YC_SCAN2 September 2025 Webinar

Transcript

• 00:00It's
• 00:02my,
• 00:03my pleasure to ins to
• 00:05to introduce Krista Lister,
• 00:08who is a professor of
• 00:10psychology
• 00:11at
• 00:12the University of Wisconsin Milwaukee,
• 00:15where she directs the brain
• 00:17imaging and neuropsychology
• 00:19lab.
• 00:21Her research focuses on,
• 00:24the neurocognitive
• 00:26effects of chronic drug use
• 00:28during adolescence
• 00:30and,
• 00:31and adulthood,
• 00:33examining how substances
• 00:35such as
• 00:36cannabis, alcohol, nicotine, and ecstasy
• 00:40impact
• 00:41brain structure and function.
• 00:44She also studies predictors of
• 00:46substance use onset in youth
• 00:48and how individual
• 00:50differences that include
• 00:52genetics,
• 00:53gender, physical activity, and body
• 00:55composition
• 00:57moderate vulnerability
• 00:58to these effects.
• 01:01She is a principal investigator
• 01:03or consultant on several large,
• 01:07neuroimaging
• 01:07project,
• 01:08projects, including the ABCD study,
• 01:10which we've heard about,
• 01:12the IDEA consortium,
• 01:14and the MTA neuroimaging
• 01:16study.
• 01:18She also chairs the women
• 01:20in neuropsychology
• 01:22subcommittee of the American
• 01:25of the APA Society for
• 01:27Clinical
• 01:28Neuropsychology.
• 01:29So,
• 01:30Krista, the floor is yours.
• 01:34We we, we are looking
• 01:36forward to,
• 01:38to,
• 01:39what you have to say
• 01:40about this. I was fortunate
• 01:42to
• 01:42to attend your presentation at
• 01:44the Gordon conference, and,
• 01:46I'm sure everyone's gonna really
• 01:48enjoy your presentation.
• 01:50So I'm gonna go ahead
• 01:51and share my slides.
• 01:58So I kinda lose you
• 02:00guys when I have this
• 02:01up. Can you guys see
• 02:02the slides okay?
• 02:05Not yet. Not yet. K.
• 02:07Let me,
• 02:09let me
• 02:10do this.
• 02:19There we go.
• 02:21Now do you guys see
• 02:22it? Yes. If you can.
• 02:23There you go.
• 02:26Alright.
• 02:27Can everybody,
• 02:28also see it? Could you
• 02:29just give a thumbs up
• 02:30in the chat?
• 02:32Yes. I can see it.
• 02:35Okay. Fantastic. Thank you so
• 02:37much.
• 02:38So,
• 02:39I'm gonna go ahead and
• 02:40talk about really an overview
• 02:42of findings
• 02:43focused
• 02:44I guess I'll call it
• 02:45my kind of pandemic update,
• 02:47so mostly on the work
• 02:48kind of post pandemic last
• 02:50four or five years.
• 02:51And so this a lot
• 02:53of this work has continued
• 02:54to look at the impact
• 02:55of kind of cannabis use
• 02:57patterns
• 02:58and then also getting into
• 03:00some relationships or
• 03:04and
• 03:09So,
• 03:10Krista,
• 03:11you're breaking up?
• 03:13No.
• 03:15Yeah.
• 03:25Let me just check.
• 03:29Can you
• 03:30now?
• 03:31Like, is it am I
• 03:32still
• 03:33Yeah. Breaking up? Krista, if
• 03:35you like, you could turn
• 03:36off your camera and just
• 03:37share your screen, and that
• 03:38will help with the bandwidth.
• 03:42You got it. Let's try
• 03:44that.
• 03:51How about that? Can you
• 03:52guys hear me good now?
• 03:53It looks a lot better.
• 03:54Yeah. Okay. Alright. Well, you
• 03:56don't need to see my
• 03:57face anyway. So,
• 03:59okay. So this is just
• 04:01acknowledging some of the, NIH
• 04:03funding. I don't have any
• 04:04other financial conflicts, so I'll
• 04:06jump in.
• 04:07Today, I just like to
• 04:08orient people to what I'm
• 04:10talking about when I say
• 04:11cannabis because,
• 04:12I'm preaching to the choir
• 04:13here, but we know that
• 04:14this is a very complicated
• 04:16plant
• 04:17with, over a hundred cannabinoids.
• 04:20I'm primarily talking about really
• 04:22the recreational
• 04:23use of delta nine THC
• 04:25with the intent of getting
• 04:26high. And in particular,
• 04:28talking about users who are
• 04:30using pretty regularly,
• 04:32which I would define as
• 04:33at least once a week,
• 04:34but on average, more like
• 04:35almost every day.
• 04:38I do have some very
• 04:39preliminary data on cannabidiol,
• 04:42and cannabidiol
• 04:43exposure is getting increasingly interesting
• 04:46with, of course, the two
• 04:47thousand eighteen farm bill.
• 04:49Generally, in recreational cannabis to
• 04:52get highs, cannabidiol
• 04:54levels have really gone down
• 04:56over the years, but now
• 04:57CBD is very available, you
• 04:59know, at just,
• 05:01at at stores, grocery stores,
• 05:03you know, salons, etcetera.
• 05:05And we're certainly seeing young
• 05:07people taking CBD,
• 05:09not necessarily
• 05:10recreationally as we think about
• 05:12it, but at at fairly
• 05:13high rates. And so I'm
• 05:15gonna talk about CBD a
• 05:16little bit later in the
• 05:17talk.
• 05:19Of course, cannabis for recreational
• 05:21purposes does start in the
• 05:22teenage years. This is just
• 05:24highlighting that, cannabis or marijuana
• 05:27continues to be a very
• 05:28popular drug.
• 05:29Nearly about forty percent have
• 05:31used by twelfth grade. It's
• 05:33the second most popular after
• 05:35alcohol.
• 05:37And this is occurring during
• 05:38that, very critical adolescent neurodevelopmental
• 05:42stage, which we think of
• 05:43as this real gateway into
• 05:45adulthood
• 05:46where a lot of health
• 05:47behaviors are established during these
• 05:49teenage years, and the brain
• 05:51gets continuing to be quite
• 05:53plastic
• 05:54and having, you know, ongoing
• 05:55neural,
• 05:57neuronal pruning in the prefrontal
• 05:59cortex and parietal cortex and
• 06:01ongoing,
• 06:02increases in white matter and
• 06:03improvements in white matter quality
• 06:06all the way into the
• 06:07early forties.
• 06:10The endocannabinoid
• 06:11system plays a really important
• 06:12role in that neurodevelopment,
• 06:14both during the prenatal stage,
• 06:16but also during adolescence.
• 06:18And, of course, delta nine
• 06:19THC is a partial agonist
• 06:21at the CB one receptor.
• 06:24The endocannabinoid system,
• 06:26plays a role in white
• 06:27matter development, neuroplasticity,
• 06:29functional coupling,
• 06:30And there's some evidence that
• 06:32through the, mycogliel
• 06:33or astrocytes that might be,
• 06:35you know, tagging weaker connections
• 06:37for that pruning.
• 06:39The underlying,
• 06:41constructs that it plays a
• 06:42role in are things like
• 06:43emotion, we reward processing, executive
• 06:45functioning, and memory, which are
• 06:47all very important for, you
• 06:49know, understanding neurodevelopment, but also
• 06:51the development of addiction over
• 06:53time.
• 06:54And it also plays roles
• 06:55in peripheral functions of interest
• 06:57interest like immune inflammation,
• 06:59analgesia, and metabolic processing.
• 07:02Importantly,
• 07:03the CB one receptor density,
• 07:06peaks during adolescence
• 07:07as does two a, two
• 07:09a g and anandamide levels
• 07:11and and anandamide mobilization.
• 07:16So the theory is that
• 07:17repeated,
• 07:18exogenous use of cannabis, especially
• 07:21high THC product,
• 07:23might disrupt that, underlying endocannabinoid
• 07:26system and therefore result in
• 07:28neurocognitive
• 07:29abnormalities.
• 07:32This is a pretty busy
• 07:33slide, but,
• 07:34and I know a lot
• 07:35of you you folks do
• 07:36this work or are very
• 07:38closely tied to it. So
• 07:39I'm not gonna go into
• 07:40every one,
• 07:41but this is just some
• 07:42of the preclinical
• 07:43evidence that, myself as a
• 07:45human researcher,
• 07:48gets interested in because it
• 07:49shows that,
• 07:51exposure to THC, especially kind
• 07:53of high doses during the
• 07:54teenage years
• 07:55disrupts a lot of the
• 07:57neuronal,
• 07:59markers that we'd be interested
• 08:00in. So we see downregulation
• 08:02or desensitization
• 08:03of the CB one receptors.
• 08:05You know, there's some,
• 08:07disagreement in the literature, but
• 08:08there's a little bit of
• 08:09evidence that that might be
• 08:11especially
• 08:12relevant in females.
• 08:13We see changes in the
• 08:15structures of dendrites,
• 08:16like reduced length or complexity
• 08:18in areas like the hippocampus
• 08:20and prefrontal cortex,
• 08:22and therefore, downstream changes in
• 08:24the connectivity
• 08:25patterns between those structures.
• 08:27We see altered glutamate and
• 08:29GABA signaling,
• 08:30altered glial cell function and
• 08:32synaptic plasticity,
• 08:34increased inflammation,
• 08:36abnormal abnormalities in microglial function.
• 08:38Now this is also a
• 08:40bit of a mixed literature.
• 08:41Some have found,
• 08:43stimulated microglia. Some have found
• 08:46blunted microglia that might depend
• 08:48on the sex of the
• 08:49animal or the timing of
• 08:51the exposure or the extent
• 08:53of the dose.
• 08:54There have been evidence of
• 08:55epigenetic changes in opioid and
• 08:58neurodevelopmental
• 08:59genes, as well as endocannabinoid
• 09:01genes.
• 09:04THC exposed adolescent animals with
• 09:06a large dose have been
• 09:07shown kind of blunted responsivity
• 09:10to stressors, including social stress.
• 09:13And interestingly, on the metabolic
• 09:15side,
• 09:17heavy THC exposure during adolescence
• 09:19resulted in kind of a
• 09:20pseudo lean state. So although
• 09:23it's lower weight, there's a
• 09:24disruption in the thermogenesis
• 09:27and the lipolysis
• 09:29so that the brain might
• 09:30actually have kind of abnormal
• 09:31energetics during physical activity or
• 09:33energetics during physical activity or
• 09:34stress
• 09:35because these mechanisms rely on
• 09:37fatty acids from,
• 09:39the body fat.
• 09:41Importantly for neurocognitive
• 09:43effects, we see that adolescent
• 09:45exposed animals have functional deficits
• 09:48that last into adulthood
• 09:50that are quantitatively
• 09:51and qualitatively
• 09:52different than when you expose,
• 09:56adult animals to THC.
• 09:59So this just provides,
• 10:00you know, some really nice
• 10:02preclinical evidence that this might
• 10:03be an important thing to
• 10:04look at,
• 10:05especially since such a high
• 10:07number of teenagers
• 10:09are being exposed to THC
• 10:11products during their development.
• 10:15Before I jump into some
• 10:16of the studies, I just
• 10:17wanna anchor people into some
• 10:19of our main methods here.
• 10:22A series of now some
• 10:24of my studies come from
• 10:25the IDEA consortium, which is
• 10:27a larger
• 10:28combination or harmonized dataset across
• 10:31a few different r o
• 10:32ones, and then others are
• 10:34just from,
• 10:35my relative. Now I call
• 10:37it a smaller study. It
• 10:38felt good. It felt big
• 10:39before a, b, c, d.
• 10:42And I'll talk about a,
• 10:43b, c, d methods a
• 10:44little later. But these are
• 10:45generally sixteen to twenty five
• 10:47year olds. They came in
• 10:48weekly for three weeks,
• 10:50to confirm abstinence from THC
• 10:53as well as other drugs.
• 10:54So they wore sweat patches
• 10:56over the week and also
• 10:57gave urine toxicology and breathalyzers.
• 11:00They received a mini repeated
• 11:02measures, neuropsych battery and mood
• 11:04battery as long as, also
• 11:06withdrawal symptoms from cannabis.
• 11:08And then they came in
• 11:09for final sessions with a
• 11:11full neuropsychological
• 11:12battery,
• 11:13structural and functional MRI,
• 11:16as well as VO two
• 11:17max testing, which I am
• 11:18gonna touch on, but this
• 11:19is an objective marker of
• 11:21their aerobic fitness.
• 11:24The cannabis users
• 11:26are not treatment seeking, but
• 11:28they are regular to heavy
• 11:29users. So they've used at
• 11:31least fifty times in the
• 11:32past year. But on average,
• 11:33they're daily users, and they
• 11:35have primarily smoked,
• 11:37THC flower products.
• 11:39There's a little bit of
• 11:40edibles and a little bit
• 11:41of oil use in there,
• 11:43but it's, the study ended
• 11:45data collection before the, like,
• 11:46the really
• 11:47strong proliferate
• 11:49proliferation of vaping.
• 11:51It did exclude for very
• 11:52heavy drinking. They hadn't used
• 11:54other drugs more than twenty
• 11:55times.
• 11:56And the controls couldn't use
• 11:58any cannabis or marijuana in
• 11:59the past year, but they
• 12:00might have used a few
• 12:01times in their lifetime, and
• 12:02they also had similar exclusions.
• 12:05It's notable that this is
• 12:06a very healthy sample.
• 12:08They couldn't have any MRI
• 12:10contraindications.
• 12:12There's they couldn't have an
• 12:13independent access one psychiatric disorder.
• 12:16And notably, there were a
• 12:17good number of people that
• 12:18were excluded because they had
• 12:21a history of depression in
• 12:22particular
• 12:24or ADHD.
• 12:25They couldn't be on psychiatric
• 12:26medications.
• 12:28No, complicated or premature birth
• 12:30or prenatal alcohol and drug
• 12:32exposure. We did interview the
• 12:33parents to confirm this information
• 12:35along with the teens and
• 12:36young adults,
• 12:37and they couldn't have any
• 12:39neurologic major medical illnesses
• 12:41or metabolic conditions because we
• 12:43were interested in this kind
• 12:44of aerobic activity question.
• 12:47So they had to maintain
• 12:48abstinence for at least fourteen
• 12:50days, and this was confirmed
• 12:52by toxicology.
• 12:55On average, these,
• 12:57this cohort is about twenty
• 12:59one years old. They have
• 13:01some college.
• 13:03Certainly, there's people that didn't
• 13:04go to college, but that's
• 13:05kind of their average.
• 13:07Their,
• 13:08verbal
• 13:09IQ estimate is in the
• 13:10average to high average range.
• 13:13Their depressive symptoms
• 13:15were within the normal level,
• 13:16although the,
• 13:18cannabis users did have a
• 13:19significantly
• 13:20increased,
• 13:22number of symptoms.
• 13:24They were a little bit
• 13:25skewed towards male and Caucasian,
• 13:27non Hispanic.
• 13:30And I already talked about
• 13:31their kind of average drug
• 13:32use.
• 13:34I will note that their
• 13:35past year alcohol use, even
• 13:37though we controlled for very
• 13:38heavy drinkers that which got
• 13:40rid of the, like, really
• 13:41repeated binge drinkers.
• 13:43The cannabis users still had,
• 13:46statistically
• 13:46higher alcohol use and cotinine
• 13:49levels,
• 13:50although nicotine use was relatively
• 13:52low in the sample.
• 13:56Okay. So this is just
• 13:58highlighting a couple of cognition
• 14:00studies. These are a little
• 14:01bit earlier, and I'll I'll
• 14:03touch a little bit on
• 14:04cognition. But just to kind
• 14:05of give a little bit
• 14:06of what we've seen across
• 14:08studies for the the downstream
• 14:09cognitive effects that we see.
• 14:12And typically we see, kind
• 14:14of reduced psychomotor speed,
• 14:17reduced complex or sustained attention,
• 14:21and poor inhibitory
• 14:22control. And this is after
• 14:25two to four weeks of
• 14:26abstinence.
• 14:27We do see that in
• 14:28the younger cohorts. So on
• 14:30the left there, I have
• 14:31an older study. My prior
• 14:33name was Medina.
• 14:36These are adolescent, so more
• 14:38like,
• 14:39sixteen to nineteen year olds.
• 14:41We do see that the
• 14:42effect sizes are larger in
• 14:44the younger cohorts versus the
• 14:46later adolescent, young adult cohorts,
• 14:49but the type of cognitive
• 14:50functioning that's impaired is pretty
• 14:51similar.
• 14:53And I just wanna highlight
• 14:54that there's been now several
• 14:56meta analyses kind of looking
• 14:58at, you know, multiple studies
• 15:00and multiple cohorts.
• 15:02And the most consistent finding
• 15:03is is in the verbal
• 15:05memory, although, notably, that's
• 15:07when there is only a
• 15:09few days of abstinence required.
• 15:11And, the the more sustained
• 15:14deficits are in complex attention,
• 15:16processing speed, and aspects of
• 15:18executive functioning, especially inhibitory control,
• 15:21and the effect sizes are
• 15:22relatively small.
• 15:25So speaking of inhibitory control,
• 15:29this cohort received an emotional
• 15:31no go task. And, this
• 15:33analysis specifically looked at
• 15:36processing during the,
• 15:39no go or inhibitory trials
• 15:40while they were processing calm
• 15:42faces.
• 15:43So although it's within the
• 15:45context of this affective state,
• 15:47the, calm faces are considered
• 15:49neutral.
• 15:50And what we found is
• 15:51that despite
• 15:52similar performance, you know, on
• 15:54the behavioral task in the
• 15:55scanner,
• 15:57the cannabis users had increased
• 15:59fold activation versus the controls
• 16:01and left medial superior frontal
• 16:04and left cingulate cortex.
• 16:06So this pattern was interpreted
• 16:08as kind of using greater
• 16:09prefrontal resources to complete the
• 16:11same task
• 16:13even after two to three
• 16:14weeks of abstinence.
• 16:16And because behavior was the
• 16:17same at this point,
• 16:19it's thought that that for
• 16:20the most part, this was
• 16:21successful compensation.
• 16:26We are also interested in
• 16:28this study to start getting
• 16:30at more of the affective
• 16:32side or the interplay between
• 16:34affect inhibitory control
• 16:37because,
• 16:38mostly because for one thing
• 16:39that maps onto the endocannabinoid
• 16:41system. But also in the
• 16:43clinic, we tend to see
• 16:45that, it's that interplay between
• 16:47kind of cold cognition and
• 16:49affective states that really gets
• 16:51people into kinda trouble or
• 16:52or,
• 16:53has them facing a lot
• 16:55of challenges.
• 16:56So what we saw here,
• 16:58first off,
• 16:59in several studies, we we've
• 17:01seen abnormal,
• 17:02rostral anterior cingulate volume in
• 17:05cannabis users.
• 17:06And once again, in the
• 17:07sample, we see the same
• 17:09thing.
• 17:09And the smaller volume was
• 17:11related to worse emotional discrimination
• 17:14on a on a behavioral
• 17:15task outside of the scanner.
• 17:18We also saw that as
• 17:20they were processing,
• 17:21the the fearful faces presented
• 17:24during the go trials,
• 17:26that we they actually had
• 17:28blunted bold response in the
• 17:30same region
• 17:31despite having kind of similar
• 17:32connectivity patterns.
• 17:35So
• 17:36what we see here is
• 17:37that after those three weeks
• 17:38of abstinence, the rostereus
• 17:40anterior cingulate
• 17:42is kind of blunted in
• 17:43response to this fearful,
• 17:45go, and that's linked with
• 17:47worse emotional processing outside of
• 17:50the scanner.
• 17:51And we're beginning to think
• 17:52of this as per perhaps
• 17:54kind of some biological evidence
• 17:56of some emotional numbing.
• 17:58And I'd love to talk
• 17:59to you guys more about
• 18:00that because I know you've
• 18:01looked into this concept in,
• 18:03people with PTSD diagnosis.
• 18:07On the other side,
• 18:09we wanted to look at
• 18:11the happy faces
• 18:12because we think of this
• 18:13as kind of a reward
• 18:15processing task. This is an
• 18:16appetitive cue.
• 18:18And what we, so we
• 18:20looked at the ventral striatum
• 18:21specifically and then also whole
• 18:23brain response.
• 18:24And what we see is
• 18:25the cannabis users in the
• 18:27whole brain analysis have increased
• 18:29bold response in the left
• 18:31cingulum
• 18:32and and diminished response in
• 18:34the left pre SMA.
• 18:36When we look specifically
• 18:38at the ventral striatum, we
• 18:39see an exaggerated or increased
• 18:41bold response to this reward
• 18:43stimuli.
• 18:44And that's, you know, pretty
• 18:46consistent
• 18:47with the,
• 18:49other reward type processing tasks
• 18:51or cue reactivity
• 18:53that you see in cannabis
• 18:54users, either adolescents or adults.
• 18:57So we see kinda similar
• 18:59findings here.
• 19:01Where it got kind of
• 19:02interesting is
• 19:04when there is the interplay
• 19:06between
• 19:07processing the happy faces but
• 19:09having to engage the inhibitory
• 19:11controlled network, so having to
• 19:13no go on happy faces,
• 19:16We see this diminished bold
• 19:18response in the left superior
• 19:19frontal region.
• 19:21And this is typically seen
• 19:23like, in hap healthy adolescents,
• 19:25what you typically see is
• 19:26more recruitment of the prefrontal
• 19:28area with these appetitive faces.
• 19:31And so we're wondering if
• 19:32this might be signaling a
• 19:33little bit less of that
• 19:35top down prefrontal
• 19:36control.
• 19:38And when we look specifically
• 19:40at the ventral striatum, we
• 19:41actually see blunted
• 19:43response. So there's a disruption
• 19:45to that reward processing
• 19:47when they're having to engage
• 19:48in the in their inhibitory
• 19:49control.
• 19:52Notably, for all of these
• 19:53studies thus far,
• 19:55we don't know for sure
• 19:56if this is a consequence
• 19:58of their repeated cannabis use
• 20:00or a risk factor for
• 20:01heavy cannabis use. So that's
• 20:03something that we really need
• 20:04to look at in the
• 20:05in the longitudinal
• 20:06design.
• 20:09I wanted to highlight a
• 20:11few
• 20:12of our resting state functional
• 20:14connectivity.
• 20:15So for those of you
• 20:16who don't do imaging work,
• 20:18this is when,
• 20:19the teenagers or young adults
• 20:21are just at rest. So
• 20:22they're relaxing in the scanner,
• 20:24and we're just recording what
• 20:26their, brain is doing in
• 20:28kind of the natural state
• 20:29or at rest.
• 20:31The first analysis looked at
• 20:33the default mode network at
• 20:34rest. And, typically,
• 20:37there's a few different ways
• 20:38you can analyze this. For
• 20:39for these studies, we we
• 20:40did a seed based analysis.
• 20:42So we kinda picked
• 20:43a hub of the neural
• 20:45network that we were interested
• 20:46in and saw how it
• 20:48was kind of correlated or
• 20:50coactivating
• 20:51with other areas.
• 20:53In the default mode network,
• 20:54which is that self differential
• 20:56network, we see actually diminished
• 20:59intranetwork connectivity.
• 21:01So
• 21:02the posterior cingulate in this
• 21:04case is the seed, and
• 21:05we saw diminished,
• 21:07connectivity with the precuneus
• 21:09and the hessicles and parahippocampal
• 21:12gyri,
• 21:13and then actually some kind
• 21:15of abnormal increased connectivity between
• 21:17the posterior cingulate and cerebellar
• 21:20regions.
• 21:21So the cerebellum usually isn't
• 21:22part of that default mode
• 21:24network.
• 21:25This pattern of,
• 21:27diminished intranetwork and increased intranetwork
• 21:31connectivity
• 21:31was related to poor selective
• 21:34attention and verbal memory,
• 21:36and these are cognitive tasks
• 21:37that we see oftentimes
• 21:39impaired in the cannabis users,
• 21:40including in the sample.
• 21:44Next, we're interested in the
• 21:45dorsal attention network because that's
• 21:47a top down attention network
• 21:49that has been linked with
• 21:50things like selective attention and
• 21:52sustained attention.
• 21:54And what we found was,
• 21:55again, reduced,
• 21:57intra network connectivity
• 21:58between the right inferior parietal
• 22:00region and the anterior insula.
• 22:04And this pattern of diminished
• 22:05connectivity
• 22:06was linked with increased cannabis
• 22:08use in the past year,
• 22:09shorter periods of abstinence, and
• 22:11increased symptoms of cannabis use
• 22:13disorder.
• 22:15And finally, the, we looked
• 22:17at relationships between frontal and
• 22:19limbic networks because, again, we're
• 22:21kind of interested in this
• 22:22interplay
• 22:23between executive functioning and affective
• 22:25regulation
• 22:27and found actually evidence of
• 22:29increased connectivity
• 22:31between,
• 22:32the right and a rostral
• 22:34anterior cingulate, the bilateral kind
• 22:36of relationship as well as
• 22:37with the left amygdala
• 22:39and the left insula, so
• 22:41other areas within this kind
• 22:42of emotion regulation network.
• 22:45And this increased connectivity at
• 22:47rest
• 22:48was linked with increased depressive
• 22:50symptoms, which we've also seen
• 22:52kind of in the depression
• 22:53literature.
• 22:55Notably,
• 22:56the sample did not have
• 22:57diagnoses of depression.
• 23:00Okay. So
• 23:02this pattern of results,
• 23:04overall made us start thinking,
• 23:06you know, but this is
• 23:07interesting within these specific networks,
• 23:09but it's a little limited
• 23:11because we're only looking at
• 23:12one network at a time.
• 23:13What about intrinsic connectivity
• 23:15across networks?
• 23:17So one of my current
• 23:18graduate students, Cal Baike,
• 23:21noted here,
• 23:22wanted to use more network
• 23:24topology and network based statistics
• 23:26to look at the impact
• 23:27of cannabis on,
• 23:30intrinsic conductivity
• 23:32at rest across multiple networks
• 23:34simultaneously.
• 23:36Just to, highlight a couple
• 23:38of terms that I'm gonna
• 23:39be referring to,
• 23:42so this network topology is
• 23:43really looking at the functional
• 23:45brain activity, look
• 23:47highlighting the flow of information.
• 23:49Global efficiency
• 23:51refers to, for the most
• 23:53part, global strength of connections
• 23:55or representing how quickly information
• 23:57can flow in a network.
• 23:59And a sortativity is the
• 24:00degree to which nodes are
• 24:02more likely to be neighbors
• 24:03with similar nodes or
• 24:05might represent more of a
• 24:06degree or clustering coefficient.
• 24:10The, intrinsic
• 24:11networks that we are interested
• 24:12in are the frontal parietal
• 24:14control network, which underlies executive
• 24:16functioning and planning,
• 24:19to some extent working memory,
• 24:21the ventral attention network, which
• 24:23is more bottom up attention,
• 24:24and that dorsal attention network,
• 24:26which is top down, the
• 24:28default mode network, which is
• 24:29that self self referential network.
• 24:31And then we also add
• 24:32in the somatic motor network
• 24:34because there's some evidence of
• 24:35abnormalities in cannabis users there.
• 24:40Overall, when we looked at
• 24:41the network topology, so that
• 24:43assortativity
• 24:44and,
• 24:45global efficiency measures, we saw
• 24:47that just cannabis group status
• 24:49was not significantly linked,
• 24:52but more of the nuanced
• 24:53measures of cannabis use, including
• 24:55past year dose,
• 24:57the sex of the user,
• 24:58age of onset, and length
• 24:59of abstinence were significantly related.
• 25:03So more specifically,
• 25:06past year cannabis use,
• 25:09was so increased past year
• 25:10use was linked with increased
• 25:12global efficiency
• 25:14in that frontal parietal control
• 25:16network.
• 25:17And this was primarily driven
• 25:18by the male cannabis users
• 25:20as we did see a
• 25:21significant interaction.
• 25:23And we found that in
• 25:24those male users, past year
• 25:26use was also related to
• 25:28increased global efficiency in the
• 25:30van network and increased assertivity
• 25:33in the somatic motor network.
• 25:36We found in the whole
• 25:37sample that a shorter length
• 25:38of abstinence from cannabis
• 25:41was related to increased whole
• 25:43brain as well as,
• 25:44ventral attention network assertivity.
• 25:47And there was this kind
• 25:49of small caveat
• 25:50of within, again, the male
• 25:52cannabis users
• 25:53in earlier of age of
• 25:55onset
• 25:56was actually linked with decreased
• 25:58ventral attention and somatic motor,
• 26:01network assertivity.
• 26:04Generally,
• 26:05the effect sizes were in
• 26:06the medium range, though they
• 26:09ranged from small to large.
• 26:13The next step was to
• 26:15look at the network based
• 26:16statistics, and so we could
• 26:18use kind of continuous,
• 26:21predictors
• 26:21of of inter and intra
• 26:24network,
• 26:25net,
• 26:26edges and strength of connections.
• 26:28And what we found again
• 26:29is that it really was
• 26:31past year use was the
• 26:32most robust,
• 26:34and consistent predictor.
• 26:35So increased use was related
• 26:37to increased connectivity.
• 26:39And this was primarily
• 26:41between network edges
• 26:43between the van, the default
• 26:45mode network, the frontal parietal,
• 26:47and the somatic motor networks,
• 26:49and this occurred at multiple
• 26:50thresholds.
• 26:52Although we couldn't examine sex
• 26:54effects, it's notable that the
• 26:55prior ICN analyses was more
• 26:57consistent in the males.
• 26:59So we suspect that this
• 27:00is primarily driven by them.
• 27:03We kinda look in. One
• 27:05thing that's notable that I
• 27:06haven't really seen much in
• 27:07the literature
• 27:09is that there seems to
• 27:10be this kind of almost
• 27:11right hemisphere dominance pattern for
• 27:14one thing. Although, you know,
• 27:15it's seen in the left
• 27:16and right, but that that
• 27:17just kind of stood out
• 27:18to me.
• 27:20And a lot of this,
• 27:21inter network functional coupling, there's
• 27:24a lot of overlap within
• 27:26that, interior cingulate region, which
• 27:29which is a part of
• 27:30several of these networks.
• 27:32It's notable that this is
• 27:33after that two to three
• 27:35weeks of abstinence,
• 27:36and we're interpreting this as
• 27:38a more disorganized connectome
• 27:40potentially due to this, you
• 27:43know, multiple hits of exogenous
• 27:45cannabis exposure, which might disrupt
• 27:48kind of the GABA
• 27:49glutamate balance
• 27:50and, excito you know,
• 27:54excitation levels
• 27:56and create connections that are
• 27:57a bit artificial.
• 27:59It might also represent increased
• 28:01switching between networks at a
• 28:03restful state, and so these
• 28:05are areas that we wanna
• 28:06continue to look into.
• 28:12So I don't know.
• 28:15One thing that we discussed
• 28:16is potentially asking questions kind
• 28:18of at midway points.
• 28:20I don't know if
• 28:21this is Yeah. Actually, Krista,
• 28:23I had put in a
• 28:24a question in the chat.
• 28:25Okay. I'm sure you were
• 28:27you were, focusing on your
• 28:29presentation.
• 28:29The question I had for
• 28:31you was,
• 28:32so it sounds like if
• 28:34if I read your first
• 28:35slide correctly,
• 28:39despite
• 28:40three weeks of abstinence,
• 28:42these,
• 28:44young adults and adolescents still
• 28:46showed
• 28:50differences in cognitive test performance.
• 28:52Is that is that right?
• 28:54That's correct. And so my
• 28:56question to you is, do
• 28:57you think it's
• 28:58if if you waited long
• 29:00enough
• 29:01that those
• 29:02those,
• 29:03cognitive deficits would disappear? Because
• 29:05in our hands, we've
• 29:07we've
• 29:08kept the dials at,
• 29:10abstinent for
• 29:12four weeks and now eight
• 29:13weeks.
• 29:14And,
• 29:16some of them don't recover,
• 29:17some of them do recover.
• 29:18And I I remember the,
• 29:20you know, important study by,
• 29:22I think, Pope
• 29:24in in when he went
• 29:26in the study at Mass
• 29:27General where they took
• 29:28college students and hospitalized them
• 29:30for a month.
• 29:31And at the end of
• 29:32twenty eight days, they didn't
• 29:33see any differences.
• 29:35So I'm curious.
• 29:36Do you
• 29:38my question is, do you
• 29:39expect that these deficits will
• 29:41go away completely if you
• 29:43just wait long enough?
• 29:45I think that's
• 29:46entirely possible.
• 29:49We do have some evidence
• 29:50that
• 29:51like, for example, the verbal
• 29:53memory
• 29:54deficits, we do see at
• 29:55that baseline session.
• 29:57But by two weeks of
• 29:59abstinence,
• 30:00they're they're no longer significantly
• 30:02different.
• 30:03We've also saw that type
• 30:04of recovery with Susan Tapert's,
• 30:06like, teenage data where we
• 30:07got we put them through
• 30:09a month of abstinence as
• 30:11well. So there is some
• 30:12longitudinal
• 30:13evidence of recovery of function.
• 30:17I still don't know of
• 30:18any studies, and there I
• 30:20think I've seen studies being
• 30:22reviewed, so I don't know.
• 30:23You know, I'm hoping that
• 30:24they'll be coming out,
• 30:27of repeated neuroimaging.
• 30:30So the the behavioral kinda
• 30:31downstream
• 30:32cognitive effects,
• 30:34we certainly see some recovery
• 30:36in
• 30:37those,
• 30:38early, you know, even within
• 30:39a few days to two
• 30:41weeks of sustained abstinence.
• 30:44And then what I don't
• 30:45know is the structural differences
• 30:48and the, bold response differences
• 30:50and and also this more
• 30:52complex sustained attention
• 30:54and some of the inhibitory
• 30:55control deficits that we still
• 30:57see despite
• 30:59three to four weeks of
• 31:00abstinence
• 31:01if they fully recover,
• 31:03you know, if we just
• 31:03follow them for another month
• 31:05or another two months.
• 31:07I I hope so.
• 31:10And, you know, in in
• 31:11in the clinic,
• 31:13part of the challenge is
• 31:14even getting people to wanna
• 31:16abstain for that long. You
• 31:17know? So I think there's
• 31:18always a cohort that we're
• 31:19concerned about that we can't
• 31:20get abstinent for even a
• 31:22few days.
• 31:23But, certainly, when I'm talking
• 31:25to the larger
• 31:26group of users and and
• 31:28especially teenagers and parents,
• 31:30I wanna give them that
• 31:31hope that sustained abstinence, there
• 31:33should be some recovery, especially
• 31:36if the abstinence is occurring
• 31:38during the teenage years.
• 31:40I think another question though
• 31:42is,
• 31:44do people get back on
• 31:46the trajectory
• 31:47that they would have been
• 31:48on if they really disrupt,
• 31:50you know, the the full
• 31:51kind of adult like, multiple
• 31:53years of that adolescent development?
• 31:56But that's a that's a
• 31:57really tricky question. I know
• 31:58that Madeline Maya had done
• 32:00that work in Dunedin. And
• 32:02if you if you
• 32:04if you believe her,
• 32:06her results, it seems like
• 32:07people don't recover despite
• 32:10quitting.
• 32:11Yeah. And that's really the
• 32:12only data point we have,
• 32:13and it's a super small
• 32:14sample.
• 32:16You know, at the end
• 32:17of the day, it started
• 32:18as a large sample, but,
• 32:20the the final sample of
• 32:21kind of comparing early adolescent
• 32:23onset to later onset, it's
• 32:25a relatively small one. So
• 32:27one of to me, one
• 32:28of the big questions with
• 32:29a the ABCD data will
• 32:31be, you know, following people's
• 32:33trajectory.
• 32:34And because we have multiple
• 32:36phenotype sessions before the onset
• 32:38of cannabis use at all
• 32:40or other substance use,
• 32:42and we can match them
• 32:44with people even in a
• 32:45twin controlled design or sibling
• 32:47controlled.
• 32:48We can match them to
• 32:49see, you know, did they
• 32:50if they stopped using, do
• 32:52they get back to the
• 32:53trajectory we would have predicted,
• 32:54or are they kinda diminished
• 32:56in adulthood
• 32:57even despite recent abstinence abstinence?
• 33:01Great. Thanks.
• 33:02Yeah. Any other questions from
• 33:04anyone else?
• 33:07Now is it you can
• 33:08ask now, or you can
• 33:09wait till the end.
• 33:14Alright. I'll throw it a
• 33:15little bit more, and then
• 33:16we can
• 33:17check-in. So maybe you can,
• 33:20you can continue, and then
• 33:21we can give people time
• 33:22at the end to ask
• 33:23more questions. Thank you. Sounds
• 33:25good.
• 33:28Can you see again? Yes.
• 33:30Okay. Good.
• 33:32Okay. So one of the
• 33:33areas that I was interested
• 33:35in that I wanted to
• 33:36share at least a a
• 33:37little bit of the, the
• 33:39results with you
• 33:40is,
• 33:42there there's a lot of
• 33:43individual differences
• 33:44in cannabis effects,
• 33:46and we know that with
• 33:47alcohol and a lot of
• 33:48other things too. You know,
• 33:49there's some folks,
• 33:51like you were saying in
• 33:52the clinic or or that
• 33:53you see that that recover
• 33:55a great deal and there's
• 33:56others that don't. We don't
• 33:57really understand, you know, all
• 33:59the moderators of the drug
• 34:00effects.
• 34:01One thing that I got
• 34:02interested in was aerobic exercise.
• 34:05The main reason is that
• 34:06it does acutely release endocannabinoids.
• 34:09So if it was kind
• 34:11of bolstering that system, that
• 34:12might be a nice mechanism
• 34:14through which we could mitigate
• 34:15some of the cannabis negative
• 34:17effects.
• 34:19But it also releases vascular
• 34:20growth factors and brain derived
• 34:22neurotrophic factor, which are also
• 34:23good for the brain.
• 34:25There's a good large literature
• 34:27linking
• 34:28increased aerobic fitness with better
• 34:30cognitive functioning, especially in verbal
• 34:32memory and executive functioning in
• 34:35middle and older adults because
• 34:36it's been used in the
• 34:37aging literature for quite a
• 34:39while,
• 34:39less has been known in
• 34:41teenagers and young adults.
• 34:45First off, we looked at
• 34:47some behavioral markers.
• 34:49Aerobic fitness has been
• 34:52validated in the treatment of
• 34:53depression. So we wanted to
• 34:54look at depressive symptoms as
• 34:56well as self reported symptoms
• 34:58of things like disinhibition
• 35:00and emotion processing.
• 35:02First off, we did see
• 35:03that increased cannabis use,
• 35:06was related to increased depressive
• 35:08symptoms, increased self reported disinhibition
• 35:11problems
• 35:12kind of in people's everyday
• 35:13life,
• 35:14as well as increased response
• 35:16time on an emotion recognition
• 35:18task.
• 35:20This is controlling for comorbid
• 35:21alcohol, nicotine use, and demographics
• 35:23that might be linked.
• 35:25Surprisingly, we didn't see results
• 35:27with aerobic fitness either independently
• 35:29or interacting with cannabis
• 35:31with these outcomes.
• 35:33That might be because we
• 35:35excluded for major psychiatric comorbidities.
• 35:38So I wouldn't generalize this
• 35:40to a more,
• 35:41clinically
• 35:42relevant or salient
• 35:45population. I'd I'd like to
• 35:47see,
• 35:48you know, people with more
• 35:49comorbid,
• 35:50affective, or,
• 35:52externalizing
• 35:53disorders,
• 35:54what the relationship would be.
• 35:57Again, we saw that increased
• 35:58cannabis use was related to
• 36:00poor working memory,
• 36:02sequencing, and psychomotor
• 36:03speed after those three weeks
• 36:04of abstinence and controlling for
• 36:07aerobic fitness.
• 36:08And aerobic fitness on its
• 36:09own are was linked with
• 36:11increased
• 36:12visual memory, verbal fluency, and
• 36:14sequencing ability. And I wanna
• 36:16note that the effect sizes
• 36:17were large for this. So
• 36:19this was a a nice
• 36:20robust effect of aerobic fitness
• 36:22for cognition
• 36:23in a very healthy,
• 36:25young
• 36:26group without metabolic conditions.
• 36:29And we also saw an
• 36:31interaction between aerobic fitness and
• 36:32cannabis use in predicting
• 36:34inhibitory control and psychomotor speed.
• 36:37In that, the cannabis users
• 36:39that were more highly fit
• 36:41did better on these cognitive
• 36:43tasks compared to the low
• 36:44fit cannabis users.
• 36:46So that is some nice
• 36:47evidence that it might,
• 36:49be something that of of
• 36:50a resilience marker at the
• 36:51very least and something that
• 36:53we could perhaps harness as
• 36:54an intervention.
• 36:57This is a little
• 36:59tricky,
• 37:00but we looked at,
• 37:02whole kinda whole brain
• 37:04structural MRI. In this case,
• 37:06it was,
• 37:07volumes,
• 37:09And there's
• 37:10two interactions going on here.
• 37:12First off, there's an interaction
• 37:13between cannabis and sex and
• 37:15volume
• 37:16that I commonly see if
• 37:18you kind of do this
• 37:19cross sectional sample of, an
• 37:21age range where there's a
• 37:22lot of pruning going on,
• 37:24and girls
• 37:26are about two years earlier
• 37:27in their pruning versus boys.
• 37:31But the cannabis using males
• 37:33had smaller regions in these
• 37:35areas, whereas the females actually
• 37:37had larger
• 37:39volumes compared to their same
• 37:40sex controls.
• 37:42And the regions were primarily
• 37:44in the frontal lobe, so
• 37:45left lateral frontal area, caudal
• 37:48middle frontal,
• 37:49frontal, and then right
• 37:51superior frontal and,
• 37:53as well as some kind
• 37:54of temporal and parietal regions.
• 37:57This increased or decreased volumes
• 38:00was not advantageous
• 38:01for either group, so both
• 38:02of them were
• 38:04linked with poor cognition.
• 38:07Notably,
• 38:08improved aerobic fitness was related
• 38:10to larger volumes in frontal
• 38:12parietal cerebellar
• 38:13as well as caudate regions.
• 38:16And there was an interaction
• 38:17with cannabis and aerobic fitness
• 38:19in the left superior temporal
• 38:21region
• 38:21and that the cannabis users
• 38:23actually had a less robust
• 38:25relationship between their aerobic fitness
• 38:27and volume in this region,
• 38:29maybe showing, like, less of
• 38:31a benefit of the aerobic
• 38:32fitness. Maybe the cannabis use
• 38:34is kinda
• 38:35disrupting some of the positive
• 38:36effects of aerobic fitness there
• 38:38in that case.
• 38:39But, overall,
• 38:41our conclusion from this is
• 38:42that at least in healthy
• 38:44people without metabolic conditions, it
• 38:46does look like aerobic fitness
• 38:48has links with,
• 38:50positive brain outcomes, both in
• 38:52cognition and brain structure,
• 38:54and might be a good
• 38:55thing to pursue for supporting
• 38:57neurocognition
• 38:58in regular cannabis users.
• 39:01And I'll also note, a
• 39:02lot of people ask, well,
• 39:03why would it only be
• 39:04effective for cannabis? Not all
• 39:06call it. No. I suspect
• 39:08it'd be, beneficial
• 39:09for
• 39:10pretty much anyone. You know,
• 39:12it might be kind of
• 39:12a cheap,
• 39:14way to boost brain function.
• 39:16Okay.
• 39:18So, overall,
• 39:20the recent recent cannabis use
• 39:22exposure during adolescence and into
• 39:24young adulthood has been linked
• 39:26in modest differences in cognitive
• 39:28function, brain structure, as
• 39:30well as bold response to
• 39:32emotional stimuli
• 39:34as well as inhibitory control
• 39:35and at rest.
• 39:38We see a lot of
• 39:38dose dependent relationships.
• 39:41Adolescence and early onset of
• 39:43use, is a vulnerability marker,
• 39:45and sex might moderate a
• 39:47lot of these effects.
• 39:48Across all my studies, what
• 39:50the pattern
• 39:51kind of emerges is that
• 39:52males might have greater effects
• 39:54and kind of cold cognition,
• 39:56whereas females
• 39:57seem to show more of
• 39:58this vulnerability
• 40:00towards things like depressive symptoms,
• 40:03lower affective state, or emotion
• 40:06regulation.
• 40:08The study effect sizes are
• 40:09generally small to medium.
• 40:11When you look at meta
• 40:12analyses that really combine studies,
• 40:14the the effect sizes are
• 40:16generally small, and some of
• 40:17them are null.
• 40:19So, you know, that might
• 40:20be to the heterogeneity
• 40:21of of the samples,
• 40:22or it might be that
• 40:24that's what the real effect
• 40:25is.
• 40:26Aerobic exercise might produce some
• 40:28resilience to the cannabis effects,
• 40:30and there is, like, like,
• 40:31we were talking at the
• 40:32start, hopeful evidence of some
• 40:34neurocognitive
• 40:35recovery with abstinence.
• 40:37I've seen it in my
• 40:38own kind of longitudinal mini
• 40:40neuropsych battery,
• 40:42and some other folks have
• 40:43seen recovery
• 40:44as rapid as three to
• 40:45fourteen days. But we really
• 40:47do need that repeated longitudinal
• 40:49imaging,
• 40:50and we also need the
• 40:52longer term trajectory analysis over
• 40:55development.
• 40:57The other thing is, of
• 40:58course, causality questions.
• 41:00You know, there's been,
• 41:02the bottom line is that
• 41:03there's been some retrospective
• 41:05analysis of larger twin studies
• 41:07where you controlled for twin
• 41:08status.
• 41:09And if you looked at
• 41:11cannabis use, it did longitudinally
• 41:13predict IQ, but then when
• 41:14you controlled for twin status,
• 41:16that went away in some
• 41:17of those studies,
• 41:19suggesting that perhaps
• 41:21there's a shared genetic load
• 41:22or environmental load that's really
• 41:24predicting,
• 41:25you know, the trajectory towards
• 41:27becoming a regular cannabis user.
• 41:29So
• 41:30that's why we really do
• 41:32need the more, national prospective
• 41:34longitudinal
• 41:35studies like the ABCD study.
• 41:37I know Yale is involved
• 41:39with this, so I I
• 41:40won't spend too much time
• 41:41on the methods, but we
• 41:43collected eight over eleven thousand
• 41:45nine and ten year olds
• 41:46across twenty one research sites.
• 41:48Most importantly,
• 41:50at at baseline and at
• 41:52one year, two year, they're
• 41:53very substance naive. So they're
• 41:55very young. They're nine to
• 41:57eleven years old.
• 41:58And, one of my former
• 41:59graduate students here, Tasha Wade,
• 42:01who is an assistant professor
• 42:02at UCSD,
• 42:04did a recent analysis looking
• 42:06at ABCD youth that had
• 42:08hair toxicology.
• 42:10And so,
• 42:12about a hundred and twenty
• 42:13three with and without
• 42:15self reported cannabis use, and
• 42:16they were matched on all
• 42:18the demographics.
• 42:19Controlling for baseline cognition,
• 42:22what she found was that
• 42:23the being a cannabis user
• 42:25at all was linked with
• 42:26poor visual memory,
• 42:28and then self reported past
• 42:29year cannabis use was linked
• 42:31with,
• 42:32lower visual memory and working
• 42:34memory.
• 42:35And then interestingly,
• 42:37the hair toxicology analysis
• 42:39of carboxy THC, so the
• 42:41metabolite from using delta nine,
• 42:43was linked with poor nonverbal
• 42:45vocabulary, inhibitory control, and visual
• 42:48memory. So it kinda added
• 42:49the sensitivity
• 42:51to pick up on some
• 42:52relationships.
• 42:53Part of that is most
• 42:54likely that we're getting a
• 42:56little underreporting
• 42:58in the self report in
• 42:59this very young, normative cohort.
• 43:02One thing that's caught my
• 43:03eye that I really wanna
• 43:04be keeping an eye on
• 43:05is that,
• 43:06although it wasn't statistically
• 43:08significant,
• 43:09the extent of CBD level
• 43:11in the hair
• 43:12was positively linked with visual
• 43:14memory in this case. So
• 43:16this might just be a
• 43:17slight early sign that that
• 43:19CBD use might mitigate some
• 43:21of the THC effects.
• 43:25But what about the mechanism?
• 43:26So this is where
• 43:28I'm gonna get in a
• 43:29little bit to the,
• 43:31circulating endocannabinoid,
• 43:33research.
• 43:34And for the sake of
• 43:35time,
• 43:35I'm gonna skip over a
• 43:37little bit of the mechanisms
• 43:38here because I I think
• 43:39your group has a good
• 43:41sense of that.
• 43:43But to just,
• 43:44really emphasize that this is
• 43:46peripheral
• 43:47levels of endocannabinoid,
• 43:50concentrations.
• 43:52These have been linked in
• 43:53both animal and adult studies,
• 43:55but there really hasn't been
• 43:56any human teenage work to
• 43:57date.
• 43:58So this is a cohort
• 44:00within the ABCD study that
• 44:01I've been, trying to collect
• 44:03the circulating endocannabinoids
• 44:05from.
• 44:06Importantly, we did measure state
• 44:08based factors that have been
• 44:09linked with endo levels, and
• 44:10we statistically
• 44:12analyzed that.
• 44:14The main thing here that
• 44:15I wanna say is that
• 44:16those circulating endos, and if
• 44:18I focus in on two
• 44:19AG and anandamide here,
• 44:21have were linked,
• 44:23significantly
• 44:23with brain volume in unique
• 44:25ways.
• 44:26So lower levels of two
• 44:28AG were linked with larger
• 44:29volumes in the parisor retalis,
• 44:32and this is a cognitive
• 44:33control region that should be,
• 44:35continuing to undergo
• 44:36significant pruning.
• 44:39Lower levels of anandamide
• 44:41were linked with lower volumes
• 44:42in the insula, the cingulate,
• 44:44the occipital cortex,
• 44:46and increased volumes of the
• 44:47caudal middle frontal, which again
• 44:49is another region that really
• 44:50should be going on ongoing
• 44:52pruning.
• 44:54PEA had its own
• 44:56relationships across the board. It
• 44:58was lower levels of PA,
• 45:00lower level lower volumes in
• 45:01the amygdala, insula, cingulate,
• 45:04as well as parietal and
• 45:05occipital regions, and that might
• 45:07actually demonstrate kind of reduced
• 45:09expansion because most of these
• 45:11are fairly,
• 45:12mature at this age range.
• 45:14And then OEA also had,
• 45:16significant relationships
• 45:18that overlapped a lot with
• 45:19the AEA and PA
• 45:21pattern, but in the opposite
• 45:23direction. So we can talk
• 45:24a little bit about what
• 45:25that might mean.
• 45:27Here, I wanna highlight some
• 45:28studies that found
• 45:30that circulating,
• 45:31an atomide and two AG
• 45:33as well as the lipid,
• 45:36modulators
• 45:37are linked with cognition.
• 45:39So lower two AG
• 45:40was actually linked with better
• 45:42visuospatial
• 45:43accuracy,
• 45:44might demonstrate a bit of
• 45:45a strength in the parietal
• 45:46cortex.
• 45:48In contrast, lower AEA was
• 45:50linked with poor working memory
• 45:52and processing speed,
• 45:53which makes me really wanna
• 45:55map that onto that frontal
• 45:56parietal network and connectivity as
• 45:58well as white matter function.
• 46:01PEA, again, interestingly linked with
• 46:04reduced visual spatial accuracy and
• 46:06math accuracy.
• 46:07And then OEA kind of
• 46:09behave once again overlapped in
• 46:11the same cognitive areas, but
• 46:12in the opposite direction. So
• 46:14I'm gonna leave that there,
• 46:16and we can come back
• 46:16to it.
• 46:18Finally,
• 46:19we looked at impulsivity
• 46:20and behavioral
• 46:22approach,
• 46:23kind of self reported symptoms,
• 46:25and found that lower two
• 46:27AG levels were linked with
• 46:28increased negative urgency in the
• 46:30females,
• 46:31but positive urgency in the
• 46:33males. Both of these are
• 46:34kind of this interplay of
• 46:36hot,
• 46:37affective,
• 46:38states that in that influence
• 46:40impulsivity
• 46:41and might map on to
• 46:42some of these
• 46:44emotional and cognitive control regions.
• 46:46And both reduced,
• 46:48anandamide and PEA levels were
• 46:50linked with increased lack of
• 46:52perseverance
• 46:53and lack of premeditation,
• 46:54which is more of this
• 46:55kind of cold sustained attention
• 46:57and planning areas.
• 46:59With OEA,
• 47:01we got a little smarter
• 47:02here, and we looked for
• 47:03some nonlinear relationships. We did
• 47:04for all of them. But
• 47:05OEA is the only one
• 47:06that had this nonlinear relationship
• 47:08where the midpoint level was
• 47:10actually linked with lack of
• 47:12perseverance
• 47:13similar to AEA and PEA,
• 47:16but lower levels were late
• 47:17linked with increased positive urgency.
• 47:22And, interestingly,
• 47:23both reduced AEA and two
• 47:25AG levels were linked with
• 47:27increased,
• 47:28risk of new onset low
• 47:30level substance use. In the
• 47:32case of AEA, it was
• 47:33linked with slightly heavier use
• 47:35compared to two AG, but
• 47:36this is something that we
• 47:37definitely wanna look at longitudinally.
• 47:41So the kind of preliminary
• 47:43conclusion here is that,
• 47:45you know,
• 47:46circulating endocannabinoids
• 47:48is really the only biomarker
• 47:49that we have available to
• 47:51us in the human teenager
• 47:53route, although there are some,
• 47:55you know,
• 47:57being developed including by your
• 47:58group that that I'd like
• 47:59to talk to you about.
• 48:01So
• 48:02we do see significant relationships
• 48:04with endophenotypes
• 48:05that we care about, such
• 48:06as, you know, the development
• 48:08of the prefrontal cortex and
• 48:09limbic system as well
• 48:11as cognitive function, inhibitory control.
• 48:14In the case of two
• 48:15AG, it looks like it's
• 48:17mapping on to,
• 48:18prefrontal volumes as well as
• 48:20affective driven impulsivity
• 48:22and very early experimentation.
• 48:25In the case of anandamide,
• 48:26we see,
• 48:28more cognitive functioning and as
• 48:29well as frontal parietal regions
• 48:32and potentially greater escalation of
• 48:34use at least in these
• 48:35very early,
• 48:36teen years.
• 48:38We do need a lot
• 48:39more evidence to try and
• 48:40understand the underlying mechanisms.
• 48:42You know, these circulating levels,
• 48:44there's some evidence that they
• 48:45map onto,
• 48:47some overflow from the brain.
• 48:48So it might be, you
• 48:49know, indirect measures of brain
• 48:51mechanisms,
• 48:52but primarily, it's peripheral functions.
• 48:54And perhaps these are meaningful
• 48:56and that they impact neurocognition
• 48:58and things like immune function,
• 49:00inflammation,
• 49:01adiposity, metabolic function, and as
• 49:03well as the gut brain
• 49:04kind of microbiome,
• 49:06communication
• 49:07pathway.
• 49:09So,
• 49:10you know, we we talked
• 49:11about it at the Gordon
• 49:11conference, but we definitely we
• 49:13we're doing pretty good with
• 49:14bench to bedside, and we
• 49:15need more of that. But
• 49:17it's also useful to do
• 49:18a little bit of that
• 49:19reverse translation and and talk
• 49:21about what we see,
• 49:22in the human side and
• 49:24try and understand from the
• 49:25preclinical side what that could
• 49:26mean.
• 49:28Just wanna acknowledge the UWM
• 49:30BrainLab.
• 49:31Lots of folks in it,
• 49:32graduate students, alumni,
• 49:34faculty, and the endocannabinoid substudy
• 49:36with the ABCD.
• 49:37And I will leave it
• 49:38at that so we can
• 49:39chat.
• 49:45Great. Thank you,
• 49:47Krista. There's a, there's a
• 49:50question in the,
• 49:51chat. I'll let, Anahita, maybe
• 49:53you can unmute yourself and
• 49:55ask the question, and I
• 49:56will follow-up through to that
• 49:58specific question.
• 50:00Sure. Thank you. Thank you
• 50:02for great talk. I'm Anahita,
• 50:04and I work with serial
• 50:06on in the in the
• 50:06cannabinoids and cannabinoids.
• 50:09I have two questions. The
• 50:10one that I put in
• 50:11chat is that is there
• 50:12like, when you look into
• 50:13the relationship between aerobic exercise
• 50:16and the cognitive benefits, is
• 50:17this a linear relationship, or
• 50:19is there some amount of
• 50:21exercise that you say, okay.
• 50:22This is good amount or
• 50:24optimal?
• 50:25Yeah. That's a great question.
• 50:27I don't feel like I
• 50:29would say that it's
• 50:30I think that there's a
• 50:31diminishing
• 50:32rate of return on the
• 50:34really
• 50:34higher end, like, ultra endurance
• 50:36athletes where you're getting,
• 50:39actually a lot of inflammation
• 50:41and perhaps cellular damage. So
• 50:43my guess would be that
• 50:45it's not perfectly linear, you
• 50:46know, that there there is
• 50:47that tipping point that it
• 50:49can become maybe problematic for
• 50:51brain health. I would say
• 50:52in the sample that I
• 50:53have, it's not quite big
• 50:54enough.
• 50:56But when I do a
• 50:57plot, I see a couple
• 50:58at the higher end drop
• 50:59down. It's just, like, not
• 51:01enough of a sample for
• 51:02me to prove it.
• 51:04But in in talking with
• 51:06our lab, like, those were
• 51:07the the, like, really
• 51:09intense almost over exercisers.
• 51:12Yeah. And I'd say that
• 51:13they also fell into
• 51:16we did exclude for eating
• 51:17disorders, but they almost fell
• 51:19into kind of impulsive exercise,
• 51:22you know, perhaps problematic eating
• 51:24patterns. Yeah. Yeah. So too
• 51:26much exercise is not healthy.
• 51:28Yeah. I mean, when I
• 51:29talk to my exercise physiology
• 51:31folks, they're like, that's definitely
• 51:33been shown. It's just not
• 51:34usually with neuroimaging.
• 51:36You know? Yeah. Okay. Thank
• 51:37you. And my second question
• 51:39is about the
• 51:40relationship between,
• 51:42lower to AGN and under
• 51:43my with early substance use.
• 51:45And I believe it was
• 51:47an ABCD study,
• 51:49if I'm right.
• 51:50Yeah, every substance use. So
• 51:52is it like cross section,
• 51:53like, at the same time
• 51:54that their levels were low,
• 51:56also they already started the
• 51:58substance use, or is it,
• 52:00like, before or after?
• 52:01Yeah. In that case, it's
• 52:03it's actually looking at just
• 52:05the time point after,
• 52:07so whether or not they
• 52:08had, like, a new onset
• 52:10after.
• 52:11After. So it's not the
• 52:12same time. So it's it
• 52:14cannot be because of that
• 52:16substance that they are using.
• 52:19Correct.
• 52:20Yeah. It's not perfect. Like,
• 52:22that analysis isn't perfect at
• 52:24at disentangling
• 52:25that, but the the use
• 52:26is very
• 52:27low. So we're really interpreting
• 52:29it more as, like, new
• 52:31onsets because it it's like
• 52:33they've had a few puffs
• 52:35of nicotine or they've had
• 52:36a few puffs of cannabis
• 52:38or some sips of alcohol.
• 52:40In the case of two
• 52:41AG with anandamide,
• 52:43they might have had, like,
• 52:43a full drink
• 52:45and a little bit more,
• 52:46but it it's still very
• 52:47low level use. Yeah. But
• 52:49our goal is now that
• 52:51we've we've collected some longitudinal
• 52:53data to look at exactly
• 52:54that to try and disentangle,
• 52:56certainly cannabis effects, but alcohol
• 52:58could also affect Yeah. The
• 53:00endocannabinoid levels. So we'll be
• 53:01looking at that kind of,
• 53:04more of a cross linked
• 53:05analysis to see more of
• 53:07the causal pathways.
• 53:09And may I ask what
• 53:10was your sample size?
• 53:12For that one, it's about
• 53:13four hundred and thirty. Okay.
• 53:15So that's a good spot.
• 53:16Yeah. But we're up to
• 53:18about eighteen hundred. The goal
• 53:20is is to get two
• 53:21thousand.
• 53:22Wow. That's that's wonderful.
• 53:24Yeah.
• 53:26It's Thank you so much.
• 53:27On that in the background.
• 53:28So yeah.
• 53:29Very exciting.
• 53:31Yeah. Thank you.
• 53:32Other questions?
• 53:36I just wanted to draw
• 53:37your attention, Krista, to this
• 53:38paper in JAMA Psychiatry that
• 53:40just came out, I think,
• 53:42last,
• 53:43last week showing that exercise
• 53:45did not
• 53:48seem to have an effect
• 53:50on hippocampal,
• 53:53volume in cannabis users.
• 53:56I thought that would be
• 53:58very relevant to your Yes.
• 54:00Absolutely. To your work. So
• 54:03I my I have a
• 54:04kind of more basic question
• 54:06that,
• 54:07that I've been struggling with,
• 54:09and that is in many
• 54:10of many grant applications
• 54:12we've considered, for example,
• 54:15we've flirted with the idea
• 54:17of collecting endocannabinoid
• 54:19levels, peripheral endocannabinoid levels. And,
• 54:22the the times that I
• 54:23proposed them, we often got,
• 54:25you know,
• 54:27pushback from reviewers saying, well,
• 54:30what is
• 54:31peripheral anandamide and two AG
• 54:33tell you about what's happening
• 54:34in the brain if you're
• 54:35already interested in the brain?
• 54:36And
• 54:37I'd be curious what, you
• 54:39know, what your take on
• 54:40that is.
• 54:42Yeah. No. I think that
• 54:43it's,
• 54:48it's one of those things
• 54:49where we're still figuring out,
• 54:51admittedly.
• 54:52You know? And
• 54:55the animal research does show
• 54:57that it it is highly
• 54:59correlated with the brain levels
• 55:00and, you know, and it's
• 55:01and some of it is
• 55:02overflow
• 55:03from the brain,
• 55:04but that needs to be
• 55:06reconfirmed. Like, I don't think
• 55:07that that's fully accepted across
• 55:09everyone by any stretch.
• 55:14And, you know, I think
• 55:15what's really compelling to me
• 55:16is that there's been a
• 55:17lot of research in adults
• 55:19linking these circulating levels with
• 55:21phenotypes that we're very interested
• 55:23in, like stress response,
• 55:25like in response to exercise,
• 55:28mood,
• 55:30executive functioning, memory.
• 55:32And so, you know, if
• 55:33it's if it's not brain
• 55:35levels, then it's telling us
• 55:37something about the peripheral health
• 55:39system that maybe we're ignoring
• 55:41too much.
• 55:42You know? And maybe,
• 55:44especially, you know, it's it's
• 55:45released on demand to stress,
• 55:47to pain, to exercise.
• 55:50And maybe what we're tapping
• 55:51into is more of this
• 55:52kind of stress and physical
• 55:54health characteristics
• 55:56that are that are very
• 55:58linked with brain health.
• 56:00So,
• 56:02you know, I guess it
• 56:03it depends a little bit
• 56:04on your tolerance for some
• 56:06ambiguity in science. You know,
• 56:07I think that the you
• 56:08know, I try and just
• 56:10set to set up the
• 56:11theory as much as possible
• 56:13and then test it and,
• 56:15and hopefully continue to collaborate
• 56:17really closely with more preclinical
• 56:20models that that could
• 56:22measure the peripheral levels with
• 56:23the brain and start to
• 56:25really inform us better about
• 56:26what exactly this means.
• 56:30But we're
• 56:32we're left a little bit
• 56:33with like, for me, if
• 56:34I find longitudinally
• 56:35that that the onset of
• 56:37cannabis
• 56:38and I have longitudinal data
• 56:40Right. And and it significantly
• 56:42reduces
• 56:43or increases
• 56:44or disrupts the endocannabinoid
• 56:45circulating system, and that predicts
• 56:48changes in cognition
• 56:49and brain structure.
• 56:52That's a pretty compelling model.
• 56:54That's pretty compelling evidence,
• 56:55and I put it out
• 56:57there. And I remain very
• 56:58open to someone saying, well,
• 57:00that that's not the brain.
• 57:01You're not measuring the brain.
• 57:02That's the peripheral system. Okay.
• 57:05Well, then that means that
• 57:06cannabis
• 57:07use is disrupting
• 57:09the peripheral system, including the
• 57:10immune system or maybe the
• 57:12gut microbiome.
• 57:13You know, what do we
• 57:14need to measure to tap
• 57:15into that better?
• 57:16Is it
• 57:17is it through these physical
• 57:18health aspects?
• 57:21Interesting. Do you know if
• 57:22anyone has actually looked at,
• 57:24at,
• 57:26CSF levels of endocannabinoids
• 57:29and related them to peripheral
• 57:30levels? They have. And so
• 57:32that research has been done
• 57:33and validated, and it's highly
• 57:35correlated.
• 57:35Okay. It's just we can't
• 57:37do spinal taps.
• 57:39I see there's another
• 57:40and yeah.
• 57:41Arnab?
• 57:43Hi. That was an amazing
• 57:45presentation.
• 57:47I'm a postdoc also working
• 57:49with, the synergy group. I
• 57:50just had a quick question
• 57:52about the,
• 57:53exercise study.
• 57:54Mhmm. Did you also control
• 57:56for BMI? I might have
• 57:57missed that. BMI and body
• 57:58fat percentage?
• 57:59Yes. I did. And so
• 58:01those the effects of aerobic
• 58:02fitness are,
• 58:04above and beyond BMI. And,
• 58:06interestingly, BMI,
• 58:08in this cohort wasn't
• 58:10particularly
• 58:11related because I looked at
• 58:13when I designed the study,
• 58:14I looked at BMI. I
• 58:15looked at nutrition,
• 58:16VO two max, and accelerometer
• 58:19data because
• 58:20there you know, there's people
• 58:21that are very sedentary,
• 58:24for example, but then do
• 58:25these, like, big workouts so
• 58:27their VO tax is okay,
• 58:28but they also have these
• 58:29huge bouts of sedentary behavior.
• 58:31So if you're getting into
• 58:32that field, all of those
• 58:33seem to be related in
• 58:35their own way to cognition.
• 58:37What I saw, at least
• 58:38in this cohort, that was
• 58:40the VO two max in
• 58:41particular
• 58:42was the most robust predictor.
• 58:43So that's kind of what
• 58:44I've used to look at,
• 58:46in relation to cannabis use.
• 58:49And just a follow-up, like,
• 58:50speculative question.
• 58:53If some someone stops using
• 58:54cannabis and then increases their
• 58:56VO two max by an
• 58:57exercise regimen, do you think
• 58:58it would have, like, an
• 58:59increased effect or beneficial effect?
• 59:03Like, more than someone who
• 59:05didn't stop cannabis use?
• 59:09You know, statistically,
• 59:10probably, you know, because we
• 59:11know when,
• 59:14you have an opportunity to
• 59:15see a bigger improvement,
• 59:17that effect, you know, tends
• 59:19to be more statistically significant.
• 59:21So, yeah, I I would
• 59:23suspect that they'd they'd be
• 59:25particularly benefit. Also,
• 59:27at least in theory, again,
• 59:28we don't have a lot
• 59:29of evidence in humans that
• 59:31cannabis use results in dysregulation
• 59:33of anandamide and two AG.
• 59:35But
• 59:36if part of the mechanism
• 59:37there is is reregulating
• 59:39that and having an upregulation
• 59:40of the c b one
• 59:41receptors and just having better,
• 59:43signaling,
• 59:45then I would think they
• 59:46would benefit more.
• 59:48But that's my next grant.
• 59:50You know, I have to
• 59:51write the, like, clinical trial.
• 59:52ABCD took over my life,
• 59:54so I haven't
• 59:55been Thank you so much.
• 59:57Yeah. Thank you. Nice to
• 59:58meet you.
• 60:00Thank you very much, Krista.
• 01:00:03We are,
• 01:00:05you know, it's so great
• 01:00:06that you were able to
• 01:00:07do this at, you know,
• 01:00:09and I'm sure everyone has
• 01:00:11really enjoyed this. And, again,
• 01:00:13the the talk is recorded,
• 01:00:15and it's gonna be available
• 01:00:16on our on our website.
• 01:00:17So I'm sure people are
• 01:00:18gonna look at it,
• 01:00:21in,
• 01:00:22in in the months to
• 01:00:23come. So I really appreciate,
• 01:00:25and I I'm gonna be
• 01:00:26in touch with you to
• 01:00:27talk to you about potential,
• 01:00:29collaboration.
• 01:00:30So Yeah. I wanted I
• 01:00:31wanted to hear more about
• 01:00:32your thoughts about this kind
• 01:00:34of blunting,
• 01:00:36affect
• 01:00:37Yeah. Actually, very quickly,
• 01:00:40in studies that we've, you
• 01:00:41know, we began doing studies
• 01:00:42with, IBTHC
• 01:00:44about in nineteen ninety seven.
• 01:00:47And we initially started off
• 01:00:49doing work with people who
• 01:00:50are using maybe
• 01:00:52once a month, once a
• 01:00:53week. I wouldn't call them,
• 01:00:54you know, regular cannabis users.
• 01:00:56And across
• 01:00:58cognition,
• 01:00:59cognitive measures,
• 01:01:01endocrine measures, neurochemical measures, electrophysiological
• 01:01:05measures,
• 01:01:06they all had a blunted
• 01:01:07response to THC.
• 01:01:09And our interpretation of that
• 01:01:10blunted response
• 01:01:12was either they had a
• 01:01:13blunted response to begin with
• 01:01:15as there's something different about
• 01:01:16them
• 01:01:17at, the very outset or
• 01:01:19that this was a consequence
• 01:01:21of even limited exposure to
• 01:01:23cannabis. And what we do
• 01:01:24know about the endocannabinoid
• 01:01:26system
• 01:01:27is that it's it's highly
• 01:01:29dynamic and adaptive. So, you
• 01:01:31know, within
• 01:01:32few exposures, it can change.
• 01:01:34And likewise,
• 01:01:35within few days of abstaining,
• 01:01:37it can also change. So,
• 01:01:40that so that's my
• 01:01:43working hypothesis right now that
• 01:01:44even minimal exposure can result
• 01:01:47in
• 01:01:47in,
• 01:01:48in a down regulation and
• 01:01:50desensitization
• 01:01:51of the system.
• 01:01:52Mhmm.
• 01:01:53Mhmm. Yeah. I think that
• 01:01:55that tracks. I am interested
• 01:01:57in a b c d
• 01:01:57too with the very low
• 01:01:58level users because we all
• 01:02:00exclude them.
• 01:02:02Interesting.
• 01:02:03You know, I could see
• 01:02:03especially if someone has, like,
• 01:02:05perhaps
• 01:02:06little bit lowered or diminished
• 01:02:08signaling and they're using just
• 01:02:09a little bit
• 01:02:10to, like, bolster it. I
• 01:02:11could see that actually having
• 01:02:13a positive effect on some
• 01:02:14of these outcomes.
• 01:02:17Or it it could be
• 01:02:19you know, it's just it's
• 01:02:20it's also detrimental, but it
• 01:02:22to a lesser extent, you
• 01:02:23know, we know we know
• 01:02:25almost nothing about those folks.
• 01:02:27And it's a lot of
• 01:02:28them. It's millions and millions
• 01:02:29of people that is like
• 01:02:31that. That. And it's only
• 01:02:32gonna get more and more.
• 01:02:33Yeah. Yeah. Well, thank you
• 01:02:35so much. It was really
• 01:02:36nice to meet all of
• 01:02:37you. Thank thank you. And,
• 01:02:39next month, we have,
• 01:02:41Martha DeForti from the Institute
• 01:02:43of Psychiatry.
• 01:02:44And the following month, we
• 01:02:45have Ryan Vandree who's gonna
• 01:02:47be talking about delta eight
• 01:02:49THC, which,
• 01:02:51which is, also an interesting
• 01:02:53compound. So thanks, very much,
• 01:02:55Krista. We'll be in touch.
• 01:02:58Bye. Week, guys. Thank you.