Yale Psychiatry Grand Rounds: November 11, 2022

November 14, 2022

Information

"Recreational and Medical Cannabis: Potential Implications on Cognition and Clinical Outcomes"

Jodi Gilman, PhD, Associate Professor, Harvard Medical School/Massachusetts General Hospital; Director of Neuroscience, Center for Addiction Medicine

ID9085

To CiteDCA Citation Guide

00:00Thank you. Very much.
00:01Thanks so much for that Nice introduction.
00:05It's really an honor to be here.
00:06And I was just talking to
00:08some folks before the talk.
00:09I've known folks from Yale
00:11since I was a graduate student,
00:13and I've always admired them.
00:14So it's nice to be here giving my own talk.
00:17So I'm going to cover a lot today.
00:21I just to give you an outline
00:22of what I'd like to talk about.
00:24I'd like to talk about some background
00:26about cannabis and the brain and how
00:29the landscape of cannabis and cannabis
00:31itself is changing and just rapidly changing.
00:33The product types, the the the,
00:36the characteristics of people
00:37using it are are,
00:38are dramatically changing.
00:39Then I'd like to talk about some of
00:42my work on cannabis and cognition and
00:44adolescent adolescents and young adults
00:46and talk about a super cool clinical
00:48trial that we did with adolescence.
00:51Then I'd like to talk about.
00:52Umm.
00:53The medicinal aspects of cannabis,
00:56which a lot of my work focuses on now
00:59because it's just such a hot topic right
01:01now about whether cannabis is a medicine,
01:04how it can be conceptualized as a medicine,
01:06does it work as a medicine?
01:08And then finally,
01:09I want to talk about some of my
01:12acute THC administration paradigms
01:15where we're looking at the problem
01:17of cannabis impaired driving and
01:19whether we can detect cannabis
01:20impairment from brain imaging.
01:22So it's sort of a.
01:24A lot to cover, so I'll get right into it.
01:27So what is cannabis?
01:29So, so cannabis is simply a plant.
01:32It is a dry shredded mix of leaves,
01:35flower stems and seeds from the
01:37cannabis sativa or indica plant.
01:39These are common subspecies of the hemp
01:40plant which is common throughout the world.
01:42And cannabis contains over
01:44400 chemical compounds.
01:46So when we talk about cannabis and
01:48cannabis derived products and the
01:50landscape of cannabis products
01:51in the United States,
01:52I think it's important to keep in mind.
01:55Sort of that that this is all basically
01:58originating from this hemp plant.
02:00Cannabis is the most commonly used quote
02:04illicit drug in the United States.
02:07You have to put quotes around
02:08it because as we all know,
02:10the legality of cannabis is
02:12constantly changing.
02:13I think in the election this week
02:15two more states legalized cannabis,
02:18so I have this map.
02:20I have to update it about every 10
02:22minutes about sort of the legal
02:23landscape throughout the United States.
02:25But the point of this is that
02:27cannabis use is, is,
02:28is incredibly common over 100.
02:30Million Americans have tried cannabis.
02:34And millions more people use it
02:35for the first time every year.
02:37And this is this is increasing dramatically.
02:40And a lot of the reasons for its
02:42increase has to do with sort of
02:44societal tolerance of cannabis that's
02:45really increased in the past decade.
02:51OK. So how does cannabis affect the brain?
02:55So when cannabis is smoked,
02:58THC, which is the the main
03:00psychoactive compound in cannabis,
03:01passes from the lungs into the bloodstream.
03:04Bloodstream carries the chemical to the
03:06brain and other organs throughout the body.
03:08When cannabis is orally ingested,
03:11it's absorbed more slowly,
03:12so it takes more time to reach the brain.
03:14But basically,
03:15THC acts on molecular targets and brain
03:18cells called cannabinoid receptors.
03:21These are these are endogenous receptors
03:25that are ordinarily activated by natural
03:28chemicals that are very similar to THC.
03:31And the one I have here is called
03:33anandamide that are part of a
03:35neural communication network that is
03:36called the endocannabinoid system.
03:38And this is an incredibly important
03:40system in and plays a role in normal
03:43brain development and function.
03:44So what happens is that THC's
03:46chemical structure is quite similar
03:48to anandamide and that is how
03:50it is recognized by the brain.
03:52And it can alter normal brain communication.
03:55So the endocannabinoid system is
03:57often thought of as the neurons
04:00volume control system.
04:02It dials down activity when
04:03neuronal activity is too strong,
04:05and it regulates neurotransmitters that
04:07affect things like pleasure and mood
04:09and appetite and motivation and memory.
04:11So a wide variety of of functions are
04:15affected by the endocannabinoid system.
04:18The endocannabinoid system is also
04:20incredibly important in brain development.
04:22It guides neurons to grow in the right place.
04:25It controls neuronal activity.
04:26We say neurons that that fire
04:29together wire together.
04:30So it it plays a role in making
04:32sure these neurons reach the the
04:33correct targets and destinations.
04:35And it supports myelin growth on neurons.
04:37So again,
04:38it's an incredibly important
04:40system in the brain.
04:41So thinking about THC versus anandamide,
04:43they have a very similar chemical
04:45structure and both dial down
04:47neuronal activity and change.
04:48Neurotransmitter release.
04:49But THC has this much stronger and
04:53longer effect compared to an end of mind.
04:55And what it does is it interferes
04:57with an and amide functions.
04:59So you have this distribution of THC
05:02binding sites throughout the brain.
05:04Whoops.
05:05Sorry.
05:06And throughout the prefrontal cortex,
05:09throughout somatosensory cortex, cortex,
05:11the cerebellum, thalamus, hippocampus,
05:13basically throughout the brain.
05:16And because the the binding sites are
05:20very dispersed throughout the brain,
05:23the functions that it affects
05:25our quite dispersed.
05:26So THC will affect everything from
05:30motor control to memory to anxiety,
05:33emotion, fear and it has some.
05:36Really important implications for
05:38pain processing and other functions
05:42underlying these brain regions.
05:45So let's talk about cannabis, the product.
05:48So cannabis from basically the
05:50beginning of time, this is you know,
05:53pictures from the 1960 to 2000s,
05:54canvas was this plant that
05:56I talked about before.
05:57People would smoke it in a joint,
05:59people would sometimes vape it,
06:01but it's THC content was quite low.
06:03So 1 to 3% was was fairly common
06:06for the amount of THC in cannabis
06:08that was used on the street.
06:12What's happened lately and this is really
06:15been in the past decade is that THC
06:17potency has has gone up dramatically.
06:19This has happened in plant based
06:21THC and they're they've done some
06:23studies looking at police seizures
06:24of THC and they've of cannabis and
06:27they've measured THC concentration.
06:28So even the the plant based cannabis
06:31growers have worked to make it more potent.
06:33But now even in addition to that
06:35we have all these new products,
06:38these derivatives which contain up
06:40to 98% THC. So you have hash oil.
06:42Shatter, butter,
06:44wax and these are incredibly potent products.
06:49You have novel forms of THC delivery
06:52such as you can put THC oil in
06:54a jewel pod and this is use is
06:56very difficult to detect.
06:58So something that we have seen in
07:00our adolescent studies is that.
07:03People's kids will use this
07:04in school all day long.
07:05They'll put this, this jewel pod under their
07:07shirt and they can just use it all day.
07:09So it wasn't like, you know,
07:10when I was in high school,
07:11of course kids used pot,
07:12but you had to sneak out.
07:13You had to sneak out to the corner
07:15or the bathroom or something.
07:16Now they can basically do
07:17this in class all day.
07:19And you have kids who are high.
07:20There's no odor.
07:22You can't,
07:23there's no smoke that's emitted.
07:26And oftentimes the kids don't
07:28get the bloodshot eyes,
07:29so you would just have no idea.
07:32This is to say nothing of the new
07:35market of edibles that is now prevalent.
07:38There are edibles,
07:39particularly in states with legal cannabis.
07:42These shops are everywhere.
07:43I was just in Portland last week and I was
07:46trying to get a cup of coffee and all I,
07:48you know,
07:48I couldn't even find a coffee
07:50shop shop because there were all
07:52these recreational pot shops and
07:53this was just in the windows.
07:54Just every, every edible you could think of.
07:57These products simply didn't
07:58exist 10 years ago.
07:59This is a product of of commercial.
08:02Location of cannabis.
08:04Now you know manufacturers are
08:06working to to sort of create this
08:08emerging commercial market of
08:10products and a lot of them are
08:12appealing to children because you
08:14know a lot of adults don't eat pop
08:16tarts and fruit loops and things like that,
08:18but kids do and then instead
08:20of your pop tarts you have pop
08:22tarts and things like that.
08:23So this we've seen increases in ER visits
08:26of kids getting a hold of these products.
08:29This is not uncommon and these
08:32products again are are are.
08:34Super potent, a lot of them.
08:36You know, a cookie will be,
08:37you know, 10 servings of THC.
08:40But who eats 1/10 of a cookie?
08:41Nobody eats 1/10 of a cookie.
08:42So oftentimes people do have negative
08:45side effects from these edibles
08:46because they're just not used to it.
08:51So we know that. That the brain is
08:55developing throughout adolescence.
08:57This is very well known and this is research
08:59that that's now you know 30 years old.
09:01We know that the brain has developmental
09:04changes into the third decade of life
09:06and we know that these changes take
09:08place you know in multi domain changes
09:10in connectivity and brain chemistry,
09:12in in brain morphology and the prefrontal
09:15cortex which is up here is the last
09:18to develop and that's part of the
09:21theories of adolescent development
09:22is that this prefrontal cortex.
09:24Develops later,
09:25and that's why teenagers are often,
09:29often make risky decisions,
09:31more so than than adults do.
09:33But the other thing about the
09:35prefrontal cortex is it's densely
09:36populated with cannabinoid receptors.
09:38So these prefrontal regions
09:40critically underlie higher order
09:42cognitive decision making.
09:43And they're also densely populated
09:46with cannabinoid receptors.
09:47And that means that adolescent cannabis
09:51use is particularly detrimental.
09:53So I'm going to there's been,
09:55you know,
09:55tons and tons of of studies showing
09:57that animal studies and to human
09:59studies showing that effects
10:01of cannabis are just worse in
10:02teenagers than they are in adults.
10:04And there's a lot of controversy
10:06in the cannabis field.
10:08But I would say that that's one of the
10:10least controversial statements I can make,
10:12that that cannabis is worse
10:15for kids than adults.
10:17And this is just a study that I
10:19did a few years ago now where
10:21we brought people into the lab.
10:23For all cannabis users.
10:24And we gave them a memory task and it
10:27was called the CVLT California verbal test.
10:29And we let we read them a list of words
10:32and they had to recall them back to us.
10:34And this is just the number
10:36of words recalled.
10:37And then you read them the list again
10:38and they read it back to you again and
10:40then you do it again for five trials.
10:42So what we did was everyone,
10:43these were college students,
10:44so they were all ages 21 to 25
10:47and some of them had started using
10:49cannabis before the age of 16.
10:50Some of them had been using,
10:52started using cannabis.
10:53After the age of 18,
10:54so we had these early onset users
10:57and these later onset users and
11:00what we found was that.
11:01Learning improved in both groups,
11:04all three groups actually.
11:05We had a control group also.
11:06So learning improved over time,
11:08which you would expect.
11:10The slopes were absolutely identical.
11:12The rate of learning was identical
11:14but these early onset users which
11:17are shown in the red.
11:18Had trouble with encoding.
11:20They had trouble with initial learning,
11:22they just didn't learn the
11:24information as efficiently.
11:25So these weren't even
11:26really memory differences.
11:28So this is trial 5,
11:29and then there's a delay and they call they.
11:31They basically you do something
11:32else with them and then you ask
11:34them to recall the words again.
11:35And what we found is that they
11:37remembered everything they learned
11:39the same as the controls of
11:40the late onset
11:41users, but they just never
11:42learned it in the 1st place.
11:44And that was really the first
11:45demonstration that I know of
11:47of really parsing the learning.
11:49Process and understanding that it
11:51was the initial encoding that was
11:54really affected by the cannabis
11:55and this was cross-sectional.
11:57So there's caveats to this
11:59study showing that.
12:00You know, you can say that
12:02maybe these people had poorer
12:03memory being begin with,
12:05but I thought this was a powerful
12:07illustration that that the age of onset is,
12:10is quite important and this is
12:12specific to encoding strategies.
12:16We find that this is even worse in
12:18people with psychiatric diagnosis and
12:20this has also been shown a few times
12:23and this was a study where we looked at
12:25people with depression and cannabis use.
12:29So again this is the same test
12:30and this is total number of words
12:33recalled across all trials.
12:35So you see the control participants
12:37did the best and then the cannabis
12:40users had a significant decrease.
12:42The the participants with depression
12:44had even more of a decrease and
12:48they participants with both
12:50depression and cannabis use showed
12:53the worst decrements in learning.
12:55And if you look at the memory component,
12:58so this is the learning component,
13:00this is the memory component component,
13:01the free recall after delay and you can do
13:04this with a short delay or a long delay,
13:06then you really see this.
13:07You really see this additive effect of of
13:10depression and cannabis use we also saw.
13:13To break brain imaging on all
13:15these people and we also saw not
13:17only did their performance suffer,
13:18but they had reduced cortical thickness
13:20in the middle middle temporal gyrus,
13:22which is also important in memory
13:24in this group.
13:28So something that comes up quite
13:29often is the question of whether
13:32cognitive deficits are reversible.
13:33So we we've shown that that you know,
13:36when when people are acutely
13:38intoxicated from cannabis,
13:40they have memory weaknesses.
13:41And we've shown that chronic
13:43users have memory weaknesses.
13:45But these are all people who
13:46are still using cannabis.
13:47What happens if people stop using cannabis?
13:52So we did a trial, and this was led
13:54by my colleague Randy Schuster.
13:57Where we use something called contingency
14:00management to pay kids to stop using
14:03cannabis for a specific period of time.
14:05Contingency management is is widely
14:07used in the substance use field.
14:10And basically it's it's what it's it
14:12sounds like you pay people for negative
14:15drug screens and you have escalating
14:17payments over time so that they're
14:19invested in in stopping use, you know,
14:22for longer periods of time because
14:24they keep making more and more money.
14:25The reason why we we we chose to
14:27do this contingency management
14:29study is that you cannot randomize
14:31kids to use or not use cannabis.
14:34That's unethical,
14:34but it was not considered unethical
14:37to pay some kids for stopping.
14:39So what we did was we did this,
14:40this randomized trial where
14:41we paid some kids to stop.
14:44Other kids, we did not pay to stop.
14:45They were called a monitoring condition.
14:47We said you can stop if you'd like,
14:48but we're not going to pay you to do so.
14:50And you can imagine how many stopped.
14:52And we looked at changes in
14:56cognition with abstinence.
14:58So these were high school
14:59and college students.
15:00They used cannabis weekly or more.
15:02They were not seeking treatment.
15:03And as I mentioned after baseline,
15:07the kids who are abstained to cannabis
15:09were asked to stop using cannabis for
15:11a month and there was urine samples
15:13to verify this and those assigned to
15:15monitoring were not asked to change
15:18their patterns of cannabis use.
15:20And we we assess cognition with
15:22the cantab battery and and and
15:24the two domains we were interested
15:26were attention and memory.
15:27So we had a series of of cognitive
15:30tasks in each of these domains.
15:33OK.
15:33So.
15:34The first thing we found was that
15:37kids will abstain for money.
15:39So this study worked beautifully.
15:41So this is the group that was randomized
15:44to CM and this is their carboxy THC levels.
15:47And you could see they just plummeted and
15:50stayed really low throughout the study.
15:52I think we had something like
15:54a 90% abstinence rate.
15:55And then this was the group that
15:56continued to use and of course there
15:58was a lot more variation in their
16:00carboxyl levels because we had, you know,
16:02kids with different use patterns,
16:03but the randomization worked quite well.
16:07And this is what we found.
16:09So for attention, they improved over time.
16:12They're given the same tests
16:14throughout four weeks.
16:15So as you can imagine,
16:16there's learning that occurs.
16:19So attention,
16:20you saw no difference between the kids
16:21who stopped and the kids who continued.
16:23But something really interesting
16:25happened with memory.
16:26So the kids, this is a monitoring group.
16:28This is the kids who didn't
16:30change their cannabis use.
16:31They just didn't improve
16:32from week zero to week four.
16:35We're giving them the same test four times.
16:36They showed no improvement.
16:38The kids who were abstinent showed
16:41dramatic improvement in week one,
16:43and then they sort of.
16:45Stayed the same.
16:47So a week of abstinence was enough
16:50to really improve the amount
16:52that they that they learned,
16:54which was quite interesting because
16:55you think about kids who, you know,
16:57smoke pot on the weekends and then
16:59they go to school on the weekdays
17:00and there are not learning as well,
17:02is what this study indicates.
17:04So what we found in this study
17:06is that memory improved among
17:08adolescents who abstained,
17:10but not among those who continue to use.
17:12We didn't see this for attention.
17:13So this really seems specific
17:15to learning and memory.
17:16Um, this finding is consistent
17:18with other studies that show that
17:20neurocognitive dysfunction persists
17:21after several days of abstinence.
17:23And the improvement occurred within
17:26one week of continuous abstinence,
17:28which was super interesting.
17:29So we thought that this study provides
17:31evidence that adolescents and young
17:33adults may experience improvements in
17:35their ability to learn information
17:36when they stop using cannabis,
17:38which has a lot of implications for,
17:41you know,
17:41for for adolescent cannabis use,
17:43which we know is increasing steadily,
17:45particularly among 12th graders.
17:46And I think I'm going to show you that data.
17:51So now I'd like to change gears
17:54and talk a little bit about.
17:56Cannabis is a medicine.
17:58So is cannabis and medicine right?
18:01Is there anything to this?
18:03So my answer to this is it's not simple.
18:06So cannabis is a medicine for some
18:10and there have been components of
18:12cannabis that have been FDA approved
18:15for different medicinal purposes.
18:17So Epidiolex is,
18:18is a CBD medication that's FDA approved
18:20for children and adults with epilepsy
18:23and we're studying that in one of our
18:25trials now journal is a synthetic THC.
18:28That's approved for AIDS
18:30patients with severe weight loss.
18:31But the thing to keep in mind is for
18:34all other indications other than
18:36the epilepsy for Epidiolex and the
18:39severe weight loss for dronabinol,
18:42there are too few studies and
18:44poor data quality to really know.
18:48And I think effective regulation
18:49using a public health framework
18:51is really key to mitigating risk.
18:52And people ask me sometimes,
18:54well are you for or against legalization?
18:56And I say, well it's not that simple.
18:58It's it's.
18:59You know, it's it's how are you?
19:00How are you legalizing?
19:03I think, you know,
19:04at the Center for Addiction Medicine,
19:06we we believe in treatment, not punishment.
19:07Nobody needs to go to jail,
19:09but there is a way to regulate safely,
19:13and I'm going to talk about that a
19:15little bit in the next few minutes.
19:17So medical cannabis products from
19:19dispensaries are not FDA approved.
19:22And FDA approval is important.
19:24It assures that medicines are effective
19:26and safe and properly labeled.
19:28The FDA can't really evaluate medical
19:30cannabis as a drug since it's a plant,
19:32it's not a standardized medical
19:34formulation and it's quite different
19:35depending on how it's bred,
19:37the conditions that it's grown
19:39and a million other variables.
19:41So when we say medical cannabis,
19:42we're not talking about one drug,
19:44we're talking about you know, this, this.
19:47Wide variety of of dispensary products.
19:51Umm.
19:51Commercial cannabis that you buy
19:53at dispensaries just has not been
19:55tested to medicinal standards.
19:57I don't think that's a
19:58controversial statement,
19:58I think everyone would agree with that.
20:01The gold standard in medicine are these
20:03double-blind placebo-controlled trials and
20:05few exist for these cannabis products.
20:07And clinical trials unfortunately
20:10have been quite mixed,
20:12particularly for chronic pain which
20:14is the indication that people use
20:17medical cannabis for most frequently.
20:19There have been a lot of systematic
20:21reviews and meta analysis.
20:22And and the the evidence just isn't strong.
20:26Some find small effects,
20:27some find no effect,
20:28so it's really up in the air.
20:31So I'd like to talk to you about a
20:34clinical trial that we conducted
20:35in my lab of medical marijuana.
20:37And this was, this was my first R1.
20:40It was an RCT of medical
20:42marijuana card holders.
20:43And what we did was we wanted to
20:45test the products that people
20:46were using in the real world.
20:48So we randomized people to either an
20:51active study group and and we told them
20:54to go out and get a medical cannabis card.
20:57We didn't provide the cards for them,
20:59but we said go out and get a card.
21:01Here are some resources and the other
21:03group agreed to be in a weightless
21:05control and we said will you wait
21:07three months before getting a medical
21:09cannabis card and they had to agree to
21:11wait before randomization and then we
21:13would randomize them to the two groups.
21:16So we had a baseline of two week
21:17or one month and a three month
21:20visit during the randomized phase
21:21and then after the three months
21:23they could do whatever they want.
21:25Because I didn't think about 12
21:27month wave was controls feasible
21:28even though we were interested in,
21:30you know the the.
21:32The development of of cannabis
21:35use over a year and everybody was
21:37followed up at 6 and 12 months.
21:40So the patients were between
21:4218 and 55 years old.
21:43They were seeking medical
21:44marijuana cards for pain,
21:45insomnia or or depression and anxiety.
21:48The reason we chose those conditions was
21:50those are the most common conditions
21:51that people seek medical cannabis for,
21:53and they're often comorbid.
21:56And we also did brain imaging
21:57at baseline and at 12 months.
22:02So the interesting thing about this
22:04trial is our exclusion criteria was
22:05daily cannabis use because we didn't
22:07want people who were using already.
22:09We wanted people were interested
22:10in using and cannabis use disorder
22:12or at screening or baseline.
22:14Also things like current psychosis
22:16and other substance use disorders.
22:17The patients were responsible for
22:19arranging for and paying for the cost of
22:22obtaining their cards and their products.
22:24We didn't provide the products,
22:25we didn't pay for the products,
22:26but we paid them for their
22:28for their participation.
22:30Our outcome measures.
22:33Where cannabis use disorder and then
22:35the changes in the symptoms that they
22:37were seeking the medical marijuana for.
22:39So depression, anxiety, pain and sleep.
22:43This is our concert diagram.
22:45So the the the reason I'm showing
22:46this the most interesting thing here,
22:48we randomized 2 to one to the
22:49cannabis card or the control group,
22:51because this is the group
22:54we really cared about more.
22:56And about 50 of them didn't even end
22:58up getting a medical marijuana card.
23:00So they were interested in the study.
23:01They passed the screen, they got
23:03randomized and they changed their minds.
23:05And a lot of that had to do with
23:06the process for getting the card.
23:08A lot of the cannabis doctors
23:11were really sketchy.
23:12We can talk about that in the Q&amp;A.
23:15I can, I can write a book on some of
23:16the stories I heard and a lot of people
23:18were quite turned off to the system.
23:20But in the end we had 100,
23:23we had about 100 in the medical cannabis
23:26group and about 75 in the wait list
23:28control group that we could compare.
23:31We also did an analysis of
23:33their urine because, again,
23:35we're not giving the cannabis.
23:37We don't know what's in it.
23:38So we sent off their Urnes to a lab
23:40in Colorado and we got measures
23:42of THC and the metabolites of THC
23:45and CBD and other cannabinoids,
23:46which was kind of Nice.
23:49OK.
23:50So the first thing we found was
23:52that the randomization worked.
23:55The group that got the card increased
23:58their use basically right away to
24:00about three to four days per week.
24:03We had some daily users,
24:05we had some people who used less,
24:06and the delayed acquisition group was
24:08basically from less than once a week to,
24:11you know,
24:11less than once or twice a month.
24:14We did not tell them they
24:16couldn't use cannabis,
24:18but we said please don't get a card because.
24:20A lot of these people were were very
24:23light cannabis users in the beginning
24:25of the study and then we didn't want
24:27to introduce another intervention.
24:28We thought,
24:29oh should we do CM and pay them not to use.
24:31But it got too complicated.
24:32But as you can see there is a
24:35nice separation and use patterns.
24:37OK,
24:37so the biggest finding from this
24:40trial was that people in the
24:42medical marijuana card group
24:44developed cannabis use disorder.
24:46So again,
24:47cannabis use disorder was
24:49exclusionary at baseline.
24:51And what we saw was that in the 12 weeks,
24:54there was almost 20% of
24:57people who developed CVD,
24:59particularly in the depression
25:00and Anxiety group,
25:02in the pain and insomnia group,
25:03very little CD,
25:04not any different than the
25:06weightless control group.
25:07Um, but the pain,
25:08the Depression anxiety group.
25:09We saw this increase in
25:11cannabis use disorder symptoms.
25:13Now I will say most of it was mild.
25:15Most of it was was.
25:16I mean you need two or more symptoms of
25:18of cannabis use disorder for diagnosis.
25:21And people have asked me,
25:22well,
25:23you know,
25:23are these appropriate this is UD scale
25:26appropriate for medical cannabis users.
25:28And I think there's there
25:29there are things that we
25:31could do better in assessing
25:32cannabis use disorder.
25:33But people were developing tolerance.
25:37They were using despite negative consequences
25:39they were using in risky situations,
25:42which I'll talk about a
25:43little bit in a few minutes.
25:44So we definitely did see people were
25:48developing some problematic use.
25:50What about symptoms?
25:51So we found no effect of medical cannabis
25:55compared to the way it was control on pain,
25:58on depression or anxiety.
26:01There was just nothing.
26:03We found worsening OCD symptoms,
26:05which I just told you in
26:07the medical cannabis group,
26:08and we saw improvement in insomnia symptoms.
26:11So it helped people sleep better and
26:13that was a pretty robust finding,
26:15a large effect size,
26:16but no effect on pain or depression
26:18or anxiety, which was.
26:20Um, surprising to some people?
26:24We also saw no effect on cognition.
26:26So we did this nice cognitive battery
26:28throughout the trial and we saw
26:30that cognition didn't change in the
26:32medical marijuana group group versus
26:34the way it was controlled group.
26:37And we also saw no significant brain changes.
26:39So this was an end back task that we did.
26:41This was a 2 back versus 0 back
26:44condition at baseline and this is at
26:45one year in the Medical cannabis group.
26:48And there were no significant differences,
26:49which is really good news and not
26:51surprising because a lot of the
26:53brain changes that we've seen with
26:54cannabis have been in adolescence.
26:56So these were generally older adults
26:59and these were generally people who
27:03weren't using heavily somewhere,
27:05but we didn't, we didn't see changes
27:07in cognition or the brain.
27:09After one year of use in in these patients.
27:13We also looked at patterns
27:15of use post randomization,
27:17so this is month 4 to 12.
27:18And we did a trajectory analysis where
27:21we looked at sort of their naturalistic
27:23patterns of use and we found that
27:25most people were pretty stable.
27:27So this is our low use category,
27:31this is our moderate use category,
27:33this is our high use category.
27:35And most of the participants
27:36were in one of these three.
27:38And then we had two smaller groups that
27:40either went from low to high or high to low.
27:43But most people were pretty stable.
27:45Which is important to know.
27:48But what we found was that, and I'm sorry,
27:51these categories are not very descriptive,
27:54but this is our low stable use category and
27:57this is CD diagnosis and it was quite low.
28:00And as the patterns emerge
28:02emerged for more cannabis use,
28:04you had greater CD likelihood,
28:07which is not surprising,
28:08but it was an interesting
28:10proof of concept that you know,
28:11medical cannabis users can
28:14develop CD people thought,
28:16you know, well,
28:17they're not using to get high.
28:19They're using because you know,
28:20they have pain.
28:21They're not going to develop CD and
28:22we've shown that some people do.
28:25Also, I'm just going to read
28:27this to you because this was
28:28something that really struck me.
28:30This is what a patient said.
28:32I was taking what I thought was CBD oil and
28:34apparently it wasn't what I thought it was.
28:36I started feeling the effects when I
28:37was driving, which was really scary.
28:39I got home as quickly as I could.
28:41I felt so high I didn't know where I
28:43was and could have focused and the only
28:45way I got home was the noises from GPS.
28:48I was paranoid that I might
28:49have hit someone or something,
28:51but I checked my car and there was no damage.
28:53So I call this the downside
28:55of poor regulation. So.
28:57These products are not very well regulated.
29:00So this person was not an
29:02experienced cannabis user.
29:03They thought they were taking CBD
29:06and obviously it had THC in it.
29:08They took it before going somewhere
29:10and it they they could have,
29:12they could have really injured
29:14themselves or somebody else.
29:15So I think it's,
29:16it's just going forward and thinking
29:18about how we deal with this new
29:20system of medical cannabis products.
29:22I think you know education and proper
29:24labeling is just critically important.
29:29So from this trial, what we found
29:31was that medical marijuana cards were
29:33associated with developing CD symptoms
29:34and no significant improvement in pain,
29:37anxiety or depression.
29:38So you think about risk reward.
29:40And people talk to me a lot about, well,
29:43isn't cannabis better than opioids?
29:45Well, yes, of course nobody's
29:47dying from cannabis.
29:48People are dying from from opioids,
29:50from overdoses.
29:51But even though it has to have a benefit too.
29:55So what we found here is that it really
29:57didn't have any benefit on pain and.
29:59And and you know the effect of
30:01cannabis on opioid reduction is a
30:02really hot topic right now and I
30:04have another grant to assess that
30:06and it really remains to be seen.
30:09We did see that the medical marijuana
30:10cards were associated with improved,
30:12improved sleep quality in the short term.
30:15And the nice thing about this trial,
30:17the reassuring thing was that there
30:18were no adverse events related
30:20to psychotic symptoms.
30:21Mania, hypomania,
30:22suicidal ideation didn't differ
30:24between the groups.
30:25So that was all reassuring.
30:28And I think the results warrant
30:30further investigation of benefits
30:32of cannabis for insomnia and also
30:35understanding the risk for CVD.
30:40OK. So in the last 10 or 15 minutes,
30:44I want to talk to you about
30:46something a little bit separate,
30:48but I think we'll be interesting
30:49to some people here who are
30:51working on similar projects,
30:52looking at THC impairment using
30:55functional brain imaging.
30:57I know there's some people here,
30:59Godfrey Pearlson and and Cyril Disa who
31:01are doing work very similar to this,
31:03so I wanted to include this so.
31:06Driving while high is not good.
31:09Despite what anyone will tell you,
31:11cannabis does not make you a better driver.
31:14I have heard this in talks,
31:16it is just not true.
31:17But the true rate crash risk of
31:19THC is actually quite challenging.
31:22We know that cannabis impairs
31:24psychomotor skills, divided attention,
31:26lane tracking, things like that.
31:28But the epidemiological literature
31:30is really quite divided and
31:32knits this crash risk study.
31:34They found the unadjusted odds
31:35ratio for THC in.
31:37In crashes was 1.25,
31:38which is a 25% increase.
31:40But when they adjusted this
31:42for other demographics,
31:44they did not find an effect.
31:45And a lot of the epidemiological
31:48research is similarly mixed.
31:50I would like to argue that part of the
31:53reason why the the literature is mixed is
31:55we're not getting people at the right time,
31:57we're we're measuring carboxy THC,
31:59which I'm going to talk about in a minute,
32:01sticks around for quite some time.
32:03So if you measure somebody in an
32:06accident and you look at carboxy THC.
32:09You know,
32:09they're,
32:10they're that doesn't mean they were
32:12high when they when they crashed.
32:14So US state THC driving impairment laws are,
32:18excuse the pun all over the map.
32:21So some states have 0 tolerance,
32:23so if you have any THC you're
32:25considered to be THC impaired.
32:28Some states have THC per se laws,
32:30which it just means a specific
32:31amount and it's usually two to
32:33five nanograms per milliliter,
32:34which I don't think makes much sense
32:36and I'll talk about that in a minute.
32:38And most states don't have anything,
32:40although Gray states,
32:40they don't have any laws on the books.
32:42It's sort of up to the the cop.
32:44To determine whether they're
32:46impaired from THC.
32:47And this is a really challenging problem.
32:51The model for alcohol is breath
32:53alcohol concentration that
32:54you blow into a breathalyzer.
32:56We've decided as a society that
32:58.08 BAC is the legal limit.
32:59We decided that based on,
33:03you know,
33:04an exponentially rising curve
33:05of BAC and crash risk.
33:07This does not exist for cannabis.
33:09We don't have this nice curve,
33:10and a lot of it is because
33:12cannabis is unique in its
33:14pharmacokinetics and pharmacodynamics.
33:15It's not as easy as alcohol.
33:18THC peaks in about 10 minutes
33:21post smoking or vaping,
33:23as you can see here it in
33:26breath and in blood.
33:27Your THC levels are quite
33:28high right after you use,
33:30and they return to baseline quite quickly.
33:34And carboxy THC,
33:35which is what THC is metabolized into
33:38and this is probably what if you,
33:40if you're given a drug test or a
33:41clinical drug test,
33:42that this is what these tests detect sticks
33:45around for a very long period of time.
33:48So this is detection window of
33:50marijuana drug tests in breath,
33:52in saliva, this is urine. It can.
33:56You can test positive for a month.
33:59If you're a heavy cannabis user
34:01and you stop so so carboxy THC is
34:03not water soluble, lipid soluble.
34:05It's stored in fat cells,
34:07it stays in the system for a long
34:09time and therefore it's not a very
34:11good test of impairment. And then?
34:13So we have THC is too quick,
34:16carboxy THC is too long.
34:17Well, how long are people
34:19actually reporting impairment?
34:20And this also varies dramatically.
34:23So this was a smoking study and you
34:25can see in after an hour about 50%.
34:28We're still impaired after three hours.
34:3310% were still impaired.
34:35So there's just and it also
34:37depends how much you use.
34:39So impairment can last for for four hours,
34:42particularly for oral THC,
34:43which I'm going to talk about in this study,
34:45impairment lasts for a
34:47very long period of time.
34:50The other thing we know is that people
34:51have poor insight to their own impairment.
34:53This was a super cool paper that just
34:56came out where they did this driving task
34:59and people pre smoking did very well.
35:02After they smoked,
35:0230 minutes later they did a
35:04lot worse and they knew this
35:06was their perceived impairment.
35:08They knew they weren't doing very well.
35:09This is how impaired are you,
35:10but that in an hour and 30 minutes
35:13something interesting happened.
35:14So there's still quite impaired,
35:16not as impaired at 30 minutes,
35:17but they're still quite impaired.
35:19But now sorry, I'm I did that backwards.
35:22This is their composite Dr score.
35:24So there's still quite impaired from driving,
35:26but they're perceived impairment
35:28is quite low.
35:29So you have this gap where
35:30people are still impaired,
35:31but they don't think they are.
35:33So that's not good for when
35:35you're deciding to drive a car.
35:38Dozens of studies have now shown
35:40that there's no association between
35:42THC biomarkers and impairment there.
35:44It's just really hard to detect THC
35:46impairment using a blood or a breath level.
35:49These are three papers.
35:50There are dozens more.
35:53So our idea was, is there a test that
35:55can go to the source of impairment
35:57so when you break a bone you
36:00take an X-ray if you're impaired,
36:01the affected organ is actually the brain.
36:04These other methods all look for body
36:05fluids which replicates the alcohol model,
36:07but as I mentioned that doesn't work for THC.
36:10So we wanted to use F near as
36:12functional near infrared spectroscopy.
36:14Not many people haven't heard of Fnirs,
36:16it's not as popular as F MRI,
36:18but it it's an optical imaging
36:21technique that's non invasive.
36:22It'll it'll allows measurement of
36:25brain tissue concentration changes or
36:27HBO following neuronal activation.
36:29It uses light to measure brain activity.
36:32Same principles of F MRI.
36:33F MRI uses magnets, FNIRS uses light.
36:36And the cool thing about F nears
36:38is it's non invasive.
36:39It's safe, it's inexpensive,
36:40it's portable, it's wireless,
36:42it can be used in natural environments
36:44without restraints without sedation.
36:47F MRI will never be useful on the roadside,
36:49obviously for obvious reasons,
36:50but you can imagine that.
36:53If news is a good indicator
36:54of impairment that you know,
36:56someday it might be useful,
36:58like the breathalyzer.
37:00And just if anyone's curious
37:02about how F nears works,
37:05basically brain activation could be inferred
37:07by this oxygenated hemoglobin concentration.
37:09So you have your neuronal activation,
37:11metabolic demand, increased blood flow
37:13and then you have this increase in,
37:15in,
37:16in,
37:16in oxyhemoglobin and wash out of
37:18D deoxyhemoglobin and you can
37:20measure that with light.
37:24This is the first breathalyzer.
37:26It took up a whole desktop and
37:28now it's smaller than your iPhone.
37:30And I think a similar thing is happening
37:32with Fnirs where these things are big
37:34and bulky and have wires sticking out,
37:36but I think they are just becoming smaller
37:38and smaller and more user friendly.
37:41So. For our study,
37:44what we did was we had 169 participants
37:47who were weekly or more cannabis users.
37:49They had two visits a week apart.
37:51They got placebo one day
37:52and THC and other day.
37:54And we did Fnirs recording during an
37:56in back task before they received
37:58THC or placebo at 100 minutes when
38:01peak effects were expected and at
38:03200 minutes and we got actual cops to
38:05come in and do and do assessments.
38:08They're called Dre drug drug recognition
38:10experts. We didn't train CRC's.
38:12To do this, we wanted,
38:13we wanted the real cops to come in.
38:15We told them don't worry your uniforms,
38:16we don't want to scare people,
38:17but they did their whole field sobriety test.
38:21And we did something in this
38:23study that was controversial,
38:24but we thought it was necessary
38:27is we did individualize dosing
38:29of THC to achieve impairment.
38:31So how much THC does it take
38:33to get somebody impaired?
38:35We have no idea.
38:36We have no idea.
38:37So what we did was we took a a very
38:41detailed medical history of their
38:43cannabis use and we looked at age
38:45and gender and tolerance and BMI
38:47and their patterns of cannabis
38:49use and determined the dose.
38:51That we thought would achieve impairment
38:52and that was different for everybody.
38:54So some people we gave them
38:5610 milligrams of THC,
38:57some people we gave up to
38:5980 milligrams of THC,
39:00some people who we gave 80 milligrams
39:02of THC didn't even get impaired.
39:04Dosing is really difficult.
39:05We couldn't figure out a dose
39:07for everybody and particularly
39:09after commercialization,
39:10people are using these, you know,
39:12high potency products.
39:15So we estimate that a little
39:16over half got impaired,
39:17even though we tried our darn
39:19hardest to get everybody impaired.
39:23How? How do we know who's impaired?
39:25So we're like, oh,
39:26we'll let the cops tell us, you know,
39:28this is what they do for a living.
39:30We found that the cops weren't very
39:31good at telling us were impaired.
39:33About 20% of those who received
39:35placebo were judged as impaired,
39:37which was kind of disturbing.
39:39And then the DRE's were really inconsistent.
39:42One of them was fantastic
39:44and had a 92% accuracy.
39:46One was 5050.
39:47So we didn't want to use the DRES
39:50as our ground truth of impairment.
39:52So what we did was we had this sort of,
39:55I don't know this this cumbersome but very
39:58thorough assessment of impairment where
40:00we had a clinical assessment, we, we,
40:03we decided this was me and my colleague,
40:05we looked at all the indications
40:07during the study visit,
40:09how they were acting, you know the
40:11blinded study nurse her her assessment,
40:14if they said they were high,
40:15if they said they felt the drug effect.
40:17And then we had a computer based
40:19algorithm of of heart rate change
40:21and self reported high and both
40:23methods needed agreement for us
40:24to consider that person impaired.
40:26So the clinical consensus we have to
40:27say yeah, I think they were impaired,
40:29it was like a chart review and then
40:31the computer algorithm had to say yes,
40:32this was indicative of impairment.
40:35And this is just an example of our
40:39time course and this is a person
40:42self reported high and this is a
40:44person's heart rate change in red.
40:46And you can see this person had a
40:48dramatic increase in heart rate.
40:49This is on the THC day, on the placebo day.
40:52We didn't see anything on this person.
40:54And then this is an example of
40:55somebody who we just did not give
40:57them a high enough dose.
40:58They had very minimal,
41:00minimal,
41:00minimal heart rate change and
41:02they reported zeros all day and
41:04they both got 30 milligrams of.
41:06HC. So that's just an example.
41:09And then what we found was that
41:12subjective and physiological responses
41:14clearly distinguish the two groups.
41:16So this is the impaired group,
41:19this is their self reported high,
41:21this is the non impaired group.
41:23So they got a little impaired but not
41:24dramatically and this is our placebo group,
41:26this is heart rate.
41:27This is you know the the heart
41:29rate change or the impaired group,
41:30the heart rate change of the unimpaired
41:33group and placebo and this shading is
41:36this was our pre pre dose effner scan,
41:39this was our post dose EFFNER
41:41scan and that was the second one.
41:43So we did get sort of at the
41:46peak of using the ether scan.
41:48So that was nice.
41:49Now the important thing for me to
41:51point out here no dose difference.
41:52So the the people who got high,
41:54the people who did not get clearly high,
41:57there was no significant dose
41:59in difference in dose in THC.
42:01OK.
42:02So question is do impaired
42:03and non impaired groups
42:05differ on effner's measures.
42:06So again this is our end back task,
42:10this is our, our prefrontal probe.
42:12We looked at these different ROI.
42:15And what we found was that
42:16there was increased activation
42:18throughout the prefrontal cortex
42:19only in those who were impaired.
42:21So this is the scan at baseline is in blue,
42:26the scan after the drug is
42:28administered is in red.
42:30And we had significant differences in
42:32every ROI in the people who are impaired,
42:34people who are not impaired.
42:35We didn't see any significant
42:37differences and we didn't see
42:39any differences on placebo.
42:41And again, no dose difference.
42:45So, you know, looking at this group
42:48difference, this is super interesting.
42:49You could get a good publication out of it,
42:51but it's not very useful.
42:52So group level impairment data
42:53is not useful in the real world.
42:55And psychiatry has really struggled with
42:57the ability to diagnose an individual with
43:00a condition based on functional brain data.
43:02So could we do this with impairment?
43:04Maybe impairment is such a global
43:06change that it would work.
43:07So we, we basically,
43:08we broke this etnier signal into
43:11features and gave them to our machine.
43:14Morning colleagues and said could you
43:16use a machine learning algorithm to
43:18determine who was impaired and who
43:20was not based on fnirs data alone?
43:26And yes, So what this graph shows
43:29is our machine learning results.
43:33And in the blue we have the Dre,
43:36so this is the cop.
43:37So the cop was about 72% accurate
43:39in judging people who are impaired.
43:42The positive predictive value of
43:43of those who are called impaired,
43:45how many were really impaired
43:46using our ground truth method
43:48and then a false positive rate.
43:49So what we found with Fnirs
43:51is we were a little better.
43:54From the cop about equal,
43:55a little better than the cop,
43:56much better in positive predictive
43:58value and we had half of
44:00the false positive rate.
44:01So that was kind of exciting.
44:05Umm. Something that came up is, you know,
44:08you're giving people an end back task.
44:09How realistic is that?
44:10And we thought, well,
44:11what if it was just a resting state scan.
44:13So we looked at resting state connectivity,
44:16which is a measure of how regions of
44:18the brain interact with each other
44:19without need for a cognitive task.
44:21And basically with that,
44:23with functional connectivity,
44:24you're looking for patterns of
44:26temporally correlated but face but
44:28spatially distinct brain activity.
44:30And again what we found is that the
44:33people who are impaired after THC,
44:37they had this reduction in
44:39functional connectivity.
44:40The people who are not impaired,
44:41you see no difference between
44:44pre and post Drug Administration.
44:46Another way of looking at that
44:48is placebo and THC.
44:49So on placebo and THC,
44:53if you were not impaired from THC,
44:55there was no significant
44:56difference in brain connectivity.
44:58But for the people who are impaired,
44:59they had this dramatic decrease
45:01in brain connectivity.
45:02The groups are matched with placebo,
45:04which indicates to us that
45:05we're measuring the state level
45:07and not trade level effect,
45:08which was exciting.
45:11And then finally,
45:12as part of this, the study,
45:14we gave some people some alcohol,
45:16a subset of participants, 20 of them,
45:18also received an alcoholic beverage.
45:20So we had this nice two by two design
45:22THC and placebo, alcohol, placebo,
45:24THC, real alcohol, THC and alcohol,
45:26and then double placebo to see if
45:29alcohol interferes with our ability to
45:33detect THC intoxication using F nears.
45:35And we found that even with alcohol
45:37on board we could still decrease
45:39detect this decreased functional
45:41connectivity in people who are impaired.
45:43And this is different channels in the
45:45brain that I showed you and this is
45:48pre dose before they got anything and
45:50this is after both THC and alcohol.
45:52So you have this reduction in connectivity.
45:55So I think this is real and
45:56I think this is robust.
45:59So what can we say?
46:00So prefrontal cortical activation
46:02collected with portable fnirs
46:04appears to be a biomarker of THC
46:06impairment and not exposure that could
46:08potentially be collected in the field.
46:11It's different only in
46:12people who are impaired.
46:14It's the first biomarker that
46:15we know of impairment from THC,
46:17not just THC exposure.
46:18This biomarker can be detected when people
46:21are doing a task or at risk at rest.
46:24And what we're doing now is we're
46:26writing a grant with folks from MIT
46:28to incorporate a driving simulator.
46:30So we'll have.
46:30People do the fears getting the
46:32driving simulator and see how
46:33they actually drive because again,
46:35you know,
46:35F nears task doesn't really have
46:37a lot of ecological validity.
46:41So just to wrap up,
46:45I hope I've convinced you that
46:46this is a really active area of
46:48research with so many more questions,
46:50so studies that we're working on now,
46:53we have an RO one looking at medical
46:55marijuana pain and opioid use in
46:57patients on chronic opioid therapy.
46:58And we want to see if medical cannabis does
47:01in fact help people taper their opioid dose.
47:03There's a lot of speculation out there.
47:05This hasn't really been shown very well.
47:07So we're doing,
47:08we're doing a trial to see if that's true.
47:10And something else that I thought of
47:12might might be interested interesting to
47:14this group is we're also doing PET scans.
47:17We're we're evaluating CBD for
47:19reduction of brain neuroinflammation.
47:21There's a a pet marker called PBR
47:2328 that's a a marker of microglial
47:25activation and we want to see if
47:28CBD reduces neural glial activation
47:30in patients with chronic pain.
47:34So with that, I just need to
47:36acknowledge everyone in my group
47:38who helped with this research.
47:40My the director of our center.
47:42You didn't Evans,
47:43our project manager Gladys Patches,
47:45Randy Schuster,
47:45who did the the adolescent studies,
47:47Kevin, our statistician, Michael,
47:48our programmer Nissan who did
47:50a lot of the Effner's analysis,
47:52and all of the CRC's who did
47:54fantastic work in collecting
47:55all this data and of course,
47:57funding sources.
48:01So thank you. Thank you so much,
48:04Jody. That was a wonderful talk.