YC-SCAN2 October 2025 Webinar

Transcript

• 00:01Good afternoon, everyone. It's, it's
• 00:03my great, pleasure to introduce
• 00:06my friend and today's speaker,
• 00:08professor Marta DeForti.
• 00:11She is a
• 00:13clinician scientist whose work has
• 00:15has really fundamentally
• 00:17shaped
• 00:18our, understanding of the link
• 00:21between cannabis
• 00:22and psychosis.
• 00:24Professor DeForti holds the chair
• 00:26in drug use, genetics, and
• 00:28psychosis
• 00:29in the department of social,
• 00:31genetics and developmental psychiatry at
• 00:34King's College in London
• 00:36and serves as an honorary
• 00:38consultant,
• 00:40adult psychiatrist,
• 00:41with the South London and
• 00:43Maudsley,
• 00:44NHS Foundation Trust.
• 00:47Her research,
• 00:49sits at the crossroads
• 00:51of psychiatry,
• 00:52genetics, and substance use,
• 00:54epidemiology.
• 00:57Through her clinical work with
• 00:58young people experiencing first episode
• 01:00psychosis,
• 01:02professor DeForti has observed firsthand
• 01:04the impact of cannabis use,
• 01:06particularly high potency,
• 01:09high THC varieties,
• 01:12and she's gone on to
• 01:13provide some compelling evidence linking
• 01:15use of these,
• 01:17of these products with the
• 01:18increased risk of psychotic disorders.
• 01:21Amongst her many contributions,
• 01:23as a clinician,
• 01:24she has
• 01:26founded the the the United
• 01:27Kingdom's
• 01:28first dedicated cannabis clinic
• 01:31for patients with psychosis, creating
• 01:33a bridge
• 01:34between clinical care,
• 01:36mechanistic research, and public health.
• 01:39In twenty twenty, she was
• 01:40awarded a senior research fellowship
• 01:42from the u UK's medical
• 01:44research count council
• 01:46to continue her work.
• 01:47And most recently, and I
• 01:49had the pleasure of being
• 01:50present for this, she was
• 01:52she received the twenty twenty
• 01:54five outstanding
• 01:55translational research award
• 01:57from the Schizophrenia International Research
• 01:59Society.
• 02:01Her vision is to illuminate
• 02:03how individual vulnerability genetics and
• 02:05epigenetics
• 02:07interacts with cannabis exposure
• 02:10to influence
• 02:11psychosis onset and outcomes.
• 02:14She
• 02:16so please
• 02:17join me in welcoming professor
• 02:18Marta DiForti.
• 02:20And
• 02:23in today's presentation,
• 02:24feel free to,
• 02:26to jump in and ask
• 02:27questions during the talk. Don't
• 02:30wait till the end. We'd
• 02:31like to make this as
• 02:32interactive as prop as possible.
• 02:34So,
• 02:35Marta, the stage is yours.
• 02:38Thank you very much, Cyril.
• 02:39And I would like to
• 02:40say that it's very embarrassing
• 02:42when friends introduce you because
• 02:44they are far too kind.
• 02:45But, actually, I still remember
• 02:48the first time I've ever
• 02:50met Cyril at a conference
• 02:51in Washington, and I was
• 02:52blown away
• 02:54by his data. So I
• 02:55would like to say that
• 02:56anything that I might have
• 02:58done since
• 02:59has been heavily influenced
• 03:00by actually
• 03:02Cyril pioneering work
• 03:04in understanding how cannabinoid
• 03:06can sort of exacerbate
• 03:08and precipitate,
• 03:10psychosis. So thank you, serial,
• 03:12for having me in in
• 03:13your home.
• 03:15So I guess
• 03:17I very interested in cannabis
• 03:19use and psychosis because this
• 03:20is something that where I
• 03:22work as a psychiatrist, as
• 03:23a clinician in inner city
• 03:25London
• 03:25is in your face. You
• 03:27cannot ignore it, and I
• 03:28will tell you a little
• 03:29bit more,
• 03:31about it. So first of
• 03:33all, I just want to
• 03:33start by reminding us all
• 03:36that there have been, to
• 03:38date, free meta analysis, which
• 03:39are really the way in
• 03:41research we tend to make
• 03:43sense of all the studies
• 03:44that have been published in
• 03:46a specific area. And in
• 03:47this case, all the studies
• 03:49that have explored
• 03:51the association between cannabis use
• 03:53and psychotic disorder. And what
• 03:55is quite interesting is that
• 03:56while the phase two meta
• 03:58analysis suggested
• 03:59that if you use cannabis,
• 04:01you double your risk of,
• 04:03psychotic disorder, the third meta
• 04:05analysis approached this question in
• 04:07a different way. Now if
• 04:09we were all together,
• 04:10perhaps in the beautiful Yale
• 04:12library where Cyril is,
• 04:14I would ask you this
• 04:15question.
• 04:16Have you ever used alcohol?
• 04:17Yes or no? So I
• 04:19can't see you, but if
• 04:20I ask people to put
• 04:21their hand up is the
• 04:22answer is yes.
• 04:24And I would suspect probably
• 04:26most of you would say
• 04:27that you have tried alcohol
• 04:29at some point in your
• 04:30lifetime.
• 04:31Now the first two met
• 04:32Analia, I can see Wendy.
• 04:33Thank you. Put her hand
• 04:34up. Well, Wendy, I guess
• 04:36this would tell me nothing
• 04:37about your risk
• 04:38of developing either liver disease
• 04:40or or or even neurological
• 04:42consequences of alcohol consumption because
• 04:44I don't know if you
• 04:45mean that you've tried it
• 04:47twice or that you drink
• 04:48a bottle of whiskey every
• 04:49day. So it's interesting that
• 04:51these first studies,
• 04:52even if they had a
• 04:53very sort of vague approach
• 04:55to the question, have you
• 04:56used cannabis? Yes or no?
• 04:58They were able to identify
• 05:00a signal of increased risk.
• 05:02And then there was a
• 05:03third meta analysis that is
• 05:04the most recent
• 05:06done as a senior author
• 05:08by doctor Vasus
• 05:09who works in the same
• 05:10department as me. And what
• 05:12Vangelis
• 05:13did, he identified
• 05:15studies that had some sort
• 05:17of measure of amount of
• 05:18consumption,
• 05:20and he created statistically
• 05:22a continuous measure of cannabis
• 05:23exposure that you can see
• 05:25here on the x axis.
• 05:27And each line represent
• 05:29actually one of the study
• 05:31enter on the meta analysis.
• 05:32And you can see that
• 05:33for each of the study,
• 05:35greater is the cannabis exposure,
• 05:37higher is the probability,
• 05:39of developing a psychotic disorder.
• 05:41And in this case, for
• 05:43heavy cannabis use, the overall
• 05:45effect went up to a
• 05:46fourfold
• 05:47increase in the risk for
• 05:48psychotic disorder,
• 05:50indicating that when you get
• 05:51close to understand actually how
• 05:53much people are using,
• 05:55you get a better sense
• 05:56of how strong is,
• 05:58this association. And Vangelis knows
• 06:00I always make the comment
• 06:02that you can see him
• 06:03lying flat because cannabis is
• 06:05not only bad for who
• 06:07takes it, sometimes also for
• 06:09people that heavily research it
• 06:10because it can be quite
• 06:12time consuming. So he's resting
• 06:14after the publication of of
• 06:16the meta analysis.
• 06:17But now I'm going to
• 06:19let
• 06:20one of the people with
• 06:21lived experience
• 06:22of cannabis use and psychosis
• 06:24to share with you a
• 06:25message that is very dear
• 06:27to him, but is also
• 06:29very important to him. And
• 06:30this is Adam
• 06:33that works with me at
• 06:33the cannabis clinic.
• 06:35Oops. Sorry. I pressed the
• 06:37wrong bit.
• 06:44Two ninety five, I started
• 06:45getting high, and that's, like,
• 06:47thirty years ago. And I'm
• 06:49only just coming back to
• 06:50thinking of career, you know,
• 06:51serious things in the future.
• 06:53So if I can say
• 06:55somebody thirty years,
• 06:57I'll easily do that because
• 06:58I would I would like
• 06:59it if they did it
• 07:00to me.
• 07:01So
• 07:02I think this is a
• 07:03very powerful message because
• 07:06Adam was a very skilled
• 07:08psychology student.
• 07:09He went to Canada
• 07:11for a gap year,
• 07:13and he found himself in
• 07:15a circle a social circle
• 07:17where everybody were using cannabis.
• 07:19He developed very severe psychosis.
• 07:21He didn't really see the
• 07:22association between the two, and
• 07:24he started a vicious circle
• 07:26of
• 07:27using, becoming unwell, going to
• 07:28hospital, getting better, becoming unwell,
• 07:30and so on. And took
• 07:31him fifteen years before he
• 07:34stopped cannabis, and he's now
• 07:36thirty years since he's first
• 07:37joined that he's really beginning,
• 07:40as he says,
• 07:41you know, a new life.
• 07:42And so he feels very
• 07:44strongly about sharing a message
• 07:46and, as he said himself,
• 07:48saving people the thirty years
• 07:50have been absorbed for in
• 07:52his own experience by
• 07:54cannabis associated psychosis.
• 07:56And if we had more
• 07:57time, I would have let
• 07:58you listen to Adam until
• 08:00the end of the video
• 08:01where he also explained what
• 08:03actually is psychosis in the
• 08:04context of cannabis use was
• 08:06about.
• 08:07And instead, to to make
• 08:08it shorter, I'm going to
• 08:09use this cartoon
• 08:10that has actually been
• 08:12created by people
• 08:14under my care where
• 08:16they begin to experience the
• 08:18outside environment as progressively
• 08:21more and more intrusive and
• 08:23and and hostile.
• 08:24They feel under surveillance. They
• 08:26feel that people in the
• 08:27street are not just looking
• 08:28at them randomly, but they're
• 08:30actually looking at them intentionally,
• 08:32meaning,
• 08:33in in a threatening meaning.
• 08:35And this sense of persecution
• 08:37tends to leak
• 08:39as well into the place
• 08:40where we should all feel
• 08:42safe by definition, which is
• 08:43their own house. And they
• 08:45begin to worry that the
• 08:47neighbors are against them. They
• 08:48are spying upon them. They
• 08:50put a microchip under the
• 08:51floorboards.
• 08:52They feel the television is
• 08:54referring to their own life.
• 08:55They describe their brain as
• 08:58transparent
• 08:59and on fire. And you
• 09:00can imagine how this is
• 09:02something that has a huge
• 09:03disabling impact
• 09:04on the ability to go
• 09:06out, to get by with
• 09:07everyday life, and also in,
• 09:09having sort of a healthy
• 09:11and trusting relationship with with
• 09:13other people.
• 09:14And these symptoms are not
• 09:16just subjective experience.
• 09:18They've also been described in
• 09:20research as a characteristic of
• 09:22people that develop psychosis in
• 09:23the context of cannabis use
• 09:25where paranoia, if you like,
• 09:27persecutory belief are actually at
• 09:29the core of, cannabis associated
• 09:32psychosis. And this is something
• 09:33that also professor D'Souza has,
• 09:35has shown in in in
• 09:37many of his,
• 09:39of his of his paper
• 09:40with his with his team.
• 09:42And,
• 09:43one thing we have always
• 09:45been interested is in the
• 09:46question, of course, by all
• 09:48means, not all cannabis use
• 09:50a developed psychosis.
• 09:51And so going back to
• 09:53the meta analysis, something that
• 09:54I've always wanted to understand
• 09:57was
• 09:58the nature of this dose
• 09:59response,
• 10:00which were the sort of
• 10:02aspect of the pattern of
• 10:03use that perhaps were driving
• 10:05the strongest association.
• 10:07I mean, you would know
• 10:08that if you are trying
• 10:10to understand if somebody, maybe
• 10:12a dear one, a friend
• 10:13is drinking too much alcohol,
• 10:15you would not just ask
• 10:16them again, have you drinking
• 10:18alcohol? Yes or no. You
• 10:19would want to know perhaps
• 10:20how many units, how frequently
• 10:22they are using, what type
• 10:23of alcohol they are using.
• 10:25And so in a very
• 10:26similar way,
• 10:27we had data on detail,
• 10:29cannabis use
• 10:31from, a very large collaboration
• 10:33study that included eleven sites
• 10:36across Europe
• 10:37where, first of all, we
• 10:39were trying to
• 10:40measure the incidence rate of
• 10:42psychotic disorders. So how many
• 10:43people in each site were
• 10:45developing psycho psychosis every year
• 10:48per one hundred thousand, which
• 10:49is the way you measure
• 10:50incidence, and then explore how
• 10:52different risk factors
• 10:54were contributing to this.
• 10:56And, of course, as you
• 10:57can imagine, I was interested
• 10:58in cannabis use. And so
• 11:00in this graph, I'm just
• 11:01going to show you the
• 11:03data from the three largest
• 11:05city of the study, London,
• 11:07Amsterdam,
• 11:08and, and Paris.
• 11:09And what we did was
• 11:11we combined
• 11:13data on how frequently people
• 11:15were using cannabis
• 11:17with the potency of the
• 11:18cannabis we were they were
• 11:19using. And the potency was
• 11:21described in terms of THC
• 11:24concentration of the type of
• 11:25cannabis available.
• 11:27And we had a cutoff,
• 11:28which was mostly informed
• 11:30in a conservative way by
• 11:31experimental study
• 11:33where THC
• 11:35equal or greater than ten
• 11:36percent was considered hypotency,
• 11:38less than ten percent low
• 11:40potency. You will probably laugh
• 11:41at this because I know
• 11:42in the states, ten percent
• 11:44is a pretty pathetic,
• 11:46amount of THC and actually
• 11:47in London now as well.
• 11:49But in those days, it
• 11:50was a quite conservative way
• 11:52to to have a little
• 11:53begin to have a sense
• 11:54of how potency
• 11:55might shape the relationship between
• 11:57cannabis use and psychosis.
• 11:59And you can see that
• 12:00in these three cities,
• 12:02when you look at the
• 12:03green bar, which represent people
• 12:05that were using daily, this
• 12:07high potency ten percent and
• 12:09more THC type of cannabis.
• 12:11In London, they had an
• 12:13increase
• 12:14in the probability of developing
• 12:15a psychotic disorder of five
• 12:17times compared to never user,
• 12:19which is this group here.
• 12:20In Amsterdam, over nine times,
• 12:22and in Paris, over four
• 12:23time. And Amsterdam is really
• 12:26representing a place where in
• 12:28those days, ten percent wasn't
• 12:30very common. It was thirty
• 12:31percent very common. And so
• 12:33that that's what is really
• 12:34driving the this very high,
• 12:36sort of, probability. And this
• 12:37was the case even when
• 12:39we control
• 12:40for non social demographic. They
• 12:42are associated with psychosis
• 12:43and also other drug of
• 12:45abuse that we know are
• 12:46associated with risk of psychotic
• 12:48disorder.
• 12:50And we were also interested
• 12:51in calculating something that is
• 12:53called the population attributable fraction
• 12:56which is really a statistical
• 12:57way to estimate
• 12:59once you have identified
• 13:01a risk factor that you
• 13:02know has a causal role
• 13:04in the onset of a
• 13:05disease
• 13:07and you have a specific
• 13:08you have data on how
• 13:10common it is on a
• 13:10specific geographical area, you can
• 13:13actually estimate
• 13:14the proportion of new cases
• 13:16of the disease that you
• 13:17can prevent if that disorder
• 13:19was
• 13:20abolished.
• 13:21And so in this case,
• 13:22we were able to estimate
• 13:24that if hypotensive cannabis
• 13:27was no longer available in
• 13:28southeast London, which is actually
• 13:29where I work, we could
• 13:31prevent every year up to
• 13:33thirty percent of new cases
• 13:35of psychosis and in Amsterdam,
• 13:37up to fifty percent. Now
• 13:38either that you are a
• 13:39clinician or you are a
• 13:40loved one or somebody with
• 13:42with psychosis,
• 13:43you will know these are
• 13:44huge numbers,
• 13:46that that have a great
• 13:47impact to an individual and
• 13:48also at a sort of
• 13:50health services,
• 13:52level.
• 13:53And, of course, when we
• 13:55publish this data,
• 13:57people
• 13:59share their skepticism, which I
• 14:00think is is is right
• 14:01and understandable and provokes discussion.
• 14:03And they said, well, you
• 14:04know, maybe this is really
• 14:06all confounded by genetic
• 14:09vulnerability. So it might just
• 14:11be that
• 14:12people that use sort of
• 14:14cannabis, heavily,
• 14:16they are people that got
• 14:17lots of genes for schizophrenia,
• 14:19and so they would have
• 14:20developed psychotic disorder anyway. So
• 14:23we wanted to look at
• 14:24this question again in this,
• 14:27multisite European
• 14:29study because we had as
• 14:30well as data on cannabis
• 14:32use, we we we had
• 14:33DNA.
• 14:34So this is really the
• 14:35work of my postdoc, Isabel
• 14:37Austin Zimmermann, and,
• 14:40and Eduardo Spinazzola, who is
• 14:42a colleague psychiatrist
• 14:43and and and current PhD
• 14:44student.
• 14:45So we had the data
• 14:47from from this European study,
• 14:48and we also had data
• 14:49from the UK bio biobank,
• 14:51which is a very large
• 14:52population,
• 14:54sample from, from UK.
• 14:56And the first question we
• 14:58wanted to address was,
• 15:00if you look at the,
• 15:02impact that daily cannabis use
• 15:04has on risk of psychotic
• 15:05disorder,
• 15:06what happens if we estimate
• 15:07this risk
• 15:09controlling, taking into account the
• 15:11potential role of the underlying
• 15:13genetic for schizophrenia?
• 15:15And what we we show
• 15:16was that even when you
• 15:17take into account
• 15:19individual genetic load for schizophrenia,
• 15:21daily cannabis use as an
• 15:23independent
• 15:24effect on increasing the the
• 15:26risk of psychotic disorder, which
• 15:28is almost a four time,
• 15:30three point eight seven,
• 15:32and vice versa. So the
• 15:34genes for schizophrenia
• 15:35increase the risk of psychotic
• 15:37disorder as you would expect
• 15:38independently
• 15:39of daily cannabis use.
• 15:41When I talk to my
• 15:43student, and I hope you
• 15:43won't mind me using the
• 15:44same analogy with you, I
• 15:46gave them the example of
• 15:48diabetes type two. So if
• 15:50you have lots of gene
• 15:51for diabetes type two, you
• 15:52might develop diabetes type two
• 15:54anyway independently of your lifestyle.
• 15:57But if you eat
• 15:59donuts
• 16:00every day
• 16:02for a very long period
• 16:03of time, you would increase
• 16:04your risk of diabetes type
• 16:06two even if you have
• 16:07little genes for diabetes type
• 16:10two. But what if you
• 16:11have both?
• 16:12Now I suggest you don't
• 16:14eat donuts any every day
• 16:15anyway. But, of course, if
• 16:17you also have a family
• 16:18history of diabetes type two,
• 16:19the two together will really
• 16:21push your risk of the
• 16:22disease quite highly. Well, we
• 16:24looked at the same question
• 16:26in relation to
• 16:28different combination of frequency and
• 16:29potency of cannabis use and
• 16:32genetic load for schizophrenia. So
• 16:33the genetic load for schizophrenia
• 16:35is,
• 16:36expressed in a standardized continuous
• 16:38way on the x axis
• 16:40where zero really represent what
• 16:41you expect to be the
• 16:43genetic load for schizophrenia in
• 16:45the for the average of
• 16:46the pop to be the
• 16:47average for the population.
• 16:48So you can see that
• 16:50for each combination of frequency
• 16:52and potency,
• 16:53greater is the genetic load
• 16:55for schizophrenia, greater is the
• 16:56risk. This is not a
• 16:57surprise.
• 16:58But you can see that
• 16:59there is this,
• 17:00pink line, which represents the
• 17:03daily users of hypotensive cannabis,
• 17:05which already starts with a
• 17:07reasonable risk. And when they
• 17:09get to the average of
• 17:10the population for load of
• 17:11gene for schizophrenia,
• 17:13they are actually already quite
• 17:14high
• 17:15for the genetic risk, excuse
• 17:17me, for the risk of
• 17:18cyclotic disorder.
• 17:20Meaning that if you do
• 17:21use lots of cannabis, you
• 17:23don't necessarily need genes for
• 17:25schizophrenia.
• 17:26But if you have them,
• 17:27of course, you get that
• 17:28faster and and probably with
• 17:30a much higher,
• 17:32magnitude of, of of risk,
• 17:34which again is not discovering
• 17:37sliced bread again, but is
• 17:38something that although is intuitive,
• 17:40is important to to have
• 17:42data that that that supports
• 17:44it.
• 17:45Is that clear? Yes. I'm
• 17:46going to There's a question
• 17:48in the in the chat
• 17:50from Anahita. Are there any
• 17:52sex differences in the association
• 17:54between cannabis use and psychosis?
• 17:57Well, in the study that
• 17:58I've shot just shown you,
• 18:00we didn't actually find
• 18:02any sex differences except
• 18:04psychosis
• 18:06is,
• 18:07tends to be more prevalent.
• 18:08Particularly, psychosis who has an
• 18:10onset in late teens, early
• 18:11twenties tends to be more
• 18:13prevalent in male than in
• 18:14female.
• 18:15And when we look at
• 18:16may we we look at
• 18:17lifetime use, it was the
• 18:19same, but we found that,
• 18:22female who tended
• 18:24to have
• 18:25an earlier onset of psychosis
• 18:27were using more cannabis than
• 18:29male. So it seems to
• 18:31have an important role in
• 18:32female
• 18:33in bringing them at the
• 18:35same age group as male,
• 18:37which we thought it was
• 18:37interesting.
• 18:38We also found that female
• 18:40are more susceptible
• 18:42to withdrawal symptoms when they
• 18:44try to stop cannabis,
• 18:46which is quite interesting. And,
• 18:48I would like actually to
• 18:49have a discussion with Cyril
• 18:51on why he thinks that
• 18:52might be the case.
• 18:53So there are certainly gender
• 18:55gender differences
• 18:56in,
• 18:57in pattern of use, but
• 18:58surprisingly, we found that in
• 19:00our courts of patient with
• 19:02first episode psychosis,
• 19:04the female were using more
• 19:06than,
• 19:07than than males,
• 19:09which made them very different
• 19:11from the general population cannabis,
• 19:13cannabis users. I don't know,
• 19:15Cyril, if you have found
• 19:17something different in in in
• 19:18the sample you work on.
• 19:24You are muted.
• 19:28Sorry. I I don't know
• 19:29if Mohini is on the
• 19:30call, but Mohini did find
• 19:32some sex differences in the
• 19:34effects of THC in the
• 19:35lab. And maybe Anahita
• 19:37can,
• 19:39can say a little bit
• 19:40about that.
• 19:42Yes. Hi.
• 19:43So Hi. Hi. So we
• 19:45do we did look into
• 19:47the sex differences in acute
• 19:48effects of THC, both IV
• 19:50and oral, and we found
• 19:52in lower doses, women reported
• 19:55higher
• 19:56subjective effects, like more intense
• 19:58subjective effects.
• 20:01Yeah. But not in the
• 20:02cognitive effects or physiological
• 20:04effects, not other effects of
• 20:06THC.
• 20:08So that that's that that's
• 20:10very that's very interesting.
• 20:13I,
• 20:14what what what you'll see
• 20:16later on I mean, predominantly,
• 20:18people that come to my
• 20:19clinic
• 20:20are male. So we we
• 20:22have,
• 20:23a seventy five percent male,
• 20:25female ratio. But I think
• 20:27that's also to do because,
• 20:30their overrepresentation
• 20:31in in psychosis at their
• 20:32at their age.
• 20:34So it would be very
• 20:35interesting to see now that
• 20:37we are beginning to look,
• 20:38at least in my in
• 20:39my work, at, a much
• 20:41broader age group that go
• 20:43that also includes a second
• 20:44peak of onset, which is
• 20:46the one common in women,
• 20:47which is the sort of
• 20:48post sort of round menopause,
• 20:51what role cannabis might have
• 20:53in this group, particularly because
• 20:54in UK, cannabis is advertised
• 20:56for menopause. So it would
• 20:57be is is an interesting
• 20:59area I'm I'm looking, I'm
• 21:01looking at.
• 21:02Interesting. Thank you.
• 21:04Pleasure. Thank you very much.
• 21:06Thank you very much indeed.
• 21:07Ashley and something else I
• 21:08wanted to say given that
• 21:09we are on the topic
• 21:10of of of of DNA
• 21:12is that the relationship between
• 21:14cannabis use and DNA,
• 21:16it's actually much more dynamic
• 21:17than we might think. It's
• 21:19not just about how the
• 21:20structure of our DNA, the
• 21:22code of our genes
• 21:23might makes us more or
• 21:25less susceptible to its effect,
• 21:26but it's also the impact
• 21:28that cannabis use has actually
• 21:30on where, when, and how
• 21:32much our DNA is expressed,
• 21:34which in simple terms
• 21:36in, where, when, and how
• 21:37much our DNA is translated
• 21:39into biology and then physiology.
• 21:42And these processes
• 21:43are called broadly,
• 21:45epigenetic,
• 21:46and they are those processes
• 21:48then, for instance, make it
• 21:49possible that
• 21:50although we have exactly the
• 21:52same genes
• 21:53in the cell that make
• 21:55our skin as well as
• 21:56in the neurons in our
• 21:57brain,
• 21:59we still have two sets
• 22:01of cells that have a
• 22:02very different function
• 22:03just because not all the
• 22:05genes in the skin
• 22:07are expressed as they are
• 22:08in in neurons.
• 22:10And I always say that
• 22:12we share fifty percent of
• 22:14our genes with a banana,
• 22:15which is something that always
• 22:16surprised me when I say
• 22:17it. But, luckily, we do
• 22:19function and we look very
• 22:20different from a banana.
• 22:21This is again to do
• 22:22with the the sort of
• 22:24epigenetic
• 22:24regulation of DNA structure, which
• 22:27is otherwise very well conserved
• 22:29in in in nature.
• 22:30So we wanted to explore
• 22:32if,
• 22:34cannabis use and particularly hypothesis
• 22:36cannabis use did have an
• 22:37impact in particularly DNA methylation,
• 22:40which is a way,
• 22:42by adding a material group,
• 22:43you can switch on and
• 22:44off genes and therefore
• 22:46them being read or not
• 22:48into biology.
• 22:49And we found and this
• 22:50is some work we have
• 22:51done in collaboration with Emma
• 22:53Dempster
• 22:54from,
• 22:55from, Exeter University where they
• 22:57they they do lots of
• 22:58epigenetic work in mental health.
• 23:01We found that hypotensive copies
• 23:04leads a distinct
• 23:06DNA methylation
• 23:07Yeah. Signature,
• 23:08which means that it does
• 23:10affect
• 23:11where and and and how
• 23:13much of the DNA is
• 23:14switched on and off. And
• 23:16this,
• 23:17signature is different when you
• 23:19look at people who use
• 23:20hypotency
• 23:21and have developed psychosis from
• 23:23healthy control
• 23:24while using hypotency.
• 23:26We don't know yet what
• 23:27this means, but might be
• 23:28a sort of biological hint
• 23:30to what makes particular people
• 23:33susceptible.
• 23:34And the two biological system
• 23:36that are affected by this,
• 23:38signature of hypotensive cannabis are
• 23:41the immune system,
• 23:42which we're all familiar with,
• 23:44and also the mitochondrial system.
• 23:47And mitochondrial
• 23:48are the energy factory of
• 23:50our cell, so are a
• 23:51very important system
• 23:53which is really at the
• 23:54base of the of the
• 23:55life of of,
• 23:57our functioning.
• 23:59And
• 24:01one thing I always say
• 24:03that when we think about
• 24:04susceptibility,
• 24:06we tend to think about
• 24:07biology, what makes us biologically
• 24:09susceptible.
• 24:10But, also, there are and,
• 24:11actually, the question about gender
• 24:13is very important because
• 24:15it makes me think that
• 24:17there are not only biologically
• 24:19biological differences across gender, which
• 24:21might makes us
• 24:22susceptible in a different way,
• 24:24but there might also be
• 24:26different environmental exposure,
• 24:28that separate sort of, the
• 24:30the, male from female that
• 24:32could shape
• 24:33the vulnerability to cannabis
• 24:35use. And one of them,
• 24:37is the interest of one
• 24:38of my PhD student who,
• 24:40has been exploring the relationship
• 24:43between cannabis use and childhood
• 24:45adversity.
• 24:46And this is the work
• 24:47of Julia Trotter that you
• 24:48can see with a little
• 24:49boy,
• 24:50Luca, who I have in
• 24:51the picture with her because
• 24:53he was in a tummy
• 24:54when she was doing this
• 24:55work. So he's an honorary
• 24:57co author of,
• 24:59of, of of the paper.
• 25:01And so what Julia has
• 25:02really shown in her work
• 25:05is that adolescence cannabis use
• 25:08seems to mediate
• 25:10the association
• 25:11between childhood adversity, which has
• 25:13been very well, described before,
• 25:15and,
• 25:16and psychotic and psychotic disorder.
• 25:19And also that often people
• 25:21who have experienced childhood adversity,
• 25:24even in adolescence,
• 25:26turn to cannabis use rather
• 25:27than just to have fun
• 25:28with their friends
• 25:30to sort of, self medicate
• 25:32the negative affect
• 25:33associated with the experience of
• 25:35abuse,
• 25:36which in turns
• 25:37increases their risk of,
• 25:40of psychotic disorder. And this
• 25:42is, for psychotic disorder, I
• 25:43mean, these are people who
• 25:44actually have developed the clinical
• 25:46condition.
• 25:47But Julia has also been
• 25:48interested in exploring this relationship
• 25:50in a general population sample.
• 25:52So to look rather that
• 25:54at clinical psychosis and paranoia,
• 25:57which I mentioned before is
• 25:58an important
• 25:59component of the qualitative of
• 26:01of this the the the
• 26:02psychosis people experience
• 26:04when they use cannabis.
• 26:06And so this is a
• 26:06study that,
• 26:09managed to recruit
• 26:10three thousand seven hundred and
• 26:12thirty seven cannabis user from
• 26:13the London area and also
• 26:15a sample of people who
• 26:16never used.
• 26:17And what Julia did was
• 26:20she, first of all, reported
• 26:21a proportion of people that
• 26:23had experienced childhood trauma, which
• 26:24is actually quite high, and,
• 26:27and
• 26:28show that
• 26:29childhood trauma by itself was
• 26:31a strong predictor of paranoia
• 26:33in this general population sample.
• 26:36But then she also looked
• 26:37at different subtypes of trauma,
• 26:40their relationship with cannabis use
• 26:43and paranoia, and she looked
• 26:45at cannabis use in terms
• 26:46of THC units
• 26:48that I know,
• 26:50Cyril is becoming something that
• 26:52NIDA is, sort of advocating
• 26:54to to be used more
• 26:55widely.
• 26:56So Julia used the data
• 26:58that we had on the
• 26:59potency
• 27:00of cannabis that people were
• 27:01using
• 27:02and,
• 27:03the amount they they were
• 27:04using weekly
• 27:05to develop,
• 27:07these weekly THC unit consumption.
• 27:10And you can see in
• 27:11this graph that when she
• 27:13looked at people who had
• 27:14reported emotional,
• 27:16abusing in childhood,
• 27:18greater were the THC unit,
• 27:21even in people without trauma,
• 27:23greater was the predicted,
• 27:25paranoia score. To give you
• 27:27a sense, on average, when
• 27:29you look at this scale
• 27:30for paranoia, average of the
• 27:32population would be around thirty
• 27:34seven forty.
• 27:35So already, fifty one is
• 27:37quite, significantly highly
• 27:39higher than the general population
• 27:41average on on paranoia.
• 27:43But when you look at
• 27:44the people who have experienced
• 27:45the trauma, the blue line
• 27:47with an increase in,
• 27:49THC unit, you see there
• 27:50is a much sharper
• 27:53increase in, in in paranoia,
• 27:56which is very similar when
• 27:57you look at people with
• 27:59household
• 28:00discordance,
• 28:01which, again, it's another childhood
• 28:03trauma that increases the risk
• 28:05for psychosis. These two childhood
• 28:07trauma by themselves
• 28:09mildly increase the risk for
• 28:10psychosis
• 28:11on their own. But when
• 28:12you add cannabis,
• 28:14this actually,
• 28:16is of a of a
• 28:17quite striking magnitude.
• 28:19And is it quite interesting
• 28:20because we got reports that
• 28:21these were people
• 28:23who were actually trying to
• 28:24self medicate
• 28:26that discomfort of,
• 28:27having been emotionally abused and
• 28:29and living in a family
• 28:30environment,
• 28:31which was, dysfunctional.
• 28:33So this is certainly a
• 28:34group to to keep an
• 28:35eye on for primary prevention
• 28:38because this might be young
• 28:39people that
• 28:40are identifiable, you know, at
• 28:42school or in in, in
• 28:44youth club or in primary
• 28:45care
• 28:46settings. So before they get
• 28:48actually to the clinical,
• 28:50to the clinical psychosis.
• 28:53Sil, any any any question?
• 28:56Yes. There's a question from
• 28:58your countrymen,
• 29:00Nicola Mitali.
• 29:02Nicola
• 29:03asked the question, when you
• 29:04say the cannabis users present
• 29:06present many schizophrenia
• 29:08risk genes,
• 29:09how many genes do you
• 29:10mean to show risk poly
• 29:12polymorphisms?
• 29:14Well, the polygenic risk score,
• 29:17which is the way we,
• 29:19calculated the genetic load in
• 29:21the study,
• 29:22really includes
• 29:24hundreds and hundreds of,
• 29:26common gene of small effect.
• 29:28And it doesn't really tell
• 29:30you anything about which are
• 29:31the genes that perhaps drive
• 29:34the most of the association.
• 29:36To do that, you probably
• 29:37need to do a different
• 29:38type of work, which is
• 29:39to look at biological pathway.
• 29:42So to see if
• 29:44when you think about people
• 29:45who develop psychosis in the
• 29:47context of cannabis use, if
• 29:48out of this overall
• 29:50genetic load for schizophrenia, there
• 29:52are some genes that drive
• 29:54particularly
• 29:55the susceptibility.
• 29:56And this is some work
• 29:57that actually professor D'Souza team
• 30:00has been doing, and I
• 30:01can't give away his, his
• 30:02his data on his behalf.
• 30:05But also my my postdoc
• 30:07has been looking at that,
• 30:08and we have,
• 30:10the paper in review. And
• 30:11just to give you a
• 30:12sense, it's quite interesting because
• 30:15some of the genes, for
• 30:16instance, are genes involving the
• 30:17GABA system, which is not
• 30:19surprising because,
• 30:22THC,
• 30:23when it gets into our
• 30:24body and it binds the
• 30:26targets in in in in
• 30:27our brain,
• 30:28has a a an effect
• 30:30on regulating the the the
• 30:31GABA signaling.
• 30:33So,
• 30:34there there are some pathway
• 30:35which
• 30:36makes sense,
• 30:38biologically, but you can't tell
• 30:39this from from the polygenic
• 30:41risk score, which is a
• 30:42very noisy overall,
• 30:44measure. I I don't know
• 30:45if that helped.
• 30:49Thank you. Absolutely.
• 30:51Thank you. Pleasure.
• 30:53And, I want to then
• 30:55give a positive message in
• 30:56all of this risk increasing
• 30:58here and there, which is
• 30:59actually we were interested to
• 31:01explore a question that people
• 31:02have looked at in relation,
• 31:04for instance, to tobacco smoking
• 31:06and lung cancer.
• 31:07You know that, obviously, tobacco
• 31:09smoking increases the risk of
• 31:10lung cancer, but you also
• 31:11know that when people stop
• 31:13smoking tobacco, smoking cigarettes,
• 31:15longer they abstain,
• 31:17greater they experience a reduction
• 31:19in the risk they had
• 31:20acquired when they were smokers.
• 31:23And so we wanted to
• 31:24see if that was the
• 31:25same in relation of, cannabis
• 31:28use and psychosis.
• 31:29And, this is, of course,
• 31:30a study that will need
• 31:31to be to be replicated,
• 31:32but we were quite pleased.
• 31:34And this is, again, the
• 31:35European study I mentioned to
• 31:37you about.
• 31:38We were able to show
• 31:39that, again, and this is
• 31:40my favorite combination of frequency
• 31:42and potency you have become
• 31:43familiar with by now,
• 31:45that when we look at
• 31:47weeks since the session, so
• 31:49how long people had been
• 31:50since, had stopped using cannabis.
• 31:53And, of course, when you
• 31:54look at zero, zero means
• 31:56that people are still using
• 31:57and then you would have,
• 31:59the the accumulation of weeks
• 32:01since they have stopped.
• 32:02You can see that,
• 32:04each of the line that
• 32:06represent a combination of potency
• 32:07and frequency,
• 32:08longer people abstain,
• 32:11lower it becomes, which means
• 32:13that indicates
• 32:14a decrease in the risk
• 32:15for psychotic disorder which is
• 32:17represented by the y
• 32:19vertical axis.
• 32:20But the pink line is
• 32:22the is the tricky one
• 32:23is again the people that
• 32:24use frequency,
• 32:25everyday,
• 32:26hypotensive cannabis. And you can
• 32:28see that for them, there
• 32:29is a decline in the
• 32:30risk. But at five hundred
• 32:32weeks, which is a very
• 32:33long time, they still have
• 32:35above a twenty five percent
• 32:37increased risk. So this is
• 32:38a group that takes longer
• 32:40to wash out the accumulated
• 32:42risk. And I would like
• 32:43to say that when you
• 32:44get to the majority of
• 32:46these people had started using
• 32:47the early teens. And for
• 32:49those who had stopped
• 32:51shortly after, you know, five
• 32:53hundred weeks is pretty much
• 32:54close to when you are
• 32:55at risk of developing a
• 32:56psychotic disorder. So this is
• 32:58really a group which is
• 32:59a significant risk
• 33:01and should be supported in
• 33:03in in in understanding it.
• 33:06Well and this is my
• 33:07overall message. Anyway but now
• 33:09I'm going to
• 33:10come towards the the end
• 33:11of the talk by sharing
• 33:13with you something that is
• 33:14very dear to me as
• 33:16a clinician.
• 33:17So often, I share this
• 33:19data with the family of
• 33:21people under my care that
• 33:23as, professor D'Souza mentioned are
• 33:26young people experiencing psychosis for
• 33:28the first time, most of
• 33:29the time, in the context
• 33:30of cannabis use. And they
• 33:32say to me, well, thank
• 33:32you very much for all
• 33:33this data, but what are
• 33:34you actually doing for our
• 33:36loved ones?
• 33:37Particularly because
• 33:38they struggle to stop and,
• 33:41and the continuing of the
• 33:42cannabis use
• 33:44perpetuates the the the sort
• 33:46of severity of the illness.
• 33:48And
• 33:49important work had actually shown
• 33:52beyond what family will tell
• 33:54me and I will see
• 33:54in my clinic that that
• 33:56indeed if you develop a
• 33:57psychotic disorder and you continue
• 33:59to use cannabis after the
• 34:00onset of the illness and
• 34:02particularly, and this time it's
• 34:03not in pink, it's in
• 34:04green,
• 34:05you do that by using
• 34:07everyday hypo and c cannabis,
• 34:09you are much more likely
• 34:10to relapse and you are
• 34:12faster to relapse than people
• 34:14who are using much less
• 34:15or people that have actually
• 34:16stopped. And you're more likely
• 34:18to be admitted in a
• 34:19psychiatric intensive care unit because
• 34:21of the severity of your
• 34:22symptoms to have longer hospital
• 34:24admission and shorter period of
• 34:25remission
• 34:26between the relapses. So really
• 34:28a huge negative impact on
• 34:30the outcome of the illness.
• 34:32So in two thousand and
• 34:34nineteen,
• 34:34we were able to get
• 34:36some funding from a local
• 34:37charity
• 34:39And, we developed a service
• 34:41which professor D'Souza mentioned, which
• 34:43is called the cannabis clinic
• 34:44for patient with psychosis. And,
• 34:45actually, this logo is very
• 34:47dear to my heart because
• 34:48it was designed with the
• 34:50first group of patients who
• 34:51were part of developing the
• 34:53clinic,
• 34:54and it really represents
• 34:55where they want to be
• 34:57with their journey.
• 34:58Some of them don't even
• 34:59think about psychosis. They just
• 35:00think about having a brain
• 35:02which is entirely filled with
• 35:03cannabis
• 35:04and wanted to go back
• 35:05to do more in their
• 35:06life, such as starting again
• 35:08with some hobbies, doing more
• 35:10exercise, music,
• 35:11studying.
• 35:12And CAO knows I always
• 35:14say this, and one of
• 35:15them said to me, doctor
• 35:16Mars, can I get a
• 35:18girlfriend if I stop using
• 35:19cannabis? I I can't make
• 35:20these promises,
• 35:21but I always say that
• 35:23his social network
• 35:24certainly flourished,
• 35:26when he was able to
• 35:27to stop his his cannabis
• 35:29use.
• 35:30And we were able to
• 35:31do this because we put
• 35:33together all the expertise I
• 35:35could go get get hold
• 35:36of across our clinical
• 35:38and academic site,
• 35:40and we had people with
• 35:41great experience in addiction as
• 35:42well as psychosis,
• 35:44the nursing staff who are
• 35:46usually the driving force of
• 35:47any care we we we
• 35:49deliver in medicine,
• 35:50and also our head of,
• 35:53of of pharmacy.
• 35:54And, we were able to
• 35:55put together a team, which
• 35:57is still a baby team,
• 35:58but I'm very proud of
• 35:59this team because,
• 36:01we are very keen in
• 36:02UK on diversity.
• 36:04And this is certainly a
• 36:05team that scores very highly
• 36:06because it's very good in
• 36:07terms of gender, ethnicity,
• 36:10age, and species because you
• 36:12can see there are some
• 36:13of our pets that feature
• 36:15as well
• 36:16in the,
• 36:18in the team.
• 36:20And we have two wonderful,
• 36:22members of the team who
• 36:24are our peer mentor with
• 36:25lead experience, Stacey and Adam,
• 36:27that you saw in the
• 36:28video at the very beginning,
• 36:30and a wonderful
• 36:31and new every year, new
• 36:33cohort of clinical placement students
• 36:35that as students always do
• 36:36bring really a breath of
• 36:38fresh air and lots of
• 36:39new ideas. And also they
• 36:40are much closer to my
• 36:41patients than I am. So,
• 36:43they they they connect with
• 36:45them very, very, very well.
• 36:47And one of the jewel
• 36:49if you ask me, the
• 36:50jewel of the crown, and
• 36:51and Cyril has been one
• 36:52of our speakers,
• 36:54is the peer group. So
• 36:55we have a peer group
• 36:57that runs online
• 36:58every Tuesday. We happen today
• 37:00four to five where we,
• 37:02invite
• 37:03world leading experts like Cyril
• 37:05to come and
• 37:07open the peer group with
• 37:08a song or music of
• 37:09their choice, and actually Cyril
• 37:11delighted us with his own
• 37:12band.
• 37:13And then we go into
• 37:14science. And,
• 37:16the the patients that join
• 37:18the peer group, some of
• 37:19them are on the inpatient
• 37:20unit quite unwell.
• 37:22Some are in the community.
• 37:23And they are given the
• 37:24science as you are getting
• 37:26it or we might get
• 37:27it when we go to
• 37:28conference. It's not filtered.
• 37:30And they will ask questions.
• 37:31They will share their experience.
• 37:32They might disagree.
• 37:34But I have learned more
• 37:36from them and from this
• 37:37experience that probably have learned
• 37:39from from me because to
• 37:40see their interaction, their interest,
• 37:42and also
• 37:43enrich the science with their
• 37:45lead experience
• 37:46is actually very powerful for
• 37:48them, but also from us.
• 37:49And I'm actually going to
• 37:50let Stacy tell you why
• 37:53she thinks in a role
• 37:54of a peer mentor that
• 37:55the peer group has a
• 37:56value. I see a lot
• 37:58of change through people using
• 38:00the cannabis clinic. I mean,
• 38:01there was one guy that
• 38:02started, I cannot say his
• 38:03name, Confidentiality,
• 38:05but he was smoking, like,
• 38:07twenty a day.
• 38:09And through the group, he
• 38:11started
• 38:12five a day to two
• 38:13a day to actually stop.
• 38:15And without the group, that
• 38:17would not have happened.
• 38:18Because a lot of the
• 38:19time, when you go in
• 38:20front of the clinician,
• 38:22you're thinking this person can't
• 38:23relate to what I'm going
• 38:24through. They don't have a
• 38:25clue.
• 38:27Do you know what I
• 38:27mean? This person's got it
• 38:28all together. Look at me.
• 38:29My life's falling apart. How
• 38:31can you guys got it
• 38:31all together understand
• 38:33understand where I'm coming from?
• 38:35So with people like me
• 38:37and Adam, it gives them
• 38:38that safe space that they
• 38:39can say, yeah. They were
• 38:40once like me. I can
• 38:42be like them too. So
• 38:43in a way, it kinda
• 38:44motivates them and inspires them
• 38:46to say I wanna be
• 38:47like Adam. I wanna be
• 38:48like Stacy.
• 38:50And, actually, I I don't
• 38:51think I could ever say
• 38:52it as as eloquently as
• 38:54Stacy. Stacy has actually started
• 38:55university this year,
• 38:57which for her is is
• 38:59is a wonderful,
• 39:01milestone.
• 39:03So just to give you
• 39:04a sense of what we
• 39:05do, so we have the
• 39:06peer group. And then weekly,
• 39:08we also offer one to
• 39:09one,
• 39:10session.
• 39:11And I always say,
• 39:12we haven't actually invented anything
• 39:14new. For those of you
• 39:15who are familiar with addiction,
• 39:17we just use tools that
• 39:19are very well established
• 39:20and to to work in
• 39:22addiction across substances. They're not
• 39:23specific to cannabis.
• 39:25But what we do,
• 39:27excuse me, we make them
• 39:28flexible and adjusted to the
• 39:30need of somebody who would
• 39:31come to the clinic while
• 39:33they are actually experiencing psychosis.
• 39:35These are no people in
• 39:36remission.
• 39:37And we have flexibility not
• 39:39only in,
• 39:40which of this model we
• 39:42use, but actually the combination
• 39:44and the timing.
• 39:45So sometimes people ask me,
• 39:46oh, what is your protocol?
• 39:48Well, our protocol is that
• 39:49there is no protocol,
• 39:50that we have all these
• 39:51tools. They are available
• 39:53to the therapist
• 39:55and, to the patient, and
• 39:56the therapist and the patient
• 39:58decide together
• 39:59where to start from, what
• 40:01to start with.
• 40:02And sometimes,
• 40:03they might use one main
• 40:05tool for the role duration
• 40:06of the twenty session that
• 40:07on average that they,
• 40:10they,
• 40:12receive. And one thing that
• 40:14we do, we link also
• 40:15with the local resources. So
• 40:16this is not a work
• 40:17that is done in isolation.
• 40:19And, also, we collect outcome
• 40:21measure
• 40:22at the beginning and at
• 40:23the end. And it's because
• 40:24of this outcome measure that
• 40:25I'll be able to show
• 40:26you
• 40:27what we recently
• 40:29published in a sort of
• 40:31proof of concept paper.
• 40:33So we were able to
• 40:34publish the data from the
• 40:36first forty six
• 40:37patients that completed the intervention.
• 40:41And
• 40:41this first,
• 40:43graph shows you where
• 40:46people in red
• 40:47were at the start of,
• 40:49the intervention,
• 40:50and the horizontal
• 40:52darker line represent the threshold
• 40:54for cannabis dependence.
• 40:56You can see that they're
• 40:56all well above this this
• 40:58threshold.
• 40:59And you can see that
• 41:00at the end of the
• 41:01intervention,
• 41:02they are pretty close to
• 41:03zero. The reason they are
• 41:04not zero is because some
• 41:05of them decided to just
• 41:07reduce their frequency of use
• 41:09from daily to once a
• 41:10week or even less than
• 41:11once a week.
• 41:13But
• 41:14do we care about this?
• 41:15Well,
• 41:15when we look at, for
• 41:17instance,
• 41:18the red and the green
• 41:20boxes, they represent changes
• 41:22between before and after the
• 41:24intervention
• 41:25in delusion or persecution
• 41:27in terms of frequency intensity
• 41:29and distress. And you can
• 41:30see that there is a
• 41:31sort of quite striking reduction,
• 41:33which is actually clinically relevant.
• 41:36Then you look at the
• 41:37blue and the red, which
• 41:38is paranoia,
• 41:39and that's actually one of
• 41:41the greatest differences you you
• 41:42will see, going along between,
• 41:45the beginning and the end
• 41:46of the intervention.
• 41:48And then we also look
• 41:49at anxiety and and and
• 41:51depression. And the reason is
• 41:52because often my patients say
• 41:53to me, well, I appreciate
• 41:55it might be bad for
• 41:56my psychosis, but it helps
• 41:57me very much with my
• 41:58anxiety and with my mood.
• 41:59And I always show them
• 42:00this graph because these are
• 42:01no data I created. These
• 42:03are things they told me,
• 42:04how things have changed for
• 42:05them. And, actually, this shows
• 42:07in purple and orange that
• 42:09the the anxiety,
• 42:10does
• 42:11change does reduce
• 42:13when they stop or significantly,
• 42:15reduce their cannabis use. And
• 42:17their mood,
• 42:18yellow and, and green also
• 42:21improves
• 42:22when they stop or significantly
• 42:24reduce their cannabis use. But
• 42:26very strikingly,
• 42:27we don't always have a
• 42:29perfect mood state. We all
• 42:30can be a bit anxious
• 42:31or paranoid.
• 42:33But what often is very
• 42:34difficult for this population is
• 42:36to regain a good level
• 42:37of functioning
• 42:38after the onset of the
• 42:39psychosis.
• 42:40And you can see here
• 42:41where there is a sharp
• 42:42improvement
• 42:43in the level of functioning,
• 42:45which is not just about
• 42:46a clinical measure.
• 42:48Does actually translate in ninety
• 42:50one percent of them
• 42:52having become again socially active,
• 42:54engaging in work paid work,
• 42:56I should say, and going
• 42:57back to education. So having
• 42:59a sort of meaningful
• 43:01quality of life. I see,
• 43:03Cyril, there are lots of,
• 43:04things in the chat. Do
• 43:05you do you want me
• 43:07to stop?
• 43:09Sure.
• 43:10Can you read the questions,
• 43:11or would you like me
• 43:12to read them out?
• 43:14I I can
• 43:16I can, read them? Okay.
• 43:20So what do I think
• 43:21is the synergistic effect of
• 43:23childhood trauma and cannabis use
• 43:24increase in risk of psychosis?
• 43:25We're going to play a
• 43:26pilot study,
• 43:28which showed lower c b
• 43:29o one availability in adults
• 43:31with a history of childhood
• 43:32trauma.
• 43:33Could this reduce ecbitone,
• 43:35increase the risk of both
• 43:37cannabis use and psychosis?
• 43:39I don't see why not.
• 43:40We haven't actually Julia is
• 43:41looking at the biology,
• 43:43right now as part of
• 43:45the of the,
• 43:46at, PhD. I mean, the
• 43:48endocannabinoid
• 43:49system
• 43:50really sits also
• 43:52I mean, sits in between
• 43:54so many of the effects
• 43:55of, of cannabis, but also
• 43:57of potentially stress reactivity.
• 44:00So it is certainly possible
• 44:02that
• 44:02exposure to to cannabis in
• 44:04people who have been
• 44:06subject to to trauma
• 44:08change their stress response
• 44:10and increases, for instance, their
• 44:11social anxiety and intense,
• 44:14the the risk of of
• 44:15a paranoid interpretation
• 44:17of reality. And their biology
• 44:19could be mediated directly by
• 44:21the dopamine system and downstream
• 44:23by by dopamine. Also, serotonin
• 44:26might have a role. We
• 44:27know that
• 44:28the,
• 44:29the endocannabinoid system also,
• 44:32impacts on serotoninergic,
• 44:34not just glutamate
• 44:35and GABA. So I think
• 44:36it's going to be probably
• 44:37quite complex and involve a
• 44:39variety of,
• 44:41of biological pathway,
• 44:43which I would suspect have
• 44:45also the HPA axis, you
• 44:47know, the hypothalamus pitcher,
• 44:50adrenal gland axis that regulates
• 44:53stress, stress response.
• 44:56There's a question about there
• 44:57any data?
• 44:59Sorry.
• 45:00Sorry, Cyril.
• 45:01No. You go.
• 45:02There's a question about,
• 45:04the chemotype of, of cannabis,
• 45:08whether one to one CBD
• 45:10to THC ratio.
• 45:12What's the risk of psychosis
• 45:14with that?
• 45:17Well, this is a Shiaquest.
• 45:18You have the world experts
• 45:19on this with professor D'Souza.
• 45:21No. Me.
• 45:22I haven't done any, actually,
• 45:23experimental work where we have
• 45:25played with the ratio.
• 45:27What I can tell you
• 45:29is that
• 45:30our data when, epidemiological
• 45:32data, when people in Landau
• 45:34were using a a type
• 45:36of cannabis, which was, Ashish
• 45:39that had a one to
• 45:40one ratio of THC and
• 45:41CBD,
• 45:42when we compared them with
• 45:43people who were using a
• 45:45type of cannabis with high
• 45:46THC and no CBD
• 45:48and compared them with people
• 45:49who did not use cannabis,
• 45:51the one with the ratio
• 45:52one to one of low
• 45:54THC and equal CBD
• 45:56had no increased risk of
• 45:57psychosis compared to the one
• 45:58that never used. But this
• 46:00is what we found in
• 46:01those days in cannabis.
• 46:02I know data have been
• 46:04sort of,
• 46:05have have been less consistent
• 46:07in other studies. But I
• 46:09don't know, Cyril, if you
• 46:10want to comment on your
• 46:11experimental work.
• 46:13Yeah. Actually, I'm hoping Mohini
• 46:15is on the call where
• 46:16she can speak about
• 46:18the the impact of CBD
• 46:19on THC effects.
• 46:21Mohini, do you wanna respond
• 46:22to this?
• 46:24Sure.
• 46:25Hi there. This is and
• 46:26such a pleasure to hear
• 46:27this,
• 46:28talk always. Hi, Mohini.
• 46:30Hi. How are you?
• 46:33So with in our lab,
• 46:35we do studies with acute
• 46:37THC and acute CBD, and
• 46:39we have tested a few
• 46:40combinations
• 46:41of,
• 46:42of the drugs.
• 46:44And what we found
• 46:46is actually,
• 46:47so when we administer THC
• 46:49and CBD in as close
• 46:51to a one is to
• 46:51one ratio as possible,
• 46:53CBD
• 46:54was
• 46:56able to attenuate some of
• 46:57those psychosis like effects of
• 46:59THC.
• 47:00We did not see that
• 47:02with higher or lower doses
• 47:04of, CBD.
• 47:05Now these are small studies
• 47:07because challenge studies, as you
• 47:09know, tend to be much
• 47:10smaller in size,
• 47:12but it's consistent with some
• 47:13of the other literature suggesting
• 47:15that this one is to
• 47:16one ratio in some way
• 47:17is is, kind of more,
• 47:22ameliorates those negative effects of
• 47:24THC.
• 47:25And,
• 47:26I think, you know, now
• 47:27for many other studies as
• 47:28well that people are examining
• 47:30a one is to one
• 47:31ratio of THC to CBD.
• 47:33K. Thank you. Thank you,
• 47:35Mohini. And, actually,
• 47:36in in London,
• 47:38one of my colleague at
• 47:39Chesney,
• 47:40with professor Philip Maguire team,
• 47:43I've also looked into these.
• 47:44And, actually, they found what
• 47:45you say, and they found
• 47:46that
• 47:47when the ratio was
• 47:49with in favor of CBD,
• 47:51so high doses of CBD
• 47:53and little THC.
• 47:54Actually, this didn't make things
• 47:55better. Sometimes it made them
• 47:57worse. So I think the
• 47:58story is is is quite
• 48:00complicated, but I think I'm
• 48:02with you that the one
• 48:03to one ratio seems to
• 48:04be perhaps the one that
• 48:05consistently
• 48:07gives the same result across
• 48:08study even if small study
• 48:10and at least in our
• 48:12epidemiological
• 48:12data as well. I just
• 48:14wanted to show you this
• 48:16this slide for the skeptics.
• 48:18People sometimes say to me,
• 48:19well, you know, you see
• 48:20an improvement
• 48:21in the cannabis use, in
• 48:23in this pop clinical population,
• 48:25and then you also see
• 48:26all these changes in the
• 48:27symptoms. But they could be
• 48:28a coincidence.
• 48:29Well, we did actually look
• 48:31at that statistically,
• 48:32and this is something I
• 48:33do show to my patients
• 48:35because
• 48:36we were able to show,
• 48:37Ashley, that
• 48:39the changes in cannabis use
• 48:41explain twenty seven percent of
• 48:43the variance in the delusion,
• 48:44twenty six percent in the
• 48:46anxiety, thirty two in the
• 48:48depression, forty seven in the
• 48:49paranoia, and sixty one
• 48:51in the gulf. And what
• 48:53I say to them, this
• 48:54means that
• 48:55this is something you have
• 48:56control over, that you can
• 48:58modify by making a choice
• 49:00and and receiving support by
• 49:02all means in in in
• 49:03in acting on this choice.
• 49:05And I think this is
• 49:06very important to them because
• 49:07it gives them a role
• 49:09in their in their recovery
• 49:11rather than feeling passive in
• 49:13in in the context of
• 49:14of other type of inter
• 49:16intervention. And what we often
• 49:17find is that when we
• 49:19do, they do succeed in
• 49:21reducing their cannabis use or
• 49:22even stopping,
• 49:24they can also negotiate with
• 49:25a psychiatrist a little reduction
• 49:26in the medication,
• 49:28which by by all means
• 49:29are taken into account in
• 49:31this,
• 49:32in in this analysis.
• 49:33We've also developed I don't
• 49:35know if there are any
• 49:36carers at this talk talk,
• 49:38but we have also developed
• 49:39a monthly, meeting
• 49:41for the carer to support
• 49:43them with,
• 49:45communicating better and understanding the
• 49:47journey that the loved one
• 49:48are have embarked on and
• 49:49the complexity
• 49:51of that journey.
• 49:52We also have,
• 49:54a branch club. It's got
• 49:55it was started as breakfast,
• 49:56but because it's at twelve
• 49:57o'clock, I I said I
• 49:59forbid
• 49:59my students to call it
• 50:01breakfast at twelve. I said
• 50:02you have to call it
• 50:02brunch.
• 50:03And our wonderful students
• 50:05meet with our patients who
• 50:07can tolerate to meet in
• 50:08person,
• 50:09and they don't find that
• 50:10too intrusive.
• 50:12And they do lots of
• 50:13activities, and one of my
• 50:14students created this idea of
• 50:15the craving box.
• 50:17Each patient can build their
• 50:19own craving box where they
• 50:21include tools, ideas, thoughts, and
• 50:23take it with them so
• 50:24that when they crave, rather
• 50:26than panicky about it, they
• 50:27can open the box and
• 50:28remind themselves
• 50:29the tools that stay they
• 50:31have agreed might help to
• 50:32overcome
• 50:33the,
• 50:34the the the the craving.
• 50:36And work in progress, we
• 50:38are very interested in the
• 50:39cannabis withdrawal. I I mentioned
• 50:41this to you. I don't
• 50:42think we have we have
• 50:43time to to watch the
• 50:44video, but,
• 50:46Ed Chesney have been leading
• 50:47on,
• 50:48the developments
• 50:49of,
• 50:50the the time scale of
• 50:52of the of when you
• 50:53expect withdrawal symptoms who have
• 50:55an onset, which is pretty
• 50:56delayed compared, for instance, to
• 50:58tobacco and alcohol.
• 51:00And not only on
• 51:02these more general sort of,
• 51:04symptoms
• 51:06that can,
• 51:07can can develop during withdrawal,
• 51:09but also
• 51:10a a series of case
• 51:11reports that he has now
• 51:12published of people that stop
• 51:14using cannabis and develop psychosis
• 51:16after they stopped.
• 51:18And,
• 51:19and so he's been interested
• 51:20in how
• 51:21abrupt cannabis,
• 51:23secession can precipitate
• 51:25some psychotic symptoms
• 51:27and how important it is
• 51:28to be aware of, of
• 51:30it as well when people
• 51:31are supported in a journey
• 51:33of reducing or changing their
• 51:34cannabis use. And we have
• 51:36an online portal where our
• 51:38patient can access all these
• 51:40resources, lots of the video.
• 51:41There are lots of TikTok
• 51:42type video
• 51:43for short attention span. One
• 51:45of them is, professor D'Souza,
• 51:48a shorter version of his
• 51:49original talk and many more.
• 51:51And this has been great
• 51:52because people can watch this
• 51:54on their own mobile phone
• 51:56anytime of the day and
• 51:57night when clinical service are
• 51:59not available.
• 52:00They can self assess. They
• 52:01can build their own cannabis
• 52:02diary. And as I said,
• 52:04they can watch what other
• 52:05people have have experienced.
• 52:07And
• 52:09about to start, you don't
• 52:10get any credibility,
• 52:11and she should be if
• 52:12you don't do a randomized
• 52:13controlled trial. So we're just
• 52:15about to start a randomized
• 52:16controlled trial of the intervention
• 52:18of, of of the cannabis
• 52:20clinic.
• 52:20And to conclude,
• 52:22none of what I said
• 52:23could
• 52:24happen if it wasn't for
• 52:26the inspiration I get for
• 52:28the people in my clinic,
• 52:29under my care, their family,
• 52:31my clinical colleagues, and, of
• 52:33course, my research team,
• 52:35our mentor with lived experience
• 52:37who you have met in
• 52:39in the video,
• 52:40people like professor D'Souza who
• 52:41have guided and inspired my
• 52:43work, and my pets who
• 52:45feature
• 52:45in the slides. And you
• 52:46can't see them, but they're
• 52:47also behind me right now.
• 52:49Thank you very much.
• 52:52That was I'm happy to
• 52:54answer.
• 52:55That was really great. There
• 52:57are some questions in the
• 52:58in the chat. Tom McMahon,
• 53:00do you wanna,
• 53:02do you wanna ask your
• 53:03question?
• 53:05Sure. Thank you very much.
• 53:08This is very interesting
• 53:09to me,
• 53:10particularly that I work with
• 53:12this age group and we
• 53:13see
• 53:14this combination
• 53:16of
• 53:17difficulty pretty frequently.
• 53:19My question is, can you
• 53:20talk a little bit about
• 53:21the role of antipsychotic
• 53:22medication
• 53:24at the CCP
• 53:25and the role how you
• 53:26deal with with issues around
• 53:29continuation of antipsychotic
• 53:31medication that's usually
• 53:33begun in the hospital?
• 53:36So this is a very
• 53:37important question. So I don't,
• 53:41so in my role as
• 53:42a consultant of the cannabis
• 53:43clinic, I don't have any
• 53:45control on what people are
• 53:46prescribed in terms of the
• 53:47antipsychotic
• 53:48because if you think about
• 53:49the way we work, we
• 53:50are a tertiary service. What
• 53:52it means that these people
• 53:53are under
• 53:54a main community mental health
• 53:56team for psychosis.
• 53:58So they are under a
• 53:59general psychosis team, and then
• 54:00they get referred to us
• 54:02to support them with the
• 54:03cannabis use. So I don't
• 54:05directly
• 54:06interfere on their antipsychotic.
• 54:08Nevertheless,
• 54:10they're beginning to be
• 54:12more and more evidence suggesting
• 54:14that in this population,
• 54:16if you give them a
• 54:17powerful d two blockade antipsychotic
• 54:19d two antagonist,
• 54:21you're more likely to precipitate
• 54:23craving and make them less
• 54:25likely to take their antipsychotic
• 54:27and also to get them
• 54:28to ramp up their cannabis
• 54:29use to maintain the same
• 54:30level of pleasure.
• 54:32So some there've been studies
• 54:33now that suggested that perhaps
• 54:35using partial agonist,
• 54:37say, areoprazole or cariprazine,
• 54:40are a better tailor intervention
• 54:42and particularly to consider initially
• 54:45a long acting
• 54:46to guarantee compliance.
• 54:48Now
• 54:49what we do find is
• 54:50that,
• 54:52in general, when people start
• 54:54reducing their cannabis use, they
• 54:56can also negotiate either that
• 54:58they are on a partial
• 54:59agonist or a d two
• 55:00blockade,
• 55:01a little reduction of the
• 55:02dose with that psychiatrist, particularly
• 55:04if the symptomatology
• 55:05improves.
• 55:06And this in turn
• 55:08improves the therapeutic relationship and
• 55:10starts a negotiation or perhaps
• 55:12what it might be
• 55:14a better antipsychotic that suits
• 55:15their need or if they
• 55:17can even I mean, we
• 55:18had twenty percent of the
• 55:20people in the sample I
• 55:21show you the data from
• 55:22actually were able to stop
• 55:23their antipsychotic altogether,
• 55:26or even been on a
• 55:27dose such as two point
• 55:28five of aripiprazole.
• 55:31But I think we would
• 55:32need a longer follow-up to
• 55:33see which proportion is able
• 55:35to come off completely antipsychotic.
• 55:38So one of the things
• 55:39I would like to do
• 55:40is to develop a protocol,
• 55:42to to to work around
• 55:44it with my clinical colleagues
• 55:45who prescribe the antipsychotic.
• 55:48At the moment, I just
• 55:49gently interfere when I feel
• 55:50I have to, but
• 55:52not too much.
• 55:54There there was also a
• 55:55question from, Eden Evans from
• 55:57MGH.
• 55:58Eden, do you wanna
• 56:00do you want to ask
• 56:01your question now?
• 56:04No. No. If you're still
• 56:05on the call.
• 56:06No. We are. I was
• 56:07just trying to here with
• 56:08Jody and Gladys Patas from
• 56:10our group. And and I
• 56:11asked it before you went
• 56:12through,
• 56:13your your more description of
• 56:15your your cannabis clinic for
• 56:17patients with psychosis. But my
• 56:18question was, what is your
• 56:20intervention? What is the treatment?
• 56:21And it looks like it's
• 56:23primarily behavioral,
• 56:24and that you don't have
• 56:25a protocol.
• 56:27Is that is that right?
• 56:28So I was I was
• 56:28Exactly. Describe it. Yeah. But
• 56:30thank you so much for
• 56:31all your work. So thank
• 56:32you. All your papers. We
• 56:33are very inspired by your
• 56:34work. So I'll I'll add
• 56:36that too. But,
• 56:37you know, if we were
• 56:38to to start a a
• 56:39a cannabis clinic here, I'm
• 56:40not clear what we would
• 56:42do,
• 56:43to
• 56:44Well, what you would do,
• 56:45you would get some wonderful
• 56:46people with lived experience to
• 56:48support you. You will get
• 56:49people in a room once
• 56:51a week for sixty minutes,
• 56:53get them to talk about
• 56:54their cannabis use, and let
• 56:55them lead the way.
• 56:56So what what is really
• 56:58the feedback? We've done a
• 56:59qualitative
• 57:00study, which is also included
• 57:02in the paper, where we
• 57:04ask them what has really
• 57:05been helpful of what you
• 57:07have done with us. And
• 57:08the answer has been consistency,
• 57:10flexibility,
• 57:11not to be told what
• 57:12to do,
• 57:14not to be led, but
• 57:15to be supported in finding
• 57:18the way to make the
• 57:19change. So I give you
• 57:21I give you an example.
• 57:22Some of the people that
• 57:23come to the first session,
• 57:24they come to the first
• 57:25session, say, I love my
• 57:27cannabis use, but I'm spending
• 57:29too much money on it.
• 57:30And you work with that.
• 57:32You don't start by saying,
• 57:33oh, cannabis is bad for
• 57:34your psychosis and multi complicated
• 57:36motivation. You just work on
• 57:37the fact they want to
• 57:38save money. And then when
• 57:40they start
• 57:41reducing their cannabis with some
• 57:42very practical
• 57:44craving tools and harm reduction,
• 57:46you begin to get them
• 57:48to reflect on, hold on
• 57:49a second, you are getting
• 57:50a bit more money in
• 57:51your pocket. Have you actually
• 57:52noticed anything else changing?
• 57:54And then you bring their
• 57:55attention into
• 57:57perhaps how their cognitive function
• 57:59has changed, how the fact
• 58:01that they've introduced more activity
• 58:03and how play much pleasure
• 58:04they are getting from it.
• 58:05So I don't know if
• 58:06that makes sense.
• 58:07And then then there might
• 58:09be people that come to
• 58:10you and say, I want
• 58:10to go to university in
• 58:11September, but right now, I
• 58:13spend all my days smoking
• 58:14cannabis.
• 58:15Can you help me? So
• 58:16we work with what people
• 58:17bring into the session.
• 58:19And depending what
• 58:20is their goal, their motivation,
• 58:23we use the tools that
• 58:24fits them rather than the
• 58:26other way around. So the
• 58:28protocol is that we use
• 58:29anything that addiction has shown
• 58:31it does work,
• 58:32and we tailor it to
• 58:33the individual.
• 58:34That's the key. Fantastic. Thank
• 58:36you.
• 58:37We have one last question
• 58:39from, from Godfrey. Godfrey, do
• 58:41you wanna ask
• 58:43your question?
• 58:45Sure. Yeah. Marta, thank you
• 58:47so much. It's lovely to
• 58:48see these data.
• 58:49Thank you. In in the
• 58:51b SNP sample
• 58:53of psychosis from multiple sites,
• 58:55we see something
• 58:57similar to you
• 58:58in that individuals with early
• 59:01childhood trauma
• 59:02who use lots of high
• 59:03potency cannabis
• 59:05are at increased risk, and
• 59:07they look a little biologically
• 59:09different.
• 59:10But our effect is seen
• 59:12almost exclusively in people who
• 59:14are early adopters,
• 59:15people who use
• 59:17high potency cannabis early in
• 59:19early adolescence.
• 59:22And I I wondered if
• 59:23you see similar effects that
• 59:25those individuals are more vulnerable
• 59:26in some way or more
• 59:28liable to develop psychosis
• 59:30with earlier use.
• 59:33So in thank you very
• 59:34much. Thank you very much
• 59:35for for the question. So
• 59:37in the work that Julia
• 59:38has done, it's difficult to
• 59:40to see this particularly because
• 59:43practically
• 59:44everybody starts at around age
• 59:46sixteen. So we don't really
• 59:48have enough in the sample,
• 59:50say, to,
• 59:51separate
• 59:52out people that might start
• 59:54at age thirteen, fourteen, or
• 59:56people that start later. It's
• 59:58really a sort of qua
• 59:59homogeneous and represents a little
• 01:00:01bit,
• 01:00:02you know, what happens in,
• 01:00:04in, in Europe and and
• 01:00:06in UK.
• 01:00:07What I I can tell
• 01:00:08you is that
• 01:00:10in the general population sample,
• 01:00:12the, cannabis and mis study,
• 01:00:14what I've been quite struck
• 01:00:16about is that there are
• 01:00:17some people
• 01:00:19who actually start
• 01:00:21using cannabis,
• 01:00:22having experienced trauma in childhood.
• 01:00:25They start using cannabis
• 01:00:27later in life, particularly women
• 01:00:29in, their sort of, thirties,
• 01:00:33mid thirties,
• 01:00:34which are
• 01:00:36they they experienced
• 01:00:37a very striking increase in
• 01:00:39the paranoia,
• 01:00:40which I was not expecting.
• 01:00:42Now I don't know if
• 01:00:43it's just a gender
• 01:00:44thing. I don't think we
• 01:00:45have enough to say, but
• 01:00:47I've been going around saying
• 01:00:49that it's all to do
• 01:00:49with early cannabis use. I
• 01:00:51mean,
• 01:00:53adolescent being a critical window
• 01:00:55of exposure, the brain is
• 01:00:56developed and so on. But
• 01:00:58in the cannabis and me
• 01:00:59sample, we have quite
• 01:01:00a good group of of
• 01:01:02later users. Also, people that
• 01:01:04have been prescribed cannabis
• 01:01:05for pain
• 01:01:06or for medicinal reason in
• 01:01:08UK where it is now
• 01:01:09legal,
• 01:01:10who are actually running on
• 01:01:11very high paranoia as well.
• 01:01:13So I don't know. I
• 01:01:14wonder if we ever look
• 01:01:16at this group enough,
• 01:01:18and what we will find
• 01:01:20if we explore people of
• 01:01:21my age,
• 01:01:22using lots of cannabis.
• 01:01:24We might be surprised. But
• 01:01:26Julia when Julia in in
• 01:01:27Julia data with childhood adversity,
• 01:01:29it is earlier than I
• 01:01:31mean, I don't know how
• 01:01:32you define early, but it's
• 01:01:33around
• 01:01:34fifteen, sixteen year of age.
• 01:01:36Alright. Thank you.
• 01:01:38Well, Marta Thank you very
• 01:01:40much. This was an amazing
• 01:01:41talk, I mean, from ready
• 01:01:44epidemiological
• 01:01:45data to actual clinical implic
• 01:01:48implementation
• 01:01:49of,
• 01:01:50so I'm sure people are
• 01:01:51gonna reach out to you
• 01:01:53to about how to start
• 01:01:54a clinic and to get
• 01:01:55your guidance.
• 01:01:56Would you mind if people
• 01:01:57emailed you questions that we
• 01:01:58won't be able to answer?
• 01:02:00No. No. Not not at
• 01:02:01all. And my greatest advice,
• 01:02:03I don't have sophisticated advice.
• 01:02:05You want to do it.
• 01:02:05Start it. Don't wait and
• 01:02:07think, oh, how do we
• 01:02:08do it? There's no such
• 01:02:09a thing as perfection.
• 01:02:11Start, see how it goes,
• 01:02:12and shape it all the
• 01:02:12way. And and the patient
• 01:02:14will tell you if you're
• 01:02:15doing it right or not.
• 01:02:16They they they've been the
• 01:02:17main advisory group of this
• 01:02:19project, I would like to
• 01:02:21say.
• 01:02:22Well, thank you again. We
• 01:02:23really enjoyed this and this,
• 01:02:25and I'll be in touch
• 01:02:26with you.
• 01:02:28Lovely to see you all.
• 01:02:29And thank you very much.
• 01:02:29You have wonderful question. Bye,
• 01:02:31Cyril. See you soon. Bye.
• 01:02:32See you. Thank you, everyone.
• 01:02:33Bye, Wendy.
• 01:02:34Bye bye, Mohini.
• 01:02:36Bye, everybody.