YC-SCAN2 August 2025 Webinar

Transcript

• 00:01When we get started. So
• 00:02it's my pleasure to introduce,
• 00:05doctor Hilary Marasek,
• 00:08who is
• 00:09a developmental neuroscientist,
• 00:12and associate professor of psychiatry
• 00:14and behavioral neurosciences
• 00:16at Wayne State University,
• 00:19School of Medicine.
• 00:20She directs the division of
• 00:22cannabinoids
• 00:23in neurodevelopment.
• 00:24I like the acronym candid,
• 00:27and the trauma history investigation
• 00:29of neurodevelopment
• 00:30in kids or the or
• 00:31the think lab, another nice
• 00:33acronym,
• 00:34where her research focuses on
• 00:36how
• 00:37childhood
• 00:38adversity
• 00:39and the endocannabinoid
• 00:40system shape brain development and
• 00:42mental health.
• 00:43Doctor Marasik's work spans neuroimaging,
• 00:46behavioral neuroscience,
• 00:48and psychophysiology
• 00:50with a particular emphasis
• 00:53on the impact of cannabis
• 00:54and cannabinoids during sensitive periods
• 00:56of development.
• 00:58Her research is supported by
• 01:00NIH,
• 01:01One Mind,
• 01:03the Michigan Cannabis Regulatory
• 01:05Agency.
• 01:07She's recognized,
• 01:09with the One Mind rising
• 01:10star award
• 01:12and named a notable woman
• 01:13in STEM by Crain's Detroit.
• 01:17She is deeply engaged, committed
• 01:19to in, public engagement and
• 01:21mentorship.
• 01:23She cofounded the Science Policy
• 01:26Network
• 01:27of Detroit and hosts BrainSTEM,
• 01:29a podcast to promote broader
• 01:31understanding
• 01:32of neuroscience and its societal
• 01:34impacts.
• 01:35I had the pleasure of,
• 01:37seeing Hillary just a week
• 01:39ago at the Gordon Conference
• 01:40on cannabis and can on
• 01:41on cannabinoids
• 01:43last week.
• 01:44So it's my pleasure to
• 01:45introduce Hillary. Hillary, take it
• 01:47away.
• 01:48Thanks so much. Yeah. I'm
• 01:49sorry. Some of this is
• 01:50a repeat, but you got
• 01:51a a sneak peek to
• 01:52today.
• 01:54Thanks, everybody. So as, doctor
• 01:55D'Souza mentioned, I am a
• 01:57developmental scientist. And probably like
• 01:59many of you, I didn't
• 02:00realize the, importance of the
• 02:02endocannabinoid
• 02:03system until very recently in
• 02:05key neurodevelopmental
• 02:07processes. So I'm really excited
• 02:09to share with you today
• 02:10some of the work we've
• 02:11been doing
• 02:12on the role of the
• 02:13endocannabinoid
• 02:14system in really two critical
• 02:16periods,
• 02:16that we think about, which
• 02:17is before you're born and
• 02:19also during the teen years
• 02:20when we know that the
• 02:21brain is very sensitive to,
• 02:24external exposures.
• 02:26And also psychiatric risk,
• 02:27happens during that time. Also,
• 02:29really facing some unique challenges
• 02:31with the legalization of cannabis,
• 02:33and, we'll get into that
• 02:34a little bit more.
• 02:35But to give you a
• 02:37lay the the road of
• 02:38what I'm gonna cover today,
• 02:39I'll I know this is
• 02:40the the cannabis,
• 02:41center, so I don't have
• 02:42to spend a ton of
• 02:43time laying the foundation for
• 02:44what the system is. But
• 02:46just so everyone is on
• 02:47the same page,
• 02:48starting with a brief overview
• 02:49of what the ECB or
• 02:50endocannabinoid
• 02:51system does and then really
• 02:53zooming in on its critical
• 02:55role in neurodevelopment.
• 02:57As I mentioned, focusing on
• 02:58two really sensitive windows, pregnancy
• 03:00and the adolescent period.
• 03:02And then I wanna end
• 03:03on a high note and
• 03:04talk more about how we
• 03:05can intervene
• 03:06during those sensitive windows to
• 03:08build more resilient brains before
• 03:10I hopefully put a nice
• 03:11bow on everything.
• 03:13So just so to begin
• 03:15with, you know, again, in
• 03:16medical school and graduate school,
• 03:18I didn't receive any education
• 03:19about the cannabinoid system.
• 03:22Yet there's work being done,
• 03:23you know, at your university
• 03:24and others showing just how
• 03:26widespread,
• 03:27ubiquitous this system is and
• 03:29how important it is for
• 03:30for a variety of, brain
• 03:32functions. So this is a
• 03:33PET study of, cannabinoid type
• 03:35one receptors,
• 03:37showing availability
• 03:38really across the the brain.
• 03:40Obviously, areas where,
• 03:42CB one receptors are more
• 03:44densely located, which,
• 03:46helps us understand some of
• 03:47the acute effects of things
• 03:48like, THC and other cannabinoids
• 03:51on the brain.
• 03:53But I just wanna highlight
• 03:54a couple key areas,
• 03:55especially
• 03:56dense
• 03:58availability,
• 03:59in cortical limbic regions, amygdala,
• 04:02hippocampus, we know are really
• 04:03important for
• 04:04emotional learning and memory,
• 04:06and also prefrontal regions involved
• 04:08in emotional control and top
• 04:10down,
• 04:11top down functioning. So very
• 04:12important. Those obviously undergo dramatic,
• 04:15development across the teen years
• 04:17in particular.
• 04:19And then, just wanna distinguish
• 04:20between exogenous
• 04:21cannabinoids up top. So think
• 04:23of those produced,
• 04:24in a cannabis plant or,
• 04:26you know, in a lab
• 04:27synthesized,
• 04:28outside of the body,
• 04:30versus endocannabinoids
• 04:31or endogenous
• 04:32endogenously
• 04:33produced,
• 04:34within the body. And the
• 04:36the two most commonly,
• 04:37you know, studied in are
• 04:39nandamide and two AG, which
• 04:40are not the names of
• 04:41my dogs.
• 04:42But,
• 04:44very interesting system, you know,
• 04:45neurobiologically
• 04:46speaking. We have two ligands
• 04:48that both work on the
• 04:49same receptor, which is very
• 04:50weird. You know, I come
• 04:51from a
• 04:53neuroscience background, and we have,
• 04:54like, what, five or six
• 04:55different serotonin
• 04:57receptors. So very interesting system,
• 04:59and I know I'm preaching
• 05:00to the choir here, but,
• 05:02still a lot that we
• 05:02need to know about it.
• 05:04So what do cannabinoids
• 05:06do? They turns out they
• 05:07play a role in a
• 05:07variety of homeostatic functions. These
• 05:09are this is just a
• 05:10snapshot I'm showing you on
• 05:12the screen.
• 05:13Cece Hillard, who was at
• 05:14the conference last week,
• 05:16you know,
• 05:17wrote a wonderful review about,
• 05:19what do cannabinoids do, where
• 05:21do they come from. We
• 05:22call her the queen of
• 05:23cannabinoids in my lab. She's
• 05:24a fantastic,
• 05:26researcher.
• 05:27But I wanna highlight stress
• 05:28and anxiety regulation.
• 05:30We really think of these
• 05:32as our
• 05:33stress management professionals. This is
• 05:35a a term that,
• 05:36Terry Duran Cassini coined, which
• 05:38I think is really important.
• 05:41Endocannabinoids
• 05:42are synthesized on demand
• 05:44in response to stress, and
• 05:45they really help us cope
• 05:47with stress. So in my
• 05:48area, which is anxiety and
• 05:50PTSD, this becomes super relevant
• 05:52for understanding
• 05:53potentially the physiology or the
• 05:54pathophysiology
• 05:55of those disorders. But, of
• 05:57course, stress plays a role
• 05:58in in everything. So,
• 06:01one benefit of endocannabinoids
• 06:02that we're still debating in
• 06:03the literature is,
• 06:05you know, we can measure
• 06:06them in circulation with a,
• 06:08a blood sample on either
• 06:09plasma or serum, which gives
• 06:11us some insight,
• 06:13into the system in living
• 06:14human beings. And, you know,
• 06:16I work with kids. We
• 06:17don't have access to pet
• 06:18imaging. We're not gonna do
• 06:19spinal taps,
• 06:21celibary, CVs. I don't know
• 06:23how some of the folks
• 06:24feel on the call, but
• 06:25I haven't seen really, you
• 06:26know, compelling data showing that
• 06:28they're super, reliable. Love to
• 06:30talk more about that. But
• 06:31as far as working with
• 06:32developmental populations,
• 06:34we do have ECDs in
• 06:35circulation.
• 06:36There's a bigger discussion about
• 06:38where they come from, what
• 06:39we're actually measuring.
• 06:40And I think last week,
• 06:41the consensus is we need
• 06:42to do more to understand,
• 06:45what the signal is measuring,
• 06:46but it does provide, again,
• 06:47some unique insights into developing
• 06:49populations.
• 06:51So of all the things
• 06:53that the cannabinoid system does,
• 06:54as I mentioned, I was
• 06:55shocked as a developmental scientist
• 06:57that this wasn't part of
• 06:59our standard education.
• 07:00And I talked to physicians
• 07:02in many different disciplines. You
• 07:03know, this isn't a part
• 07:04of what they're they're taught.
• 07:06But,
• 07:07on the development side, it
• 07:08turns out the system is
• 07:10established very early during pregnancy,
• 07:12and it's functional at about
• 07:13week seven
• 07:14when many people are just
• 07:16finding out that they're pregnant
• 07:17and maybe using cannabis, for
• 07:19example.
• 07:20But it plays a critical
• 07:21role in a variety of
• 07:23basic
• 07:24neurodevelopmental
• 07:25processes
• 07:26ranging from axonal migration all
• 07:28the way up to the
• 07:29fine tuning of of neural
• 07:30networks across the lifespan.
• 07:33And it turns out that
• 07:34it likely fluctuates dynamically
• 07:37across the lifespan. This is
• 07:39work that's being done right
• 07:40now. A lot of this
• 07:41work comes from animal models,
• 07:42but showing that different
• 07:44components of the cannabinoid system
• 07:46like the ligands or receptors,
• 07:48the degradatory enzymes like Faa,
• 07:50they vary dynamically across,
• 07:53particularly the first two decades
• 07:55of life, which is, again,
• 07:56we know a really critical
• 07:58period of brain development and
• 08:00when a lot of psychiatric
• 08:01disorders and symptoms begin to
• 08:03emerge.
• 08:04So there's some interesting,
• 08:06research going on to look
• 08:08at the role of the
• 08:08cannabinoid system
• 08:10in psychiatric risk and the
• 08:11psychosis space we heard about
• 08:13last week with doctor D'Souza's
• 08:14work and also in anxiety
• 08:16and PTSD.
• 08:18In addition to playing a
• 08:20critical role in fetal neurodevelopment,
• 08:23there's emerging data suggesting that
• 08:25the system itself plays a
• 08:26role in pregnancy timing and
• 08:28actually maintenance.
• 08:30So if you measure,
• 08:31circulating endocannabinoids
• 08:33in moms during pregnancy, it
• 08:34looks like the levels are
• 08:36pretty low, but there's this
• 08:37interesting increase around the time
• 08:39of labor suggesting that the
• 08:41endocannabinoid system itself
• 08:43has something to do with
• 08:44that process.
• 08:46And moreover, there's at least
• 08:47one study that looked at
• 08:49circulating endocannabinoids
• 08:50in moms,
• 08:52who are have high risk
• 08:53pregnancies, and they found that
• 08:55those that went on
• 08:57to deliver prematurely
• 08:58had higher circulating anandamide concentrations
• 09:01than those who did not,
• 09:03suggesting
• 09:04potentially there's,
• 09:06this could be a potential
• 09:07biomarker of high risk pregnancies,
• 09:09for example.
• 09:11So why does all this
• 09:12matter? At the outset, I
• 09:14talked a little bit about
• 09:15legalization
• 09:15and the importance of, these
• 09:17really important brain development,
• 09:20stages. But, you know, at
• 09:22least in Michigan and everywhere
• 09:23around the country, I know
• 09:24you guys have legal cannabis
• 09:26for recreational use age twenty
• 09:28one and above. You're seeing
• 09:30the same pattern where the
• 09:31the cannabis that people using
• 09:33today are nothing like what
• 09:34our parents use, what, you
• 09:36know, you may have used
• 09:37in the seventies or eighties.
• 09:39And there's data to support
• 09:40that. This is just one,
• 09:42dataset from NIDA,
• 09:44showing the increase in percent
• 09:46THC in cannabis flower, and
• 09:48this stopped at about twenty
• 09:49twenty. You can imagine what
• 09:50it is now in twenty
• 09:51twenty five.
• 09:52And, I think we were
• 09:53talking last week that within
• 09:55my house in,
• 09:57Detroit,
• 09:57there's about five dispensaries
• 10:00next to some psychiatry clinics,
• 10:02which is really fascinating, but,
• 10:03you know, this really way
• 10:04raises some public health concerns.
• 10:07And I haven't been to
• 10:08New Haven, but I did
• 10:09a I found Lit New
• 10:11Haven, which I think is
• 10:12pretty close to you guys
• 10:13right around campus.
• 10:15And I perused their products
• 10:16available, and some of the
• 10:17cannabis flower is approaching thirty
• 10:19percent THC.
• 10:21So this is,
• 10:22you know, part and parcel.
• 10:23The market is really driving,
• 10:25the percent THC concentrations higher,
• 10:27things like CBD.
• 10:29The, percent is getting much
• 10:31lower. And this is not
• 10:32to mention the high potency
• 10:34concentrates that folks are using
• 10:35where we're approaching ninety percent
• 10:37or even higher in some
• 10:38places.
• 10:39So this is a whole
• 10:40new,
• 10:41ballpark. You know, data couple
• 10:43decades ago on prenatal cannabis
• 10:45exposure,
• 10:46we're talking about a totally
• 10:47different exposure nowadays with with
• 10:49some of these new products.
• 10:52And then another thing relevant
• 10:53for development is, you know,
• 10:55I I drive around Detroit,
• 10:56and we see some really
• 10:58interesting and funny cannabis billboards.
• 11:00And then we've got edible
• 11:01products that are,
• 11:03marketed, and they look, you
• 11:04know, for teenagers and for
• 11:06kids. So there's been a
• 11:07ton of data looking at,
• 11:09children coming into emergency departments
• 11:11who get into their their
• 11:12parents' edible stash.
• 11:14So, you know, all of
• 11:15these things are raising concerns
• 11:17about,
• 11:17developing brains.
• 11:20And the two populations I'm
• 11:22gonna zoom in on,
• 11:23are children and adolescents and
• 11:25then pregnancy as well. So
• 11:27in teens, what I think
• 11:29is super interesting right now
• 11:30is we're seeing this perception
• 11:32of risk of cannabis come
• 11:34down over time.
• 11:36These are data from monitoring
• 11:37the future. That's a longitudinal
• 11:39study of,
• 11:40kids' use of substances
• 11:42and perceptions of risk. And
• 11:44it's very unlike alcohol where
• 11:47alcohol and cannabis are actually
• 11:48having this crossover effect where
• 11:50teens are seeing regular alcohol
• 11:52used to be more risky
• 11:53than cannabis for the first
• 11:54time ever. So,
• 11:56very concerning patterns there.
• 11:58And then, of course, during
• 11:59pregnancy,
• 12:00we see a doubling of
• 12:01use of cannabis during pregnancy
• 12:04over the past decade.
• 12:06Toxicology reports, obviously,
• 12:08you know, are better estimate
• 12:09than self report, but nonetheless,
• 12:11we're seeing a very similar
• 12:12pattern of rates of use
• 12:14increasing over time,
• 12:15especially in younger populations. Or
• 12:17in Detroit where I work,
• 12:19I'll get to later, we're
• 12:20seeing, almost a third are
• 12:22using cannabis during pregnancy, so,
• 12:25very, very concerning.
• 12:28So I wanna give you
• 12:28a snapshot again of some
• 12:30of our work we're doing
• 12:31in pregnancy and then adolescence.
• 12:33So
• 12:34despite a surgeon general warning,
• 12:37suggesting that no use of
• 12:38cannabis is safe during pregnancy,
• 12:40we know that people are
• 12:41still using. There are
• 12:43emerging data suggesting adverse health
• 12:46effects on offspring, including lower
• 12:48birth weight, greater risk of
• 12:49preterm birth,
• 12:51greater risk of child symptoms
• 12:52of psychopathology.
• 12:54And a lot of this
• 12:55is coming from
• 12:56the large ABCD dataset, which
• 12:58I think everyone on this
• 12:59call should probably be aware
• 13:00of. It's the largest study
• 13:02of neurodevelopment ever conducted.
• 13:04And we'll see more more
• 13:06data come,
• 13:07out through that study in
• 13:09the next couple of years,
• 13:10but they're seeing a really
• 13:11broad scale
• 13:13increased risk of psychopathology,
• 13:15associated with prenatal cannabis exposure
• 13:18a decade later or a
• 13:19decade before that.
• 13:20So quite concerning,
• 13:22even after we adjust for
• 13:23things like prenatal tobacco exposure
• 13:25and other potential confounds.
• 13:28So during COVID, we weren't
• 13:29able to collect our own
• 13:30data, so we thought why
• 13:31not mine this giant dataset
• 13:33of over ten thousand kids
• 13:35and see if prenatal cannabis
• 13:36exposure does affect neurodevelopmental
• 13:39outcomes.
• 13:40So a couple of my
• 13:41former students led this work,
• 13:43and this was over ten
• 13:44thousand kids.
• 13:46Of their caregivers, only four
• 13:48percent of them endorsed using
• 13:50cannabis during pregnancy.
• 13:52One percent went on to
• 13:53use after they found out
• 13:54that they are pregnant.
• 13:56And from that, we looked
• 13:58at child neurodevelopmental
• 13:59outcomes.
• 14:00And Mohammed found that those
• 14:02exposed to cannabis in utero
• 14:04had lower resting state functional
• 14:06connectivity between the salience network
• 14:09and the ventral attention network.
• 14:11These are two really core
• 14:13large scale neurocognitive
• 14:14networks important for
• 14:16redirecting your attention
• 14:18to salient or biologically relevant
• 14:20information in the environment.
• 14:22Interestingly, doctor D'Souza, I didn't
• 14:24mention this to you, but,
• 14:26some of these outcomes were
• 14:27related to psychotic like experiences,
• 14:30in this in these youth.
• 14:32So, of course, it'll be
• 14:33interesting to see if as
• 14:34these children age, do they
• 14:36actually convert into,
• 14:38you know, more of a
• 14:39a clinical phenotype? But, obviously,
• 14:41this was very early on.
• 14:42This was during their their
• 14:43early adolescent phase.
• 14:46Julia was interested in structural
• 14:48signature, so she looked at
• 14:49some of the diffusion tensor
• 14:50imaging data data,
• 14:52and she found
• 14:54those exposed to prenatal cannabis
• 14:56had lower fractional anisotropy,
• 14:58which is a marker of
• 14:59white matter microstructure. It's very
• 15:01nonspecific,
• 15:02but in the left and
• 15:03the right fornix,
• 15:04which is a really interesting
• 15:05white matter pathway for
• 15:07learning and emotional memory. So
• 15:09again, this was very early.
• 15:11It's
• 15:12to be determined if any
• 15:13of these neural,
• 15:14changes we're seeing relate to,
• 15:17psychiatric outcomes as these children
• 15:19age, but that will definitely
• 15:20be an, important area for
• 15:22for this line of work.
• 15:27So another thing we're looking
• 15:28at is what is happening
• 15:30during pregnancy. So what I
• 15:31just showed you was age
• 15:33ten and eleven, so a
• 15:34decade later. But what's happening
• 15:36during pregnancy? Do endocannabinoids
• 15:38relate to birth outcomes related
• 15:40to maternal mental health?
• 15:42So Tamar Gir at Ohio
• 15:44State University has, a really
• 15:46interesting,
• 15:48dataset of prospective stud
• 15:50prospectively collected data during pregnancy
• 15:53in a low risk cohort,
• 15:55and she took blood samples
• 15:56and measured maternal mental health
• 15:58as well as, neonatal outcomes.
• 16:01And we were able to
• 16:02do a secondary analysis to
• 16:03see if endocannabinoids
• 16:05relate to any of those
• 16:06outcomes.
• 16:07So we found that in
• 16:08placental tissue,
• 16:11the individuals with greater,
• 16:13adverse obstetric outcomes like preterm
• 16:15birth, like low birth weight,
• 16:17showed greater anandamide
• 16:18concentrations in placenta. So this
• 16:20replicates what we've seen
• 16:22previously in the literature in
• 16:23a high risk cohort. This
• 16:25is now a low risk
• 16:26cohort, so very similar pattern.
• 16:28I do wanna mention, though,
• 16:29because it's low risk, we
• 16:31did have very few,
• 16:33abstract abstract abstract abstract abstract
• 16:34abstract abstract abstract abstract abstract
• 16:34abstract abstract abstract abstract abstract
• 16:34abstract abstract abstract abstract abstract
• 16:34abstract abstract abstract abstract abstract
• 16:34abstract abstract abstract abstract abstract
• 16:34abstract abstract abstract abstract abstract
• 16:35abstract abstract abstract abstract abstract
• 16:35abstract, and,
• 16:37it'll
• 16:47be,
• 16:50We have very few biomarkers
• 16:51of maternal depression. So we
• 16:54looked at some of our
• 16:55maternal serum samples, and we
• 16:56found that those who had
• 16:58higher depressive symptoms in the
• 17:00second trimester
• 17:02showed lower two AG concentrations
• 17:04in the third trimester,
• 17:06which is super interesting to
• 17:07me because this replicates one
• 17:09of the first studies of
• 17:10endocannabinoids
• 17:11in a psychiatric population, which
• 17:13is done by Matt Hill,
• 17:15Cece Hillard, and colleagues,
• 17:16over two decades ago now.
• 17:18And what they found,
• 17:20was a very similar pattern
• 17:22in unmedicated
• 17:23women with depression. They also
• 17:25had lower
• 17:26CRM two AG. So, potentially,
• 17:28this could be,
• 17:30a very, similar pattern across
• 17:32across studies and across,
• 17:34women.
• 17:36So as I mentioned, one
• 17:36of the limitations is we're
• 17:38working with a low risk
• 17:39cohort here.
• 17:40Again, I work in Detroit.
• 17:42We have, some of the
• 17:43highest rates of cannabis use,
• 17:46across the country, I would
• 17:47bet, and we also have
• 17:49some of the worst perinatal
• 17:50outcomes. It's worse than some
• 17:52third world countries.
• 17:54So do we see similar
• 17:55findings in our Detroit cohort?
• 17:58And that's something I wish
• 17:59I could tell you. We're
• 18:01working on that right now.
• 18:02We've just wrapped up data
• 18:03collection, so we're waiting for
• 18:04basically the children to be
• 18:06born.
• 18:07But we're looking to replicate
• 18:08this study. And what I
• 18:09can tell you is
• 18:11in a the baseline cohort
• 18:13when we're asking women about
• 18:15their substance use during pregnancy
• 18:16and their mental health outcomes,
• 18:18We are seeing super high
• 18:19rates of cannabis use much
• 18:21higher than national averages,
• 18:23and a good portion are
• 18:25using one or more times
• 18:26a day.
• 18:28Interestingly, this is something we
• 18:29talked about at the conference
• 18:30last week. They were quite
• 18:31skeptical of CBD or cannabidiol,
• 18:33which all of you know
• 18:35is an unregulated
• 18:36supplement. It's not scheduled.
• 18:38But yet they had no
• 18:40qualms about using a schedule
• 18:41one, you know, drug
• 18:42during pregnancy. So there's this
• 18:45huge,
• 18:46public health misconception.
• 18:47We have green doula groups
• 18:49in Detroit. You know, people
• 18:51think it's all natural. It's
• 18:52all safe. Cyril, I'm sorry.
• 18:54I'm sure you hear that
• 18:55from your patients all the
• 18:56time, but, you know, we
• 18:57have a big, public health
• 18:58messaging problem here.
• 19:01So I wanna
• 19:03transition now to the adolescent
• 19:05years, and this is where
• 19:07I've spent most of my
• 19:08time,
• 19:09doing research. And kids are
• 19:11hilarious
• 19:12and,
• 19:12fun to work with, of
• 19:14course, but they're really hard
• 19:15to keep still in an
• 19:16MRI scanner. So I don't
• 19:18just work with this group
• 19:19because I like to make
• 19:20my life difficult, but because
• 19:22we know that many psychiatric
• 19:23symptoms begin during the teen
• 19:25years especially.
• 19:27So what I'm showing you
• 19:28here is the age of
• 19:29onset distribution of anxiety
• 19:31shown in red. And what
• 19:32you can see is that,
• 19:34many disorders including anxiety have
• 19:36their roots traced back to
• 19:38really the first two decades
• 19:40of life.
• 19:41And then anxiety is really
• 19:44interesting for a lot of
• 19:45reasons, but we know that
• 19:47adolescent or early onset anxiety
• 19:49can predict greater risk of
• 19:51substance use disorders, depressive disorders,
• 19:53variety of other psychiatric disorders
• 19:55later in life. So we
• 19:57think it's it's interesting to
• 19:58study that as kind of
• 19:59a harbinger for for later
• 20:01psychiatric risk.
• 20:04So we are interested in
• 20:06adolescence. Are there any biomarkers?
• 20:08Is the endocannabinoid
• 20:10system involved in psychiatric risk
• 20:12given that it also changes
• 20:14dynamically during this this time
• 20:16period?
• 20:17These were questions we don't
• 20:18we didn't have answers to.
• 20:20I I argue we still
• 20:21don't, and we need much
• 20:22more research. But,
• 20:24I received a k award
• 20:25in twenty nineteen to study
• 20:27this exact topic,
• 20:29and I'm excited to share
• 20:30finally after COVID,
• 20:33some data from that grant
• 20:34with you all where we
• 20:35were interested in looking at,
• 20:37endocannabinoids
• 20:38in humans. There wasn't much
• 20:39done at that time, and
• 20:41we started with some really
• 20:42basic questions. So do we
• 20:44see sex differences? Do we
• 20:46see age differences
• 20:47in human adolescents? So this
• 20:49was ages ten to seventeen.
• 20:52And what we found was
• 20:53that,
• 20:54for these graphs, on the
• 20:55left on the left will
• 20:56be anandamide,
• 20:58right is two AG. And
• 20:59for two AG, we see
• 21:01a sex difference. There's,
• 21:03typically lower two AG concentrations
• 21:05in females compared to males.
• 21:07Some folks who are doing
• 21:09some life span cannabinoid work
• 21:10are finding a really similar
• 21:11pattern even in, older adults.
• 21:13So that'd be interesting to
• 21:15do a life span
• 21:17analysis of these circulating levels
• 21:19and see if that's,
• 21:20something that replicates across the
• 21:22life span.
• 21:24As far as age effects,
• 21:25we do see a linear
• 21:26decline in two AG concentrations,
• 21:29in particular. I think it's
• 21:31too soon to tell. We
• 21:32don't have the sample size
• 21:33to get into nonlinear effects
• 21:34with
• 21:35anandamide, but it'd be really
• 21:37interesting I'd be really interested
• 21:39to see if these coincide
• 21:40with,
• 21:41puberty onset in in the
• 21:42future.
• 21:43And then we see some
• 21:45relationship
• 21:46with body mass index, obviously,
• 21:48a proxy of body size
• 21:49and adiposity, but this is
• 21:51a really well replicated
• 21:52finding
• 21:53that, those with higher BMI
• 21:55show higher anandamide concentrations.
• 21:57And then endocannabinoids
• 21:59also show an interesting circadian
• 22:01rhythm. So similar to adults,
• 22:02we're seeing that there's an
• 22:04early peak in two AG
• 22:05concentrations
• 22:06that declines in the afternoon.
• 22:08So we're about here. I'm
• 22:09gonna blame the decline in
• 22:10my two AG for not
• 22:12being as alert as
• 22:14but all of this is
• 22:16is really important for us
• 22:17for just understanding the system.
• 22:19Also, what what should we
• 22:20be co varying for when
• 22:21we're designing an experiment
• 22:23or controlling an experiment,
• 22:25to look at these,
• 22:26concentrations.
• 22:28So with that foundation in
• 22:30mind, we were interested in
• 22:31looking at whether
• 22:33these circulating levels relate to
• 22:35anxiety in youth.
• 22:36And we found that youth
• 22:38with higher anxiety symptoms show
• 22:40higher anandamide and lower two
• 22:42AG concentrations.
• 22:44And this study was interesting
• 22:45because we collapsed across our
• 22:47Detroit cohort.
• 22:48We also have a collaborator
• 22:50at University of Cincinnati who
• 22:52has youth on the higher
• 22:53end that are treatment seeking,
• 22:55who actually have a a
• 22:56GAD or generalized anxiety disorder
• 22:59diagnosis.
• 23:00And they were part of
• 23:01a clinical trial, which was
• 23:02very rare looking at whether,
• 23:05it was a double blind
• 23:06placebo controlled trial of,
• 23:08an SSRI
• 23:09escitalopram,
• 23:11over eight weeks. And, again,
• 23:12in adolescence, this is a
• 23:13pretty rare study. But,
• 23:16doctor Strahan had this dataset,
• 23:18so we were able to
• 23:19see
• 23:20not only do endocannabinoids
• 23:22relate to anxiety symptoms at
• 23:23baseline,
• 23:24but do they predict treatment
• 23:26response
• 23:27to a first line pharmacotherapy,
• 23:29or do those levels change
• 23:31in in treatment responders?
• 23:33And,
• 23:34this was really interesting. What
• 23:36we found was that those
• 23:37who responded to treatment across
• 23:39both the active drug and
• 23:40the placebo condition
• 23:42showed elevations in two AG
• 23:44over time. So
• 23:46this is has us thinking
• 23:47that potentially two AG might
• 23:49be a biomarker of treatment
• 23:50response,
• 23:52and that's something that we're
• 23:53interested in exploring in the
• 23:54future.
• 23:56So this is a team
• 23:57two AG finding.
• 24:00I work in Detroit. Again,
• 24:01most of my career has
• 24:02been studying the effects of
• 24:03childhood trauma on brain development
• 24:05and psychiatric risk. Ninety percent
• 24:08plus of our kids have
• 24:09experienced one or more traumas.
• 24:10This is the norm and
• 24:11not the exception.
• 24:13So we were really interested
• 24:14in seeing whether these levels
• 24:16correlate with PTSD symptoms in
• 24:18youth. And
• 24:19we found an association with
• 24:21anandamide.
• 24:22Similar to anxiety, we found
• 24:24higher anandamide
• 24:25relating to higher,
• 24:26PTSD symptoms severity in our
• 24:28in our sample.
• 24:30So what we're thinking with
• 24:31anandamide and, again, this is
• 24:33all speculative.
• 24:34This is team two AG,
• 24:35but that anandamide
• 24:37might just be a a
• 24:38a stress sensitive
• 24:40biomarker potentially across disorders. I
• 24:42know there's,
• 24:43some data in the psychosis
• 24:44area I'd love to chat
• 24:45about as well, but maybe
• 24:47a nonspecific biomarker of,
• 24:49of stress.
• 24:51So these studies in youth
• 24:53were really interesting because they
• 24:54filled some gaps in research
• 24:56in adults
• 24:57where we had enough data
• 24:58to finally put together a
• 24:59meta analysis of stress related
• 25:01disorders. So PTSD,
• 25:03depression, anxiety is what we're
• 25:05we limited it to in
• 25:06this case.
• 25:08And across these twenty studies,
• 25:10on average, if we look
• 25:11at resting
• 25:12endocannabinoids
• 25:13in plasma or serum,
• 25:15there is, higher anandamide and
• 25:17higher two AG concentrations
• 25:19in those with the disorders
• 25:21compared to without.
• 25:23So I'm saying that, but
• 25:25also I wanna highlight there
• 25:26is so much heterogeneity
• 25:28across studies.
• 25:29The most consistent findings and
• 25:31the most common were in
• 25:32PTSD.
• 25:34Depression and anxiety was a
• 25:36little bit more mixed. So
• 25:37I just wanted to,
• 25:38to clarify that.
• 25:41What was super interesting to
• 25:42me was that not only
• 25:44do you see this elevation
• 25:45in in endocannabinoids
• 25:47perhaps ramping up in response
• 25:48to chronic stress,
• 25:50at rest. But some of
• 25:51the studies actually introduced a
• 25:53laboratory stressor,
• 25:55to the psychiatric population.
• 25:57And at least in a
• 25:58couple of studies, they're finding
• 25:59that people with PTSD in
• 26:00this particular example,
• 26:02they showed higher levels at
• 26:03baseline,
• 26:04but they weren't able to
• 26:06appropriately ramp up
• 26:07a response to stress,
• 26:09when you introduce that psychosocial
• 26:11stressor.
• 26:12So,
• 26:14this got us thinking that
• 26:15perhaps there's some dysregulation at
• 26:16baseline.
• 26:17The endocannabinoid system isn't coming
• 26:19online in response to stress
• 26:21like it should.
• 26:22But I will say that
• 26:23that's not the a very
• 26:25common paradigm. As you can
• 26:26imagine, it's harder to do
• 26:27that.
• 26:28I think it'll be interesting
• 26:29for
• 26:30more studies looking at, laboratory
• 26:33stressors to see how different
• 26:34psychiatric populations respond to acute
• 26:36stress.
• 26:38So wanna highlight two more
• 26:40studies we've got going on
• 26:41in the area of psychiatric
• 26:43risk in youth, and one
• 26:45is,
• 26:46led by my graduate student,
• 26:47Samantha Ealy, who is super
• 26:50interested in the endocannabinoid system
• 26:52as a biomarker of suicide
• 26:54risk, where we have very
• 26:56few to little to none,
• 26:58no biomarkers. A lot of
• 26:59youth and individuals don't disclose
• 27:01to someone before they,
• 27:04attempt suicide. And in some
• 27:05of our data in Detroit,
• 27:07we're finding that the rates
• 27:08of suicidal ideation are about
• 27:10one in five in the
• 27:11past year, have seriously considered
• 27:13taking their own lives.
• 27:15So this is a huge
• 27:15public health concern. So,
• 27:18Sam is looking at whether,
• 27:20youth with,
• 27:21active suicidal ideation,
• 27:24have differences in circulating endocannabinoids
• 27:26at rest in a response
• 27:27to a laboratory stressor,
• 27:30compared to those without who
• 27:31are matched on depressive symptoms.
• 27:34She's also using functional imaging
• 27:36to see if those circulating
• 27:37levels relate to dorsal lateral
• 27:39prefrontal cortex activation,
• 27:42during emotion regulation, which a
• 27:43couple of studies have found
• 27:45relate to suicidal ideation in
• 27:47youth.
• 27:48So, hopefully, next time I
• 27:49see you all, I'll have
• 27:50some more data to share.
• 27:52Another thing
• 27:53we're really interested in is
• 27:55with trauma, back to that
• 27:57PTSD finding,
• 27:58does that elevation
• 28:00in anandamide
• 28:01in people with PTSD,
• 28:03is that
• 28:04a result of trauma exposure?
• 28:06Is that a result of
• 28:07PTSD? Is it a biomarker
• 28:09of risk of future PTSD?
• 28:11Obviously, that's really hard in
• 28:12humans
• 28:13to tease out. We don't
• 28:15we can't predict who's going
• 28:16to go on to develop
• 28:17a trauma
• 28:18to follow prospectively,
• 28:19but we do have some
• 28:21really interesting naturalistic
• 28:22studies done in adults
• 28:24where they leverage
• 28:26people coming in for emergency
• 28:27departments,
• 28:28after an acute injury, for
• 28:29example, a car accident or
• 28:31an assault.
• 28:32And they're able to study
• 28:33that population to see who's
• 28:35going to develop PTSD over
• 28:36time versus not.
• 28:38So that got us thinking
• 28:40about, okay, how can we
• 28:41apply that model to the
• 28:42pediatric space?
• 28:44And we actually have a
• 28:45really, unfortunately, a great model
• 28:47of that of a tram
• 28:48a trauma, which is having
• 28:50a child in the pediatric
• 28:51intensive care unit or PICU.
• 28:54And as you can all
• 28:55probably imagine or maybe you've
• 28:57experienced this,
• 28:58this is a really stressful
• 29:00and traumatic experience for children
• 29:02and their caregivers,
• 29:04and the rates of PTSD
• 29:05are also quite high. We
• 29:07see about thirty percent of
• 29:08children
• 29:09who were admitted to the
• 29:10p the PICU will go
• 29:12on to develop PTSD
• 29:14up to eighty percent of
• 29:15caregivers. So for us, this
• 29:17is a really interesting model
• 29:19to see if we can
• 29:20identify biomarkers of risk and
• 29:22also really direct those resources,
• 29:24to the most at risk
• 29:25individuals.
• 29:27So this is something we're
• 29:28working on through the division
• 29:30I established in partnership with
• 29:31Children's Hospital of Michigan.
• 29:33Again, I don't have data
• 29:34to share with you. We're
• 29:35just getting this study up
• 29:36and running, but we're really
• 29:38interested to see if we
• 29:39can if the endocannabinoid system
• 29:41will predict PTSD risk in
• 29:43children as well as their
• 29:44caregivers.
• 29:46So I think I'm gonna
• 29:47skip a little bit forward
• 29:48just in interest of time
• 29:50because I hear you guys
• 29:50give really amazing questions.
• 29:52I wanna jump to the
• 29:54positive side. So I just
• 29:56talked a lot about risk,
• 29:57but
• 29:58can we leverage the endocannabinoid
• 30:00system,
• 30:01as a way to, intervene
• 30:03early?
• 30:04And
• 30:05I wanna mention a couple
• 30:06of things we're doing in
• 30:07this space. One is our
• 30:08state of
• 30:10funded grants, which
• 30:12we have just been through
• 30:13two years of regulatory hurdles,
• 30:15as you can all imagine,
• 30:16to,
• 30:18give, cannabis flower to veterans
• 30:20with PTSD.
• 30:21So we are finally cleared.
• 30:23Our clinical holds from FDA
• 30:25have been lifted,
• 30:27to run really big studies
• 30:28of cannabis as a treatment
• 30:30for PTSD in veterans.
• 30:33And there are multiple components
• 30:35to this study. We're looking
• 30:36at a twelve week trial
• 30:37of different cannabis cultivars that
• 30:39vary
• 30:40in THC and CBD concentrations.
• 30:42We are,
• 30:44pairing cannabis
• 30:45acutely with, prolonged exposure, which
• 30:48is a
• 30:49form of c CBT for
• 30:51people with PTSD.
• 30:53My role in the studies
• 30:55is to look at endocannabinoids
• 30:57and exogenous cannabinoids as biomarkers
• 30:59in the blood.
• 31:01And then I'm also co
• 31:02PI with Eric Woodcock who
• 31:03actually did his pet imaging
• 31:05training at Yale,
• 31:07to look at,
• 31:08functional neuroimaging and pet,
• 31:11pet imaging correlates of this
• 31:12treatment response. So
• 31:14on the MR side, which
• 31:15is what my expertise in
• 31:17is in, we're looking at
• 31:19functional networks. We're looking at
• 31:20functional activation
• 31:22during,
• 31:23a couple of tasks, tacking
• 31:25into emotion regulation, working memory.
• 31:28And then Eric is using
• 31:29a radio tracer for the
• 31:31kynurenine system to see if
• 31:33cannabis treatment affects
• 31:35neuroinflammation
• 31:36markers. So, hopefully, next time
• 31:38I see you, we will
• 31:39have begun. We just started
• 31:40recruitment,
• 31:41but this is coming down
• 31:42the pipe.
• 31:44So,
• 31:46this was written for a
• 31:47specific RFA.
• 31:48You know, we would not
• 31:49have used cannabis flower if
• 31:51we were to write this
• 31:52RFA, but no one asked
• 31:53the scientists when they do
• 31:54this. So,
• 31:56we all know cannabis is
• 31:57really hard to dose
• 31:59appropriately, and it's smoked in
• 32:01this case.
• 32:02So, obviously,
• 32:03you know, there's a ton
• 32:04of ways to target the
• 32:05system itself that's more precise
• 32:07in my opinion.
• 32:09There's a lot of excitement
• 32:10here.
• 32:11Although I will say some
• 32:12of the FA trials for
• 32:14PTSD that were super promising
• 32:15had failed. That was a
• 32:16big topic of discussion,
• 32:19last week. Those were really
• 32:20high profile studies about PTSD.
• 32:23But nonetheless, I think there's
• 32:24a lot of opportunity to
• 32:26target the system for a
• 32:27variety of psychiatric disorders.
• 32:29And just to underscore how
• 32:30exciting this is,
• 32:32the number of clinical trials,
• 32:33if you go to clinical
• 32:34trials dot gov, have just
• 32:36exploded, and I know a
• 32:37lot of you guys are
• 32:37doing some fantastic work there
• 32:39at Yale.
• 32:41So one one pilot say
• 32:43I wanna mention in the
• 32:44use space we're working on
• 32:46is we are looking at
• 32:47the FDA approved,
• 32:49cannabidiol medication called Epidiolex
• 32:52that was approved back in
• 32:53twenty eighteen for seizure disorders.
• 32:56And we tagged up with,
• 32:58Amy Louat, who's a pediatric
• 33:00neurologist
• 33:00who's been using this medication
• 33:02for several years
• 33:04with her pediatric epilepsy patients.
• 33:06And we were interested in
• 33:07seeing if they add this
• 33:09medication on board, do we
• 33:11see changes not only in
• 33:12seizures,
• 33:13but also some secondary outcomes
• 33:15like anxiety symptoms,
• 33:17circulating endocannabinoids
• 33:18as well?
• 33:19Because there's a lot of,
• 33:20like, pop media culture saying
• 33:23that CBD is, you know,
• 33:24effective for anxiety, for sleep,
• 33:27curing cancer, all crazy stuff,
• 33:30but not a ton of
• 33:31empirical data to to support
• 33:33this.
• 33:34So
• 33:35we just wrapped up this
• 33:36pilot study. I'm excited to
• 33:38share some data with you
• 33:39all.
• 33:40Very small sample, but what
• 33:42we did find is that
• 33:43from baseline to about week
• 33:44four or five, which is
• 33:45when they reached their their
• 33:47target dose,
• 33:49we saw a significant reduction
• 33:50in seizure frequency, particularly dropped
• 33:52seizures. This is really consistent
• 33:54with what we know about
• 33:55epidiolex
• 33:56after we exclude one person
• 33:58who showed an atypical elevation
• 34:00in seizures.
• 34:01What is most interesting to
• 34:02me is that they also
• 34:04showed lower anxiety symptoms and
• 34:06particularly in the generalized anxiety
• 34:08domain.
• 34:09So this matches some data
• 34:11coming out of, McLean Hospital,
• 34:12Stacy Gruber, and colleagues.
• 34:15Saw a very similar pattern
• 34:16in an open label study,
• 34:18in adults with GAD as
• 34:20well.
• 34:21And then for, endocannabinoids,
• 34:24we saw an overall increase
• 34:25in two AG concentrations,
• 34:27from baseline to study end.
• 34:29So, again, it fits with
• 34:31the idea that maybe two
• 34:32AG is a biomarker of
• 34:34treatment response. So that's something
• 34:36we'd love to dig into
• 34:37more.
• 34:39Obviously, the anxiety symptoms are
• 34:40really fascinating to me as
• 34:42someone who studies anxiety, but
• 34:44we have a big chicken
• 34:45or the egg problem. You
• 34:46know, are these kids,
• 34:48less anxious because they're having
• 34:49fewer seizures or vice versa?
• 34:51Or is
• 34:52there, you know, a real
• 34:53effect of cannabidiol on anxiety?
• 34:56So we
• 34:57were fortunate enough to right
• 34:59before my wedding actually, which
• 35:00was fun to scramble, we,
• 35:03got a an NIH grant
• 35:04to look at cannabidiol,
• 35:07in the form of epidiolex
• 35:08as a way to adjunct,
• 35:11or augment the effects of
• 35:12cognitive behavioral therapy for people
• 35:14with anxiety disorders.
• 35:16So CBT is a first
• 35:17line behavioral treatment.
• 35:19And the idea here is
• 35:20that,
• 35:21at least in the seizure
• 35:23space,
• 35:24cannabidiol
• 35:24really works to stabilize some
• 35:27of the signatures
• 35:28of epilepsy, which is hyperactivity
• 35:30of limbic regions. So
• 35:33in anxiety, we see a
• 35:34really similar pattern. So can
• 35:35we bring cannabidiol
• 35:37on board to really stabilize
• 35:38that limbic hyperactivity
• 35:40and allow those prefrontal control
• 35:42regions to regain control over
• 35:44emotional responding?
• 35:46So they'll be on chronic
• 35:47dosing
• 35:48of five to seven weeks,
• 35:50and then we will introduce,
• 35:52CBT to see if we
• 35:54can use cannabidiol to augment
• 35:56those effects.
• 35:57And this is an interesting
• 35:58phased mechanism through NIMH. Our
• 36:00target is actually brain activation
• 36:02for the first
• 36:03phase. If that's successful, then
• 36:04we'll move on to the
• 36:05second phase to look at
• 36:07clinical outcomes.
• 36:10So
• 36:11as a developmental scientist,
• 36:13I don't love to think
• 36:14about, you know, pharmacotherapy
• 36:16as a as a first
• 36:17first way to approach this.
• 36:19I was wondering if there's
• 36:20other ways
• 36:22to modify the endocannabinoid system
• 36:23that involve behavioral interventions.
• 36:26And turns out there's some
• 36:27interesting data on a variety
• 36:29of behavioral interventions
• 36:31that may all target the
• 36:32endocannabinoid
• 36:33system. And, doctor D'Souza, I
• 36:34didn't include hiking here, but
• 36:36that actually might
• 36:37boost endocannabinoids
• 36:39as well.
• 36:40Cite a really talented undergraduate
• 36:42student who, for her first
• 36:44project, she she was a
• 36:46runner. She was really into,
• 36:48to running. I am as
• 36:49well. She wanted to know
• 36:51if running or other forms
• 36:52of exercise can modify circulating
• 36:54endocannabinoid
• 36:55concentrations.
• 36:57So she did a systematic
• 36:58review and meta analysis, which
• 37:00I would not I would
• 37:01not recommend for a first
• 37:02year undergraduate student, but she
• 37:03did amazing.
• 37:05And she found that across,
• 37:06a bunch of different studies
• 37:08in animal models and in
• 37:09humans,
• 37:10in adults with depression, fibromyalgia,
• 37:13trained athletes, she found a
• 37:15really similar and robust pattern
• 37:17of
• 37:18increased anandamide, to a lesser
• 37:20extent, to a g, following
• 37:22acute exercise.
• 37:24And this was across different
• 37:26types of exercise, aerobic,
• 37:29yoga, resistance.
• 37:31She did find some dose
• 37:33dependent effects. So
• 37:35moderate intensity
• 37:36was associated with a greater
• 37:37increase than lighter intensity.
• 37:40So thinking running versus, like,
• 37:41a brisk walk.
• 37:43But this is a pretty
• 37:44uniform,
• 37:45finding across studies.
• 37:47So this got us thinking,
• 37:49how does this relate to
• 37:51what people think of when
• 37:52they when they run, which
• 37:53a lot of people experience
• 37:55something called the runner's high,
• 37:56which sometimes I feel, you
• 37:58know, less anxious after a
• 38:00run, the euphoric effects. And
• 38:02it turns out that the
• 38:03runner's high is related to
• 38:05cannabinoid signaling. It's not related
• 38:07to endogenous opioids like I
• 38:08had thought for for probably
• 38:10a couple decades that I'm
• 38:11gonna go out and get
• 38:12my my,
• 38:15endorphin boost with a run.
• 38:16But there's been a series
• 38:17of studies
• 38:18in animal models and then
• 38:20in human adults,
• 38:22showing that if you block
• 38:23the,
• 38:24endogenous opioid receptor, you still
• 38:26get the endocannabinoid
• 38:27boost, you still get the
• 38:28anxiolytic,
• 38:29and euphoric effects of exercise.
• 38:32So I won't go, much
• 38:33into that, but this got
• 38:35us also thinking about,
• 38:37can we kind of pack
• 38:38this system
• 38:39and introduce,
• 38:41exercise as a way to
• 38:42augment endocannabinoid
• 38:43signaling,
• 38:45which is really important for,
• 38:48consolidation of memories,
• 38:50including the fear extinction memory.
• 38:52So
• 38:53we're doing that in a
• 38:54randomized controlled trial that I'm
• 38:56in year three right now.
• 38:57And
• 38:58in, teenagers,
• 39:00we're having them undergo a
• 39:02laboratory based Pavlovian fear extinction
• 39:04paradigm.
• 39:05And then after that, they're
• 39:06randomized either to a treadmill
• 39:08exercise for thirty minutes or
• 39:10a control condition.
• 39:12And the idea is that
• 39:13those randomized to the exercise
• 39:14condition will show elevations in
• 39:16anandamide,
• 39:17hopefully, and reductions
• 39:19in their
• 39:21condition fear the next day.
• 39:22So they're better able to
• 39:24retain or recall that extinction
• 39:25learning.
• 39:27And this is a laboratory
• 39:28based study, so we're using,
• 39:30measures of physiological
• 39:32arousal, skin conductance,
• 39:34neuroimaging,
• 39:35bold response.
• 39:37And this sounds kind of
• 39:38weird, but if it's successful,
• 39:39this could be, something that
• 39:41we could apply to the
• 39:42clinic.
• 39:43So youth coming in for
• 39:44a CBT session could undergo
• 39:46their session,
• 39:48then they could go on
• 39:48a treadmill and hope that,
• 39:50they require fewer CBT sessions.
• 39:53Perhaps they respond better to
• 39:54CBT treatment. So that would
• 39:56be the next phase.
• 39:58And, actually, since last week,
• 39:59we got some preliminary data
• 40:01in. So you guys are
• 40:01the first to see this
• 40:02besides my lab manager.
• 40:05We,
• 40:06looked at skin conductance in
• 40:08nineteen
• 40:09of our youth. Nine randomized
• 40:11to exercise, ten to control,
• 40:13and we're already seeing the
• 40:14next day when they come
• 40:15in. So they they didn't
• 40:17exercise previously before right before
• 40:19this.
• 40:20We're seeing that those randomized
• 40:21to the exercise condition shown
• 40:23in blue are showing lower
• 40:25skin conductance.
• 40:26So, potentially, they're recalling that
• 40:28extinction memory,
• 40:30a little better than the
• 40:31the control group. Obviously, we're
• 40:33underpowered here. I'm just gonna
• 40:34stop data collection, and then
• 40:35we'll be done.
• 40:37I'm just kidding. But, very
• 40:38exciting that we might be
• 40:39on the right track here.
• 40:42So last thing before I
• 40:44wrap up and,
• 40:45open it up for questions,
• 40:47I wanna just highlight,
• 40:49kind of a a a
• 40:50new thing that we're doing
• 40:51that's not that I didn't
• 40:53ever think I'd be doing
• 40:54in the the cannabis realm.
• 40:56But we have an environmental
• 40:58health center at Wayne State.
• 41:00My postdoc is
• 41:01super interested in air pollution.
• 41:03She's found that air pollution
• 41:04levels
• 41:05relate to anxiety symptoms in
• 41:07youth, relate to brain developmental
• 41:09outcomes.
• 41:10And, you know, I study
• 41:11trauma, so I've never really
• 41:12thought about, you know, built
• 41:14environments and air pollution and
• 41:15how it relates to psychiatric
• 41:17risk until she joined the
• 41:18lab.
• 41:19But she has these cute
• 41:20little air monitors
• 41:22that I'll show you, that
• 41:23she gives our kids to
• 41:24strap to their backpacks
• 41:26and,
• 41:27measure their particulate matter exposure.
• 41:29And I think you guys
• 41:30were also affected by the
• 41:32wildfires
• 41:33earlier this summer, but we
• 41:34had some of our kids
• 41:35wear these around, and we
• 41:36just saw huge spikes
• 41:38in particulate matter, which is
• 41:39a a pretty harmful, air
• 41:42pollutant.
• 41:43So we took these air
• 41:44monitors, and we had one
• 41:47of our friends, who will
• 41:48not be named,
• 41:49wear the air monitors when
• 41:51they use cannabis.
• 41:52And this was either smoking
• 41:54cannabis flower
• 41:56or vaporizing it with a
• 41:57cartridge.
• 41:58And what we found was
• 42:00really startling
• 42:01that if we look at
• 42:03particulate matter two point five
• 42:05levels on the vertical axis
• 42:06here, this is over time,
• 42:08instances
• 42:09when they smoked cannabis flower
• 42:11or even vaped
• 42:12registered super high levels of
• 42:14air pollution.
• 42:16And what I'm showing you
• 42:17in this red line is
• 42:18the EPA's daily limit. So
• 42:20we're talking single instances of
• 42:22using
• 42:23cannabis even with vaping, which
• 42:24people think is safer than
• 42:26than combustion,
• 42:27is
• 42:28registering toxic levels of PM
• 42:30two point five. And
• 42:32this got us really thinking
• 42:33about not only secondhand effects,
• 42:35which for some reason, you
• 42:37know, we think that secondhand
• 42:38tobacco smoke is negative, but
• 42:40for cannabis, again, it's all
• 42:41green. It's all safe.
• 42:43This got us really thinking
• 42:44about the harmful effects of
• 42:45secondhand cannabis smoke.
• 42:47And, actually, the PM two
• 42:48point five levels from cannabis
• 42:50are four times higher than
• 42:52tobacco smoke.
• 42:53So
• 42:54a lot of, a lot
• 42:56of parents use it in
• 42:57the room, in the car
• 42:58with their kids. They use
• 42:59it, and then they pick
• 43:00up their kid from school.
• 43:02So this stuff is hanging
• 43:03around in these areas.
• 43:05So we got some pilot
• 43:06funding recently
• 43:07with, Claire, who's my fantastic
• 43:09postdoc,
• 43:10as well as Dave Ledgerwood,
• 43:12who is a, an expert
• 43:13in behavioral interventions for substance
• 43:16use disorders.
• 43:17And we're really interested in
• 43:18looking at, can we measure
• 43:20PM two point five levels?
• 43:22Can we work with parents
• 43:23to develop safer ways to
• 43:24use cannabis
• 43:25around their homes? We know
• 43:27parents aren't gonna stop using.
• 43:28We're not asking people to
• 43:29stop using. I think that
• 43:30ship has sailed, but can
• 43:32they use it in a
• 43:33more, safe way around their
• 43:34children to protect them during
• 43:36these really important periods of
• 43:37brain development?
• 43:39So with that, I will
• 43:41wrap up, and I just
• 43:42hope that I have not
• 43:43bored you and convinced you
• 43:45actually that this is worth
• 43:46studying that, you know, the
• 43:47endocannabinoid
• 43:48system is really important for
• 43:49pregnancy outcomes for mental health.
• 43:52And then during adolescence,
• 43:54it's really important potentially a
• 43:56biomarker of risk
• 43:57as a target for interventions
• 43:59either behavioral or pharmacological
• 44:01or or both.
• 44:03And then, you know, thinking
• 44:04of, applying this to different
• 44:06spaces, which I know you
• 44:07are all doing in in
• 44:08a variety of different arenas.
• 44:09So,
• 44:11I'd just love to hear
• 44:12some questions, and thank you
• 44:13so much.
• 44:17Hey. Thank you, Hillary.
• 44:19There are some questions in
• 44:21the chat.
• 44:22I'm gonna start off with
• 44:24probably the most controversial one.
• 44:26Sure. This is from Mohit.
• 44:29What is the safe amount
• 44:30of THC, and how much
• 44:31should be ingested in a
• 44:33day maximum?
• 44:37I I
• 44:38that's so hard. Is there
• 44:40a specific population,
• 44:42Mohit, you're interested in?
• 44:46Because I would say I
• 44:46don't know about you, doctor
• 44:47D'Souza. I'm not a clinician,
• 44:49but, you know, I think
• 44:50if you're talking to an
• 44:51older adult who's looking for
• 44:53pain management,
• 44:54there's probably a route of
• 44:55administration and dose that might
• 44:57be manageable there. I think
• 44:59for developing populations,
• 45:01we always tell people that
• 45:02no
• 45:03amount is safe. Although I
• 45:05will direct you and go
• 45:07ahead and email me later
• 45:08if you are interested in,
• 45:10this. The Canadian government has
• 45:11fantastic,
• 45:13lower risk guidelines on cannabis
• 45:15use for teenagers
• 45:16because, you know, we could
• 45:17tell them abstinence all day,
• 45:19but, they are going to
• 45:20use. So they have fantastic
• 45:22ways to talk to teams
• 45:24about things that they can,
• 45:26ways that they can mitigate
• 45:27risk.
• 45:28But, yeah, that's a complicated
• 45:30question.
• 45:31Okay. So,
• 45:33there's a question from
• 45:35Cameron Davidson.
• 45:37I don't know if you
• 45:37can see it. Would you
• 45:38like me to
• 45:39I do see it now.
• 45:40Okay. The question is between
• 45:43there's a strong correlation between
• 45:45PM and environment. So how
• 45:47does secrecy of use among
• 45:49youth lead to use in
• 45:50smaller and close environments further
• 45:52increasing risk?
• 45:53Yeah.
• 45:54Amazing question.
• 45:56I think there's a lot,
• 45:57that we don't know and
• 45:59understand about this yet.
• 46:01A lot of studies that
• 46:02have been done on secondhand
• 46:04cannabis smoke have been done
• 46:06actually in dispensaries, which is
• 46:08really interesting. There's been a
• 46:09couple of,
• 46:10I think, security guards at
• 46:12concerts, and I always think
• 46:13about this when I'm at
• 46:14a concert that we're all
• 46:15being exposed.
• 46:17But to my knowledge, there's
• 46:18not a ton of information
• 46:19about how teens are using,
• 46:20where they're using.
• 46:22You know, we know that
• 46:23using outdoors obviously helps to
• 46:25mitigate that risk,
• 46:26introducing ventilations,
• 46:28opening a window. But I
• 46:30think back to what we
• 46:30were just talking about, if
• 46:32we can offer
• 46:33some suggestions like that to
• 46:34to lower people's risk, I
• 46:36think that's the direction we
• 46:37need to go in.
• 46:40Great. There there's a there's
• 46:43a comment question from Diana
• 46:45Augustine.
• 46:47Diana, do you wanna ask
• 46:48your question?
• 46:57Okay.
• 46:58I see that Anahita Vasunia,
• 47:01has,
• 47:02her hand up. Anahita, do
• 47:04you wanna ask your question?
• 47:05Yeah. Of course.
• 47:07Hi.
• 47:08Thank you so much for
• 47:08a great talk.
• 47:10I have a question for
• 47:11the studies that you measure
• 47:13the preferred levels of the
• 47:14cannabinoids.
• 47:15How do you control for,
• 47:17like, all the
• 47:19confounders,
• 47:20like Yeah. Food,
• 47:21I don't know, sleep, physical
• 47:23activity,
• 47:24stress, like, everything else that's
• 47:26going on? I know. Aren't
• 47:27humans fun? Right?
• 47:29Also, fantastic,
• 47:31talk at the Gordon conference.
• 47:32I meant to introduce myself
• 47:33there.
• 47:34Yeah. It's it's really tricky
• 47:36because as I showed everyone
• 47:37at the outset, there's so
• 47:38many things that can affect
• 47:40peripheral levels.
• 47:41We do our best to
• 47:42control for them. So we,
• 47:45either ask them to fast
• 47:46in the morning.
• 47:47We tell them to refrain
• 47:48from physical activity for twenty
• 47:50four
• 47:51hours.
• 47:51You know, we try to
• 47:52control for time of day
• 47:54between
• 47:55blood measurements.
• 47:56But for things that we
• 47:57can't, we usually just measure
• 47:59those things and try our
• 48:00best to Cobari. But that's
• 48:01been kind of our approach.
• 48:03Do you usually measure the
• 48:04plasma levels in the afternoon
• 48:06or morning? What time do
• 48:08you think is the best?
• 48:09Yeah. It's dependent on our
• 48:11study, which is,
• 48:12built around,
• 48:14nonscientific
• 48:15things like when our scan
• 48:16center is available. But, you
• 48:18know, between participants who are
• 48:20doing the same study, we
• 48:21try to keep the time
• 48:22of day really consistent. So
• 48:23sometimes we've done studies in
• 48:25the morning
• 48:25versus the afternoon, and we
• 48:27are actually able to leverage
• 48:28that to look at things
• 48:29like time of day. But
• 48:30it's complicated. Right? People are
• 48:32people are and sleep also
• 48:34affects it. Oral contraceptive use,
• 48:36caffeine.
• 48:37Yep.
• 48:38Yeah. Thank you. Thank you
• 48:40so much.
• 48:41I I have a a
• 48:42follow-up question to that, and
• 48:43then there's a question from,
• 48:45from my colleague, Mohitur Nandan
• 48:46Pranganathan, in the in the
• 48:48chat. My follow-up question is,
• 48:52can you
• 48:53summarize very quickly for those,
• 48:55who may not be familiar?
• 48:57What is the relationship between
• 48:59central
• 49:00and peripheral endocannabinoid levels, and
• 49:02to what extent
• 49:04do the, peripheral estimates reflect
• 49:06what's happening in the brain?
• 49:08Yeah. That I mean, that's
• 49:10the million dollar question that
• 49:11everyone's been talking about.
• 49:13To my knowledge, there have
• 49:14been a couple of studies
• 49:15finding a small to moderate
• 49:18correlation. Obviously, those are really
• 49:19hard to do for obvious
• 49:20reasons.
• 49:21There have been studies,
• 49:23looking at,
• 49:24like, c v one receptor
• 49:26availability
• 49:27and, peripheral
• 49:28endocannabinoids.
• 49:30Also, there's
• 49:32a common genetic,
• 49:33polymorphism
• 49:34in the gene encoding FA,
• 49:36which is the enzyme that
• 49:37regulates
• 49:38endocannabinoid
• 49:39concentration. So they do see
• 49:41some correlation between
• 49:43availability
• 49:44and peripheral levels. You may
• 49:46know better than I, but
• 49:47I think, you know, it's
• 49:48it's really difficult. And, at
• 49:50least in the exercise literature,
• 49:52there's a lot of discussion
• 49:53about where
• 49:54those endocannabinoids
• 49:56are produced. Because if you're
• 49:57exercising,
• 49:59there's some, I think, animal
• 50:00data showing that they the
• 50:02endocannabinoids
• 50:03might be produced actually in
• 50:04skeletal muscle,
• 50:06and then they go into
• 50:07circulation.
• 50:08They obviously have to make
• 50:09their way into the brain
• 50:09if they're having those anxiolytic
• 50:11effects, but I think it's
• 50:12a really open question, and
• 50:14I'd love to hear your
• 50:15take on it. Yeah. I
• 50:16mean, it's something that we've,
• 50:18thought about quite quite a
• 50:20lot. I know there are
• 50:21some groups, there was a
• 50:23group in Germany, Marcus Leveque,
• 50:24who looked at both CSF
• 50:26and peripheral levels and and
• 50:29had some,
• 50:31weak correlations between the two,
• 50:32but I've often wondered about
• 50:34that. I suppose
• 50:37studying endocannabinoids
• 50:39in blood might be
• 50:42interesting to do if you
• 50:43have some kind of stimulus
• 50:45as in you measure baseline
• 50:47levels, then you have someone
• 50:48exercise and you look at
• 50:49the change.
• 50:50Right. Your if you're,
• 50:52so that might be a
• 50:53a
• 50:55you know,
• 50:56that's that's where measuring it,
• 50:58you might be able to
• 50:59make some interpretations. But I'm
• 51:01still curious about,
• 51:05about,
• 51:05the extent to which the
• 51:07peripheral levels actually reflect what's
• 51:09happening in the brain. But
• 51:10as you as we heard
• 51:12in the Gordon conference, we,
• 51:14we need a lot more
• 51:15work in this space.
• 51:16Yeah. I can't wait to
• 51:17see what we find out
• 51:18in the next couple years,
• 51:19and then we laugh at
• 51:20ourselves
• 51:21in this moment.
• 51:23Mohini, you have a,
• 51:25question?
• 51:26Sure.
• 51:27Hi. Thanks. Really nice talk.
• 51:29So many questions in on
• 51:30different domains, so I'll
• 51:32restrict myself to the nonpharmacological
• 51:36effects.
• 51:38I was just curious. You
• 51:39know, that was really nice,
• 51:40the the the exercise,
• 51:42effects on boosting endocannabinoid
• 51:45levels.
• 51:46But,
• 51:47so I was just wondering
• 51:48if you could just share
• 51:48a little bit more about
• 51:49that, the time course of
• 51:50that, how long it stayed,
• 51:52whether it correlated with other
• 51:54effects. And then I feel
• 51:55like sometimes
• 51:57in medicine
• 51:58or or medical sciences, I
• 51:59suppose, biological sciences, we
• 52:02if we think something is
• 52:03beneficial, we assume that
• 52:07more is better. And so
• 52:08I was just curious with
• 52:09that.
• 52:11How long should I mean,
• 52:13there might be elevated. What's
• 52:14a good
• 52:15time course?
• 52:17Yeah. I'm yeah.
• 52:18Thanks. Thanks.
• 52:20No. Thank you so much.
• 52:21Those are amazing questions. I've
• 52:22been thinking a lot about
• 52:23exactly that.
• 52:25With respect to the time
• 52:26course, there are very few
• 52:27studies. You know, we work
• 52:29with kids, so we don't
• 52:30put a catheter in them.
• 52:31We just limit it to
• 52:31the one pre post draw.
• 52:33But, in adults, there have
• 52:35been some interesting studies
• 52:37looking at how long that
• 52:38lasts. There are very few,
• 52:40but,
• 52:41I think we don't know.
• 52:43And it would be really
• 52:44important, at least for me,
• 52:45when I talk to teachers
• 52:46where, you know, they're trying
• 52:48to schedule physical activity throughout
• 52:50the day, which is already
• 52:51packed. So, you know, when
• 52:53are they gonna,
• 52:54schedule a test? Are they,
• 52:56you know, doing it within
• 52:57that window where you're still
• 52:58getting that endocannabinoid boost? So
• 53:00there's so many unopened,
• 53:02unanswered questions that I I
• 53:03don't think we know at
• 53:04this point.
• 53:06With respect to more chronic
• 53:08exercise, like you're saying, I'm
• 53:09also a marathon runner, so
• 53:10I
• 53:11I I love your question.
• 53:13Kevin Crombie at the conference
• 53:15presented data on chronic exercise.
• 53:17So think like a ten
• 53:18week or a twelve week,
• 53:20aerobic or resistance exercise program.
• 53:23He actually found that their
• 53:24resting levels are kind of
• 53:26dialed down. Albeit this was
• 53:28in overweight obese population where
• 53:30we see a very similar
• 53:31kind of higher resting anandamide
• 53:33as we do in some
• 53:34of our psychiatric population. So
• 53:36I think the acute versus
• 53:37chronic effects differ.
• 53:39He also showed it differs
• 53:41by aerobic versus resistance.
• 53:43My takeaway was the aerobic
• 53:44was better at kind of
• 53:45dialing that down, but wasn't
• 53:47clear if that had, benefits
• 53:49for lower BMI and things
• 53:50like that.
• 53:52The beta analysis I presented
• 53:54did not find consistent effects
• 53:55of chronic exercise programs, which
• 53:57might just be due to
• 53:58the diversity of populations. But,
• 54:01yeah. I mean, I think
• 54:02like everything, like you're saying,
• 54:03there's probably a sweet spot.
• 54:06There was one study we
• 54:07found looking at acute high
• 54:09intensity
• 54:10exercise.
• 54:11Most people only use the
• 54:12low versus moderate, and that
• 54:14did start to hint
• 54:16at maybe moderate is actually
• 54:17better than high intensity for
• 54:19at least that endocannabinoid
• 54:21boost,
• 54:22albeit one study, but perhaps
• 54:24there is some sort of
• 54:25sweet spot for getting that
• 54:26acute endocannabinoid
• 54:28boost.
• 54:28And then layering on THC
• 54:30is a whole another thing
• 54:31that I won't even get
• 54:32into.
• 54:33A lot of people use
• 54:34THC while they exercise. So
• 54:38So,
• 54:39we have time for,
• 54:41maybe an another one or
• 54:42two questions.
• 54:44I I I if
• 54:45if you can humor me
• 54:47for a minute, I I
• 54:48was really intrigued
• 54:50by the device that you
• 54:51were using to measure air
• 54:53pollution. And while you were
• 54:54interested in air pollution, I
• 54:56was wondering whether
• 54:58that device could be used
• 54:59as a proxy measure of,
• 55:02of cannabis use.
• 55:05You know, if someone wore
• 55:06that device,
• 55:07it's really hard for us
• 55:08to estimate in clinical trials
• 55:12how many times a person
• 55:13uses cannabis during a day
• 55:15or quantify their degree of
• 55:17exposure.
• 55:18But I it would seem
• 55:19to me, I I'm I'm
• 55:20I'm asking a question. Is
• 55:22it
• 55:23is it conceivable that that
• 55:24device could be used
• 55:26to, for example, measure
• 55:29the frequency of cannabis use
• 55:30across a day?
• 55:33I'm just writing that down
• 55:35because I would love to
• 55:36do that in our pilot
• 55:37study and see if there
• 55:38is. So we're asking it's
• 55:39like an EMA study. We're
• 55:40asking parents to self report.
• 55:42We have the kid wear
• 55:44this monitor, and then we
• 55:45have,
• 55:46purple air monitors
• 55:47established within the home.
• 55:49So we can kind of
• 55:50triangulate whether or not that
• 55:52could be, but I I
• 55:53think you're right. That could
• 55:54be
• 55:54potentially a marker of,
• 55:57of PM two point five,
• 55:58which is just one of
• 55:59the the emissions of of
• 56:01cannabis. There's also VOCs, but
• 56:02there are monitors for that.
• 56:04I mean, of course, one
• 56:05negative is it's really easy
• 56:07to game it if you
• 56:08just take the monitor away
• 56:09or unplug it or put
• 56:11it outside.
• 56:12But I'd love to I'd
• 56:13love to see if that's
• 56:14the case because like you
• 56:15said, we don't have great
• 56:16biomarkers or indicators of use.
• 56:19Sounds good.
• 56:22Any last minute questions?
• 56:30Oh, Mohini wants to is
• 56:32asking what the name of
• 56:33that monitor is. Yeah. I
• 56:35will,
• 56:36I'm trying to remember what
• 56:37that one is. We use
• 56:38PurpleAir
• 56:40and then,
• 56:41oh my gosh. That one
• 56:42is slipping. I'm having, like,
• 56:43an endocannabinoid,
• 56:45wool at the moment. You
• 56:46know, I will email you
• 56:48if you wanna just, click
• 56:49on my email. And that
• 56:51goes for anyone. If anyone
• 56:52has any questions, I love
• 56:53this discussion. I'd love to
• 56:54chat offline if anyone,
• 56:56has any questions or follow-up.
• 56:59Sounds good. And and and,
• 57:01you know, many of us
• 57:03are calling, attending this meeting
• 57:05from the VA.
• 57:06So we are really intrigued
• 57:07about the findings of your
• 57:09study,
• 57:10on cannabis,
• 57:11in PTSD
• 57:12patients.
• 57:14We would be we're looking
• 57:15forward to,
• 57:17to hearing the results of
• 57:19that study. So well, thank
• 57:20you very much. We really
• 57:22enjoyed this,
• 57:24and,
• 57:25really appreciate the work you
• 57:27that you're doing. And,
• 57:30for for those of you
• 57:31on the call next week,
• 57:32we have Krista Lister,
• 57:34who will be presenting.
• 57:35She Next month.
• 57:37Sorry? Next month, Doctor. Sissette.
• 57:39Next month. Sorry. Next month.
• 57:40Yes.
• 57:41So, Hillary, thank you very
• 57:43much.
• 57:45Appreciate it. Thank you so
• 57:47much. It was nice meeting
• 57:48you all. Take care.
• 57:50Bye.
• 57:51Bye.