannabis use on SL
• 20:01twenty five,
• 20:03where there seems to be
• 20:04an effect on both CHR
• 20:06as in the first episode
• 20:07group.
• 20:09And these group differences are
• 20:10more pronounced
• 20:12in a striatal regions
• 20:13than cortical regions as well
• 20:15as these group differences.
• 20:18As sorry. These group differences
• 20:20are more in a striatal
• 20:21versus cortical regions as you
• 20:22can see here. Core these
• 20:24are the striatal regions and
• 20:25these are the cortical regions,
• 20:26and these are the group
• 20:28differences here. And here, you
• 20:30can see the effects of
• 20:31cannabis
• 20:33on MAOB on MAOB,
• 20:36or SL twenty five in
• 20:38estriatal
• 20:39regions versus,
• 20:40sorry, in cortical regions versus
• 20:42estriatal region regions. Again, showing,
• 20:46a bigger effect,
• 20:47in estriatum versus cortex.
• 20:50And I would like you
• 20:51to remember this, because,
• 20:53we've seen kind of the
• 20:55opposite,
• 20:56in the later studies that
• 20:57we have, and I'm really
• 20:59looking forward to discussing those,
• 21:01with all of you.
• 21:03So remember this because we've
• 21:04been looking into this more
• 21:06recently only.
• 21:08So,
• 21:09we found altered m a
• 21:10MAOB and astroglia marker in
• 21:13early psychosis with cannabis use.
• 21:16And
• 21:17this kind of summarizes this,
• 21:19heterogene
• 21:20heterogeneous
• 21:21small sample. We shall reduce
• 21:24MAOB concentration in cannabis use
• 21:26in CHR on Fab patients,
• 21:28reduce MAOB,
• 21:29which is which
• 21:31replicates in many ways the
• 21:33estriatal dopamine elevation in psychosis.
• 21:36This reduced MAOB supports involvement
• 21:38of astrocytes in glutamatergic
• 21:40processes,
• 21:41including biosynthesis, reuptake, and release,
• 21:44and we can discuss that
• 21:45as well, as well as
• 21:46reduced MAOB,
• 21:47supporting the involvement of astrocytes
• 21:50in energy metabolism
• 21:51alterations
• 21:52also observed in psychosis and
• 21:54I would say,
• 21:56perhaps in cannabis use.
• 21:59So just,
• 22:00very briefly,
• 22:01the complement
• 22:03proteins are involved in mediating
• 22:05microglial
• 22:06engulfment of synaptic material.
• 22:09So it is possible that
• 22:10genetically predicted brain c four
• 22:12a,
• 22:13relates to TSPO,
• 22:14and brain morphology. I'm going
• 22:16to be talking about the
• 22:17brain TSPO only today.
• 22:19So here, in this,
• 22:21study, we looked at, the
• 22:23association between genetically predicted brain
• 22:26c four a,
• 22:27as
• 22:28as well as,
• 22:30TSPO and cannabis use. And
• 22:32based on all the literature
• 22:34up until that until that
• 22:35point,
• 22:36we hypothesize
• 22:37that,
• 22:38c four a, genetically predicted
• 22:40c four a, which is
• 22:41not brain c four a,
• 22:42it's genetically predicted c four
• 22:44a,
• 22:45will be associated with TSPO
• 22:47and, brain morphology,
• 22:49and we also hypothesize that
• 22:51higher c four a in
• 22:52patient populations.
• 22:54And this is,
• 22:56the sample. It's a pretty
• 22:58big sample for a two
• 23:00hour arterial PET scan, with
• 23:02FIFA. As you can see,
• 23:04it includes
• 23:05forty six healthy controls, forty
• 23:07three clinical high risk individuals,
• 23:10and forty
• 23:11participants with,
• 23:13psychotic disorders.
• 23:15These are the mean ages,
• 23:17and and the sex, ratios.
• 23:21And you can see here
• 23:22of within these cohorts,
• 23:25nine of the forty six
• 23:26were using, tobacco and twenty
• 23:29seven were cannabis users.
• 23:31Here in for the clinical
• 23:33high risk, from this,
• 23:35forty three,
• 23:37eleven were also, using tobacco,
• 23:39and eight were using cannabis.
• 23:42And here,
• 23:43sixteen
• 23:44of the forty first episode
• 23:46psychotic patients were,
• 23:48using tobacco and two,
• 23:51cannabis.
• 23:54So, again, we found the
• 23:56opposite of what we hypothesized.
• 23:57We thought we will find
• 23:59an increase in,
• 24:01schizophrenia patients,
• 24:02of of genetically predicted,
• 24:05c four a,
• 24:07brain c four a, and,
• 24:09we we found no difference
• 24:10between healthy controls and psychotic
• 24:12patients.
• 24:13These are first episode of
• 24:14psychotic French patients. Not all
• 24:16of them have schizophrenia.
• 24:17And in the clinical high
• 24:19risk group, we found a
• 24:20reduction, a significant reduction,
• 24:23and not an increase.
• 24:25However, what we did find
• 24:27is that genetically predicted brain
• 24:29c four a expression was
• 24:30significantly
• 24:31associated across the board,
• 24:33with c four a. So
• 24:35here on all these different
• 24:37brain regions,
• 24:38you've seen the y axis,
• 24:39f eighteen, and
• 24:41on the x axis, you
• 24:43have the genetically predict brain
• 24:44c four a expression that
• 24:46came from,
• 24:47the work from the Broad
• 24:48Institute. We calculated,
• 24:50following their,
• 24:52their
• 24:53their advice.
• 24:55And we report a significant
• 24:57effect of group, a significant
• 25:00effect of sex,
• 25:01and a significant effect of
• 25:03cannabis use. So in other
• 25:05words, there was a significant
• 25:07in other words, males and
• 25:09cannabis users had higher TSPO
• 25:11levels, and there was no
• 25:12difference as I showed you
• 25:13before,
• 25:14between,
• 25:15clinical groups.
• 25:20So with this, we moved
• 25:21into the studies,
• 25:23to look into,
• 25:25SYNBEST one, or,
• 25:28SV two a.
• 25:30And, of course, all of
• 25:31you are well,
• 25:34they know this very well.
• 25:36Synaptic vesicle glycoprotein
• 25:38two a or c s
• 25:39v two a can be
• 25:40used can be used to
• 25:42quantify synaptic density.
• 25:44It's located in synaptic vesicles
• 25:47and,
• 25:48really, it's important in vesicular
• 25:50processes.
• 25:51It's has an obit ovidis
• 25:54distribution,
• 25:57in the brain and,
• 25:59quite importantly,
• 26:01significant correlation
• 26:02found in many studies,
• 26:04with synaptic markers.
• 26:06It highly correlates,
• 26:08with the gold standard synaptophysin
• 26:11in postmortem samples, and this
• 26:12was shown previously.
• 26:14So our study,
• 26:16was done in the context
• 26:18of four previous studies.
• 26:20The first two studies,
• 26:22included,
• 26:23a group of, patients,
• 26:25with schizophrenia,
• 26:27and they were scanned with
• 26:29UCV J, carbon eleven UCV
• 26:31J. They have a longer
• 26:32duration of illness of about
• 26:34seventeen years, both studies, and
• 26:36both studies as well
• 26:38reported a reduction in SV
• 26:40two a, using the outcome
• 26:42measure of, total distribution volume,
• 26:46in different brain regions.
• 26:49There were two studies after
• 26:50that in younger cohorts.
• 26:52The first is the study
• 26:53by Yoon,
• 26:55only includes
• 26:56nine,
• 26:57participants
• 26:58with only three years of,
• 27:00duration of illness,
• 27:02and very odd,
• 27:05ROI,
• 27:06selection.
• 27:07And they report a significant
• 27:09reduction in s v two
• 27:10a,
• 27:12BP,
• 27:13ND in this case.
• 27:15And the,
• 27:17sec the the fourth study,
• 27:18was later published with a
• 27:20larger sample also using carbon
• 27:22eleven UCBJ
• 27:24at smaller or shorter duration
• 27:26of illness,
• 27:27wider
• 27:30regions of interest of ROIs.
• 27:32And in this case, there's
• 27:34no significant difference,
• 27:36between,
• 27:37first episodes of psychotics psychotic
• 27:38patients and controls.
• 27:42And in this case, they
• 27:42use both SB to a,
• 27:45the total volume of distribution
• 27:46or VT as well as
• 27:47DVR as outcome
• 27:50measure.
• 27:51So for us,
• 27:52what we wanted to do
• 27:53at the time,
• 27:55is to answer these three
• 27:56questions.
• 27:57Is synaptic density reduced in
• 27:59first episode and in clinical
• 28:01high risk? And this second
• 28:02part was done for the
• 28:03first time.
• 28:04Is synaptic density related to
• 28:06environmental factors
• 28:07or documented
• 28:09environmental factors such as cannabis
• 28:11use, both in Fab and
• 28:12CHR?
• 28:14Does synaptic density
• 28:15relate to grain matter microstructure?
• 28:18And I'm not going to
• 28:19be presenting that, But for
• 28:20that, we used, a special
• 28:22acquisitions called NODI.
• 28:27So
• 28:28for image acquisition,
• 28:29we acquired,
• 28:32a ninety minute Synvest,
• 28:34t one
• 28:36scan.
• 28:37We,
• 28:38used the simplified reference tissue
• 28:40model. In this case, we
• 28:41used highly selected
• 28:43white matter,
• 28:45which is,
• 28:46was masked across the whole
• 28:48brain and then look localized,
• 28:50very neatly,
• 28:51in the center of Simul
• 28:52Valley.
• 28:53And, we used Cymbes one
• 28:56binding potential
• 28:58b bp and d. We
• 28:59would have used BT, but
• 29:00at the time, we started
• 29:01this study right when we
• 29:03moved. We did not have
• 29:04the, radio, metabolite lab at
• 29:07the time or the equipment.
• 29:09So we decided to start
• 29:10start this study during the
• 29:11pandemic anyways,
• 29:14and, this is what I'm
• 29:15going to be showing you
• 29:16to do to to you
• 29:17today.
• 29:18We also acquired a naughty,
• 29:21acquisition, which is a special
• 29:22acquisition,
• 29:23and this was presented in
• 29:25ACMB here in December and
• 29:27it's also in the paper.
• 29:29And we also acquire MRI
• 29:31for each participant, and we
• 29:32use this to select the
• 29:34regions of interest in the
• 29:35PET scans as we have
• 29:36done over many, many
• 29:38couple of decades.
• 29:41So we wanted to investigate
• 29:42whether synaptic density is reduced
• 29:45in FEP and CHR,
• 29:46whether there was a relationship
• 29:48with, the severity of psychotic
• 29:50symptoms.
• 29:51We wanted to investigate the
• 29:52role of cannabis use, and
• 29:53for this was the first
• 29:54time as compared to the
• 29:56previous four studies.
• 29:57And, we wanted to look
• 29:58at,
• 29:59gray matter microstructure as I've
• 30:01mentioned previously.
• 30:03So this is the sample.
• 30:04At the time, we are
• 30:06still connecting,
• 30:07individuals under this protocol. Specifically,
• 30:10we are interested in the
• 30:11longitudinal
• 30:12follow-up.
• 30:13And so, this study is
• 30:15still now ongoing, and this
• 30:17is the data presented up
• 30:18until
• 30:20a date in publishing the
• 30:21paper. I can't remember exactly,
• 30:23when we submitted the, the
• 30:25paper. It's in the paper
• 30:26at to what date,
• 30:28the data acquisition was done.
• 30:31But I have to tell
• 30:32you, when we continue the
• 30:33study,
• 30:34now, the latest,
• 30:36work is going to be
• 30:38presented
• 30:38at SOBP
• 30:40in Toronto. We have a
• 30:41little bit of a larger
• 30:42sample, and we we see
• 30:43exactly the same the same
• 30:45results.
• 30:46So,
• 30:47what about this sample? It
• 30:49includes sixteen healthy controls, seventeen
• 30:52CHR. These are the first,
• 30:55time we are seeing this,
• 30:56as well as sixteen healthy,
• 30:58first episode psychosis, very young
• 31:00people, twenty one, as you
• 31:01can see here for the
• 31:02high risk.
• 31:03This is BMI
• 31:05as well as, sex, ratio
• 31:07across groups.
• 31:08Some of them were using
• 31:09tobacco, mostly,
• 31:11in the clinical high risk
• 31:13group, and some of them
• 31:14had, documented cannabis use,
• 31:17in urine drug screens. And
• 31:19you as you can see,
• 31:20two seven and five, two
• 31:21of fourteen, seven of ten,
• 31:23and,
• 31:24five of eleven.
• 31:26Or significant difference again in
• 31:28antipsychotic exposure.
• 31:31No no PET,
• 31:33parameters differences between the groups,
• 31:35and these are the,
• 31:37scores,
• 31:38for, psychopathology
• 31:40for the clinical, the clinical
• 31:42groups.
• 31:43And what we found is
• 31:44that synoptic density,
• 31:46SYNBEST one, BPMD
• 31:48is different between groups as
• 31:49you can see here,
• 31:51with,
• 31:52small,
• 31:53effect size
• 31:55as compared to the other
• 31:56studies in chronic schizophrenia
• 31:58or long term schizophrenia.
• 32:00And, we also see,
• 32:02significant ROI by group interaction.
• 32:06And this is a table
• 32:08I would like to spend
• 32:09a little bit of time,
• 32:11because to me, this is
• 32:12the most interesting part of,
• 32:15of what we are starting
• 32:16to see with,
• 32:17s v two a. So
• 32:19we did two two set
• 32:21of analysis.
• 32:22We did,
• 32:24we included all the ROIs
• 32:25here,
• 32:26that I mentioned previously. I
• 32:28just wanna show you prefrontal
• 32:29cortex, ACC,
• 32:31hippocampus,
• 32:32and then the striatal,
• 32:34subdivisions
• 32:35based on the functional subdivisions,
• 32:37the AST,
• 32:38SMST, and LST.
• 32:40And, this is including all,
• 32:43cortical and subcortical regions. As
• 32:45you can see,
• 32:46this is the model fit
• 32:47for the parameters, and this
• 32:49is the one with no
• 32:50covariates,
• 32:51which is similar to what
• 32:52has been presented before. Although,
• 32:56in reality, what has been
• 32:58presented before has only been
• 33:00this model here where,
• 33:02only cortical regions are investigated.
• 33:06And in this case, you
• 33:07can see there is a
• 33:08drop of almost, half
• 33:10of the model fit parameters.
• 33:12And I find this quite
• 33:13important because it suggests that
• 33:15in many ways,
• 33:16we are better able to
• 33:18quantify SV two a in
• 33:19cortex,
• 33:21versus in striatum,
• 33:22as you can see by
• 33:23as I've said, by the
• 33:24drop in the model fit.
• 33:26So these are the effect
• 33:27of group when we include
• 33:29different covariates
• 33:30here and here, and these
• 33:32are the,
• 33:34the effects of the covariates
• 33:35themselves.
• 33:37So when are we looking
• 33:38to this here? This is
• 33:40what has been done previously.
• 33:42This is, when, no covariates
• 33:44are included in the analysis.
• 33:46We can see a significant
• 33:48group effect in terms of
• 33:49the groups between healthy fat
• 33:51and,
• 33:52and first episode psychosis.
• 33:55Adding antipsychotic,
• 33:56to the model, reduces,
• 33:59or reduces the effect size
• 34:00and the significance.
• 34:02However, antipsychotics
• 34:04do not have an effect
• 34:05on SV two a, and
• 34:06this is a replication of
• 34:07previous findings. So this can
• 34:09be a proxy of,
• 34:11some other measure.
• 34:12We started to explore these
• 34:14other measures. We look at,
• 34:16age,
• 34:17group effect is still present,
• 34:19no effect on SV two
• 34:21a, sex.
• 34:24Again, no effect on group,
• 34:26no effect on SV two
• 34:27a.
• 34:29When I say no effect
• 34:30of of group, what I
• 34:30mean is that the group
• 34:31is still significant
• 34:33even when adding this covariate.
• 34:35Same with BMI.
• 34:37Again, no effect on the
• 34:39s b two a.
• 34:41Nicotine and cannabis,
• 34:43you can see there is
• 34:44no change in the group
• 34:46differences,
• 34:47and,
• 34:49no effect on s v
• 34:50two a either in cortical
• 34:52regions.
• 34:53When we look into the
• 34:54whole brain, and this includes
• 34:56cortical regions and perhaps in
• 34:57order for this presentation, I,
• 35:00and no one asked actually,
• 35:01when we published the paper,
• 35:02what happens only in estuarial
• 35:04regions?
• 35:05I think this would be
• 35:05a good question now that
• 35:06I think about this. But,
• 35:07anyways,
• 35:08here you see,
• 35:10the group effects. They're unaltered,
• 35:13when adding different covariates
• 35:15except when adding nicotine and
• 35:16cannabis.
• 35:18And that likely, it's,
• 35:20potentially driven by,
• 35:22estriatal
• 35:23effects
• 35:24of cannabis on s b
• 35:26two a,
• 35:27which is here. You can
• 35:28see it. It's the only
• 35:29one that's significant in terms
• 35:30of the effect of covariates
• 35:32on the outcome measure, which
• 35:33is SV two a.
• 35:35To me, also, what was
• 35:37really, really interesting
• 35:38is that the there was
• 35:39a significant association between negative
• 35:42symptoms and synaptic density,
• 35:44and we saw that. And
• 35:45here you can see in
• 35:46the y axis, you have
• 35:47SV to a. And on
• 35:48the x axis, you have
• 35:49the PANS negative scores
• 35:51and you have the SANS
• 35:52scores. This was replicated with
• 35:54two different measures.
• 35:57And indeed, also, we found
• 35:59the same when looking at
• 36:00the SOPS negative scores in
• 36:02the clinical high risk group.
• 36:04To me,
• 36:05this
• 36:06suggests
• 36:07that there might be,
• 36:09really an effect of synaptic
• 36:10density,
• 36:11of negative symptoms or synaptic
• 36:13negative
• 36:14of on negative symptoms
• 36:16or rather way around,
• 36:18but clearly shows across three
• 36:20different scales, that this may
• 36:22be related.
• 36:23And we are now,
• 36:24in in the work that
• 36:26we're going to be presenting
• 36:27in SOBP,
• 36:28trying to explore other facets,
• 36:31of these, relationships.
• 36:34So in summary, we showed
• 36:36lower synaptic density in FEP
• 36:38and CHR with a significant
• 36:39effect of cannabis.
• 36:41PHEP cohorts, mean duration of
• 36:43illness in our study was,
• 36:45lower than what or shorter
• 36:47with from what has been
• 36:48shown previously. In ours, it's
• 36:50less than one year versus
• 36:51three years or two point
• 36:52seven.
• 36:53The other study,
• 36:55we showed,
• 36:56for the first time evidence
• 36:57of alterations,
• 36:59in the CHR state
• 37:01as well as significant associations
• 37:03between synaptic and neck negative
• 37:04synaptic density and negative symptoms
• 37:06across, across the board.
• 37:09So SV two a may
• 37:11serve as a molecular target
• 37:12in the, in intervention trials
• 37:14in CHR and FEP, especially,
• 37:17for negative symptoms,
• 37:18I think.
• 37:19And with this,
• 37:22again, always recruiting postdocs,
• 37:24and,
• 37:26none of this can be
• 37:27done with a million,
• 37:29people,
• 37:30really working together. And thank
• 37:32you
• 37:33for listening, and happy to
• 37:35answer any questions.
• 37:40So thank you, Romina for,
• 37:43a great presentation.
• 37:44What I I'm going to
• 37:46ask you,
• 37:47is
• 37:48given that this,
• 37:51our center is focused on
• 37:52cannabis,
• 37:53a lot of what you
• 37:54presented
• 37:55was,
• 37:57about
• 37:58psychosis,
• 37:59clinically high risk first episode
• 38:01psychosis and cannabis. Can you
• 38:03distill
• 38:04and crystallize
• 38:06all what you presented
• 38:07that's related to cannabis per
• 38:09se?
• 38:11Right. Yeah. This is an
• 38:12excellent question. So the the
• 38:14first study, the study that
• 38:15we've done,
• 38:17on cannabis users, this one
• 38:19here, This is, regular
• 38:21it's only cannabis users and
• 38:23cannabis use disorder.
• 38:25This is these are not
• 38:26psychotic patients. These are only
• 38:27cannabis users and cannabis use
• 38:29disorder patients.
• 38:32And in this case, we
• 38:33found an increase in TSPO.
• 38:35This is specifically about cannabis
• 38:37use. No, no psychotic,
• 38:40differences. The MAOB study
• 38:42in cannabis use disorder, so
• 38:44the second study I presented
• 38:46here with MAOB,
• 38:47it's a combination
• 38:48of,
• 38:50cannabis use in patients.
• 38:52But the the study on
• 38:54MAOB and cannabis use disorder,
• 38:57we are finishing up right
• 38:58now.
• 39:00So,
• 39:01this is the critical question.
• 39:02What happens in cannabis use
• 39:04disorder and in cannabis users?
• 39:05So we are,
• 39:07we've done already about maybe
• 39:09fifteen subjects
• 39:12here, and we've scanned them
• 39:13with SL twenty five,
• 39:15the same protocol that you
• 39:17see here.
• 39:18And now we are, we
• 39:19are
• 39:21finalizing the study and we
• 39:22hopefully will be presenting,
• 39:24the data soon.
• 39:26And for SV two a
• 39:27and cannabis use, that study
• 39:29was done by you, so
• 39:30there was no point in
• 39:30doing it again.
• 39:35Any specific questions for,
• 39:38for Romina?
• 39:43May I ask a question?
• 39:45Hi, Romina.
• 39:47Thank you, Garrett. This was
• 39:48really great presentation. Thank you
• 39:50so much.
• 39:51I just had a question
• 39:52about TSPO,
• 39:54and you mentioned that,
• 39:56it was increased in cannabis
• 39:58users. It was the higher
• 39:59levels in cannabis users.
• 40:01How do I interpret this
• 40:03finding? Like, what does that
• 40:04mean?
• 40:06So I'm I was surprised
• 40:08when we saw that. I
• 40:09was expecting the opposite. We
• 40:10hypothesized the opposite.
• 40:12It was really
• 40:14it was clear. It was,
• 40:15like, to me,
• 40:17I remember,
• 40:18it had happened to me
• 40:19before when I was looking
• 40:20at dopamine and was dopamine
• 40:22function, and I thought we
• 40:24would find
• 40:25increase,
• 40:26dopamine release, and we found
• 40:28the opposite.
• 40:30So, it happens,
• 40:32that, we see the opposite.
• 40:33So in this case, what
• 40:34does it mean? So it
• 40:35means that we don't really
• 40:36understand what cannabis,
• 40:38use does in the brain.
• 40:39That that to me what
• 40:41it is what it means.
• 40:43There are some newer studies
• 40:44which are starting to suggest
• 40:45that, indeed, cannabis use may
• 40:47be pro inflammatory.
• 40:49And in my view, the
• 40:50fact that the fact that
• 40:51cannabis use
• 40:53has been,
• 40:54associated with increased stress levels,
• 40:57as well as, mood disorders,
• 41:00in mostly clinical and epidemiological
• 41:03studies
• 41:04suggest that, at least for
• 41:05some people,
• 41:07there is there an interaction
• 41:10between what we used to
• 41:11call neuroinflammation,
• 41:14cannabis use,
• 41:15and likely depression and suicide
• 41:17depression and,
• 41:18depression and, anxiety,
• 41:21which is why,
• 41:23I wanted to highlight this
• 41:25relationship between,
• 41:28TSPO
• 41:29and stress measures.
• 41:32We had,
• 41:33and we are trying we
• 41:34are working now in collaboration
• 41:36with, a group,
• 41:38in California.
• 41:40There we have so much
• 41:41data that, I'm I'm always
• 41:43happy to give it away,
• 41:45for, someone to analyze it
• 41:47and work with us. So
• 41:49she's looking into,
• 41:51the relationship between TSPO and
• 41:53trauma,
• 41:55because we also obtained, measures
• 41:57of, childhood trauma. So we
• 41:59are trying to look into
• 42:00that.
• 42:01But to me, what it
• 42:02means is that really,
• 42:04this
• 42:05group this,
• 42:07to me what it means
• 42:08is that new neuroinflammation
• 42:10or neuroimmune function,
• 42:13cannabis use,
• 42:15depression and anxiety, or,
• 42:17or the inflammasome
• 42:19are are actually,
• 42:21interrelated
• 42:22in some way, and likely
• 42:23not in everyone,
• 42:25because not everyone actually developed
• 42:28high stress levels and higher,
• 42:31mood symptoms,
• 42:32but some people do and
• 42:33perhaps it is through,
• 42:36neuroimmune activation.
• 42:39Mhmm. Do you have any
• 42:40measure of the acute versus
• 42:42chronic effects of cannabis? Like,
• 42:43if cannabis users stop using
• 42:45cannabis or haven't used cannabis,
• 42:48like, recently,
• 42:49do you see any difference?
• 42:52Yes. So we we obtained
• 42:53information on cannabis use,
• 42:55like, it's a long questionnaire.
• 42:57We also look into hours
• 42:59since since last use,
• 43:02and I don't remember the
• 43:03results
• 43:04of that.
• 43:05But but we did do
• 43:06it. I think in the,
• 43:07Dasilva study,
• 43:10there was no relationship with
• 43:12last hour or maybe there
• 43:13was with hours of last
• 43:15use.
• 43:15We always have this information
• 43:17because we obtained,
• 43:19URI so what we tell
• 43:20all participants
• 43:21is not to, come high
• 43:23to the scan, which means,
• 43:25we ask them not to
• 43:27change their patterns of use,
• 43:29but
• 43:29to we scan them in
• 43:31the morning, and we tell
• 43:32them not to,
• 43:33smoke in the morning, basically.
• 43:35And we ask them when
• 43:36was the last time they
• 43:37used, and sometimes they may
• 43:39use the night before, although
• 43:40we tell them, you know,
• 43:41not to change the pattern.
• 43:42And sometimes,
• 43:43you know, they if they're
• 43:45regular use our our people
• 43:46are really,
• 43:47heavy users or meet criteria
• 43:49for cannabis use disorder.
• 43:51And when I say heavy
• 43:52users, it means at least
• 43:54four times a week.
• 43:57Right? So it depends on
• 43:58when the scan falls.
• 44:00It could be the night
• 44:01they smoke.
• 44:02And we don't change that.
• 44:04We just quantify,
• 44:05the hours since last use.
• 44:07And in many occasions, we
• 44:09have attempted,
• 44:10as we've done in the
• 44:12Dasilva study to look at
• 44:14concentration of THC,
• 44:16and CBD
• 44:17in, in the periphery,
• 44:19and we did not find
• 44:20the relationship with THC. From
• 44:22what I remember, we could
• 44:23not, at the time, quantify
• 44:24CBD,
• 44:26in our cannabis users.
• 44:28Okay. Thank you so much.
• 44:30Romina, can you remind me,
• 44:31was there a clear relationship
• 44:33between
• 44:35the lifetime exposure to cannabis
• 44:37and TSPO?
• 44:38I don't think so. Not
• 44:40lifetime exposure. There wasn't a
• 44:42lifetime exposure?
• 44:43I don't remember. I don't
• 44:45think so.
• 44:46Okay. And,
• 44:47and related to that,
• 44:49do you have any data
• 44:51on
• 44:52PSPO
• 44:53in
• 44:54former cannabis users as a
• 44:55as a some proxy measure
• 44:57of what happens
• 44:58when someone stops
• 45:01using cannabis?
• 45:02That's an excellent question. I,
• 45:04we don't have that information,
• 45:06actually, in our in our
• 45:07samples.
• 45:09But from other molecular targets
• 45:11that have been have gone
• 45:12through abstinence, I think you
• 45:14would expect
• 45:16norm there would be, it
• 45:17would come to normal levels
• 45:19after six weeks.
• 45:21But I'm not I'm not
• 45:22sure. I mean, it has
• 45:23been reported for c b
• 45:24one, if I remember correctly,
• 45:27or other molecular targets for
• 45:29TSPO.
• 45:29We have not looked into
• 45:31that,
• 45:34but I have to say
• 45:35that
• 45:36our healthy controls
• 45:37are super healthy.
• 45:39So all the cohorts in
• 45:41all the studies that we've
• 45:42done over two decades,
• 45:44all the healthies are really
• 45:46super healthy individuals.
• 45:48Super healthy, which means they've
• 45:51almost they've never used cannabis
• 45:53or tobacco
• 45:54or seen a psychiatrist.
• 45:56They have no first degree
• 45:58family member,
• 45:59and
• 46:01perhaps this is a problem,
• 46:03because,
• 46:05this is not perhaps
• 46:07the everyone. I mean, that's
• 46:08not really represented the general
• 46:10population.
• 46:12But, yeah, our our samples
• 46:13are usually our healthy cohorts
• 46:15are super healthy.
• 46:18Great.
• 46:19Other questions for Romina?
• 46:26I I if not, I
• 46:27did have a follow-up question,
• 46:29Romina. Given that,
• 46:31one of
• 46:33the leading hypotheses of schizophrenia
• 46:35is that it may be
• 46:36a disorder
• 46:37of altered pruning.
• 46:40Can you speculate on,
• 46:42can you connect your TSPO
• 46:44findings,
• 46:46if,
• 46:47if microglia
• 46:49are important in in pruning,
• 46:52and can you relate that
• 46:53to schizophrenia?
• 46:55Right. So
• 46:56the reason I put in
• 46:57the the c four study
• 46:59is because I think the
• 47:00link has to go through
• 47:02there.
• 47:03So
• 47:05let me just try to
• 47:06find it because
• 47:08it's it's
• 47:09important to note that
• 47:11we when we looked into
• 47:13the relationship
• 47:15between when we looked into
• 47:16c four a,
• 47:17we did not find group
• 47:19differences.
• 47:20But that's because
• 47:21we did not
• 47:25go
• 47:26and
• 47:28identify the participants
• 47:30who were
• 47:31actually,
• 47:33having high c four a.
• 47:38But in our case,
• 47:39our samples had low c
• 47:41four a.
• 47:42This is,
• 47:43We we can't see that
• 47:45slide, and you probably put
• 47:46need to put it in
• 47:47presenter view.
• 47:48Okay. So anyway, so I
• 47:49won't waste the time. So
• 47:50anyways, so when we look
• 47:52so I think the pathway
• 47:54through which this is happening
• 47:56is through c four a.
• 47:57So the best study design
• 47:59is the one that Rajeev
• 48:01was, trying to implement, which
• 48:03is to go into the
• 48:04general population
• 48:05and identify the participants
• 48:07who have high c four
• 48:09a.
• 48:09In this case,
• 48:11one would expect
• 48:12very high,
• 48:14TSPO.
• 48:16And
• 48:17when there is high TSPO,
• 48:19you would expect very low
• 48:20SV two a.
• 48:23The problem that we have
• 48:24had is that our sample
• 48:26has very few with very
• 48:29high
• 48:29c four a expression.
• 48:31And, in fact, when you
• 48:32look at the group differences,
• 48:34it's either no significant
• 48:37significantly different between the groups
• 48:41or it's even lower.
• 48:44Do you know what I'm
• 48:44saying? Yep.
• 48:46Yes. So I think the
• 48:48this the study was not
• 48:49designed
• 48:50to actually
• 48:52look into this,
• 48:54relationship.
• 48:55And I think
• 48:56the study that Rajiv,
• 48:58was trying or I hope
• 49:00he's he's doing,
• 49:02is the right design to
• 49:03answer this particular question. And
• 49:05I hope it's funded so
• 49:07that,
• 49:08these participants
• 49:09with very high c four
• 49:11a can actually be scanned
• 49:13with, TSPO radio ligand and
• 49:15SV two a at the
• 49:16same
• 49:18time.
• 49:19Sounds good.
• 49:22Other questions?
• 49:28I went too fast.
• 49:32Well, I I want I
• 49:33just want to remind people
• 49:35that in
• 49:37in, you know, the the
• 49:38first,
• 49:39series of webinars,
• 49:42by the Yale Center for
• 49:43the Science of Cannabis and
• 49:44Cannabinoids is focused on the
• 49:46effects of cannabis
• 49:47on the brain.
• 49:49And we've had two great
• 49:50presentations in Yasmin Hurd and
• 49:52Romina.
• 49:53Next month,
• 49:54we have,
• 49:56Romina's colleague from, from McGill,
• 50:00Lina Palianapan,
• 50:02who will be speaking about
• 50:03the role of dopamine
• 50:05and cannabis and psychosis,
• 50:07and that should make for
• 50:08an interesting presentation too.
• 50:10Any last thoughts,
• 50:12Romina, about about your work?
• 50:15And I would imagine that,
• 50:17given that cannabis,
• 50:18cannabis is,
• 50:20is much more available
• 50:22in general in Canada than
• 50:23in the US,
• 50:25are there any,
• 50:26any words of wisdom in
• 50:28in doing these pet studies
• 50:29and how to select patients
• 50:32to pass out these different
• 50:33effects?
• 50:35Right. So
• 50:36I I think, a couple
• 50:37of things. So in terms
• 50:38of, dopamine
• 50:40and, cannabis, you know, the
• 50:42same happened to me, where,
• 50:44I was hypothesizing increased dopamine
• 50:46release and we found the
• 50:47opposite.
• 50:48Then I was doing the
• 50:50studies on TSPO. I thought
• 50:51there's gonna be a reduction
• 50:52and we found an increase.
• 50:55All of this to say
• 50:56again is that we really,
• 50:57really
• 50:58don't understand
• 51:00the role of cannabis,
• 51:02in the brain.
• 51:03And I think,
• 51:04we should really do an
• 51:06effort,
• 51:07to to
• 51:08to understand.
• 51:10And this is because with
• 51:12legalization,
• 51:13the increase of cannabis use
• 51:16has continued to grow across
• 51:18the world.
• 51:19In Canada, since legalization,
• 51:22we have found, yes, a
• 51:24decrease in,
• 51:26criminalization
• 51:27of cannabis users. People are
• 51:29not going to the, jails
• 51:30anymore, which is, a good
• 51:32thing.
• 51:34But at the same time,
• 51:35the visits to the emergency
• 51:36room have increased, intoxication
• 51:39has increased,
• 51:41driving under the influence of
• 51:43cannabis use has increased,
• 51:45patient with schizophrenia, the people
• 51:47that I see, and high
• 51:48and very young people are
• 51:50now vaping cannabis.
• 51:52And so,
• 51:53this is all to say
• 51:54that because so many people
• 51:56now are using cannabis because
• 51:57there is a perception that
• 51:58there is low
• 52:00danger, which is likely true
• 52:01for most people, but not
• 52:03for young people,
• 52:05then we are starting to
• 52:06see a lot of
• 52:10behavioral changes, which are actually
• 52:13presented,
• 52:14in the emergency room and
• 52:15in the in epidemiological
• 52:17studies. That the relationship between
• 52:19cannabis and, suicide,
• 52:21for instance, which we are
• 52:23pursuing in a new grant
• 52:24we have,
• 52:27we we need to do
• 52:27better, actually, because young people
• 52:29really have no clue
• 52:31when they come to the
• 52:32emergency room. They they are
• 52:33clueless.
• 52:34And it's it is our
• 52:36job, really, to do a
• 52:37better job.
• 52:38Is it hard to find,
• 52:40controlled subjects without any cannabis
• 52:43use?
• 52:48It's hard.
• 52:51Yes. It's difficult. To find
• 52:53people in their twenties with
• 52:55no cannabis use is hard.
• 52:57We,
• 52:58have, we usually in our
• 52:59studies, we we exclude if
• 53:01they have used recreational more
• 53:03than three or four times,
• 53:06lifetime.
• 53:09But if they have tried
• 53:11it, you know, lots of
• 53:11people have tried it, they
• 53:12didn't like it, they tried
• 53:13second time, they didn't like
• 53:14it, third time, they didn't
• 53:15like it, And then they
• 53:17don't try again. Those people,
• 53:19we include them in in
• 53:22as healthy controls if they
• 53:24have nothing else.
• 53:26But people who have not
• 53:28tried, almost impossible, I think.
• 53:30Young people. Great.
• 53:31Any other questions for Romina?
• 53:35So, Romina, thank you very
• 53:37much for a a very
• 53:38enlightening talk. I have just
• 53:40one last question for you,
• 53:42and that is
• 53:43whether Canada will be joining
• 53:44the United States.
• 53:47We are joining Europe. Seems
• 53:48that
• 53:49they are, they are being
• 53:50nicer to us.
• 53:52We're joining actually Grow Inlandia
• 53:54first,
• 53:55or maybe we should take
• 53:56over Alaska
• 53:57and Grow Inlandia and then
• 53:59join Europe.
• 54:01Well, good luck with that.
• 54:02Thank you again for your
• 54:03great talk.
• 54:06Alright. And thanks, everyone.
• 54:08Next talk is, scheduled for
• 54:10the eighteenth of March.
• 54:12Bye.
• 54:13Bye. Thanks for having me.