YCSCAN2 January 2025 Webinar

Transcript

• 00:06Good afternoon, everyone,
• 00:08and,
• 00:10welcome.
• 00:12Welcome to this, inaugural
• 00:14webinar lecture,
• 00:16presented by the Yale Center
• 00:17for the Science of
• 00:19Cannabis and Cannabinoids.
• 00:21I'm, Deepak Cyril D'Souza.
• 00:24I'm thrilled,
• 00:26as we launch this webinar
• 00:28series, which was designed to
• 00:29support
• 00:30our mission and provide a
• 00:32platform,
• 00:34for meaningful dialogue and discovery
• 00:37about the science of cannabis
• 00:39and cannabinoids.
• 00:40The next four web webinars,
• 00:42which we will announce soon,
• 00:44are focused
• 00:45on the impact of cannabis
• 00:47on brain development.
• 00:49This is the inaugural webinar.
• 00:51And to kick it off,
• 00:53we are honored to have
• 00:54no other than, Yasmin Hurd
• 00:57as our inaugural,
• 00:59speaker.
• 01:00Doctor Hurd needs no introduction.
• 01:03She is award Coleman chair
• 01:05of translation neuroscience
• 01:07and the director of the
• 01:08Addiction Institute at Mount Sinai.
• 01:11She's a she has a
• 01:12prolific
• 01:13publication
• 01:14record in in the top
• 01:16tier scientific journals.
• 01:19She was, she has many
• 01:20honors and awards, which I'm
• 01:21not going to spend time
• 01:23on,
• 01:24but, some important ones, she
• 01:26is, she was elected to
• 01:28the National Academy of Sciences,
• 01:31and this is one of
• 01:32the highest honors a scientist
• 01:33can receive recognizing
• 01:35their groundbreaking work. She's also
• 01:37elected to the National Academy
• 01:39of Medicine.
• 01:41She's a renowned neuroscientist,
• 01:43whose research has significantly,
• 01:46advanced our understanding of, drug
• 01:48addiction and related disorders.
• 01:51So we are really excited,
• 01:53Yasmin, that you could join
• 01:55us and help us kick
• 01:56off this webinar series. Thanks.
• 01:59Thanks so much for having
• 02:00me. Let me share my
• 02:02slide.
• 02:02And I do wanna say
• 02:04congratulations,
• 02:08to getting this,
• 02:10honor to be able to
• 02:12have the center for science
• 02:13the science of cannabis and
• 02:15and cannabinoids. So I look
• 02:17forward to seeing how your
• 02:19center develops and in continue
• 02:21to impact,
• 02:22you know, given all the
• 02:23work that you guys have
• 02:25all done and more to
• 02:26come, I know.
• 02:27Let me just move over
• 02:29all of these
• 02:30things floating around.
• 02:32So,
• 02:35clearly, for me, you know,
• 02:37as I said, I'm I'm
• 02:38really happy that you you
• 02:39received this this the center
• 02:42and the focus that it
• 02:44will have in the beginning,
• 02:45as you said, on development.
• 02:47Development, since a large part
• 02:48of the work that I
• 02:49I do on cannabis relates
• 02:50to that and in terms
• 02:51of thinking about pathways
• 02:54to addiction.
• 02:55But it also is important,
• 02:56and I'll end with
• 02:58where we're seeing cannabis in
• 03:00regard to and cannabinoids
• 03:02in particular
• 03:04to, giving us pathways from
• 03:05addiction.
• 03:07And
• 03:08I have nothing to disclose,
• 03:10unfortunately, right now. Hopefully, some
• 03:12things will come later on
• 03:13as we do more cannabis
• 03:14work.
• 03:15As all of you know,
• 03:17cannabis is now legal in
• 03:18most of the states in
• 03:20United States
• 03:21and in many different flavors.
• 03:23And one of the big
• 03:24issues is that this patchwork
• 03:26of
• 03:27legality,
• 03:28some have states having,
• 03:30legal use for recreational purposes
• 03:33or for medicinal purposes or
• 03:35both. And this definitely has
• 03:37led to a lot of
• 03:38issues statewide
• 03:40and where I think it
• 03:41even contributes to what I
• 03:43call today's perfect storm for
• 03:45cannabis.
• 03:46One, obviously, the increase in
• 03:48THC
• 03:49concentrations
• 03:50over time
• 03:51while another cannabinoid, CBD,
• 03:54is decreased because as you
• 03:56guys know, this very complex
• 03:57plant with so many cannabinoids.
• 03:59So this is, I think,
• 04:01one of the bases when
• 04:02you think about this complex
• 04:04plant with so many chemicals
• 04:06that, including over a hundred
• 04:08cannabinoids that we still do
• 04:10not know
• 04:11most of their biological,
• 04:13function.
• 04:14And the fact that
• 04:16it's not just
• 04:18the flower that has changed
• 04:19in regard to the amount
• 04:21of THC, but the the
• 04:23potency of a lot of
• 04:24the products that are out
• 04:25there today, I mean, there's
• 04:27a cornucopia of,
• 04:28you know, the the shutters,
• 04:30the damps,
• 04:31and many different routes of
• 04:32administration, obviously, not just smoking,
• 04:35the edibles that have all,
• 04:37you know, led to, again,
• 04:38more complexity of the storm.
• 04:40Another thing is not just
• 04:42the
• 04:43the cannabis and THC from
• 04:45the natural flower, but the
• 04:47semi synthetic products that are
• 04:49being created,
• 04:50again, because the federal government,
• 04:52when they they,
• 04:54made hemp, cannabis,
• 04:56legal,
• 04:57and so less than one
• 04:58point three percent THC,
• 05:01what it meant was that
• 05:02people then could take the
• 05:03the CBD that's in this
• 05:04hemp plant and chemically
• 05:06change them to THC,
• 05:08products, which are themselves potent.
• 05:11And then also
• 05:12rare cannabinoids that were found
• 05:14in the plant
• 05:15that were extremely potent, even
• 05:17greater than thirty percent more
• 05:19potent than delta nine THC,
• 05:21they can now make it
• 05:22synthetically.
• 05:22So that's what we're up
• 05:23against in our society. That's
• 05:25why I call it today's
• 05:26perfect storm.
• 05:28That perfect storm of increasing
• 05:30concentrations has also led, as
• 05:31you can see, to more
• 05:33cannabis being used in terms
• 05:34of as cannabis has become
• 05:36legal and the stigma.
• 05:38And I think rightly so
• 05:39in terms of, you know,
• 05:40decreasing the stigma of,
• 05:42and I should say the
• 05:42criminalization
• 05:44of cannabis use. But it
• 05:45has consequences, such as you
• 05:47see the increase in cannabis.
• 05:49But if you take that
• 05:50number of the increase in
• 05:52the,
• 05:53the use of cannabis, those
• 05:54who are using daily or
• 05:56near daily are now higher
• 05:58than,
• 05:58than,
• 06:00people using alcohol daily.
• 06:02So that's where cannabis has
• 06:04gone.
• 06:05And one of the things
• 06:06that we have seen if
• 06:06we take, for example,
• 06:08a state that legalized cannabis
• 06:10early, for example,
• 06:11California, I was gonna say,
• 06:13Canada, which will barely be
• 06:14certain people want it. Cannabis
• 06:16used during early pregnancy, we
• 06:18saw that when the recreational,
• 06:22cannabis legalization occurred and was
• 06:24implemented, you see now that
• 06:25there is even a a
• 06:27a bigger jump up in
• 06:28terms of pregnant women using
• 06:30cannabis. And it's mainly in
• 06:31within even can California,
• 06:34those places where their the
• 06:36retail
• 06:38sales,
• 06:39are allowed, that's what's driving
• 06:40a lot of that,
• 06:42use.
• 06:43So for me and, obviously,
• 06:45for for many of you,
• 06:46the issue about,
• 06:49cannabis per se is the
• 06:51aspect of addiction risk.
• 06:53But we studied often along
• 06:55with the psychiatric risk of,
• 06:58the psychiatric disorders. We studied
• 07:00them mainly in adulthood.
• 07:01But we know that there's
• 07:02a developmental origin to most
• 07:04of them and not just
• 07:06adolescents
• 07:07for,
• 07:08for adult psychiatric and addiction
• 07:10risk, but also in regard
• 07:12to understanding even prenatal.
• 07:14And cannabis is an important
• 07:16part of that because of
• 07:17the numbers I just showed
• 07:18you that more women pregnant
• 07:20women are using cannabis that
• 07:22I didn't show you the
• 07:23numbers, but that increase in
• 07:24the frequency and daily use,
• 07:26were also there in in
• 07:28adolescence.
• 07:29And a major issue for
• 07:31this the
• 07:33concern
• 07:34regarding,
• 07:35the the exposure of cannabis
• 07:37early on is that we
• 07:39know that the endogenous cannabinoid
• 07:41system
• 07:41does play a really critical
• 07:43role,
• 07:44throughout the you know, throughout
• 07:46life, but especially during early
• 07:48development in terms of not
• 07:50just neurogenesis, but also the
• 07:52the the
• 07:53the birth of of many
• 07:55different types of cells, their
• 07:56migration, the synapses that they
• 07:58form, and even program cell
• 08:00death.
• 08:01And and later on, in
• 08:03terms of late adulthood
• 08:05sorry. Late adolescence into early
• 08:06adulthood,
• 08:07the fine tuning and maturation
• 08:10of the of the cortex,
• 08:12a lot of the endocannabinoid
• 08:14system is critical in the
• 08:15in these, processes.
• 08:17And as I said, we
• 08:18know that there's more exposure
• 08:21to cannabis
• 08:22in during these,
• 08:24important key developmental
• 08:25stages,
• 08:26not just adolescence,
• 08:28but, throughout,
• 08:29from fetal infancy,
• 08:31childhood, and so on. So
• 08:32this is one of the
• 08:33things that you know, the
• 08:34question is, what are the
• 08:35lit the long term impact
• 08:37on on behavior?
• 08:39And when we look at
• 08:41where does THC,
• 08:43the cannabinoid that leads to
• 08:45the, you know, the reinforcing
• 08:47effects and even obviously,
• 08:49at Yale shown, you know,
• 08:51its importance for,
• 08:53for the psychosis that
• 08:55acute cannabis use can induce.
• 08:57We know that it binds
• 08:58to the cannabinoid receptor,
• 08:59the CB one receptor, which
• 09:01is the most abundant key
• 09:03protein coupled receptor in the
• 09:04brain. So it's highly abundant
• 09:06throughout most,
• 09:07brain regions.
• 09:09But when you look in
• 09:10the, the fetal developing brain,
• 09:13there is a developmental process
• 09:15which we would expect. But
• 09:16you do see that the
• 09:17cannabinoid receptor
• 09:19is expressed very highly
• 09:21in, for example, the amygdala,
• 09:23brain region, really critical for
• 09:25emotional regulation,
• 09:27not on this slide, but
• 09:28in the nucleus accumbens, importance
• 09:29reward, goal directed behavior, and
• 09:31so on. So we know
• 09:33from very early on
• 09:34that the endocannabinoid
• 09:36system and, therefore, exposure to
• 09:38cannabis and cannabinoids during this
• 09:40time period might have important
• 09:41implications
• 09:42relevant to,
• 09:44mental health risk.
• 09:46And so when we look
• 09:48at I'm gonna I've separated
• 09:50the the talk in two
• 09:52parts, focusing first on the
• 09:54on fetal development, and then
• 09:56I'll go to adolescent exposure,
• 09:59to, cannabis and cannabinoids.
• 10:01So as I said,
• 10:03the endocannabinoid system plays a
• 10:05really critical role doing this
• 10:06early developmental processes
• 10:08where the oh, that was
• 10:10still did I go back?
• 10:11Where, there is a huge
• 10:13dynamic change
• 10:15in the endocannabinoid
• 10:17system during this time period.
• 10:18So a big question for
• 10:20us was, does early exposure
• 10:22during prenatal
• 10:23exposure, does that have a
• 10:25long term impact on on
• 10:26on future,
• 10:28offspring development?
• 10:29And this project actually became
• 10:31much more,
• 10:34I will say,
• 10:36real because we wanted to
• 10:37really get a sense of
• 10:38what's happening in humans. And
• 10:40so my colleague, Yoko Nomura,
• 10:42at that time was studying
• 10:43stress during pregnancy and looking
• 10:45at
• 10:46offspring,
• 10:47behavior, and they wanted to
• 10:48study cannabis. And so we
• 10:50combined our efforts.
• 10:51And one of the things
• 10:52that we were able to,
• 10:55to actually centralize
• 10:57from the stress perspective, because
• 10:58many pregnant,
• 11:00women will have different stressors.
• 11:01But there was an objective
• 11:02common stress that all,
• 11:04everybody in our study at
• 11:06that time experienced. Those, obviously,
• 11:08before we were studying people
• 11:09before, superstorm Sandy,
• 11:12around over little over a
• 11:13decade ago now and during
• 11:15and post. And we collected
• 11:17many different things and, studied
• 11:19their kids also afterwards.
• 11:21So the question was, does
• 11:24you know, what can we
• 11:25look at prenatally to be
• 11:26able to understand,
• 11:28what might be an impact
• 11:29of cannabis exposure during in
• 11:31utero,
• 11:32development?
• 11:33And we thought about the
• 11:35placenta. Obviously, you know, considered
• 11:37the third brain, the link
• 11:38between maternal and and and
• 11:40fetal brain. And as all
• 11:42of you know, the placenta
• 11:43is critical for fetal development
• 11:46on every single aspect of
• 11:48of of fetal development.
• 11:50And, also, studies have shown
• 11:52that placental programming
• 11:53is actually critical for,
• 11:56not just neurodevelopment, but psychiatric
• 11:59risks seen later in life.
• 12:01So we decided to ask
• 12:03the question, does cannabis impact
• 12:04the placental environment? And, therefore,
• 12:06we did RNA sequencing
• 12:08and just to look at
• 12:09the transcriptome of the placenta.
• 12:11And they posted at that
• 12:12time with Greg Rompala. We
• 12:14could see that,
• 12:15for example, candidate genes like
• 12:17the cannabinoid receptor gene was
• 12:19significantly
• 12:20impacted with maternal cannabis use
• 12:23and was, and even correlated
• 12:25to the amount of use
• 12:26that they the the women
• 12:28reported using.
• 12:29But what we were
• 12:31surprised about, at least initially,
• 12:33was that there was this
• 12:34really strong
• 12:36dysregulation of immune related genes
• 12:38in the placenta. No matter
• 12:40how,
• 12:41the data was analyzed, we
• 12:42could see that this had
• 12:44a really strong effect.
• 12:45We then have replicated in
• 12:47a subgroup again, and here
• 12:49trying to see if there
• 12:50are any differences in the
• 12:51sex. And one of the
• 12:52things that we could see,
• 12:53well, there are significant sex
• 12:55differences
• 12:56in regard to the placental
• 12:58transcriptome
• 12:59that it was males that
• 13:00were driving a lot of
• 13:01these changes that we saw
• 13:03in in the placenta of
• 13:05those exposed,
• 13:06to to to cannabis.
• 13:09We also then,
• 13:11to be able to understand
• 13:13causal relationships
• 13:15to cannabis. We then developed
• 13:17a translational animal model where,
• 13:20pregnant dams are exposed with
• 13:22vapor to THC,
• 13:24and a very small amount
• 13:25of of CBD,
• 13:26and also looked at the
• 13:27placenta in those animals. And
• 13:29it replicated what we see
• 13:32in the human placenta
• 13:33where, once again, there's much
• 13:35stronger effects in the in
• 13:37the male placenta than in
• 13:38the females. And in rodents,
• 13:40the the siblings are next
• 13:42to each other, So it's
• 13:43not,
• 13:44because,
• 13:45rodents have multiple births, and
• 13:47you could see still this
• 13:49this sex difference.
• 13:50One of the things that
• 13:51we saw, again, in terms
• 13:53of, replicating what we saw
• 13:54in the human, was once
• 13:56again these immune related dysregulation
• 13:59of the genes in in
• 14:00the placenta that were exposed,
• 14:02to THC.
• 14:04And we could see also
• 14:06these epigenetic changes that I
• 14:07didn't go into, with the
• 14:09with the human, but I'll
• 14:10go into a little later
• 14:12as well where there are
• 14:13these specific epigenetic
• 14:14dysregulation that we could also
• 14:16see,
• 14:17in the placenta.
• 14:19We also wanted to see,
• 14:20is it only on the
• 14:22gene expression level? Is it
• 14:23also there on the pro
• 14:25the protein level? So we
• 14:26looked at proteomics using the
• 14:28Yale,
• 14:29proteomics core, and we could
• 14:31replicate that indeed
• 14:33that there were significant differences
• 14:35in immune related,
• 14:38proteins. I'm not highlighting them.
• 14:39Not only in the in
• 14:41the human, but also in
• 14:43the rat.
• 14:44So definitely both,
• 14:47prenatal cannabis exposure
• 14:49and THC exposure in our
• 14:50animal models replicate.
• 14:53So
• 14:54the question was, okay. You
• 14:56see these placental changes. Do
• 14:58they really influence and impact,
• 15:01the future phenotype of the
• 15:03offspring?
• 15:04And so we had brought
• 15:05back in the kids yearly,
• 15:08for the women who we
• 15:09had, studied while pregnant.
• 15:12And I'll just show a
• 15:13few of of the data.
• 15:14I mean, a lot has
• 15:15happened since then, but I'm
• 15:16just showing a list of
• 15:17the published ones where we
• 15:18could see that, for example,
• 15:19in their hair, steroid hormone
• 15:21cortisol was increased in those
• 15:23who had been exposed prenatally,
• 15:25to cannabis.
• 15:27They have clinical,
• 15:29measures,
• 15:30every year by,
• 15:32psychologists, psychiatrists, and social workers,
• 15:35and we could see that,
• 15:36again, those individuals that had
• 15:38been who had been exposed
• 15:39to cannabis predatally showed greater
• 15:42anxiety, greater aggression, greater,
• 15:44hyperactivity.
• 15:46We also saw, though, that
• 15:47there is
• 15:49a a really strong synergistic
• 15:51interaction between the prenatal exposure
• 15:54to stress
• 15:56with cannabis. So, yes, you
• 15:58get this increase in anxiety
• 15:59in those exposed to cannabis
• 16:01and stress, But the the
• 16:03combination of both in their
• 16:05offspring
• 16:06led to a much of
• 16:07this huge synergistic,
• 16:09effect
• 16:09that,
• 16:11even the earlier onset of
• 16:12the diagnosis,
• 16:14not just in the the,
• 16:16the magnitude
• 16:17of their their behavioral differences.
• 16:20So synergistic effects are really
• 16:23critical, and I think that
• 16:24also plays into I'm not
• 16:26gonna talk about the environmental
• 16:27factors that we also have
• 16:28to consider.
• 16:30But one of the things
• 16:31that that said what we
• 16:32were interested in is does
• 16:34early life
• 16:35events
• 16:36and that we
• 16:37use the placental gene, transcriptome,
• 16:40does it really predict future
• 16:41behavior? And we could see
• 16:43that, indeed, that
• 16:46off the placental transcriptome,
• 16:49the cytokine, the immune related,
• 16:52gene networks
• 16:53really predicted
• 16:54anxiety behavior in the offspring
• 16:57of those women who had
• 16:59been abused cannabis during pregnancy,
• 17:03and we did not see
• 17:04a relationship in those who,
• 17:06in the control subjects.
• 17:08We've, as I said, studied
• 17:10a subgroup of individuals, and
• 17:11we once again see
• 17:14that, the relationship of the
• 17:16immune,
• 17:17related placental gene expression,
• 17:20are associated with anxiety later
• 17:22on in their their kids.
• 17:24But we also see that
• 17:25those gene networks related to,
• 17:27for example, lipid processing,
• 17:31are really critical,
• 17:32and are so significantly
• 17:34associated with depression,
• 17:36behaviors
• 17:37in the in the offspring.
• 17:41So
• 17:42we see this in children,
• 17:43and so now,
• 17:45we are started looking in
• 17:47our animal models because when
• 17:48we first started looking at
• 17:49the prenatal effects of cannabis,
• 17:51we actually,
• 17:53looked immediately
• 17:54in adulthood.
• 17:55But our human studies told
• 17:57us that there may be,
• 18:00indices earlier in life,
• 18:02even from infancy.
• 18:03So we've started now to
• 18:05look in our animal models
• 18:06using our animal models to
• 18:07look at prenatal,
• 18:09THC exposure and looking at
• 18:11earlier outcomes.
• 18:12And,
• 18:13one of the things that
• 18:14we could see, for example,
• 18:16one of the first measures
• 18:17that you could have in
• 18:18rodents,
• 18:19as a the postnatal late
• 18:21ten in terms of ultrasonic
• 18:22vocalization, how they communicate with
• 18:24their moms. And we could
• 18:25see that there was a
• 18:26significant difference,
• 18:28sorry, significant difference
• 18:30in in the calls that
• 18:31are made in the infant
• 18:33THC exposed,
• 18:36pups as compared to vehicle.
• 18:38And these altered communication patterns
• 18:40we're still, looking into.
• 18:42A little later on in
• 18:43infancy, we can see that,
• 18:46we
• 18:47these animals underwent
• 18:48a a homing behavioral test
• 18:50for looking at social discrimination.
• 18:52And then we measured, looked
• 18:55at plasma levels the next
• 18:56day, and we could see
• 18:57that the circulating
• 18:59cytokines, these immune
• 19:01changes
• 19:01were were significantly
• 19:03different in the males
• 19:05now
• 19:07a day later after this
• 19:08homing behavior.
• 19:10And, again, we could see
• 19:11that there were,
• 19:13relationships
• 19:14with the
• 19:17an immune related gene expression,
• 19:19NF kappa b, and the
• 19:20circulating
• 19:21cytokines that was completely disrupted
• 19:24in,
• 19:25in the animals that have
• 19:26been prenatally exposed to to
• 19:28THC.
• 19:29And when they get into
• 19:31adolescence, we once again see
• 19:33that there are
• 19:35Sorry.
• 19:36We once again see that
• 19:37there are differences, but, again,
• 19:39there's a sex difference where
• 19:40males that were exposed prenatal
• 19:42to THC
• 19:43showed these really strong differences
• 19:45in, for example, social play.
• 19:47So from even infancy and
• 19:49into adolescence, you can see
• 19:51that there are significant,
• 19:53effects on behavior.
• 19:55But in adulthood, this was
• 19:56from our earlier study earliest
• 19:58studies, and so I was
• 19:59showing because
• 20:00we wanted to look at,
• 20:01is there an impact or
• 20:03relevance to,
• 20:05adult behaviors and particularly
• 20:07people
• 20:08at that time, we're talking
• 20:09about, like, gateway
• 20:11in of cannabis, and we
• 20:12could see that animal adult
• 20:14animals that had been exposed
• 20:15prenatally to THC and never
• 20:17had THC exposure again,
• 20:20if when they were,
• 20:21could choose in terms of
• 20:23the self administration of heroin,
• 20:25they self administered more heroin.
• 20:27And even when we,
• 20:29and they were when we
• 20:31made the situation such that
• 20:33the animals would take the
• 20:34same amount of heroin,
• 20:36those that had those adult
• 20:37animals that had prenatal exposure
• 20:39to THC, they would be
• 20:40the first to run to
• 20:41get the first hit of
• 20:42heroin.
• 20:43And if they were stressed,
• 20:44just mild stress, it increased
• 20:46their heroin seeking behavior.
• 20:48So there were we knew
• 20:49from very long that there
• 20:51was this long term effect
• 20:52of prenatal, cannabis
• 20:54on on behavior,
• 20:56on adult behavior.
• 20:57We could see use looking
• 20:59at other outcomes as well.
• 21:01For example, looking at progressive
• 21:03ratio schedules,
• 21:04whether or not that would
• 21:05look at motivated behavior, we
• 21:07could see that the the
• 21:09prenatal,
• 21:10exposed,
• 21:11THC animals showed changes in
• 21:12motivated behavior, changes in in
• 21:15the mobility behavior that looks
• 21:16at,
• 21:17really is a a model
• 21:18of depression like phenotype, and
• 21:21even their hedonic state
• 21:23was changed in relation to
• 21:25stress and their sucrose intake.
• 21:28So
• 21:30for us seeing these long
• 21:31term effects into adulthood, the
• 21:33question was, what are the
• 21:34mechanisms that are maintaining this?
• 21:36And that's when we started
• 21:37to look at epigenetic mechanisms
• 21:39because we know, obviously, we're
• 21:40not changing the genetic,
• 21:42sequence of these animals and
• 21:44that the environment, though, can
• 21:46change,
• 21:47gene activity. And that mechanism
• 21:49by which environment does that
• 21:50through these epigenetic
• 21:52cuts that can increase,
• 21:54open up the the DNA
• 21:56so to increase transcription
• 21:58or to close it and
• 21:59decrease transcription
• 22:00in selective ways. The epigenetic
• 22:02mechanisms are
• 22:04numerous, and they're growing daily.
• 22:06And at that time, we
• 22:08then
• 22:09wanted to look at,
• 22:12we
• 22:13we looked at the gene
• 22:14expression of known epigenetic mechanisms
• 22:17at that time
• 22:19to to be able to
• 22:20to screen to see were
• 22:22there specific epigenetic changes that
• 22:24were occurring in the brains
• 22:25of animals of adult animals
• 22:27with this prenatal THC exposure.
• 22:29And when we looked at
• 22:30all of these,
• 22:31mechanisms, one was repeated in
• 22:35in all of our,
• 22:36cohorts of our our our
• 22:38animals,
• 22:39and that was KMT two
• 22:40a, which is also m
• 22:41l o one. And this
• 22:42is a histone methyltransferase
• 22:44that really plays a really
• 22:46critical role in neurogenesis
• 22:47and is a key maintenance
• 22:49of transcriptional memory.
• 22:51And I don't know if
• 22:52you remember,
• 22:53h three k four was
• 22:55one of the epigenetic
• 22:56signatures that we saw in
• 22:57the placenta
• 22:59of those that had been
• 23:00exposed,
• 23:01to,
• 23:02to
• 23:03THC candidates.
• 23:05And we can see this
• 23:06not only prenatally
• 23:07or right at at birth.
• 23:08We can see this throughout
• 23:10their lives, not only in
• 23:11the gene expression, but also
• 23:12in the protein level as
• 23:13well. The one thing with
• 23:15animal models, we can at
• 23:16least go in and mechanistically
• 23:18see is this epigenetic
• 23:23modification critical for the behaviors
• 23:25that we see in adulthood?
• 23:27So we can go in
• 23:28and virally, for example,
• 23:30change the
• 23:32increase the expression,
• 23:34or I should say, knock
• 23:35down the expression of this
• 23:36particular gene, and we could
• 23:38actually then change their behavior.
• 23:40So for example,
• 23:42animals, as I showed you
• 23:43before, that, they've showed changes
• 23:45in motivated behavior with prenatal
• 23:47THC exposure and knocking down
• 23:49the KMT two a epigenetic
• 23:51gene, it normalized their behavior.
• 23:54We can also,
• 23:56see that,
• 23:58this particular epigenetic tag is
• 24:00a really strong
• 24:02driver
• 24:03of the genes that are
• 24:04downregulated.
• 24:05For example, here in the
• 24:06nucleus accumbens,
• 24:07this is already,
• 24:09during infancy.
• 24:11Early infancy, we can see
• 24:12that this plays a really
• 24:13key role,
• 24:14and it's related to
• 24:19the postsynaptic
• 24:19density, the synaptic organization,
• 24:23in these in these animals.
• 24:25In adulthood, we we could
• 24:27we also looked at where
• 24:29is this particular epigenetic
• 24:30tag,
• 24:33localized to all these genes.
• 24:35And we could see that
• 24:36in
• 24:38in normal animals, the relationship
• 24:40of where these tags are
• 24:41completely changed in those,
• 24:44that had,
• 24:45been exposed prenatally to THC.
• 24:48It completely reorganized,
• 24:50and it was very strongly
• 24:52enriched in immune related genes.
• 24:56And this is the, the
• 24:57nucleus accumbens of of adult
• 24:59rats with prenatal THC exposure.
• 25:02We could also see that
• 25:04consistent with what we saw
• 25:06even early in life that
• 25:07this particular tag is really
• 25:09strongly linked to,
• 25:11regulating
• 25:12aspects of synaptic plasticity.
• 25:16So,
• 25:18yes,
• 25:19the fetal or exposure to
• 25:21cannabis and and to THC,
• 25:24we can see long term
• 25:25effects. We can see specific
• 25:26changes,
• 25:28in not only in placenta
• 25:30that predicts later
• 25:32behavior both in a human
• 25:33and in our animal models,
• 25:34but we can also see
• 25:35this long term effects into
• 25:37adulthood.
• 25:38The other developmental
• 25:40window
• 25:41that we studied and actually
• 25:42perhaps we started with adolescents,
• 25:45And in in part of
• 25:46that time, as I mentioned
• 25:47earlier,
• 25:48you know, these questions about,
• 25:49quote, unquote, the gateway hypothesis
• 25:51of cannabis, as there was
• 25:52a gateway with nicotine and
• 25:53alcohol, does it lead to
• 25:55greater,
• 25:57intake of of, like, heavy
• 25:59drugs such as heroin or
• 26:00so?
• 26:01And
• 26:02the question again, you know,
• 26:04this has been a huge,
• 26:07debate in our society.
• 26:09And so
• 26:10we now have a lot
• 26:11of studies looking into this.
• 26:13And one of the things
• 26:14about the adolescent brain that,
• 26:15as I mentioned earlier, you
• 26:17know, this is the last
• 26:19window and into the young
• 26:20adulthood of the fine tuning
• 26:22and maturation of the prefrontal
• 26:24cortex.
• 26:25And we know now that,
• 26:26you know, more teens are
• 26:27using cannabis in terms of
• 26:29more frequently
• 26:30and more near daily use
• 26:32of cannabis.
• 26:34And
• 26:35at the end of the
• 26:36day, we also know that
• 26:38adolescence is a really important
• 26:40window if we wanna talk
• 26:41about or intervene and reduce
• 26:43and mitigate some of the
• 26:45adult substance use disorders that
• 26:47we see. And sadly, a
• 26:49large percentage of teens already
• 26:50meet a cannabis use disorder.
• 26:52So it's really an important,
• 26:54I think, developmental window for
• 26:55us to look at.
• 26:57So the question, you know,
• 26:59as we see it is
• 27:01that the you know, we
• 27:03know that a number of
• 27:04studies
• 27:05this is where I thought
• 27:05I had
• 27:06a number of studies have
• 27:08shown that,
• 27:09in humans,
• 27:11population, longitudinal studies, that there
• 27:13are changes in the prefrontal
• 27:14cortex with cannabis,
• 27:16exposure during use during adolescence.
• 27:18And there there are studies
• 27:20that
• 27:21will contradict those results and
• 27:23more of the studies being
• 27:25done like the a, b,
• 27:26c, d and imaging from
• 27:28the Europe,
• 27:29neuroimaging studies are really helping
• 27:31to give us some insights.
• 27:32But what we wanted to
• 27:33look at is, like, using
• 27:35an animal model, not to
• 27:36worry about their friends or
• 27:37their mothers,
• 27:38does adolescent TFT exposure impact
• 27:41prefrontal cortical development? And so
• 27:43we can actually look at
• 27:44cortical cells,
• 27:46and we could see that
• 27:47in, young adults that had,
• 27:50adolescent exposure to THC
• 27:53that their the cortical their
• 27:54prefrontal
• 27:55pyramidal cells
• 27:57look very different compared to
• 27:59normal,
• 28:00That there was a difference
• 28:01in the complexity
• 28:03of the neurons,
• 28:04both in the apical branching
• 28:05and basal branching.
• 28:07And the thing that was
• 28:08interesting is that
• 28:10where these changes were occurring
• 28:12really resembled
• 28:13what morphological change that had
• 28:15been documented in the prefrontal
• 28:17cortex
• 28:18with stress. So that was
• 28:19very interesting to us. And
• 28:21one of the things
• 28:23oh, this is strange. One
• 28:24of the things that we
• 28:25could also see is that
• 28:27we could pick up these
• 28:27cells and let the in
• 28:29the video is not going.
• 28:30Don't know why. And we
• 28:31could pick up with lasers
• 28:32and then sequence these cells.
• 28:34And we could see that
• 28:36in adults with,
• 28:38normal development of vehicle animals,
• 28:40that what what were gene,
• 28:43expression patterns that were changed
• 28:44were consistent with what we
• 28:46know
• 28:47happens during the normal developmental
• 28:49process into into adulthood.
• 28:51But there was a complete
• 28:53reorganization,
• 28:54complete
• 28:55reprogramming
• 28:56of the prefrontal cortical transcriptome
• 28:59in those adults that have
• 29:00had adolescent THC exposure.
• 29:02And where the changes were
• 29:04located,
• 29:06reflecting what we saw morphologically,
• 29:08meaning that the gene networks
• 29:10related to, you know, dendritic
• 29:11development and the the cell,
• 29:14projections and so on. But
• 29:16there was also this huge
• 29:18change in these epigenetic
• 29:19signatures.
• 29:20And interestingly,
• 29:22similar to what we saw
• 29:23in the placenta to what
• 29:24we saw in prenatal
• 29:26prenatally exposed adults,
• 29:29this particular epigenetic mark,
• 29:31trimethylation of of of lysine
• 29:33four with the k m
• 29:34t two a gene were
• 29:36the strongest,
• 29:37functional networks that were changed.
• 29:40They were changed in such
• 29:41a way that,
• 29:43that these epigenetic related genes
• 29:46and these dendritic or synaptic
• 29:48blastocystis related genes
• 29:51are you know, they're not
• 29:52really
• 29:53a strong,
• 29:55correlation in normal animals. But
• 29:57in those adults with the,
• 29:59adolescent THC exposure, there was
• 30:01a complete,
• 30:02again, reorganization.
• 30:04And there was an overlap
• 30:06between these differentially expressed genes
• 30:09in our animal models and
• 30:10when we studied the prefrontal
• 30:12cortex
• 30:13of individuals who had been
• 30:14diagnosed with schizophrenia.
• 30:16So it's interesting that
• 30:18the THC
• 30:19is, is impacting on some
• 30:21similar networks
• 30:23that you see with schizophrenia.
• 30:26One of the things that
• 30:27we had seen from very
• 30:28early was that adolescent THC
• 30:30exposure increases heroin self administration.
• 30:33So it's not about the
• 30:34friends. It's not about, you
• 30:35know, their parents and their
• 30:36neighborhoods, just in terms of
• 30:38changing the biological signatures
• 30:40and sensitivity to opioids.
• 30:45But one of the things
• 30:46that we also wanted to
• 30:47look at was this aspect
• 30:48that we saw repeatedly coming
• 30:50up is this aspect of
• 30:51stress. And at that time,
• 30:52a new post doc of
• 30:53the team at that time,
• 30:54Jackie Furlan, who now runs
• 30:55her own show, was interested
• 30:57also in understanding this aspect
• 30:59of stress.
• 31:00And the reason is when
• 31:01we gave THC to adolescent
• 31:03animals,
• 31:04we see this huge increase
• 31:06in their stress hormone, corticosterone.
• 31:08We, we had also seen
• 31:10increased cortisol levels in our
• 31:12human subjects, but this lasted
• 31:13for a very long time
• 31:14after their last injection
• 31:16in these animal models. And
• 31:18if we had,
• 31:20exposed them to an acute
• 31:21isolation
• 31:22stress,
• 31:23those animals that had and
• 31:25I should have said sorry,
• 31:26that we looked at two
• 31:27doses. And because
• 31:29the dose of THC,
• 31:31in cannabis has has increased
• 31:33so much over the years,
• 31:35we decided to look at
• 31:35what does a low dose,
• 31:37which was, you know, what
• 31:38the cannabis THC doses were
• 31:40back then
• 31:41to today,
• 31:42THC doses. And we can
• 31:43see that the dose matter
• 31:45so that the stress levels
• 31:47were or hormone levels were
• 31:49maintained mainly
• 31:51in the high dose animals,
• 31:53and their response to,
• 31:55a reward
• 31:56reward
• 31:58after being isolated,
• 32:00social isolation,
• 32:01was again in the high
• 32:02dose animals, not the low
• 32:04dose.
• 32:06Now decision making, again, we
• 32:08see these changes in the
• 32:09prefrontal cortex, and decision making
• 32:11is really a critical feature
• 32:12of of a lot of
• 32:14substance use disorder,
• 32:17phenotypes.
• 32:18And we know that decision
• 32:19making in human cannabis users,
• 32:22we this they were studied
• 32:23with the Iowa gambling task.
• 32:26So they're this task basically
• 32:28measures,
• 32:29you know, as as a
• 32:30decision making for,
• 32:32understanding that the the decks
• 32:34of cards
• 32:35may give,
• 32:36advantageous
• 32:38money reward,
• 32:39but those are over time,
• 32:41you will actually lose if
• 32:43you choose continue to choose
• 32:45those.
• 32:46And
• 32:47most,
• 32:48healthy individuals
• 32:50learn very quickly to make
• 32:51optimal choices.
• 32:53But individual adults with cannabis
• 32:55use disorder,
• 32:56they make the riskier choices
• 32:58in this Iowa gambling task.
• 33:00And this actually fits with
• 33:01what you see with other
• 33:02substance,
• 33:03use disorders. So it's not
• 33:04just only cannabis users.
• 33:07But we then want to
• 33:08see, can we look at
• 33:09the same thing in our
• 33:10animal models? And so we
• 33:12would use the rat gambling
• 33:13task, and they don't care
• 33:15about money, but they care
• 33:16about, for example, sucrose. And
• 33:18it's the same thing where
• 33:20they the pope,
• 33:21in
• 33:24nose pokes for
• 33:27either getting, like, one pellet
• 33:29or four pellets, and these
• 33:30the pellets that initially,
• 33:32look like they're gonna give
• 33:33you a lot turn out
• 33:34in the end to be,
• 33:36disadvantageous.
• 33:37And similar to what we
• 33:38see in our humans,
• 33:39at least for the high
• 33:40dose,
• 33:41the animals that had high
• 33:43dose THC during adolescence, they
• 33:45show more riskier decision making.
• 33:47Interesting, the low dose animals
• 33:50seem to stick to one
• 33:51and does which interesting those,
• 33:53quote, unquote, optimal.
• 33:54So
• 33:56decision making is impacted also
• 33:58by dose.
• 34:00Another thing that we could
• 34:01see is when they were
• 34:02exposed once again in adulthood
• 34:04to THC,
• 34:05once again, it's those animals
• 34:07that had
• 34:09oops. I don't know why
• 34:10I keep on pressing too
• 34:11quickly. Those animals that had
• 34:13the high dose THC exposure
• 34:14during adolescent that continue to
• 34:16show,
• 34:17risk and decision making,
• 34:20greater impulsivity
• 34:22when in in adulthood.
• 34:25So the question is, what
• 34:27are the neurobiological underpinnings? Because
• 34:28that's a key thing for
• 34:30us. And so for this
• 34:31particular study, we've looked at
• 34:33I know we've looked in
• 34:34the prefrontal cortex. We also
• 34:35see significant changes there, just
• 34:37emphasizing one aspect of the
• 34:39amygdala here because the amygdala
• 34:40people only think about, you
• 34:41know, in terms of emotional
• 34:43regulation and, yes, definitely anxiety
• 34:44and stress, but it's also
• 34:46critical for decision making. And
• 34:48we could see that the
• 34:49gene expression profile in the
• 34:51amygdala
• 34:52of these animals were really
• 34:54dramatically changed when they were
• 34:56stressed with this isolated stress.
• 34:58But it was the high
• 34:59dose in the combination with
• 35:01stress that showed the greatest
• 35:02effects.
• 35:03And the what we saw
• 35:05that was interesting was that
• 35:06these changes
• 35:07were really prominent in reducing
• 35:10expression
• 35:12in astrocytes, these glial cells
• 35:14that are really critical
• 35:16for regulating glutamate and GABA
• 35:20at the synaptic homeostasis,
• 35:22and they're really important for
• 35:24regulating oxidative stress and inflammation
• 35:27in the brain.
• 35:28And we could see it's
• 35:29not only on the gene
• 35:30expression level, but the actual
• 35:32structure, the morphology of these
• 35:33astrocytes
• 35:34were changed in the high
• 35:35dose animals, but not the
• 35:37low dose animals.
• 35:39So
• 35:41the stress sensitivity,
• 35:42we're looking into a lot
• 35:43of the perturbation, but the
• 35:45thing that's interesting is that
• 35:47these astrocyte related sorry. These
• 35:49astrocyte related changes
• 35:51actually correlated to their decision
• 35:52making and their impulsivity.
• 35:58So
• 36:01for us, what we have
• 36:02seen with a lot of
• 36:02our data and in terms
• 36:04of,
• 36:05not going into
• 36:07didn't show you all of
• 36:08this, but in terms of
• 36:09what also the field knows
• 36:11is that cannabis use disorder,
• 36:12the risk and outcomes are
• 36:13very
• 36:15are getting more clear.
• 36:16We definitely know that the
• 36:18male sex are more vulnerable,
• 36:19that frequent use before age
• 36:21sixteen,
• 36:22that there's, I didn't talk
• 36:23about the psychiatric vulnerability,
• 36:25but stress reactivity is really
• 36:27key. And a number of
• 36:29the studies showing and including
• 36:31ours showing,
• 36:32cortical,
• 36:33thinning.
• 36:34So
• 36:35it's really critical that we
• 36:37understand these early predictors because
• 36:40even here
• 36:41for cannabis use disorder, prenatal
• 36:43exposure
• 36:44I don't know what prenatal
• 36:46exposure,
• 36:47of cannabis really contributes a
• 36:49lot. Obviously, aces the environments
• 36:51that these individuals are in
• 36:53and, of course, early exposure
• 36:55to other,
• 36:57recreational,
• 36:58substances such as alcohol and
• 37:00tobacco.
• 37:01So
• 37:04adolescent use but also prenatal
• 37:06exposure is really critical for
• 37:09addiction risk.
• 37:10So at the we'll
• 37:13wanna end when I've talked
• 37:15about the pathways
• 37:16to substance use disorders, but
• 37:18what about ways to obviously
• 37:21get out of it?
• 37:23And I mentioned in the
• 37:24the beginning of the talk
• 37:26about, you know, obviously, this
• 37:27complex,
• 37:28cannabis plant
• 37:29and that it has over
• 37:31a hundred,
• 37:33cannabinoids
• 37:34and other chemicals, the terpenes
• 37:35and so on, and that
• 37:36we still don't really know
• 37:38that much.
• 37:39But
• 37:40when we were conducting our
• 37:41human studies, we were always
• 37:43obviously
• 37:44looking at the whole plant.
• 37:45But when we conducted our
• 37:47animal studies, we mainly had
• 37:49studied THC.
• 37:50And
• 37:51we now add some CBD
• 37:53to our,
• 37:55our animal models. But I
• 37:56just wanted to know what
• 37:57the CBD by itself do
• 37:59to our animals. And in
• 38:01regard to
• 38:02that question that we're initially
• 38:04exploring in terms of, does
• 38:07cannabis increase your sensitivities
• 38:09to other drugs such as
• 38:10opioids. And we always saw
• 38:12that we showed earlier that
• 38:13TFC would invariably increase heroin
• 38:15cell phone administration even though
• 38:16behavioral traits do matter for
• 38:18animals as they do also
• 38:20for
• 38:21for humans.
• 38:23But a strange thing happened
• 38:24when we first started to
• 38:25look at CBD before people
• 38:27even knew what CBD was,
• 38:29was that
• 38:31I don't know why my
• 38:32this mouse, like, the mouse
• 38:34is very sensitive.
• 38:35Such that when, you know,
• 38:37as I said, THC would
• 38:39mainly increase self administration, but
• 38:40we saw that CBD actually
• 38:42decreased heroin seeking in particular.
• 38:44It didn't change her in
• 38:45self administration behavior. But one
• 38:47of the things that happens
• 38:48is when animals
• 38:50learn to self administer the
• 38:52drug, just like humans,
• 38:53certain
• 38:54environmental cues
• 38:56take on
• 38:58a a conditioned aspect.
• 39:00They're more salient. And so
• 39:01here, for example, you could
• 39:02have a light or a
• 39:03tone or,
• 39:05a smell
• 39:06when they get the drug.
• 39:07And if you show them
• 39:08that cue, even when they
• 39:10don't get the drug, they
• 39:10will press the lever,
• 39:12trying to get the drug,
• 39:13and that's what we we,
• 39:15frame as drug seeking behavior.
• 39:17And that's what's what we
• 39:18saw with CBD
• 39:20that,
• 39:21that even the day after
• 39:23they got their the the
• 39:25last CBD,
• 39:27even if it did not
• 39:28change their acute if they
• 39:29were already self administering heroin,
• 39:31the next day, it was
• 39:32decreasing their heroin seeking behavior.
• 39:35We have studied the postmortem
• 39:37human brain a lot, and
• 39:37we know that there are
• 39:39all of these, you know,
• 39:40significant changes that are occurring,
• 39:42especially on the blood meturtic
• 39:43transmission and so on. And
• 39:45we could actually in our
• 39:46animal models that had been
• 39:47given,
• 39:50had taken self administered heroin
• 39:51and we see these synaptic
• 39:53pluses in the related genes,
• 39:55that CBD actually we saw
• 39:56that it normalized those individual
• 39:58genes that we studied at
• 39:59that time.
• 40:00So we thought, okay. Let's
• 40:02see whether or not CBD
• 40:04might be, a
• 40:06useful as a potential treatment
• 40:08for opioid use disorder.
• 40:10Excuse me. And so we
• 40:12did some pilot studies where
• 40:14we just did double blinded
• 40:15randomized placebo control
• 40:17in individuals. These were absent
• 40:19individuals
• 40:20who, were,
• 40:22had a opioid,
• 40:24then heroin use disorder. And
• 40:25we looked at two doses
• 40:27and just did short term
• 40:28exposure to c CBD.
• 40:31And what we saw was
• 40:32similar to what we saw
• 40:33in the humans, but
• 40:36excuse me.
• 40:37Similar to what we saw
• 40:38in our rats, well, our
• 40:40rats didn't get didn't get,
• 40:42videos or even,
• 40:44participants were shown either a
• 40:45neutral video or a heroin
• 40:47video. And those who had
• 40:48received placebo,
• 40:50they showed increased craving, and
• 40:52CBD reduced that.
• 40:53Our animal model had also
• 40:55told us one thing that's
• 40:56why it was interesting for
• 40:57me,
• 40:59CBD,
• 41:00was that even a few
• 41:01weeks after their last CBD
• 41:03administration,
• 41:04it was still reducing their
• 41:05cue induced, seeking behavior. And
• 41:07when we brought people back
• 41:09in the lab a week
• 41:10later, CBD was still reducing,
• 41:13their cravings compared to the
• 41:14placebo.
• 41:17What our animals didn't tell
• 41:18us at that time, but
• 41:19our our human study participants
• 41:22did, was that
• 41:24actually,
• 41:25CBD, when they've shown the
• 41:26the
• 41:28heroin cue and they've gotten
• 41:29placebo, their anxiety increased, and
• 41:31CBD reduced that.
• 41:33A week later, it was
• 41:35still reducing that.
• 41:37We also studied,
• 41:39not just their subjective measures,
• 41:40but physiological measures,
• 41:42for example, cortisol.
• 41:44And we could see that,
• 41:47when they were given placebo,
• 41:48their cortisol levels went up
• 41:50when they got the drug
• 41:50cue and CBD reduced it.
• 41:53The same thing with their
• 41:54heart rate. When they saw
• 41:54the drug cue,
• 41:56their heart rate went up
• 41:57and CBD reduced that.
• 42:00We now just finished
• 42:02a double blinded phase two
• 42:04study with individuals' opioid use
• 42:06disorders,
• 42:07and they're, maintained on,
• 42:09opioid agonist therapy.
• 42:11This is just preliminary
• 42:12unpublished, and this was just
• 42:14an interim small analysis that
• 42:15we were,
• 42:16had to do.
• 42:18But the thing I noticed
• 42:19so that's one brief thing
• 42:20that we also see that
• 42:21it replicates in part what
• 42:23we saw. So for example,
• 42:25individuals who are in placebo,
• 42:26they spend a lot of
• 42:27time in a stressful state,
• 42:29and this is now their
• 42:30in their real world, not
• 42:31just in our lab, and
• 42:33just looking at their biometric,
• 42:35assessments. And CBD
• 42:37now reverses that, having them
• 42:38spend more time in the
• 42:40normal state.
• 42:43So now we're going back
• 42:44into our animal models after
• 42:46you know, with our following
• 42:47our human,
• 42:48results. And my postdoc, Alex
• 42:50Chosum, is looking into CBD.
• 42:52Does it you know, again,
• 42:54can,
• 42:55reduce her seeking behavior? She
• 42:56was able to replicate what
• 42:57we had seen before and
• 43:00also seen it also we
• 43:01had studied male and males
• 43:03at that time, also seen
• 43:04in females.
• 43:06But one of the things,
• 43:07as I said, our study
• 43:08participant, you know, they told
• 43:10us that we could see
• 43:10their anxiety like behavior. And
• 43:12Jackie, when she first started
• 43:14the postdoc, I said, oh,
• 43:14I just have a small
• 43:15short study for you to
• 43:17look at anxiety
• 43:18CBD effects and anxiety like
• 43:20behavior. And here, we actually
• 43:22toned,
• 43:24we we gave a shock
• 43:26for the the induced anxiety
• 43:27like behavior and and paired
• 43:29it with a lemon odor.
• 43:31And when animals were,
• 43:33given the lemon odor and
• 43:35they had been given the
• 43:36vehicle, they showed much greater
• 43:38anxiety like behavior and CBD
• 43:40reduced that. So similar to
• 43:42what our human subjects have
• 43:43told us.
• 43:44So now looking into the
• 43:46neurobiology,
• 43:47for example, looking into, like,
• 43:49the nucleus accumbens here, we
• 43:50can see one thing that
• 43:52is clear is that
• 43:54parent seeking behavior will increase
• 43:56and decrease genes as one
• 43:57would expect, and CBD tends
• 43:59to reverse or normalize that.
• 44:01Similarly, with the anxiety like
• 44:03behavior,
• 44:05and there are some shared
• 44:07behavioral,
• 44:09shared behavioral processes that are
• 44:11are changed between the heroin
• 44:13and anxiety
• 44:15behavior. I'm not gonna go
• 44:16so much into the anxiety
• 44:18results. We actually just published
• 44:19that in molecular psychiatry. But
• 44:21I wanna show one thing
• 44:23is that what we do
• 44:25see in terms of what's
• 44:26changed in, for example, the
• 44:28nucleus accumbens, we We see
• 44:29changes also amygdala,
• 44:31prefrontal
• 44:32cortex. There are differentially expressed
• 44:34genes of the strongest showing
• 44:35a very a small amount
• 44:37and in their upstream regulators.
• 44:39And what has changed with
• 44:41heroin seeking behaviors, a lot
• 44:42of these extracellular matrix, how
• 44:44how cells
• 44:46communicate,
• 44:47and these neuroinflammatory
• 44:48biological processes.
• 44:50And CBD
• 44:52normalizes those, not just on
• 44:54the the individual genes, but
• 44:56even these upstream
• 44:57regulators.
• 44:58But importantly,
• 45:02these changes
• 45:03correlate with heroin seeking behavior.
• 45:06So we are getting optimistic
• 45:08that,
• 45:10the changes that we are
• 45:12seeing
• 45:13in in,
• 45:14with CBD
• 45:17in our humans that we
• 45:18now can replicate in our
• 45:20on the behavioral level in
• 45:21our animals, and we can
• 45:23see now the specific biological
• 45:25networks where CBD might be,
• 45:27working. So we're working hard
• 45:29to translate CBD for treatment.
• 45:32We have a neuroimaging
• 45:33study,
• 45:34ongoing,
• 45:35and we just finished the
• 45:36phase two, as I said,
• 45:37and starting phase three looking
• 45:39at cannabidiol
• 45:40in as a potential treatment
• 45:41for opioid use disorder.
• 45:43So
• 45:44in
• 45:45summarizing a lot in terms
• 45:47of clearly
• 45:49prenatal exposure
• 45:51to cannabis and the THC
• 45:53potency, the dose, and the
• 45:54frequency makes a big impact,
• 45:56but so does the stress
• 45:57and,
• 45:58and biological sex.
• 46:00We also see that epigenetic
• 46:02mechanisms play a really key
• 46:03role on the synaptic plasticity
• 46:05and and the number of
• 46:06these
• 46:07neuroimmune
• 46:08and,
• 46:09certain metabolic processes in the
• 46:11cell that seems to be
• 46:12certain targets
• 46:13that CBD seems to be
• 46:15impacting, and we we'll see
• 46:16whether or not it may
• 46:17be effective as a potential
• 46:19treatment.
• 46:20So with that, I'll thank
• 46:21a lot of people. Yoko
• 46:22no more was incredible. It's
• 46:23a very difficult study. I'm
• 46:25not gonna lie. These prenatal
• 46:27studies have longitudinal effect,
• 46:29in in our human population.
• 46:32The I've shown some of
• 46:33the postdocs their work and
• 46:34their students have been amazing.
• 46:36And,
• 46:37Karen Bakke and our whole,
• 46:39clinical research team, it really
• 46:41does take a huge village
• 46:43to do,
• 46:44these studies. So I'll stop
• 46:45there as we're gonna look
• 46:46at time and so that
• 46:47we can have time for,
• 46:49questions.
• 46:52Well, thank you, Yasmin. That
• 46:53was amazing. You covered a
• 46:55lot of ground and,
• 46:57with staggering amount of data
• 46:59that you presented. So thank
• 47:00you.
• 47:01I'm I'm not gonna take
• 47:03up much time. I'm gonna
• 47:04let people ask questions. You
• 47:05have a the first question
• 47:07is from a former mentee
• 47:08of yours.
• 47:10Anahita, you wanna
• 47:12unmute and ask your question?
• 47:14Sure.
• 47:16I'm sorry.
• 47:17Hi, Yasmin, and thank you
• 47:18so much for the great
• 47:19talk, and good to see
• 47:20you here.
• 47:22Basically, my question
• 47:23is about the impact of
• 47:26THC exposure
• 47:27or trauma and stress.
• 47:29In early adult early childhood
• 47:32compared to adolescence
• 47:33because we know there is,
• 47:34like, different developmental
• 47:35periods. So
• 47:37do we have any evidence
• 47:39that can compare these two
• 47:40periods?
• 47:42I'm good. I have not
• 47:43compared
• 47:44the two periods
• 47:46with the same type of
• 47:47stressors,
• 47:48and that's the thing. You
• 47:50know? So I can't say
• 47:51that we we,
• 47:53that they're equal in terms
• 47:54of the stress that we
• 47:55give to our our
• 47:57adolescents, to the stress that
• 47:58we give to
• 48:00I I realized a slide
• 48:01was missing where we now
• 48:03have
• 48:06the animals actually
• 48:08consume
• 48:09THC themselves. So in terms
• 48:11of,
• 48:12they and we use edibles
• 48:14because it's much
• 48:16easier. And the animals will
• 48:18definitely,
• 48:20consume the edibles,
• 48:21But,
• 48:22again, stress
• 48:23increases that.
• 48:25So there,
• 48:26but it's not the same
• 48:27type of stress that we
• 48:28have in our prenatal
• 48:30model.
• 48:31So
• 48:32but I think it is
• 48:33you know, there are people
• 48:35now looking, I think, more
• 48:36at this, so we'll see.
• 48:37But I do think that
• 48:38stress
• 48:39this particular stress might matter,
• 48:41but I think stress overall,
• 48:44irrespective, we see some similar
• 48:46biological changes on, like, you
• 48:48know, immune processes,
• 48:51a number of other,
• 48:52biological processes I haven't mentioned
• 48:54today. So there's some commonalities
• 48:57even if the types of
• 48:58stress stressors may differ. But
• 49:00it is an important question,
• 49:01so I do hope that
• 49:04people start looking into that,
• 49:05but I don't know. I
• 49:06might not go down that
• 49:07path. I'm already,
• 49:09stressed myself.
• 49:11I think so. Yeah.
• 49:12Thank you so much. Thank
• 49:14you. We have a question
• 49:15from Irem,
• 49:16Azamet.
• 49:17Irem, do you want to
• 49:18unmute and ask your question?
• 49:21First, can you hear my
• 49:22voice?
• 49:23Yes.
• 49:24So thank you so much,
• 49:26first of all, for this
• 49:27amazing presentation.
• 49:28I was just wondering that
• 49:30when we consider the,
• 49:32through all of the epigenetic
• 49:34changes,
• 49:34for the cannabinoid addictions.
• 49:37I was just wondering your
• 49:38thoughts about, like, how close
• 49:40are we for,
• 49:42personalized treatment approaches
• 49:44for
• 49:45those kind of patients,
• 49:47with the informed
• 49:48epigenetic profile?
• 49:50Thank you.
• 49:51Thanks. No. Great question. And
• 49:53the one thing I I
• 49:55perhaps should have emphasized, the
• 49:57aspect about epigenetics, I think,
• 49:59is really important for me.
• 50:00So we actually have characterized
• 50:03epigenetic changes, for example, in
• 50:05heroin users and other substance
• 50:06users.
• 50:07And we can
• 50:10reverse the heroin
• 50:12taking and heroin seeking behavior
• 50:13by targeting
• 50:15pharmacologically, not even just going
• 50:16into the brain, pharmacologically
• 50:18these epigenetic marks. But they're
• 50:19not yet ready for
• 50:22psychiatry
• 50:23populations.
• 50:24They're mainly using cancer.
• 50:25So, you know, we're still
• 50:27working and hoping in that
• 50:28way. But your question about
• 50:29the personalized profiling, I think,
• 50:31is really important.
• 50:33And
• 50:34epigenetic mechanisms, by their very
• 50:36nature,
• 50:38are reversible.
• 50:39And so to me, that's
• 50:41you know, it gives us
• 50:42the opportunity
• 50:43to indeed try to see,
• 50:45can we
• 50:47are there aspects of behavioral
• 50:49interventions? Are there aspects of,
• 50:51you know,
• 50:53again, perhaps certain pharmacological drugs,
• 50:55even certain
• 50:58medications are used in psychiatry
• 51:00impact on the epigenetic mechanisms.
• 51:02But if you know what
• 51:03might be changed
• 51:05in those individuals so one
• 51:06of the things that we're
• 51:07doing, we're also,
• 51:09piloting, looking at peripheral,
• 51:12epigenetic marks
• 51:13to see whether or not
• 51:15there are indeed these individual
• 51:17differences that might lend itself
• 51:19to
• 51:20understanding who might benefit by
• 51:22this particular,
• 51:23quote, unquote, epigenetic target versus
• 51:26another. So I completely agree
• 51:28with you, and let's see
• 51:29if, you know, we can
• 51:30get I never believed in
• 51:32the beginning that looking at
• 51:33peripheral biomarkers was gonna be
• 51:35helpful because epigenetic tags by
• 51:38their nature also are very
• 51:39cell specific.
• 51:40But I might have to
• 51:41eat my words. So I'll,
• 51:42you know, I'll let you
• 51:43know how the results go,
• 51:45but there are some interesting
• 51:46things there that I think
• 51:47your question is really critical.
• 51:51Thank you so much.
• 51:53We have a question for
• 51:54Marjorie.
• 51:55Marjorie, do you want to
• 51:56unmute and ask your question?
• 52:01Yes. Hi. Thank you so
• 52:02much for this presentation.
• 52:04You've certainly given us a
• 52:05lot to think about. It
• 52:07was,
• 52:07definitely
• 52:08a very dense, full packed
• 52:10with information.
• 52:12I work more in the
• 52:13OB arena,
• 52:15with women with substance use
• 52:16disorder. So,
• 52:17just caught my eye, obviously,
• 52:19going through from the placenta
• 52:20all the way through and
• 52:21all of these changes, and
• 52:23appreciate the,
• 52:25that you are doing this
• 52:26ongoing work now on using
• 52:28CBD.
• 52:29So I guess my question
• 52:31is because right now, we
• 52:33don't have a lot of
• 52:34concrete
• 52:35evidence based information out there
• 52:37on CBD use during pregnancy.
• 52:41How would you be able
• 52:42to
• 52:43recruit
• 52:44pregnant women, or will you
• 52:45be using pregnant animals? I
• 52:47mean, would this be amazing?
• 52:50And, also, I wanna say
• 52:51on the side note,
• 52:53it just kind of everything
• 52:54you said just reminds me
• 52:55of how important,
• 52:58treating stress
• 52:59is in this population as
• 53:00well. So whether that's counseling
• 53:02or if they have a
• 53:03diagnosis and they need medication.
• 53:06Stress is the the pathological
• 53:09agent, and we all have
• 53:10to, I think, pay more
• 53:12attention to it. And it
• 53:14exacerbates
• 53:14all the other things, but
• 53:16stress is a key aspect.
• 53:18So,
• 53:19yeah, the question, you know,
• 53:20with CBD in pregnancy is
• 53:22very tough. A lot of
• 53:23pregnant
• 53:24women are being told, you
• 53:25know,
• 53:26one cannabis today, you know,
• 53:28can help them with their
• 53:29their nausea and all these
• 53:30things, but also CBD. And
• 53:32we really don't know enough
• 53:33about CBD
• 53:35during pregnancy.
• 53:36And I think the problem
• 53:37also is,
• 53:40even if CBD we don't
• 53:41see actually has any real
• 53:44major side effects in our
• 53:45adult population,
• 53:47they're not pregnant because we
• 53:49exclude,
• 53:50with, pregnant,
• 53:52individuals.
• 53:53The problem I have is
• 53:56dose.
• 53:57So something like everything in
• 53:59biology, you know, we know
• 54:01that it can be great
• 54:02and beneficial beneficial,
• 54:04but then there's also this
• 54:05down then it starts having
• 54:07adverse events.
• 54:09So for me, I think
• 54:10that
• 54:11it's really
• 54:12difficult to tell a pregnant
• 54:13person that CBD actually looks
• 54:15relatively safe. But we really
• 54:17do not know that, as
• 54:18I said, for pregnancy, and
• 54:20we don't know if the
• 54:20dose range might differ for
• 54:23the mother
• 54:24and what it might differ
• 54:25for the fetus.
• 54:26And so
• 54:27I I think that a
• 54:29lot of research should be
• 54:30done. A lot of research
• 54:31should be done with CBD
• 54:33before we say it's
• 54:34okay or that it's not.
• 54:36I know there's some preclinical
• 54:38studies showing that it can
• 54:40actually reduce the,
• 54:42quote, unquote, schizophrenia like behavior
• 54:45seen later in the animals.
• 54:46I,
• 54:48and others that showed that
• 54:50it actually have worsened outcome
• 54:52on certain behaviors.
• 54:54Mhmm. So CBD is not
• 54:56something I think that we
• 54:57should
• 54:59encourage even in pregnant
• 55:01you know, for pregnant women,
• 55:03I think harm reduction is
• 55:05tough to say when we
• 55:06don't know what concentrate doses
• 55:07that they're using.
• 55:09Okay. Thank you.
• 55:11I think we have time
• 55:13for one last question. I
• 55:15and and, Nicola, would you,
• 55:16unmute and ask your question?
• 55:21Hi. You do you hear
• 55:22me? Yes. Hi. Hi. Thanks
• 55:25a lot
• 55:26for a very, very interesting
• 55:27talk. I was wondering if
• 55:29you have some, a candidate
• 55:31mechanism
• 55:32which you find, you found,
• 55:34affected,
• 55:36during the development of the
• 55:37the brain in a in
• 55:38a euro that's that's more
• 55:39than,
• 55:40like, differentiation of the neurons
• 55:42or path finding or or
• 55:44even maybe
• 55:45more, related to earlier events
• 55:47like neural stem cell differentiation,
• 55:49etcetera.
• 55:50And I also was wondering,
• 55:52what is the difference between
• 55:53the the mechanism where, you
• 55:54know, found affected in a
• 55:56in a or if you
• 55:57found any affected mechanism in
• 55:59the development
• 56:01during the development
• 56:02compared to the to the
• 56:04to the mechanism affected, during
• 56:05Adolescence administration?
• 56:11We haven't done the same,
• 56:13I think, degree of, like,
• 56:15morphological
• 56:15changes in the adults with
• 56:18prenatal as we did with
• 56:19the adolescent exposure.
• 56:22I mean, others have looked
• 56:23at it, and I've seen
• 56:25some similar similarities.
• 56:27I I don't know though
• 56:28that I've seen any data
• 56:30with the astrocyte related morphological
• 56:32changes
• 56:33with prenatal.
• 56:34So that may be
• 56:37be one thing there. But
• 56:39on the pre on the
• 56:40mechanistic side, one of the
• 56:41things that we saw, you
• 56:42know, early in number with
• 56:43t bone harkening,
• 56:45what we saw like, the
• 56:46past findings in terms of
• 56:48the pathways in,
• 56:50in
• 56:51adults with the with prenatal
• 56:53THC exposure,
• 56:54there was a significant difference
• 56:56that we and we could,
• 56:58link to even CB one
• 56:59receptor.
• 57:02I have to say there's
• 57:03so much that has changed
• 57:04in our work because of
• 57:06what's happened in society
• 57:07with the dosing.
• 57:09So the dose has made
• 57:10such a huge difference. And
• 57:12so now when we
• 57:13go back and we, you
• 57:15know, look at both our
• 57:16our
• 57:17our prenatal and our adolescent
• 57:19model, and that's why we
• 57:20actually, you know, are using
• 57:22a a model of self
• 57:23administration, for example, with edibles
• 57:26because that was easier to
• 57:27do, and we have our
• 57:28big vapor model trying to
• 57:29have a more translation to
• 57:31our human,
• 57:32work.
• 57:33You know, we see that
• 57:36there are these
• 57:37very strong changes in relation
• 57:39to, for example, mitochondria, like
• 57:41I said,
• 57:42and neuroinflammatory,
• 57:43processes
• 57:45that
• 57:47that CBD actually seems to
• 57:49even normalize.
• 57:51We
• 57:52we saw, like, the lipids
• 57:54are,
• 57:55not surprising,
• 57:57are are are changed really
• 57:59dramatically.
• 58:01And,
• 58:02again, that we can see
• 58:03that, you know, CBD can,
• 58:05impact on some of those
• 58:07from a at least from
• 58:08a treatment perspective.
• 58:09But
• 58:11a lot of the mechanisms
• 58:13I that we and and
• 58:14when I say we meaning
• 58:15the field had looked at
• 58:17earlier in terms of looking
• 58:18at the developmental effects of
• 58:19cannabis,
• 58:20I don't know if we're
• 58:21there with today. And this
• 58:23is what I think we
• 58:24need a lot more research,
• 58:26and I hope your center
• 58:27will, you know, will fund
• 58:29people within your groups that
• 58:31are really looking at dosing.
• 58:33That to me and and
• 58:34like I said, in the
• 58:35aspect of the interaction with
• 58:36stress, there's a greater pathological
• 58:38change with that combination of
• 58:40the high dose and the
• 58:41mechanisms that are occurring.
• 58:44But probably because of the
• 58:45you you in your experiment,
• 58:47you you,
• 58:49administer,
• 58:51cannabis by vape. Right? Not
• 58:53just few pure THC.
• 58:56Did I understand correctly? No.
• 58:58No. No. So for our
• 58:59animals, we still use vape
• 59:01of the cannabinoids.
• 59:02We use of THC and
• 59:03CBD.
• 59:04So we don't use the
• 59:05flower.
• 59:06And and I and there's
• 59:07there's there are groups that
• 59:08are looking at the flower,
• 59:10and of vape in the
• 59:11animal models, and so we'll
• 59:13we'll see how those those
• 59:14results also turn out. So
• 59:16So why did you inject
• 59:17HCC?
• 59:19And we've in we have
• 59:20injected also, and injection is
• 59:21more, you know, like, this
• 59:22very high
• 59:24high dose kind of of
• 59:25of model.
• 59:27The one thing for me
• 59:28that I feel
• 59:30comfortable in what our animal
• 59:32in in our models
• 59:34is because we actually replicate
• 59:36what we see in the
• 59:37human
• 59:38placenta.
• 59:39I see. In the human
• 59:40you know, so those to
• 59:42me are are
• 59:43that's why, at the end
• 59:45of the day, I do
• 59:45these translational studies. They're I'm
• 59:47not gonna like I said,
• 59:48I'm not gonna lie. They're
• 59:49they're painful.
• 59:50But at least you know
• 59:52that
• 59:53the biological
• 59:54systems that at least your
• 59:55model is is impacting is
• 59:57what you see in humans.
• 59:58It's not ideal. There's nothing
• 60:00that's gonna replicate
• 01:00:01exactly the human condition,
• 01:00:03especially, you know, prenatal because
• 01:00:05even that, rodents
• 01:00:07are they're, you know, they
• 01:00:08don't their third trimester is,
• 01:00:10you know, out of the
• 01:00:11the the uterus. But the
• 01:00:13fact that we see some
• 01:00:14similar things and we actually
• 01:00:16study also
• 01:00:17the fetal brains of of,
• 01:00:20whose mothers
• 01:00:21in in people whose mothers
• 01:00:23had
• 01:00:24had used cannabis. And we
• 01:00:25we also replicate
• 01:00:27some of the the things
• 01:00:28that we see in our
• 01:00:30animal models, and that's what
• 01:00:31took us even to the
• 01:00:32amygdala. We saw these really
• 01:00:34dramatic changes in the the
• 01:00:36human fetal amygdala and mainly
• 01:00:38the males. And we thought
• 01:00:40that it was you know?
• 01:00:41And we thought
• 01:00:42early when people saw these
• 01:00:43sex differences was in adulthood
• 01:00:45and so on. But from
• 01:00:46early life, you see
• 01:00:48very significant sex differences.
• 01:00:50And so, like I said,
• 01:00:51because our animal models are
• 01:00:53not perfect, but because they
• 01:00:54replicate what we can look
• 01:00:55at in humans,
• 01:00:56I'm okay a little bit.
• 01:00:59Thank you.
• 01:01:00Thanks. So,
• 01:01:02I have many questions for
• 01:01:04you, but I'm trying to
• 01:01:05be respectful of time.
• 01:01:08I'm good. Need And, I
• 01:01:10would encourage people,
• 01:01:12to submit any more questions
• 01:01:13that have been unanswered. We'd
• 01:01:15collect them and send them
• 01:01:16on to,
• 01:01:18to Yasmin if she has
• 01:01:19time to answer them. Wendy,
• 01:01:20you had a few announcements
• 01:01:22to make. Did you?
• 01:01:25Yes. Thank you, doctor Hurd.
• 01:01:29We have our next webinar
• 01:01:30scheduled for February the eighteenth
• 01:01:32with doctor Romina,
• 01:01:34Mizrahi, who will be presenting.
• 01:01:37If you are interested,
• 01:01:39an invitation will be sent
• 01:01:41out.
• 01:01:42We also have a survey,
• 01:01:45that will be listed,
• 01:01:47by,
• 01:01:48doctor, Ranganathan
• 01:01:49in regards to,
• 01:01:51getting more information regarding pediatrics
• 01:01:54and utilization
• 01:01:55of cannabis for pediatric professionals,
• 01:01:58if anybody is interested in
• 01:01:59partaking in that as well.
• 01:02:02This meeting, this webinar is
• 01:02:03being recorded. So if you
• 01:02:05would like to have access
• 01:02:06to it, you will get
• 01:02:07an automatic,
• 01:02:09invite,
• 01:02:10and it will be shareable
• 01:02:11with anybody else as you
• 01:02:12would like to share.
• 01:02:14So so, Yasmin, thank you
• 01:02:16very, very much. We couldn't
• 01:02:17have asked for a better
• 01:02:18way to kick off our
• 01:02:20webinar series. The next four
• 01:02:22are all focused on the
• 01:02:25effect of cannabis on brain
• 01:02:26development, different kinds of data
• 01:02:28that's gonna be presented.
• 01:02:29But thank you very much.
• 01:02:31We
• 01:02:32I I certainly learned a
• 01:02:33lot. I have a lot
• 01:02:33of questions for you, which
• 01:02:35I'll email you about.
• 01:02:37But thanks thanks again, and
• 01:02:38thanks everyone for attending.
• 01:02:40Thank you.
• 01:02:41Bye.