YCSCAN2 March 2025 Webinar

Transcript

• 00:12Okay we should probably get
• 00:13started,
• 00:14It's my
• 00:15pleasure to
• 00:17to have,
• 00:19Leena Palmiapin
• 00:21and Jessica Arins to,
• 00:24to
• 00:25our webinar series, hosted by
• 00:27the Yale Center for the
• 00:28Science of Cannabis and Cannabinoids.
• 00:32You know,
• 00:33we are really delighted to
• 00:35have the two of them
• 00:37present on something that we
• 00:39haven't really heard about very
• 00:40much before. As you know,
• 00:42this seminar series, this webinar
• 00:44series is really about,
• 00:46the science of cannabis and
• 00:47cannabinoids, and I couldn't think
• 00:49of a,
• 00:51of of a better person
• 00:52to tell us one some
• 00:54aspects of the relationship between,
• 00:57cannabis and dopamine and, and
• 00:59and and so I'm I'm
• 01:01really delighted to to have
• 01:03the two of them. I'm
• 01:04not going to,
• 01:06tell you about the many
• 01:07accomplishments of,
• 01:09of of, my colleagues here,
• 01:11but I'll let you read
• 01:13that. We, I think, communicated
• 01:14that in our in our
• 01:16announcement, but we are really
• 01:18happy. And
• 01:19who knows?
• 01:20You may become,
• 01:22the fifty first state and
• 01:23we'll be working with you
• 01:24a little closer,
• 01:26over the next few years.
• 01:27So without further ado, I'm
• 01:29gonna hand it over to
• 01:30the two of you.
• 01:34Thank you. Thank you very
• 01:35much.
• 01:36So
• 01:37can you all see my
• 01:38screen?
• 01:41Okay, excellent.
• 01:42Well, I will start with
• 01:45a declaration and then an
• 01:46apology.
• 01:48The declaration is we're not
• 01:49becoming fifty first state.
• 01:52You know, this is this
• 01:53is an interesting
• 01:54time to speak about,
• 01:56but anyway, I'll just start
• 01:57with that. And then second
• 01:58thing is the the apology
• 02:00is I'm sorry I have
• 02:01this
• 02:02peculiar
• 02:03eccentric,
• 02:05liking to
• 02:06titles that rhyme, titles that
• 02:08have a clang on them.
• 02:09So don't for dopamine delusions,
• 02:12we all have d, but
• 02:13we're not gonna talk about
• 02:14delusions very much today. I'm
• 02:15actually going to talk more
• 02:16about,
• 02:17psychosis
• 02:18as a as a general
• 02:20syndrome and not about any
• 02:21specific, symptoms.
• 02:23And, sir, you're you're right.
• 02:24I you know,
• 02:26the,
• 02:28the place to really learn
• 02:30a lot about the effects
• 02:31of cannabis is, of course,
• 02:32the psychosis clinic. And I
• 02:34would say I'm not a
• 02:35I'm not a cannabis researcher
• 02:36myself. I haven't done many
• 02:37studies on cannabis, so I'm
• 02:38really learning a lot from,
• 02:40from your group and from
• 02:41others. My work is,
• 02:43in psychosis. I'm a clinician.
• 02:45I'm a psychiatrist.
• 02:47And I have to say
• 02:48I've used almost every tool
• 02:49that we can use to
• 02:50understand what is behind psychosis,
• 02:53and I continue to learn
• 02:54these tools and and use
• 02:55them as
• 02:56a natural and introduction about
• 02:58myself.
• 02:59And you see me using
• 03:00the word we very often,
• 03:01the royal we. When I
• 03:02say we, it's actually Jess
• 03:04who did all the work.
• 03:05So Jess is a PhD
• 03:06student in our group, and
• 03:07she did the the work
• 03:08that we're gonna present today.
• 03:11And my plan is really
• 03:12to start with some introduction
• 03:14to the problem,
• 03:15and then, let Jess talk
• 03:17about the methods that we
• 03:18use to address the problem.
• 03:19And then I'll come back
• 03:20and, say a few words
• 03:21about the implications and what
• 03:23can be the take home
• 03:24from, one of the studies
• 03:25that we did recently.
• 03:28So this is my conflicts
• 03:30of interest, my declarations.
• 03:31In a nutshell, I don't
• 03:32have any affiliations whatsoever with
• 03:34anything, to do with cannabis
• 03:35related industry, lobbyists, or policy
• 03:38makers. We've given some talks
• 03:39and got paid for them
• 03:41through Artsukka and Janssen Canada
• 03:43who make antipsychotic drugs.
• 03:45And Jess also reports no
• 03:47no conflicts of interest for
• 03:48the talk relevant today.
• 03:50So this is our agenda.
• 03:52We're gonna introduce the problem
• 03:53of interface between psychosis and
• 03:55cannabis. Not a new problem.
• 03:57I think your group, all
• 03:58of you have heard a
• 03:58lot about it. But I'm
• 04:00gonna present an issue that
• 04:01comes comes often in a
• 04:03clinical conversation when we talk
• 04:05to patients
• 04:06in pharmaceutical clinic
• 04:07about these two issues,
• 04:09cannabis and psychosis.
• 04:11We get into a bit
• 04:12of a,
• 04:13impasse, a junction where patients
• 04:16have a different view and
• 04:17clinicians, we have a different
• 04:18view. And I wanna present
• 04:19that impasse a little bit
• 04:21in detail.
• 04:22And then I will, let,
• 04:23just talk about methods and
• 04:25results. And, you know, we
• 04:26are people from the future.
• 04:28We are going to tell
• 04:30you about a paper that's
• 04:31going to be published on
• 04:32April the ninth. It's not
• 04:34out there yet. But if
• 04:35any of you are interested,
• 04:37we're happy to share a
• 04:38preprint link that you can
• 04:39look at this paper. It's
• 04:40posted
• 04:41in the bio archives.
• 04:43And this paper is called
• 04:44convergence of cannabis and psychosis
• 04:46on the document system.
• 04:47And you'll see many other
• 04:49co authors and Jess will
• 04:51clarify,
• 04:52the contribution from other people
• 04:53that you don't see here
• 04:54on the screen
• 04:55who made this work possible.
• 04:57So let me start with
• 04:58the problem.
• 04:59The problem is,
• 05:01we know,
• 05:03for for for a while
• 05:04now, from, I would say,
• 05:06from eighteen
• 05:07eighteen
• 05:08forty five, if I'm not
• 05:10wrong, from Moro's initial description
• 05:12that cannabis has something to
• 05:13do with psychosis.
• 05:15And one of the very
• 05:16nice demonstrations
• 05:18experimentally
• 05:19of the effect of cannabis
• 05:20on on psychotic symptoms,
• 05:22was given by none other
• 05:24than Cyril here. A very
• 05:25nice experimental study where
• 05:28injection of the active ingredient
• 05:30of cannabis, which is tetrahydrocannabinol
• 05:32nine case c,
• 05:34really,
• 05:35produced transiently,
• 05:37symptoms of, positive symptoms of
• 05:38psychosis in healthy people who
• 05:40had no previous history of
• 05:42schizophrenia and no previous history
• 05:44of established cannabis use disorder.
• 05:47And this is important because
• 05:48this is experimental evidence, double
• 05:50blind randomized trial, where, you
• 05:52give some people,
• 05:54you know, no THC and
• 05:56and others in different doses
• 05:57and you really see
• 05:59a strong,
• 06:00experimental pharmacological effect. So it's
• 06:02a very key finding and
• 06:03it's been replicated in by
• 06:05other groups as well. So
• 06:06clearly,
• 06:07we know that injecting the
• 06:09active ingredient of cannabis induces
• 06:11psychotic symptoms. It's undisputable.
• 06:15We also know a lot
• 06:16about the epidemiology in population
• 06:18level, what does cannabis do
• 06:19to psychosis risk And we
• 06:21know a lot in in
• 06:22Canada now
• 06:24given that,
• 06:25you know, we
• 06:27liberalized
• 06:28cannabis use, in twenty fifteen,
• 06:30and we legalized it in
• 06:32twenty eighteen.
• 06:33You know, we had this
• 06:35population wide laboratory set up
• 06:37in twenty fifteen and twenty
• 06:39eighteen, and we now know
• 06:40now have the observations from
• 06:41this laboratory. And this is
• 06:43an interesting study that came
• 06:44from,
• 06:45the CAMH Daniel Meiren and
• 06:46and colleagues
• 06:48not long ago, only two
• 06:49months ago in JAMA network,
• 06:51JAMA Open.
• 06:53It's a very, interesting evidence
• 06:54that, you know, this experimentation
• 06:57of liberalization and legalization has
• 06:58actually increased
• 07:00the risk attributable the risk
• 07:02of psychosis attributable to cannabis.
• 07:04It's a very large study.
• 07:05You know, it's a population
• 07:06wide administrative database based study.
• 07:09Everybody fourteen to sixty five
• 07:11who presented to one of
• 07:12the hospitals in Ontario emergency
• 07:14one of the hospitals with
• 07:15emergency units in Ontario,
• 07:17were included in this. And
• 07:19the question was very simple.
• 07:20What happened to this presentation
• 07:22rates?
• 07:23And what happened to the
• 07:24number called
• 07:26PAF, population attributable fraction
• 07:29of, psychosis and cannabis after
• 07:31legalization. So this number PAF,
• 07:33that's what you see in
• 07:34this y axis. It's a
• 07:35very interesting,
• 07:36fraction. It's epidemiologists
• 07:38know this very well, but
• 07:39I'll take a minute to
• 07:40explain this.
• 07:41Population attributable fraction is a
• 07:43number
• 07:44that tells you
• 07:45if you have hundred people
• 07:47in your population with, psychosis,
• 07:49how many of those hundred,
• 07:51have psychosis that's attributable
• 07:54to cannabis.
• 07:55That in other words, if
• 07:56you eliminate cannabis completely from
• 07:58the population,
• 07:59well, whether you can do
• 08:00it is a question. But
• 08:01if you do it,
• 08:02how many cases will be
• 08:04gone from, annual presentations that
• 08:06we see in the c
• 08:07vid psychosis.
• 08:08So that number is
• 08:10and, traditionally, conventionally, you know,
• 08:12it's been quite low. It's
• 08:13around five percent. Five percent
• 08:14of cases,
• 08:15we expect those cases will
• 08:17be eliminated.
• 08:18Will still exist. Ninety five
• 08:20percent of cases will still
• 08:21exist, but five percent may
• 08:22not exist if cannabis is
• 08:24completely gone from the face
• 08:25of this earth. But see
• 08:26what happens to the number
• 08:27is around point zero five,
• 08:29before twenty fifteen.
• 08:31The first one is on
• 08:32schizophrenia,
• 08:33which is a narrow diagnosis,
• 08:34and the second one is
• 08:35on psychosis not otherwise specified,
• 08:37which includes every kind of
• 08:38psychosis.
• 08:39And you see it's always
• 08:40around point zero five, in
• 08:42the decade before twenty fifteen,
• 08:45rising over time, but not
• 08:47massive.
• 08:47And then with legal liberalization,
• 08:50it goes up the acceleration
• 08:51of the slab. You can
• 08:52see the step up there.
• 08:54It it is nearing point
• 08:55one, which is ten percent
• 08:56of the population's
• 08:58risk. And after legalization,
• 08:59the risk is now around
• 09:00ten percent, both for schizophrenia
• 09:02and for psychosis NOS.
• 09:04So the key finding too
• 09:06is we have very convincing
• 09:08population wide laboratory evidence, epidemiological
• 09:11evidence to say that,
• 09:13cannabis is related to presentations
• 09:15of psychosis
• 09:17and this is very very
• 09:18compelling as well, equally compelling,
• 09:20to the experimental evidence we
• 09:21have.
• 09:23And we also have a
• 09:24third line of evidence that
• 09:25comes from clinical practice. I
• 09:27would say clinical wisdom really.
• 09:29You know, when you see
• 09:30people with schizophrenia,
• 09:32established psychotic disorders,
• 09:34you know that if,
• 09:35if those people with schizophrenia
• 09:37smoke cannabis continue to use
• 09:39cannabis,
• 09:40they could develop poor outcome.
• 09:41And you see them relapsing
• 09:42very often. You see them
• 09:44coming off the medications. You
• 09:45see all the kind of
• 09:46factors
• 09:47related to negative outcomes being
• 09:49higher in people who have
• 09:50ongoing cannabis use.
• 09:52And if those same patients,
• 09:54if they stop using cannabis,
• 09:55you see them having better
• 09:56outcomes. And this clinical wisdom
• 09:58is also well replicated and
• 10:00and published in in different
• 10:01format in different places
• 10:03across the world.
• 10:04So those are all, you
• 10:05know, very strong lines of
• 10:06evidence, but how useful those
• 10:09evidences are when you have
• 10:10a patient like this sitting
• 10:11in front of you in
• 10:11the clinic.
• 10:13In my clinic, I generally
• 10:14see people around twenty years
• 10:15of age, generally young men.
• 10:17Usually, they come with their
• 10:18parents.
• 10:20Not always a dad. Just
• 10:21like in this picture is
• 10:22usually the mom who comes.
• 10:23And the initial assessment conversation
• 10:25is usually about,
• 10:27the nature of the condition
• 10:28and what can the person
• 10:29and the family do to
• 10:30get better. So the conversation
• 10:32goes, something like this.
• 10:34I would say, you know,
• 10:35what you have is psychosis,
• 10:37and the patient would tend
• 10:38to agree with it and
• 10:39say, okay. Mind is playing
• 10:40tricks. What can I do
• 10:41about it?
• 10:42Well, they'll use their own
• 10:43slangs and, words to understand
• 10:45their their their experience.
• 10:48And generally, I say something
• 10:49like, I don't know exactly
• 10:50what causes it, but we
• 10:51know we can trace it
• 10:52back to high levels of
• 10:53dopamine in the brain. And
• 10:54then I'll go on to
• 10:55explain a little bit about
• 10:56dopamine.
• 10:57Generally, at this point, the
• 10:58dad or mom will will
• 10:59come in and say, okay.
• 11:00So there is something chemical
• 11:01here. What can we do
• 11:02about it? How can we
• 11:03fix
• 11:04it? That really opens up
• 11:05the discussion for medications and
• 11:07antipsychotics and so on.
• 11:09And one thing that we
• 11:10all say in practice is
• 11:11we say,
• 11:13managing psychosis involves,
• 11:15also steps we take to
• 11:17not to make it worse.
• 11:18So, you know, stopping cannabis,
• 11:20decreasing the use of cannabis
• 11:21is one thing that I
• 11:22would strongly recommend.
• 11:23Now that's the place where
• 11:25that's the point where the
• 11:26clinical conversation,
• 11:29starts running,
• 11:30parallel stream to what the
• 11:32patient has been saying so
• 11:33far. So they will say
• 11:34something like, blame the cannabis
• 11:36now, doc. Nice twist.
• 11:38For me, cannabis helps. It
• 11:39helps me to sleep, helps
• 11:41me to relax,
• 11:42and I've been smoking it
• 11:43for God knows, you know,
• 11:45how long, and I've been
• 11:46having psychosis only for the
• 11:47last three weeks or four
• 11:48weeks. So they would just
• 11:49start diverging from me and
• 11:51start not accepting the fact
• 11:53that cannabis may be contributing
• 11:54to their problems. Now at
• 11:56this stage, generally, I start
• 11:57saying things like, you know,
• 11:58I've been treating patients for
• 12:00so many years and, you
• 12:01know, we've seen people getting
• 12:02better when they stop it
• 12:03or getting worse when they
• 12:04don't. And then, the patient
• 12:06says, well, that may be
• 12:07true for your other patients,
• 12:08but I'm different. You know?
• 12:09For me, it helps. I'm
• 12:11not going to stop it,
• 12:11or they might not say
• 12:12I'm not going to stop
• 12:13it. They will just give
• 12:14me enough hints to say,
• 12:16it's a hard thing to
• 12:17swallow, a hard thing to
• 12:18swallow to to stop using
• 12:19weed.
• 12:20And, unfortunately,
• 12:22these days, increasingly, I see
• 12:23this. The parents
• 12:25would go and find some
• 12:26evidence that supports
• 12:28the use of cannabis
• 12:29to help.
• 12:31You know, they'll come either
• 12:32they will find nice trials
• 12:33published in big journals about
• 12:35cannabidiol,
• 12:36helping psychotic symptoms,
• 12:38and they will bring that
• 12:39up. I will bring some
• 12:40other, well, not so scientific
• 12:42evidence to,
• 12:43to argue the case to
• 12:44really reduce the cognitive dissonance
• 12:46that you see, in the
• 12:47family here.
• 12:49And eventually,
• 12:51the progress that we make
• 12:52in getting the person to
• 12:53stop smoking weed is very
• 12:55little in the first year
• 12:56of psychosis.
• 12:57They may reduce a little
• 12:58bit or they may just
• 12:59continue to use it in
• 13:00most cases and keep getting
• 13:01relapses and admissions in the
• 13:03hospital.
• 13:04The the whole discussion about
• 13:06complexity of psychosis, especially the
• 13:08causal complexity, there are many
• 13:10causes and cannabis is one
• 13:11of them, doesn't really sell
• 13:13well. I mean, complexity is
• 13:14good for us doing science.
• 13:16We embrace complexity. We know
• 13:17this complex. It's not simple.
• 13:19But clinical conversations,
• 13:21complexity is not a friend
• 13:22of clinicians, you know, in
• 13:23many ways. It doesn't really
• 13:25help us to to draw
• 13:26one to one line between
• 13:27problems and effects, between causes
• 13:29and and outcomes,
• 13:31which means, you know, patients
• 13:32start forming their own line
• 13:33of thinking, and therapeutic alliance
• 13:35really fails at this point.
• 13:37So one of the questions
• 13:38is, can we actually draw
• 13:39a straight line between psychosis,
• 13:42dopamine, and cannabis? If we
• 13:44can draw a straight line
• 13:45like that, we may have,
• 13:46some better evidence to to
• 13:48present and and make a
• 13:49case in clinics.
• 13:51So what I want is
• 13:52clinically applicable evidence. Really, the
• 13:54evidence that comes from patients
• 13:56like this one that I
• 13:56see in the clinic.
• 13:58Young man using cannabis for
• 14:00a period of time, qualifying
• 14:01for cannabis use disorder in
• 14:02many cases, not a new
• 14:04user, chronic user, but now
• 14:05proceeding with psychotic symptoms. Can
• 14:07I say something about the
• 14:08dopamine to them that convinces
• 14:10them to to take action?
• 14:13So in other words, the
• 14:14research question is, is there
• 14:15a common alteration in the
• 14:16dopamine system in cannabis users
• 14:18and people with psychotic disorder?
• 14:20Can I tell my patients
• 14:22the weed that you smoke
• 14:24increases the same chemical in
• 14:25the same brine region
• 14:27where we don't want it
• 14:28to go up? That's really
• 14:30what I wanna do with
• 14:30this,
• 14:31research here.
• 14:33So, just before we go
• 14:35to the methods and results
• 14:36of how we approach that
• 14:37question, it's important to realize
• 14:38that the evidence of dopamine
• 14:41access in psychosis is merely
• 14:42an, irrefutable. There's a lot
• 14:44of evidence for that. This
• 14:45is a meta analysis by
• 14:47Oliver House
• 14:48published eleven years now, I
• 14:49think, twenty thirteen, twenty twelve,
• 14:51I think. Anyway, it's really,
• 14:53PET studies based on, fluoro
• 14:55dopa studies showing dopamine synthesis
• 14:57excess,
• 14:58in, in people with psychosis.
• 15:00And you see around point
• 15:02seven effect size, point seven
• 15:03to point eight, which is,
• 15:05nearly large effect size of
• 15:07dopamine excess in stratum.
• 15:10As you may know, dopamine
• 15:11is synthesized in, the neuron
• 15:13start somewhere in midbrain in
• 15:15substantia nigra and ventral tegmental
• 15:17area, but they release hackers
• 15:19in in stratum. That's where
• 15:20the projections are, microstridal projections.
• 15:23So stratum is where you
• 15:24see excessive,
• 15:25big, vesicular storage of dopamine,
• 15:28which is increased in psychosis.
• 15:30And we we we actually
• 15:31see that with antipsychotic usage,
• 15:33in in people with resistance
• 15:35schizophrenia, the pathophysiology is different.
• 15:37But in people with acute
• 15:38psychotic symptoms and,
• 15:40schizophrenia itself, there is higher
• 15:43storage of, synthesis and storage
• 15:44of dopamine. So it's a
• 15:45it's a very well established
• 15:47line of evidence here. It's
• 15:49said to be the final
• 15:50common pathway for psychotic symptoms
• 15:51in
• 15:52schizophrenia.
• 15:54But the link between cannabis
• 15:56and dopamine is not that
• 15:57clear.
• 15:58In fact, the the early
• 15:59studies actually showed if you
• 16:01inject,
• 16:02THC just like the the
• 16:03study that I showed earlier,
• 16:05several study,
• 16:06Acute injection of THC, pet
• 16:08studies doing that actually showed
• 16:09increases triadal dopaminergic synthesis.
• 16:12So if you inject THC,
• 16:13you get increased triadal dopamine
• 16:15synthesis.
• 16:16But chronic users had a
• 16:17very different picture. Chronic cannabis
• 16:19use leads to blunted dopamine
• 16:22synthesis
• 16:23and less release. So really
• 16:24opposing effects between acute, injections
• 16:27and chronic use. And as
• 16:28you know, chronic use in,
• 16:30in real life, in real
• 16:31world, it's not just THC.
• 16:32It's cannabidiol as well. And
• 16:34cannabidiol itself has opposing effects
• 16:36pharmacologically. It's a partial d
• 16:38two agonist, has antipsychotic effects.
• 16:40So the question is in
• 16:41long term cannabis users,
• 16:43the users that we generally
• 16:44see in psychosis clinics, pharmaceutical
• 16:46clinics, what is cannabis doing
• 16:48to the physiology, the final
• 16:49common pathway of their symptoms?
• 16:51The best way to answer
• 16:52this question is to doing
• 16:53pet studies on a large
• 16:54number of first episode psychotic
• 16:55patients when they are acutely
• 16:56psychotic,
• 16:58and and see how much,
• 16:59weed they're smoking and relate
• 17:01these two. But, you know,
• 17:03your group has done a
• 17:04lot of pet studies. You'll
• 17:05know how difficult they are,
• 17:06how technically challenging they are,
• 17:08and also there's a issue
• 17:09of radiation extra for longitudinal
• 17:11studies. And the high cost
• 17:12that, that is associated with
• 17:14the pet really precludes us
• 17:16to do a a big,
• 17:17large scale clinical study,
• 17:19with with PET as an
• 17:20instrument. So I'm gonna stop
• 17:22here and invite just to
• 17:24to carry on talking about
• 17:26the methods and results. Jess.
• 17:28Thank you, Anna.
• 17:30So before I can get
• 17:31into our methods,
• 17:32I'm gonna switch gears and
• 17:34talk about something called neuromelanin.
• 17:37Next slide. Thank you. I'm
• 17:38gonna trust you to to
• 17:39do the cursive.
• 17:41So this neuromelanin synthesis pathway
• 17:44occurs with cytosolic
• 17:45catecholamines,
• 17:46so dopamine and norepinephrine
• 17:49that aren't transported into vesicles
• 17:51or degraded.
• 17:52So due to the presence
• 17:53of catecholamines,
• 17:55neuromelanin concentration is highest in
• 17:57the dopamine cells of the
• 17:59substantia nigra and ventral tegmental
• 18:01area
• 18:01and in certain norepinephrine
• 18:03cells in the locus coeruleus.
• 18:06A twenty twenty study that
• 18:07used PET imaging and neuromelanin
• 18:10imaging
• 18:11within the substantia nigra and
• 18:13ventral tegmental area did find
• 18:15that neuromelanin can be a
• 18:16proxy measure of dopamine function.
• 18:19So in our study, we
• 18:20are looking at the substantia
• 18:22nigra and ventral tegmental area
• 18:23or the SNVTA,
• 18:26And we analyzed both of
• 18:27these together due to some
• 18:29challenges in distinguishing the regions
• 18:31based on MRI signal intensity.
• 18:34Oh,
• 18:35can you hear me?
• 18:38Yeah? Okay.
• 18:40So this is because both
• 18:41regions contain neuromelanin
• 18:43producing dopaminergic
• 18:45neurons leading to similar imaging
• 18:47characteristics.
• 18:48So we also use this
• 18:50common approach where we're referring
• 18:51to this combined region.
• 18:54So the take home message
• 18:55from this slide
• 18:56is that in catecholamine
• 18:58producing areas of the brain,
• 18:59so the SNVTA
• 19:01for dopamine
• 19:02and the locus coeruleus for
• 19:03norepinephrine,
• 19:04excess catecholamines
• 19:06in the cytosol undergo this
• 19:07pathway where they are degraded
• 19:09down to neuromelanin,
• 19:10which may be a marker
• 19:11for catecholamine
• 19:13function in these areas.
• 19:15Next slide.
• 19:19So, neuromelanin granules
• 19:21accumulate gradually in the soma
• 19:23of these cells and are
• 19:24only cleared from tissue following
• 19:26cell death.
• 19:27Therefore, neuromelanin content within the
• 19:30substantia nigra and ventral tegmental
• 19:32area increases steadily throughout life
• 19:34and similar effects are seen
• 19:36in the locus coeruleus.
• 19:39When neuromelanin content crosses a
• 19:41specific threshold of stimulation,
• 19:43neuronal dysfunction and neurodegeneration
• 19:46can occur.
• 19:47And while neuromelanin
• 19:49accumulation
• 19:49seems to have a predominantly
• 19:51protective function and health,
• 19:53in these neurodegenerative
• 19:55conditions,
• 19:56having extracellular
• 19:57release of neuromelanin
• 19:58following cell death is thought
• 20:00to trigger
• 20:01inflammatory processes
• 20:02that can,
• 20:03compound the pathological process.
• 20:06So from this side, what
• 20:07I want you to know
• 20:08is that neuromelanin
• 20:10increases with age in everyone,
• 20:12but it's difficult to infer
• 20:13if higher or lower levels
• 20:15of neuromelanin
• 20:16are representing ill or beneficial
• 20:18effects, so it's important to
• 20:20be cautious when we're making
• 20:21any inferences from higher or
• 20:23lower neuromelanin,
• 20:25especially in relation to clinical
• 20:27populations.
• 20:29Next slide.
• 20:31So historically, as Juana said,
• 20:33research on catecholamines
• 20:34has focused on pet research.
• 20:36However, limitations
• 20:38associated with this method, including
• 20:40cost and invasiveness,
• 20:42have motivated the development of
• 20:44alternative neuroimaging methods for catecholamine
• 20:47function, which can be more
• 20:49safely and readily applied, which
• 20:51is where neuromelanin
• 20:52sensitive MRI comes into play.
• 20:55So neuromelanin complexes
• 20:57are paramagnetic,
• 20:58making it possible to capture
• 21:00the magnetic signature of neuromelanin
• 21:03so they're able to be
• 21:03captured non invasively
• 21:05due to this paramagnetic
• 21:06property, and this is what
• 21:08we call neuromelanin
• 21:09sensitive MRI.
• 21:12Several MRI full sequences have
• 21:14been used for neuromelanin MRI
• 21:16and in conjunction
• 21:18with the paramagnetic nature of
• 21:20these complexes,
• 21:21magnetization
• 21:22transfer is believed
• 21:24to drive the contrast in
• 21:25the new pheromelanin rich region.
• 21:28And in short,
• 21:30MT works by
• 21:32using the exchange
• 21:34of magnetization
• 21:35between
• 21:36free water protons
• 21:38and macromolecule
• 21:39bound protons, which is neuromelanin
• 21:42in these regions,
• 21:43leading to increased sensitivity in
• 21:45neuromelanin
• 21:46rich regions.
• 21:48But now that we know
• 21:50that neuromelanin sensitive MRI is
• 21:52a noninvasive
• 21:53proxy of dopamine
• 21:54function in the SNP BTA,
• 21:57why do we care about
• 21:58this region?
• 22:00As we saw earlier, acute
• 22:01THC results in increased striatal
• 22:03dopaminergic synthesis, whereas chronic cannabis
• 22:06use blunt dopamine synthesis and
• 22:08release.
• 22:09And we also saw that
• 22:10dopamine in the striatum is
• 22:11implicated in psychosis.
• 22:14The striatum doesn't contain neuromelanin,
• 22:16so striatal's opening functioning needs
• 22:18to be examined with PET
• 22:19scans.
• 22:20However, as Lano said before,
• 22:23via the nigrostriatal
• 22:24pathway, the striatum,
• 22:26receives projections from the substantia
• 22:28nigra. So presumably,
• 22:30any
• 22:31decreases in neuromelanin MRI signal
• 22:34within the SNVTA would mean
• 22:36decreased dopamine within the striatum.
• 22:38And, in fact, a twenty
• 22:39twenty study,
• 22:41used PET imaging and neuromelanin
• 22:43imaging within the substantia nigra
• 22:45and ventral tegmental area,
• 22:48found that individuals with higher
• 22:50neuromelanin
• 22:50MRI signal had greater triatal
• 22:53dopamine release capacity,
• 22:55so this suggests that examining
• 22:57neuromelanin in this area may
• 22:58be a marker of dopamine
• 23:00function
• 23:01of the nigricidal pathway.
• 23:04So that brings me to
• 23:05why we're actually using this
• 23:06to our study.
• 23:08Our data was from a
• 23:09study called Weed Outcomes and
• 23:11White Matter funded by the
• 23:12Canadian Institutes of Health Research.
• 23:15We were lucky to have
• 23:16some really great collaborators on
• 23:17this including Phil Tibble, Aly
• 23:19Khan, Rachel Rabban, and Clifford
• 23:21Cassidy.
• 23:22At baseline, we had sixty
• 23:24four participants completing clinical and
• 23:26cognitive questionnaires,
• 23:28a saliva sample to quantify
• 23:30THC content,
• 23:31and an MRI scan that
• 23:33included a two d GRE,
• 23:36neuromelanin
• 23:37sequence.
• 23:38Of these sixty four participants,
• 23:40twenty six
• 23:42had a cannabis use disorder
• 23:43and thirty eight did not
• 23:45with some participants in both
• 23:47groups having a DSM-five
• 23:49diagnosis of schizophrenia
• 23:50from a research psychiatrist
• 23:52and the cannabis use disorder
• 23:54was diagnosed by the psychiatrist
• 23:56as well.
• 23:57The first episode of schizophrenia
• 24:00participants with and without cannabis
• 24:02use disorder were recruited from
• 24:04the prevention and early intervention
• 24:06for psychosis program
• 24:08or PEP clinic in London,
• 24:09Ontario,
• 24:10and were within six months
• 24:11of entry to the program,
• 24:13so that's why we refer
• 24:14to them as first episode.
• 24:16Controls with and without cannabis
• 24:18use disorder were recruited from
• 24:20the community, and at one
• 24:21year we had thirty seven
• 24:22participants
• 24:24come back to redo all
• 24:25questionnaires, saliva, THC,
• 24:27and the MRI. And everyone
• 24:28who completed the follow-up did
• 24:30indeed have the same diagnosis
• 24:32that they had at baseline.
• 24:35Next slide.
• 24:37Next slide.
• 24:38Next slide.
• 24:40As they're excluding three participants
• 24:42due to MRI artifacts,
• 24:44we were left with thirty
• 24:45six individuals without a cannabis
• 24:47use disorder and twenty five
• 24:49with the cannabis use disorder.
• 24:52Here, I wanna highlight that
• 24:53the sample was mostly men
• 24:55and that there were numerically
• 24:57more first episode schizophrenia
• 24:59participants in the COD group.
• 25:02Additionally,
• 25:03CUD severity was collected based
• 25:05on the number of DSM
• 25:07symptoms for for CUD that
• 25:08participants met. So if they
• 25:10had two to three symptoms,
• 25:12they were classified as having
• 25:14a mild CUD,
• 25:16Four to five was moderate
• 25:17and more than six was
• 25:19severe.
• 25:20And just as a refresher,
• 25:22the DSM five defines cannabis
• 25:24use disorder as the presence
• 25:26of clinically significant impairment or
• 25:28distress in twelve months. So
• 25:30they have at least two
• 25:31of eleven symptoms including stuff
• 25:33like tolerance, withdrawal,
• 25:35trying to cut down but
• 25:36being unsuccessful,
• 25:39etcetera.
• 25:40Next slide.
• 25:43Here, I want to highlight
• 25:45that we're looking at participants
• 25:47in their early 20s.
• 25:49There was no significant differences
• 25:51found between the group with
• 25:52CUD and the group without
• 25:53CUD regarding sex, age, or
• 25:55years of education.
• 25:57The COD group had significantly
• 25:59lower premorbid IQ and category
• 26:01fluency scores but higher nicotine
• 26:03use and saliva THC levels.
• 26:07Those with COD scored a
• 26:08mean of
• 26:10ten point six of the
• 26:11possible twenty four on the
• 26:12cannabis
• 26:13substance use questionnaire
• 26:15with a mean onset age
• 26:17of around eighteen years, so
• 26:18this suggests that most individuals
• 26:20had a moderate dependence
• 26:22with less than ten years
• 26:23duration of use.
• 26:25Next slide.
• 26:28These are the results from
• 26:29just three specific questions on
• 26:31the substance use questionnaire.
• 26:33We feel this encapsulates the
• 26:35spread of cannabis use over
• 26:36the two groups quite nicely,
• 26:38so you can see that,
• 26:40the participants without COD were
• 26:42not cannabis naive and, therefore,
• 26:44they're more representative of the
• 26:45general population that shared many
• 26:48characteristics
• 26:49of the with the group
• 26:50of participants with COD except
• 26:52they didn't have the COD
• 26:54status.
• 26:55And I want to specifically
• 26:56highlight that not a lot
• 26:57of COD participants believe that
• 26:59they ever had a problem
• 27:00due to their cannabis use,
• 27:02and this really suggests that
• 27:04there is quite a big
• 27:05disconnect between clinical diagnosis and
• 27:07subjective perception of harm.
• 27:11Okay.
• 27:12So before we look at
• 27:13our main results, I want
• 27:15to highlight two important,
• 27:18methodological
• 27:19choices that we made in
• 27:20this work.
• 27:21So first, we searched for
• 27:23voxels that were significantly related
• 27:25to cannabis use disorders in
• 27:27our sample of participants,
• 27:29and we did indeed find
• 27:31voxels that were significantly higher
• 27:33in those with COD compared
• 27:34to those without.
• 27:36So post talks, we called
• 27:37those COD voxels.
• 27:40Second, we chose to analyze
• 27:41a subset of voxels based
• 27:43on a previous neuromelanin study
• 27:46and examine the mean neuromelanin
• 27:48MRI signal for those specific
• 27:50SNVTA subsets.
• 27:53And here we chose an
• 27:54external source
• 27:56to determine the psychosis possible
• 27:58subset to prevent any, like,
• 28:00circular reasoning so that any
• 28:02evidence for convergence with psychosis
• 28:04is independent of our data
• 28:06set and comes from observations
• 28:08in individuals who have not
• 28:09taken medication.
• 28:11So you can see in
• 28:11this paper
• 28:12here that,
• 28:14the subset of voxels was
• 28:16correlated with positive psychosis symptoms
• 28:18and unmedicated
• 28:20schizophrenia in the top
• 28:22and with positive symptoms and
• 28:24clinical high risk in the
• 28:25bottom.
• 28:27Next slide.
• 28:30So here are our main
• 28:32results.
• 28:34First, I wanna draw your
• 28:35attention to figure b,
• 28:38the the red one. Thank
• 28:39you.
• 28:40So on the y axis
• 28:42is the neuromelanin MRI signal
• 28:44of the COD voxels.
• 28:46So, again, those are voxels
• 28:47that are significantly
• 28:48higher in our CUD participants,
• 28:51and you can see that
• 28:52the signal is higher compared
• 28:54to the no CUD, control,
• 28:55and FES group, but that
• 28:57CUD and FES is numerically
• 29:00higher than just FES, so
• 29:01there's an additive effect.
• 29:04And this is likely due
• 29:05to our participants being medicated,
• 29:07so they have low symptom
• 29:08burden.
• 29:10In B, we're looking at
• 29:12the neuromelanin MRI signal of
• 29:14the psychosis voxels, so this
• 29:16is from that external source,
• 29:18and we can see here
• 29:19that it is indeed higher,
• 29:21in the CZ group, but
• 29:23not in the FES group,
• 29:24And, again, this is because
• 29:26our participants were medicated, so
• 29:28they had low symptom burden.
• 29:30There was also a small
• 29:31number of voxels in each
• 29:32group that had lower pneumonia
• 29:34and MRI signal, but they
• 29:36were not statistically significant, and
• 29:38they're not shown in this
• 29:39figure.
• 29:42Next.
• 29:44Similarly, if we look not
• 29:45just at the psychosis boxes
• 29:47but at the entire SNVTA,
• 29:50we do see a trend
• 29:51towards higher neuromelanin signal in
• 29:53the FES group after adjusting
• 29:55for COD. Likely,
• 29:57this is due to the
• 29:59blunting
• 30:00that the patients are on
• 30:01antipsychotics
• 30:02reducing their symptoms.
• 30:05Next slide.
• 30:08In the psychosis voxels, we
• 30:10found a significant association
• 30:13between normelanin MRI signal and
• 30:15COD severity
• 30:17with participants grouped as no
• 30:19COD, mild and moderate or
• 30:20severe.
• 30:21We chose these groupings to
• 30:23balance sample size across groups
• 30:25while still trying to preserve
• 30:26any meaningful distinctions between CUD
• 30:29severities.
• 30:30And we did find that
• 30:31most people who satisfy cannabis
• 30:33use disorder criteria
• 30:34appear to fall in the
• 30:35mild category.
• 30:37So previous research
• 30:39shows such as necessitate this
• 30:41majority to be considered as
• 30:42a separate group. Additionally,
• 30:44surveys have found that group
• 30:46being moderate and severe makes
• 30:47a subgroup with comparable size
• 30:49to mild CUD at the
• 30:50population level.
• 30:52And based on these results,
• 30:53the higher CUD severity is
• 30:55associated with
• 30:57higher psychosis blood flow signal.
• 30:59So, this indicates that an
• 31:01escalating severity of CUD may
• 31:03be associated with an increased
• 31:05neuromelanin signal
• 31:07in midbrain regions that are
• 31:08most sensitive to psychotic symptom
• 31:10burden.
• 31:14We also ran a mixed
• 31:16model analysis between voxel subsets
• 31:18and symptom scores and found
• 31:20a trend between mean neuromelanin
• 31:22MRI signals from COD voxels
• 31:25and PAM's negative scores,
• 31:27suggesting that even in treated
• 31:29individuals with schizophrenia, higher neuromelanin
• 31:31and cannabis related voxels may
• 31:33indicate higher negative symptoms.
• 31:36But here we didn't find
• 31:37any relationship between
• 31:39signal of the COD voxels
• 31:41and PANS positive or general
• 31:42symptoms
• 31:43nor psychosis voxels and any
• 31:45of the PANS subsets.
• 31:51Of course, certain limitations exist.
• 31:54As I explained earlier, neuromelanin
• 31:56increases with age, but our
• 31:57sample is relatively young,
• 32:00and we did look at
• 32:01change in neuromelanin over a
• 32:03one year period. Although we
• 32:04found nothing significant. This is
• 32:06likely due to the length
• 32:07of the follow-up.
• 32:09Our sample was small and
• 32:10were powered only to detect
• 32:12large effects over time.
• 32:15Participants did have a history
• 32:16of using other substances, although
• 32:18they did not have
• 32:20current substance use disorders,
• 32:22and patients were taking antipsychotics,
• 32:24which we know act on
• 32:25the dopamine system.
• 32:27Additionally,
• 32:28we don't know if any
• 32:29changes in neuromelanin
• 32:30signal between groups are due
• 32:31to the CUD or if
• 32:32it's the other way around,
• 32:34but our study wasn't set
• 32:35up to be able to
• 32:36address that question. So these
• 32:37are all factors that need
• 32:39to be taken into consideration
• 32:40when looking at our findings.
• 32:42Oh, and this is from
• 32:44just ahead of this. This
• 32:46is from, a meta analysis
• 32:47that we did last year
• 32:49looking at different substances,
• 32:51different substance use disorders in
• 32:53neuromyelanin, and you can see
• 32:54that it's very it differs,
• 32:56like,
• 32:57very much depending on the
• 32:58the substance. So that's another
• 33:00limit that adds to the
• 33:01limitations that participants use other
• 33:03substances.
• 33:05And with that, I'll pass
• 33:06it back to Lena for
• 33:08the conclusion.
• 33:17Can
• 33:19you
• 33:21hear me
• 33:22now? Thank you. Thank you,
• 33:23Jess.
• 33:24I have a couple of
• 33:25slides to reflect a little
• 33:26bit on the results that
• 33:28Jess showed us now.
• 33:30And after that, we'll take
• 33:31some questions if that's okay.
• 33:33So, what are the implications
• 33:34of this? You know, in
• 33:35this individual study, we did
• 33:37observe higher neuromelanin
• 33:39in people who use cannabis
• 33:40for a longer period of
• 33:41time. And the effect of
• 33:43cannabis on neuromelanin is particularly
• 33:45pronounced in people with first
• 33:47episode schizophrenia. The effect size
• 33:49is double. And this increase
• 33:51is happening
• 33:52in the same area
• 33:54where, if increase is present,
• 33:56it reflects higher severity of
• 33:58psychosis psychotic symptoms.
• 34:00So this doesn't work well
• 34:01for our patients.
• 34:02Clearly, one of the implication
• 34:03is people with the cannabis
• 34:04use disorder
• 34:05but with higher neuromelanin MRI
• 34:07signal,
• 34:08are having a problem that
• 34:10relates to expression of psychosis.
• 34:13So cannabis
• 34:13may affect the hypothesized
• 34:15final common pathway, which is
• 34:17dopaminergic pathway here for clinical
• 34:19expression of psychosis.
• 34:22You might have also seen
• 34:23that, there are, you know,
• 34:24in the larger
• 34:25mask where we did a
• 34:26search for neuromelaninib signal changes,
• 34:29we did see
• 34:30some some spots in the
• 34:31brain within the midbrain
• 34:33where CUD use was associated
• 34:36with lower neuromelanin signal.
• 34:38It wasn't statistically significant,
• 34:40but nevertheless, it is present
• 34:41in the CD users. There
• 34:43are some areas
• 34:44areas that are not so
• 34:45relevant for positive psychotic symptoms
• 34:47that are showing lower neuromelanin.
• 34:49What does it mean? Does
• 34:50it mean
• 34:51there is some neurodegeneration?
• 34:52This is a very young
• 34:53group. I would like to
• 34:54think not.
• 34:56But there is clearly a
• 34:57a mixed picture here. Increases
• 34:59happening where psychosis is where
• 35:02it is relevant for psychosis
• 35:03and there is some insignificant
• 35:05but notable drop happening in
• 35:07other places. We need to
• 35:08further examine this before we
• 35:09can be confident what this
• 35:11means.
• 35:13But I think what we
• 35:14have so far,
• 35:15helps us to come back
• 35:17to the question that I
• 35:18raised earlier, a clinical question.
• 35:21I think we have at
• 35:22least one study that can
• 35:24support you if you want
• 35:25to say there is likely
• 35:27a common alteration
• 35:28in the dopamine system in
• 35:30both cannabis users and people
• 35:31with psychosis.
• 35:33So the the line can
• 35:34be drawn between,
• 35:36dopamine,
• 35:38dope and dilutions, so to
• 35:40speak.
• 35:41Line may not be very
• 35:42thick as a single study.
• 35:43It has its limitations,
• 35:44but nevertheless, a line can
• 35:46be drawn.
• 35:47And, you know, I'll be
• 35:48more confident now to to
• 35:50talk to my patients and
• 35:50tell them if you're smoking
• 35:52weed for a while, which
• 35:53most of my patients are,
• 35:55then they're likely to have
• 35:56higher amount of dopamine in
• 35:58the same brine region where
• 35:59we don't want it to
• 36:00go up because if it
• 36:01goes up there, that relates
• 36:03to risk of psychosis,
• 36:04in particular symptoms of severity
• 36:06of psychosis.
• 36:07So this question can be
• 36:08answered with with some conviction
• 36:10now with our patients.
• 36:12But why don't we go
• 36:13next, when you, you know,
• 36:14when you have studies like
• 36:15this? I think, it's important
• 36:17to realize the limitations of
• 36:18every measurement that we do,
• 36:19clinical measurements as well as
• 36:22imaging measurements, and,
• 36:23just highlighted some of the
• 36:25technical challenges with it. So
• 36:26one of the things we're
• 36:27trying to do now is
• 36:28to see if we can
• 36:29have more sensitive measures of
• 36:30neuromelanin,
• 36:31especially can we use an
• 36:32external extrinsic magnetization transfer, MT
• 36:35pulse to to improve the
• 36:37definition of the area, SMBDA
• 36:38area,
• 36:39and really, like, pass them
• 36:41apart better so that our
• 36:42confidence in spatial precision can
• 36:45be improved.
• 36:46Secondly, we're also trying to,
• 36:47see if we can increase
• 36:49the the the amount of
• 36:50people that we follow-up over
• 36:51a period of time. As
• 36:53you might have seen in
• 36:54the flowchart,
• 36:55we were not blindly successful
• 36:57in following everybody up, and
• 36:58that's nature of the population
• 36:59we study first episode psychosis
• 37:01in a naturalistic study like
• 37:03this, especially with kambosine disease,
• 37:05tracking them back within a
• 37:06specific period of time is
• 37:07very hard.
• 37:09And we would also like
• 37:10to study older age groups
• 37:11because neuromelanin
• 37:13is an interesting signal, but
• 37:14it is sensitive to age
• 37:16in older cohorts, not in
• 37:18younger cohorts. In fact, if
• 37:19you wanna put a seventeen
• 37:21year old or a sixteen
• 37:21year old in the scanner,
• 37:23you cannot really get good
• 37:24neuromelanin signal at all because
• 37:26it takes some time for
• 37:27neuromelanin to build up in
• 37:28the brain,
• 37:29for us to define the
• 37:30signal.
• 37:32So that's something we wanna
• 37:33do, you know, later on,
• 37:34older age groups to be
• 37:35included in a study like
• 37:36this.
• 37:37Third, we are quite interested
• 37:38in seeing what happens if
• 37:39people stop smoking weed for
• 37:41a period of time. If
• 37:42they stop for, let's say,
• 37:43six months,
• 37:45would that slow down the
• 37:46neuromelanin accumulation,
• 37:48if they already have psychotic
• 37:49symptoms? We know it helps
• 37:50with cognition. We know it
• 37:51helps with relapse risk, but
• 37:53can we show that it
• 37:54also helps with neuromelanin
• 37:56signal
• 37:56plateauing, not increasing further? It
• 37:59will increase in everyone, but
• 38:00we wanna show that people
• 38:01with abstinence
• 38:02have slower increase or flatter
• 38:03increase,
• 38:04which will help us to
• 38:06make causal claims with more
• 38:07confidence.
• 38:09And we also have this
• 38:10little pet peeve. Somehow, we
• 38:11want to
• 38:12record,
• 38:14locus coeruleus signals as well
• 38:15because the signal of neuromelanin
• 38:17in locus coeruleus reflects more
• 38:19of norepinephrine
• 38:20levels than dopamine levels. So
• 38:22we would like to be
• 38:22doubly sure that what we
• 38:24see is not simply an
• 38:25artifact of our imaging technology.
• 38:27It's really document. So we
• 38:28wanna separate the, cannabis effect
• 38:30between locus and
• 38:33substantia nigra in the future.
• 38:36Well, that's that's probably it.
• 38:38This is all we have
• 38:39to say, and I wanna
• 38:40thank, all the patients as
• 38:41well, who took part on
• 38:43the study and all these
• 38:43funding agencies,
• 38:45and all the partners that
• 38:46you saw, our collaborators, especially
• 38:48Cliff Cassidy. His technology was
• 38:50very helpful for us to
• 38:51to do what we did,
• 38:52and and Phil Tibogo, who
• 38:54is a co partner in
• 38:56partner in crime for getting
• 38:57this funding and getting this
• 38:58question,
• 38:59asked in this study. So
• 39:01thank you very much. We
• 39:01are here to take questions
• 39:03and discuss this further.
• 39:09Thanks, Jess and Lina, for,
• 39:12wonderful presentation.
• 39:14You know,
• 39:15this is the first study
• 39:16looking at
• 39:18neuromelanin,
• 39:19in cannabis use in psychosis.
• 39:21So,
• 39:22I wanna open it up
• 39:23to the floor.
• 39:24Anyone has questions, feel free
• 39:26to unmute and
• 39:28ask a question. Or if
• 39:29you'd like to, you can
• 39:30type your question in the
• 39:32chat and I can repeat
• 39:33it.
• 39:35Can I ask you a
• 39:36question?
• 39:37Sure. Hi. I'm Nikkole,
• 39:39Rakesh Lab, Yale University.
• 39:41I'm just curious to know,
• 39:43if we have data,
• 39:47with,
• 39:49patients with Parkinson's
• 39:50disease treated with HCC. I
• 39:52mean, I assume that, you
• 39:53know, if you have Parkinson's
• 39:55problem, you don't develop psychosis,
• 39:57but even after, you know,
• 39:59a lot of,
• 40:00you know,
• 40:03after exposure to high dose
• 40:04of THC?
• 40:07I mean, you know,
• 40:08the the immune system is
• 40:11is affected in Parkinson's disease.
• 40:13So so what happened to
• 40:14those people?
• 40:17Thank you for that question,
• 40:18Nicola. I think it's very
• 40:19interesting. What happens to Parkinson's
• 40:21people in terms of the
• 40:22relationship between dopamine and psychosis?
• 40:24Right. I'll let Jessica tell
• 40:26a little bit about neuromalin
• 40:27studies in in Parkinson's, but
• 40:28I would just make two
• 40:29very quick comments on psychosis
• 40:31and Parkinson's.
• 40:33Parkinson's increases the risk of
• 40:34psychosis, actually. People with Parkinson's
• 40:36disease develop psychotic symptoms, but
• 40:38generally at a later stage
• 40:39of the illness, after much
• 40:41neurodegeneration
• 40:41has happened, not as first
• 40:43presentation,
• 40:44usually as later presentation.
• 40:46And also due to iatrogenic
• 40:47effects, the drugs that we
• 40:48use to treat Parkinson's like
• 40:50levodopa
• 40:51itself can increase the risk
• 40:52of hallucinations
• 40:53and and even delusions in
• 40:55in in some patients.
• 40:56So, yeah, definitely there is
• 40:58a link. But what do
• 40:59we know about dopamine in
• 41:00in Parkinson's may not match
• 41:02clearly with what we've just
• 41:03shown in nonorganic
• 41:05functional psychotic patients here? And
• 41:08Jess will tell you a
• 41:08little bit about neuromelanin studies
• 41:10in Parkinson's.
• 41:11Yep.
• 41:12Most neuromelanin studies actually are,
• 41:15done in the Parkinson's population,
• 41:17so there's a lot of,
• 41:19research on that.
• 41:21There is a decrease in
• 41:23neuromelanin,
• 41:24but it's actually thought to
• 41:25be that
• 41:26neuromelanin accumulates too much and
• 41:28then the cells die and
• 41:29that's why we're seeing the
• 41:30decrease.
• 41:33I I don't know if
• 41:34there's anything you wanna add,
• 41:35Lana.
• 41:36Yeah. That's that's probably true.
• 41:38So
• 41:40there's a reduction in neuromelanin
• 41:41that been shown in Parkinson's
• 41:43patients. In fact, there's no
• 41:45no MRI study has documented
• 41:47any increase in the neuromelanin
• 41:48at all in Parkinson's. There's
• 41:49postmortem studies where early stage
• 41:51Parkinson's have shown signals of,
• 41:54in in some neurons, there
• 41:55is a signal of increased
• 41:56neuromelanin, but larger effect is
• 41:58a reduction of neuromelanin in
• 41:59Parkinson's. And every MRI study
• 42:00has shown the same reduction
• 42:02of neuromelanin.
• 42:03So Parkinson's psychosis may not
• 42:05be explained by increase in
• 42:06neuromelanin,
• 42:07so to speak. I see.
• 42:10There's a question by Marjorie.
• 42:11Marjorie, do you wanna ask
• 42:12your question, or do you
• 42:13want me to just read
• 42:14out your question
• 42:16from the chat?
• 42:18No. Sure. Hi. My name
• 42:19is Marjorie.
• 42:20I'm a nurse. I'm from
• 42:21VCU Health.
• 42:23So, yes, as I'm listening
• 42:25to all this,
• 42:27it's really interesting. Thank you
• 42:29all for your time and
• 42:30for, you know, for,
• 42:32presenting, giving us this knowledge
• 42:34to consider.
• 42:36Just wondering when it comes
• 42:37to other substances, and we
• 42:39we work, of course, with
• 42:40lots of patients with opioid
• 42:42use disorder,
• 42:43some treated, some that aren't
• 42:45on treatment yet.
• 42:46So just wanted to know
• 42:48if the dopamine
• 42:50surge that people on other
• 42:52substances and, of course, I'm
• 42:53really thinking about opioids.
• 42:56Does that also,
• 42:59do the same thing as
• 43:00cannabis as far as increasing
• 43:02dopamine in that particular part
• 43:04of the brain?
• 43:07Because I think again, are
• 43:09are they also now preemptively
• 43:11a precursor for psychosis development?
• 43:16Yeah. Thanks for the question,
• 43:18Marjorie. Just spent eighteen months
• 43:19of her life trying to
• 43:20answer this question, so I
• 43:21will let her tell you
• 43:22the findings she has.
• 43:24Thank you.
• 43:27Yeah. So,
• 43:30from what I Lana can
• 43:31can totally correct me,
• 43:34but I believe that opioids
• 43:35inhibit
• 43:36the GABA neurons in the
• 43:38VTA.
• 43:39So then there's increased dopamine
• 43:41release in the striatum that
• 43:42way,
• 43:44which means that there would
• 43:46be,
• 43:47with chronic opioid use, there's
• 43:49increased dromelanin levels,
• 43:51so definitely a similar
• 43:53situation happening there.
• 43:57Yeah. Just to add to
• 43:58that, you know, but imaging
• 44:00studies, the meta analysis that,
• 44:01just showed, we looked at
• 44:03all the different substance uses
• 44:05like cocaine use, you know,
• 44:06cannabis, including cannabis and other
• 44:08substances as well.
• 44:10There is no convincing evidence
• 44:11demonstrated in clinical samples that
• 44:13neuromelanin
• 44:14goes up in any other
• 44:16substance users yet. So, you
• 44:18know, the the medicines we
• 44:19showed was really like null
• 44:20result.
• 44:22Part of the problem is
• 44:23studies are very insufficiently
• 44:25sampled.
• 44:26Power is very low to
• 44:28to demonstrate something like this.
• 44:29We need more evidence to
• 44:31to really like answer this
• 44:32question with any conviction.
• 44:34Mhmm. Okay. Thank you so
• 44:35much.
• 44:37And there's a question by
• 44:38Cameron Davidson. Cameron, do you
• 44:40wanna ask a question or
• 44:42would you like go ahead.
• 44:43Sure. Absolutely.
• 44:45First off, interesting presentation. Thank
• 44:47you. Good good presentation overall.
• 44:50My question is like,
• 44:51is more of a fundamental
• 44:53question about your perception of
• 44:55of this effect. Is this,
• 44:58do you believe that this
• 44:59is,
• 45:02partially related to genetic predisposition
• 45:05and that those are those
• 45:06who are more predisposed are
• 45:08more likely to get it?
• 45:09Or do you think that
• 45:10eventually, even neurotypical people who
• 45:12have maybe some resistance
• 45:14to this interference with the
• 45:15dopaminergic system, do you think
• 45:17that they would eventually develop
• 45:19this,
• 45:20based upon enough
• 45:22extreme use and for the
• 45:24long enough duration. Is
• 45:26that sort of the argument
• 45:27that you're making or is
• 45:28it
• 45:28we're capturing the predisposition
• 45:31at least in this study
• 45:32and then,
• 45:34looking at it in a
• 45:35different way?
• 45:37That's a very thoughtful question,
• 45:40Cameron. So if I if
• 45:41I understand correctly, you
• 45:43you're thinking
• 45:44there may be some people
• 45:45who are using cannabis
• 45:47for a long period of
• 45:48time. They may not show
• 45:49any dopamine excess, no neuromelan
• 45:51excess, but they may still
• 45:52develop psychosis because
• 45:54they, they have alternate
• 45:56mechanisms to develop psychosis. Is
• 45:58that right? Correct. That that's
• 45:59part of it as well.
• 46:00That's that's part of it
• 46:02as well as may it
• 46:03may not be dopamine related
• 46:04psychosis. It might be something
• 46:06else. But,
• 46:08my question is is is
• 46:09it just the interference with
• 46:10the system
• 46:11that eventually leads to this
• 46:13or are there do you
• 46:14believe that there might be
• 46:15individuals who might be maybe
• 46:16resistant or resilient to this
• 46:17type of
• 46:18dopaminergic interaction?
• 46:20Yeah. That's, you know, I
• 46:21I'm talking deeply about it,
• 46:23but that's that's really a
• 46:23good point. I mean, one
• 46:24thing to think about,
• 46:26here is,
• 46:28is dopamine essential? Is dopamine
• 46:30excess essential for psychosis?
• 46:32I think if you look
• 46:33at all of these final
• 46:34common pathway arguments,
• 46:36the arguments take the tone
• 46:37that you need to have
• 46:38some level of dopamine excess
• 46:39to develop psychotic symptoms in
• 46:41the first place. But notwithstanding
• 46:43all that arguments, you actually
• 46:45see a substantial number of
• 46:46people not responding to antipsychotics,
• 46:47not responding to dopamine manipulation
• 46:50in any way and and
• 46:51not developing psychotic episodes after
• 46:53taking, you know, dopamine releasing
• 46:54substances like cocaine and whatnot.
• 46:56So there's clearly an alternate
• 46:58pathway to psychosis that has
• 47:00nothing to do with dopamine,
• 47:01I would say, from from
• 47:02what we know so far.
• 47:03What the pathway is a
• 47:04million dollar question. I think,
• 47:05you know, part of us
• 47:07are trying to answer that.
• 47:08And what kind of is
• 47:09addressed to that pathway will
• 47:10only become clear if you
• 47:11know what pathway we're talking
• 47:12about other than the document.
• 47:14So I I completely agree
• 47:16with your it's sympathized with
• 47:17your sentiments, but I don't
• 47:18think any of us have
• 47:19good answer for for that
• 47:21at the moment.
• 47:22Sorry. I just wanted to
• 47:23ask the, of course, fundamental
• 47:25question or philosophical question. Thank
• 47:26you for your answer.
• 47:29Sydney, you have a question.
• 47:31Would you like to ask
• 47:32it?
• 47:37Oh,
• 47:38so the question that Sydney
• 47:40has is, is there any
• 47:41information regarding the effect of
• 47:43the method of cannabis use,
• 47:46or the percentage of THC
• 47:48in products
• 47:50in relation to symptoms, diagnoses
• 47:52of psychosis?
• 47:54Cyril, you may be able
• 47:55to answer that question better
• 47:56than anyone else. I've already
• 47:58acknowledged your face.
• 48:00Sure. Sure. So I think
• 48:01there's pretty convincing evidence that,
• 48:04the THC content of of
• 48:06cannabis is what's really critical.
• 48:08There have been epidemiological
• 48:09studies shown by, you know,
• 48:11Marta De Forti et al.
• 48:13And publishing Lancet Psychiatry
• 48:15showing that
• 48:17if you use,
• 48:18high potency cannabis and by
• 48:20the way, high potency cannabis
• 48:21in that study was ten
• 48:23percent THC, which we now
• 48:25know is pretty weak cannabis
• 48:26in this day and age.
• 48:28But if you used high
• 48:29potency cannabis and you used
• 48:31it daily,
• 48:32your risk of schizophrenia was
• 48:33six times higher than if
• 48:35you didn't use cannabis at
• 48:36all.
• 48:37So there is an information
• 48:38about that. The,
• 48:41you know, the effect of
• 48:42CBD is an intriguing one.
• 48:44There's some studies suggesting that
• 48:46CBD may even have antipsychotic
• 48:48effects, but,
• 48:49I think the jury is
• 48:50still out there. Some studies
• 48:52suggesting that, but other studies
• 48:54not showing,
• 48:55not showing that. So,
• 48:57so, yeah, I hope I
• 48:58answered that question.
• 49:01If you can indulge me,
• 49:03Lena and Jess, I have
• 49:05a few questions of my
• 49:06own. One would be
• 49:07one is more a suggestion
• 49:08than anything. I think it's
• 49:09really cool that you're thinking
• 49:11about,
• 49:12about looking at what happens
• 49:14when people abstain from using
• 49:15cannabis.
• 49:16What happens to neuromelan, and
• 49:18is it something reversible?
• 49:19I would also suggest that
• 49:21you consider the the opposite,
• 49:23which is some of the
• 49:24subjects who are not using
• 49:25cannabis
• 49:26are likely to start using
• 49:28cannabis in the future.
• 49:29And so that would be
• 49:30that if the mirror,
• 49:32image of an abstinence study,
• 49:34so what happens to
• 49:36someone who's not using, who
• 49:37starts using, what happens to
• 49:38neuromelanin in in those subjects.
• 49:41That's so that's a suggestion
• 49:42that I would consider.
• 49:44My question,
• 49:45or my comment has to
• 49:46do with the role of
• 49:47dopamine,
• 49:49and in
• 49:50in cannabis related psychosis.
• 49:52So
• 49:53when you look at the
• 49:54PET studies,
• 49:56the PET studies have fairly
• 49:58mixed,
• 49:59results. There's some studies that
• 50:00have shown
• 50:01some small increase in dopamine
• 50:03release, other studies
• 50:05showing no change,
• 50:07at all,
• 50:08and,
• 50:10and clearly not anywhere in
• 50:11the range of what,
• 50:13what happens when you give
• 50:14someone say dopamine amphetamines
• 50:16or or a stimulant.
• 50:19And then in our hands,
• 50:20we found that in the
• 50:21experimental study that,
• 50:23the sister
• 50:25experimental study that you showed
• 50:26here where we gave,
• 50:28people with schizophrenia,
• 50:29invited them to take part
• 50:31in the study where they
• 50:31received THC.
• 50:33We found that treatment with
• 50:34dopamine
• 50:35antagonists
• 50:38did not blunt
• 50:39the
• 50:40effect of THC. So that
• 50:41was in people with schizophrenia.
• 50:43And then we did a
• 50:44follow-up study in healthy individuals
• 50:47where we gave them
• 50:48haloperidone,
• 50:49the prototypical tip, antipsychotic
• 50:52to see whether it would
• 50:53block the effects of THC.
• 50:55And we we really didn't
• 50:56find that convincing,
• 50:58you know, effect. So I'd
• 51:00like you to, to comment
• 51:02a little more on on
• 51:03on dopamine as being central
• 51:05to the,
• 51:06to the psychosis like effects
• 51:08of of THC.
• 51:09Yeah. That's, that's great,
• 51:12points to rely. I have
• 51:13to look up those studies
• 51:14that you mentioned in more
• 51:15detail, but fascinating to see
• 51:17antipsychotics
• 51:18do not alleviate or nullify,
• 51:21the expected dopamine mediated effects
• 51:23of cannabis.
• 51:24The, point that, you know,
• 51:25one point to take from
• 51:26the new imaging study that
• 51:28we just showed is that
• 51:29these effects, when did they
• 51:31happen cannot be answered.
• 51:33You know, these people have
• 51:34been using, cannabis for seven
• 51:35years on average, and most
• 51:37of them have been using
• 51:37for ten years, minimum,
• 51:40ten years at at at
• 51:41a stretch, you know, without
• 51:42any interruptions.
• 51:43So
• 51:44the elevation might have happened
• 51:46at a very early stage.
• 51:47It's really hard to say
• 51:48at what point the cycles
• 51:49of this is related to
• 51:50the the actual elevation.
• 51:52And the effects we see
• 51:54cannot be taken as acute
• 51:55effects at all. So, you
• 51:56know, whether antipsychotics will reverse
• 51:58any of them, I I
• 51:59would be very doubtful.
• 52:00Antisecondics will change
• 52:02them in any way. And
• 52:03and and what you what
• 52:04you just,
• 52:06discussed is all effects at
• 52:07the release level, the synthesis
• 52:09level, at the strata level,
• 52:10I guess, not really at
• 52:11the dopamine neuron count level,
• 52:14which takes longer time to
• 52:16present in the neuromyelomine signals.
• 52:19And, you know, I I
• 52:20do I'm going back to
• 52:20Cameron's question as well with
• 52:22with the point that you
• 52:23made. I I don't think
• 52:23we can say anything about
• 52:25the central or the primacy,
• 52:27the cardinal role that dopamine
• 52:29plays in in psychosis from
• 52:31studies like this in any
• 52:32way. And I think, you
• 52:33know, there is this clearly
• 52:34a
• 52:35large unknown, the unexplained variance
• 52:38of psychosis, so to speak,
• 52:40which overlaps a lot with
• 52:41the unexplained variance of the
• 52:42cannabis' effect on on psychosis
• 52:45risk as well. And unless
• 52:46we have
• 52:47some leads,
• 52:49to be investigated theoretical
• 52:51basis investigated those links, I
• 52:53think we'll continue to be
• 52:54shooting in the dark for,
• 52:56for what other mechanisms are
• 52:57there.
• 52:58Thanks for the answer. Can
• 53:00you can you just repeat?
• 53:01And then I know you
• 53:02guys have already said this,
• 53:04and maybe I didn't understand
• 53:06it really well.
• 53:08So the the neuromelanin findings
• 53:10are not findings that would
• 53:12reflect
• 53:13some acute effect.
• 53:15It's something that would reflect
• 53:17a much more,
• 53:20maybe you can just say
• 53:21it yourself. Yeah. So it's
• 53:22a it's a longer effect.
• 53:23So the the biggest difference
• 53:25between a PET study and
• 53:26a neuromyelins studies like this
• 53:27is the sensitivity
• 53:29of signal
• 53:30to change
• 53:32the time scale of the
• 53:33sensitivity
• 53:34is very different. So you
• 53:35can have a challenge that
• 53:36increases
• 53:38the pet signal, you can
• 53:39have an after treatment challenge
• 53:40that changes pet signal, but
• 53:41you cannot do those things
• 53:42to show a a difference
• 53:43in neuromelanin signal because neuromelanin
• 53:46signal comes from dopamine auto
• 53:47oxidation, which is a longer
• 53:49process. It takes time to
• 53:50accumulate in the cytosol.
• 53:52By just giving a drug
• 53:53challenging,
• 53:54challenge paradigm, you cannot change
• 53:56that that signal.
• 53:57Now having said that, there
• 53:58are studies in Parkinson's
• 54:00showing people who are doing
• 54:01exercise programs for six months
• 54:03are showing some,
• 54:04changes in in neuromelative signal.
• 54:06But mind you, those changes
• 54:08are really slowing down of
• 54:10reduction
• 54:11rather than increase or decrease
• 54:13in the pet sense is
• 54:15really slowing down of the
• 54:16trajectory and that's over six
• 54:17months period.
• 54:18So the bottom line is
• 54:19you cannot do the same
• 54:21thing that you do with
• 54:21pet studies using your mammalian
• 54:23signals.
• 54:27Great. Other questions?
• 54:30If not, I have one
• 54:31other. And I noticed that
• 54:32in your sample,
• 54:33most of the cannabis use
• 54:35disorder subjects were also smokers,
• 54:37tobacco smokers. Yes. And can
• 54:39you speculate on
• 54:41the impact of tobacco smoking
• 54:43on neuromelanin?
• 54:46Yes.
• 54:47Yeah. We we did control
• 54:48for that in all of
• 54:49our,
• 54:51analyses.
• 54:52There was no difference at
• 54:53all. So
• 54:55likely just because of it's
• 54:56the same participants where it
• 54:58could be that we're looking
• 54:59at the nicotine effect,
• 55:01and the cannabis effect together,
• 55:03but from the study, we
• 55:05we weren't able to to
• 55:06look at that exactly.
• 55:09Yeah.
• 55:10I have to also admit
• 55:10that we, you know, we
• 55:11don't have good quality nicotine
• 55:13data here, Cyril. We we
• 55:15we added a lot of
• 55:16these, assessments,
• 55:18afterthought, really, you know, especially
• 55:20with Rachel Regan's involvement. We
• 55:22started thinking more about nicotine
• 55:23and its role,
• 55:25and did some follow back.
• 55:26For example, we didn't quantify
• 55:28nicotine in any other way.
• 55:29For cannabis, we had saliva,
• 55:30THC, and all that kind
• 55:31of stuff. But for nicotine,
• 55:33it's really a self rated
• 55:35admission that people said.
• 55:40Great. Other questions?
• 55:46I wanna be respectful
• 55:48of everyone's time, but thank
• 55:50you so much, Jess and
• 55:52Lena, for this wonderful presentation.
• 55:55Thank you for the opportunity.
• 55:57No. And and and,
• 55:59hopefully, we'll have you back
• 56:00in some in, you know,
• 56:01in the following years with
• 56:02new data.
• 56:04Just for the rest of
• 56:05the group, I wanted to
• 56:06mention that next month,
• 56:08webinar, we have Ryan Bogdan
• 56:10who's gonna be presenting
• 56:12data on cannabis effects from
• 56:14the group, the big ABCD
• 56:16study.
• 56:17Please see if you can
• 56:18join and, of course, Lena
• 56:20and Jess, you're welcome to
• 56:21join if you'd if you'd
• 56:22like to.
• 56:23So thank you again, and,
• 56:26and we we really appreciate
• 56:28it.
• 56:28Thank you, Suru. Thank you,
• 56:30Wendy as well for all
• 56:30your help. See you all.
• 56:33Great.
• 56:35Thanks.
• 56:36Bye bye. Bye.