YC-SCAN2 April 2026 Webinar

April 29, 2026

This webinar features Ziva Cooper presenting cutting-edge research on the potential “THC-sparing” effects of minor cannabinoids, with a focus on cannabigerol (CBG). Drawing on controlled human studies, Dr. Cooper explores how CBG interacts with THC, highlighting findings that suggest CBG is non-intoxicating, shows no abuse liability or analgesic effects, and may offer modest anxiety-reducing benefits—particularly in mitigating some of THC’s adverse effects.

Set against the evolving landscape of cannabis legalization and increasingly potent THC products, the session also examines broader public health implications, including patterns of use, regulatory challenges, and the complexities of studying cannabinoids for conditions such as chronic pain. Attendees will gain insight into the pharmacology of emerging cannabis compounds, current research limitations, and future directions, including the role of other minor cannabinoids and terpenes. This session is designed for clinicians, researchers, and policymakers seeking an evidence-based understanding of cannabis and its therapeutic potential.

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00:04Today, we have, we are
00:06very happy to have Doctor.
00:07Ziva Cooper
00:09with us. Doctor. Cooper is
00:11a professor and vice chair
00:12of research in in the
00:14department of psychiatry and behavioral
00:16sciences at the David Giffen
00:18School of Medicine. She also
00:20serves as the director of
00:23the UCLA Center for Cannabis
00:25and Cannabinoids, a cross disciplinary
00:27hub for research and education
00:29spanning preclinical,
00:31clinical, public health and policy
00:33domains.
00:35Doctor. Cooper received, received her
00:37BS in biopsychology and anthropology
00:39and her PhD in psychology
00:42with a specialization
00:44in biopsychology
00:45from the University of Michigan.
00:47She then completed post doctoral
00:49training
00:50in human behavioral,
00:52pharmacology
00:52at Columbia University
00:54and the New York State
00:56Psychiatric
00:57Institute.
00:58Her research her research program
01:00integrates controlled human drug administration
01:02studies, observational
01:04designs, and preclinical
01:06models to better understand
01:08the therapeutic and adverse effects
01:10for, psychoactive substances with a
01:12particular focus on cannabis and
01:14cannabinoids,
01:15opioids, and their intersection.
01:18Her work has been continuously
01:20funded by the NIH and
01:21the state agencies
01:22and has contributed
01:23to key advances in sex
01:25dependent,
01:26pharmacology,
01:27public health policy, and the
01:29science of substance use disorders.
01:31She has also served on
01:33multiple committees for National Academies
01:35of Sciences, Engineering, and Medicine,
01:38focused on the health effects
01:39and public health implications of
01:41cannabis,
01:42and is the and is
01:43the past president of International
01:45Cannabis Research Society.
01:47Through her leadership and research,
01:49Doctor. Cooper has played a
01:50central role in shaping the
01:52scientific understanding of cannabis
01:54and informing evidence based clinical
01:56practice and policy in a
01:58rapidly evolving
01:59landscape.
02:01Today, she will present her
02:02work titled Potential THC Sparing
02:05Effects of Minor Investigation
02:08of CBG, Analgesia
02:10and Appetite Stimulating Effects Alone
02:12and in Combination with THC.
02:15Please join me in welcoming
02:17doctor Ziva Cooper.
02:19Thank you so much.
02:21It's so nice to see
02:22the names,
02:23on the Zoom screen. I
02:24feel like even though we're
02:26hundreds of miles apart, I
02:27you know, surrounded by friends.
02:29I just
02:30wish that we could, all
02:31be together in person, but
02:33Zoom is an amazing invention.
02:35So so that's good.
02:37Great. So I'll go ahead
02:38and share my slides.
02:42I know that kinda goes
02:43without saying at this point,
02:45but, yeah, we feel a
02:46need to say it. Let's
02:48see.
02:52Okay.
02:54So,
02:56hopefully, everybody can see the
02:57slides. And, yes, I am
02:59more than happy to
03:01pause at any point if
03:02there's a if there's a
03:04number of questions.
03:06I generally like discussion
03:08more than just speaking
03:11to myself on a on
03:12a Zoom box, so I
03:14definitely welcome,
03:16welcome questions.
03:18So first, I'd like to
03:20just point out that my
03:22research support is,
03:25comes from the NIH, and
03:26I'm extraordinarily,
03:28appreciative of that as well
03:30as
03:31different, California state agencies.
03:33And the project I'll talk
03:35specifically about today was funded
03:37by the CMCR,
03:39their Center for Medicinal Cannabis
03:40Research,
03:41which is in California
03:44and
03:45was part of the bill
03:46that,
03:48was passed when California
03:50decided to legalize cannabis for
03:52medical purposes back in ninety
03:53nine nineteen ninety six.
03:55They put aside money
03:56to actually research,
03:59cannabis and cannabinoids. And at
04:01that time, you know, NIH
04:02wasn't really putting much money
04:04into this area, And so
04:05it really spurred a lot
04:06of important work.
04:08And
04:09as you know, our the
04:10work is still not done
04:11as as we can see
04:12from all the newsreels from,
04:15Thursday, was it, when the
04:17big announcement happened with marijuana
04:19moving to schedule three, whatever
04:21that will mean.
04:22And I also wanna point
04:23out that this work, is
04:25clinical,
04:26and so it requires a
04:29number of approvals,
04:31approvals that many of you
04:32have to get for your
04:33clinical research for the IRB,
04:36the FDA,
04:37as well as the DEA
04:38because I work with sub
04:39schedule one substances.
04:41And in California, we have
04:42a very special
04:44organization called RAP C.
04:46It used to actually have
04:47the c in front of
04:48the wrap.
04:50And it is probably the
04:52one of the more difficult
04:53hurdles with respect to regulatory
04:55approvals. They have to review
04:57all preclinical and clinical research
04:59that involve schedule one and
05:00schedule two substances in the
05:01state of California.
05:03So even though you would
05:03think that California would be
05:05this burgeoning place for research
05:07where research would be much
05:08easier with cannabis and cannabinoids
05:10because of its legal history,
05:11it's actually it is quite
05:13hard here.
05:15So this isn't news. Although,
05:17I guess, this this changed
05:18dramatically,
05:19I think. Who knows really
05:20what the implications are? But
05:22as of last week, circa
05:24twenty twenty six to twenty
05:25twenty five,
05:26there were,
05:28forty states, including Washington, DC,
05:30that legalized cannabis for medical
05:32purposes, and,
05:33twenty five of those, legalized
05:36cannabis for nonmedical purposes. So
05:38for adult use,
05:40we know that, cannabidiol
05:42is federally
05:43legal as a hemp plant,
05:45or I should say,
05:48hemp is is federally legal,
05:50and so many states have
05:52legal provisions, regulations to allow
05:55for,
05:56cannabis with CBD in it.
05:57And then there are four
05:58states that don't really have
05:59any regulations at all.
06:01Now, again, this this is
06:03all changing.
06:04States where cannabis is legal
06:06twenty twenty five, of course.
06:08I guess cannabis is
06:10federally it is federally illegal.
06:12There's this question about medical
06:14marijuana now being schedule three,
06:15although we're going to see
06:16how that's implemented and and
06:18rolled out.
06:19But this doesn't change the
06:21fact that each state has
06:23different laws and different products.
06:25I don't we don't
06:27foresee that necessarily changing anytime
06:29in the immediate future. And,
06:31importantly, even with the change,
06:33there isn't any unifying body
06:35that's regulating the production and
06:36sales of these products. So
06:38even with the move to
06:39schedule three, it's not clear
06:40that the FDA necessarily is
06:41gonna be playing a role
06:43in
06:44overseeing or guiding the states
06:46on how to regulate this.
06:48And so that has led
06:49to a number of public
06:50health implications
06:51and questions with respect to
06:53how to protect the public,
06:54the consumers,
06:56when there's such a diverse
06:57market with very little oversight.
06:59And it's really up to
07:00the states at this point,
07:01and I think it's a
07:02pretty big job for for
07:03the state to be able
07:04to handle this.
07:06So there are those changes.
07:07And alongside with, you know,
07:09cannabis legalization across the United
07:11States,
07:12we've seen increases
07:13in cannabis strengths defined as
07:16percent THC over the decades.
07:18So this is a graph
07:19from the Drug Enforcement Administration,
07:21cannabis that was seized from
07:23unregulated sources over the last
07:24several decades. And you can
07:25see that THC concentration increased
07:27dramatically
07:28over the twenty years from
07:29nineteen ninety five to two
07:30thousand thirteen, and it continued
07:32to increase.
07:34Now keep in mind, of
07:34course, those are unregulated
07:36cannabis sources. When you go
07:38to dispensaries, and I see
07:39some,
07:41Washington State colleagues here, when
07:43you go to dispensaries in
07:44Washington State as well as
07:45California,
07:48and New York for my
07:49East Coasters
07:50on the on the,
07:52webinar,
07:53what you see is something
07:54very different.
07:55What you see is that
07:56it's very difficult to get
07:58cannabis with lower than t
07:59h lower than twenty percent
08:01THC. And, of course, there
08:02are a number of products
08:03that are super high in
08:05THC concentration,
08:06dabs, wax, shatter,
08:08that can be almost a
08:10hundred percent THC.
08:12And so we're seeing an
08:13emerging trend with rising increases
08:15concentrations of THC in these
08:17types of products. We know
08:18that cannabidiol,
08:19there's interest in other cannabinoids
08:21other than THC in the
08:22cannabis plant.
08:24We see cannabidiol
08:25infused athletic wear, hummus,
08:29pillowcases
08:30that promises a relaxation relaxing
08:32night of sleep, tinctures,
08:35capsules.
08:36And then we're starting to
08:37see this burgeoning interest in,
08:39you know, other minor
08:41cannabinoids, CBG, CBN, CBX, Y,
08:44Z that can be purchased
08:45across a range of of
08:47modes of administration.
08:49You know, I sometimes say
08:50that CBD is, like, so
08:52two thousand nineteen,
08:54What's gonna be the next
08:55one? I mean, CVG and
08:56CBN are also also almost
08:58coming passe at this point.
09:00So although we we don't
09:01know that much about it,
09:02but, you know, the industry
09:04is quite,
09:06entrepreneurial.
09:07And so
09:08there is a great deal
09:09of interest, from consumers as
09:11well as the industry
09:13in the other cannabinoids in
09:14the cannabis plant,
09:16as well as terpenes, which
09:17are not unique to the
09:18cannabis plant.
09:20And it's thought that these
09:21terpenes that are exist in
09:23fruits, vegetables, herbs, spices
09:25may also contribute to the
09:27effects of cannabis.
09:28And so you can see
09:29that there are a lot
09:30of different products available in
09:31dispensaries that really capitalize on
09:33terpenes either to improve the
09:35flavor or change the flavor
09:37of the cannabis product.
09:39But, also,
09:41a lot of these products
09:42suggest that it has certain
09:43types of medical benefits and
09:45symptom relief. So we have
09:46different products, and we also
09:47know that patterns of use
09:49have changed dramatically.
09:50I mean, you know, if
09:51you've gone to a cannabis
09:53lecture in the last year,
09:54you've definitely seen this slide
09:56where now daily cannabis use,
09:59outpaces daily alcohol use. This
10:01happened really quickly,
10:03if you can see over
10:04the last, twenty years.
10:07And
10:08this trend has continued since
10:10twenty twenty four, when this
10:12paper was published. So we
10:13know people are using many
10:14different products. They're using quite
10:16frequently.
10:17And when you look at,
10:18you know, patterns of cannabis
10:20use in people who are
10:21using for nonmedical reasons, this
10:23is
10:24actually a figure that was
10:25adapted from a study in
10:27Canada,
10:28but it definitely applies to
10:29the United States, has been
10:30shown with other, more recent
10:32papers.
10:33When you ask people
10:35who've used cannabis in the
10:36last three months how often
10:38they're using it,
10:39People who use for nonmedical
10:40reasons overwhelmingly are using it,
10:43you know, less than one
10:44time a month, and, of
10:45course, people are using it
10:46daily.
10:47But in general, those people
10:49who are using for nonmedical
10:50reasons, it's not everybody who's
10:52using every day.
10:54But when you ask people
10:55who are using cannabis for
10:56medical purposes, how often they
10:58use it, we see that
11:00the overwhelming majority are using
11:02it daily.
11:03And there's good reason for
11:04that because if people are
11:06using cannabis to help their
11:08symptoms or ailments that they're
11:09dealing with every single day,
11:10well, then it makes sense
11:11that they're using it every
11:12single day
11:13and most likely multiple times
11:15a day.
11:16And when people are asked
11:18why they're using cannabis, of
11:19course,
11:20you see this all the
11:22time that pain, chronic pain,
11:24sleep, anxiety
11:26are the top reasons why
11:27people are using medical cannabis.
11:30And so if you think
11:31about the changing landscape,
11:33as I've shown you, we
11:34have
11:35all these states that have
11:36different regulations. And I know,
11:38the audience members who are
11:39in Canada, you have different
11:40provinces that have different regulations,
11:43drastically different regulations from one
11:44province to the next.
11:46But, generally,
11:47given increased legality,
11:50increased accessibility, we also have
11:52increased use of cannabis. And
11:54there's definitely been an expanding
11:56scientific interest and also public
11:57health urgency
11:58to understand what are the
12:00health outcomes of cannabis and
12:02cannabinoids.
12:04So when we think about
12:05the potential medicinal effects of
12:07cannabis,
12:08and here, this whole talk
12:10is about, you know, how
12:12other cannabis constituents might have
12:14THC sparing properties.
12:16So what are we trying
12:17to spare here? What are
12:19we trying to, what types
12:20of risks are we trying
12:21to mitigate?
12:22So we know that there
12:23are risks associated with cannabis
12:25use. We know that there
12:26are associations between cannabis use
12:28and mood disorders and other
12:29serious mental illness.
12:31We know that there's an
12:32association between cannabis use, especially
12:34early onset cannabis use and
12:35earlier age of onset of
12:37psychosis.
12:38We know that there's been
12:39an increase in cannabis related
12:40ED visits across,
12:43across demographic
12:44categories.
12:45We know that there are
12:46acute effects of cannabis. You
12:47know, we've known this, you
12:49know, since the beginning of
12:50time when people started using
12:51cannabis that cannabis
12:53can
12:54does induce intoxication and impairment.
12:57Of
12:57course, this depends on the
12:59person, the dose, the mode
13:00of administration. And we also
13:02know that cannabis use can
13:03cause cannabis use disorder in
13:05a subset of the population.
13:06We know that this isn't
13:07necessarily rare.
13:09It can exacerbate other existing
13:10mental illnesses, and there's no
13:12FDA approved therapy.
13:14And so today, when I
13:14talk about the adverse effects
13:16associated with THC and how
13:17CBG might interact with those
13:19adverse effects, I'm really focusing
13:21on some of these acute
13:22effects,
13:23because that's what we study
13:25in our laboratory.
13:27We know that cannabis use
13:28disorder is associated with withdrawal
13:30symptoms, so people have seen
13:32for a certain period of
13:33time.
13:34Many papers have shown this
13:35elegantly. I just have one
13:37paper here below,
13:39just because it was easy
13:40easy to reference for me,
13:41but I could fill this
13:42whole page up with, you
13:44know, references that are in,
13:45eight point font.
13:47We know that withdrawal symptoms
13:48actually mimic
13:50the symptoms that people are
13:52using cannabis for. So, for
13:54example,
13:55withdrawal is associated with increases
13:57in anxiety, irritability,
13:58physical symptoms, reductions in sleep,
14:01reductions in appetite.
14:03There's a hypothesis
14:05that,
14:06cannabis induced withdrawal might also
14:08increase sensitivity to pain, so
14:10kind of like hyperalgesia.
14:13And so, you know, there
14:14have been a couple of
14:15groups working on that.
14:17And so when we think
14:18about the popularity of cannabis
14:20use,
14:21right now,
14:23we know that there are
14:23risks. And so how do
14:25we address these risks amidst,
14:28increases in medical use? And,
14:30specifically,
14:31one of the primary reasons
14:32why people use medical cannabis,
14:34as I showed you before,
14:35was to help with chronic
14:36pain. And so we'll talk
14:37a bit a lot about
14:38that today.
14:40Chronic pain is given as
14:41a top reason for using,
14:43cannabis, and we know that
14:44in states that have legalized
14:45cannabis,
14:46for medical purposes,
14:48thirty percent of people with
14:50chronic pain use some type
14:51of medical cannabis, or at
14:52least that that was that's
14:53what was shown a couple
14:54of years ago that might
14:56have increased
14:57now.
14:58But, you know, whether or
14:59not cannabis
15:00is helpful for chronic pain
15:03is really,
15:05a big question mark. As
15:06many of you know, you
15:07know, for every
15:09randomized
15:09controlled trial that's published, there's
15:11probably four meta analyses analyses
15:13that are published subsequently,
15:16to really understand, you know,
15:19wrap our heads around, can
15:21cannabis and cannabinoids
15:22across different modes of administration?
15:24Can it be helpful for
15:25chronic pain? What is chronic
15:27pain? What are the adverse
15:28effects? Do the adverse effects
15:30outweigh the potential benefits if
15:32the potential benefits are seen?
15:34So there are mixed findings
15:35with respect to whether or
15:36not cannabis and cannabinoids can
15:38be helpful for chronic pain,
15:40and, also, there are adverse
15:41effects.
15:42So that's the chronic pain
15:43part of it.
15:44I did mention,
15:46this improving appetite component of
15:49cannabis and cannabinoids.
15:51And there is this idea,
15:52that's been documented in literature
15:55that chronic pain
15:57is,
15:57positively associated with decreases in
16:00appetite. So another way to
16:01say this is that, frequently,
16:03you know, people who have
16:04chronic pain, there's an association
16:06with reductions in food intake.
16:09And when you improve one
16:10of those, you generally improve
16:12the other one.
16:13And so this talk is
16:14going to really tackle both
16:15the appetite,
16:17as well as the pain
16:18components.
16:19And we know that there's
16:20potential for cannabis and cannabinoids
16:22for both the chronic pain
16:24as well as the appetite.
16:27We know that there's really
16:28good data supporting the utility
16:30of THC,
16:32for improving appetite,
16:34and reducing nausea. We know
16:36this from many studies back
16:38in the nineteen eighties that,
16:40demonstrated through a series of
16:42placebo randomized controlled trials
16:44where dronabinol, the synthetic form
16:46of THC, was studied for
16:48this for this endpoint and
16:50was subsequently approved, for chemotherapy
16:52induced nausea,
16:54and and anorexia.
16:57We know that there's another
16:58formulation of the same drug
17:00that you can take as
17:01a solution that was later
17:03approved in the two thousands
17:04called Syndros. Again, it's just
17:06Tranavanol, the same thing, synthetic
17:08THC
17:09that was also approved for
17:10this indication.
17:12When you look at THC,
17:15it seems like it could
17:16be fairly promising
17:17as a therapeutic that can
17:19hit both
17:21the reductions in appetite as
17:22well as the chronic pain
17:24that co occur,
17:26in the patient population. So
17:27I'm sure if there are
17:28clinicians here in the audience
17:29who have dealt with elderly
17:31people or people with chronic
17:32pain,
17:33the reductions in appetite probably
17:35resonates.
17:37When you look at the
17:37FDA approved medications,
17:40for
17:41for appetite improvement,
17:43there are only three options
17:45as far as I know
17:46at this point.
17:47Two, which are, you know,
17:49pregnenolone
17:50and, and a testosterone derivative.
17:53Both of these have, pretty
17:55nasty side effects. And then
17:57we have dronabinol, which is
17:58the synthetic form of THC.
18:01And of the three, THC
18:03is really the only one
18:04to my knowledge that might
18:05be helpful for pain. Yet,
18:07as I showed you, THC
18:09definitely has some adverse effects
18:11that
18:13aren't as desirable as a
18:15as a clinical therapeutic.
18:17And so today, we're gonna
18:18talk about,
18:19you know, how cannabis constituents
18:21might be helpful in reducing
18:23harms and potentially improve outcomes,
18:25again, from this
18:26THC sparing type of perspective.
18:29And so when we think
18:30about the different constituents, I
18:32talked a little bit about
18:32the phytocannabinoids
18:34that I'll talk a little
18:34bit about in a minute
18:36as well as the terpenes
18:37that are not unique to
18:38the cannabis plant.
18:39And it's thought that these
18:40constituents might play an important
18:42role in cannabis effects in
18:43general, specifically related to THC.
18:46And so
18:47when we think about the
18:48cannabis plant, there are well,
18:49I guess this is debated,
18:51but there are definitely a
18:52hundred and twenty or more
18:55unique chemicals in the cannabis
18:56plant,
18:58that
18:59we know of. And delta
19:01nine tetrahydrocannabinol
19:02is the one that is
19:03most studied. As I demonstrated
19:05to you, there are a
19:06host of adverse effects associated
19:08with THC. It's intoxicating. It
19:10can have cognitive impairing effects.
19:12It can have what's called
19:13abuse liability.
19:14So people like it. People
19:16will wanna take it again.
19:17We know that when people
19:18take it frequently, there's a
19:20subset of the population that
19:21will develop physiological dependence. Not
19:23everybody develops physiological dependence,
19:26but that does exist.
19:28We know that, for example,
19:29anxiety
19:30is a,
19:31adverse effect of THC depending
19:34on the dose and route
19:34of administration.
19:36But we also know that
19:37it can be a therapeutic
19:38for improving appetite, reducing nausea,
19:40and there should be a
19:41question mark there helping with
19:43chronic pain.
19:45When you look at preclinical
19:46models,
19:47with respect to delta nine
19:48tetrahydrocannabinol's
19:49effects for antinociception.
19:51So for pain relief, there's
19:53been quite a few studies
19:54across
19:55a range of different preclinical
19:57assays looking at a number
19:58of different, pain,
20:00animal models of of pain
20:02conditions that have demonstrated that
20:04THC is promising.
20:07When you look at, population
20:08based studies for people who
20:09are using,
20:11THC based products for pain,
20:13subjects do report pain relief.
20:15And when you look at
20:15randomized controlled trials in chronic
20:17pain patients, again, there is
20:19a good signal for certain
20:20types of chronic pain that
20:22THC,
20:23might be helpful,
20:24for those indications.
20:26And then when you look
20:27at controlled laboratory studies, the
20:28work that we do that
20:30actually recruits healthy participants
20:32in order to be able
20:33to
20:34probe signals
20:35with respect to the potential
20:36therapeutic effects of cannabis and
20:38cannabinoids and variables that might
20:39impact it.
20:40We know that, THC
20:43can be analgesic in a
20:45dose dependent and route dependent
20:46way.
20:47And so this was a
20:48study,
20:49that we did back in
20:50two thousand thirteen,
20:53looking at how route of
20:54administration
20:55and dose can impact pain
20:57response in healthy participants. So
21:00we elicited a painful response
21:02using something called a cold
21:03pressor test, which I'll talk
21:04about in a minute, and
21:05we measured. We wanted to
21:07see just based off a
21:07route of administration where there
21:09are differences and also based
21:10off of dose.
21:11And what we found was
21:12that the, reduction in pain
21:14does occur, but that's not
21:16without adverse effects as,
21:18you could have predicted
21:19me to say. And so
21:20this is a modified figure.
21:22Actually, this isn't modified. This
21:23is the figure from
21:24from, that paper where we
21:27had participants,
21:28take oral THC, so dronabinol
21:31twenty milligrams or smoke
21:33nearly an equivalent amount of
21:34THC, inhale an equivalent amount
21:36of THC.
21:38So a pretty low strength
21:39of cannabis, four percent THC.
21:42And then they were also
21:43subjected to placebo.
21:45And, again, these are healthy
21:46participants who are actually pretty
21:48frequent,
21:49cannabis
21:50smokers
21:51in this particular population.
21:53And we use something called
21:54a cold presser test where
21:55we have people
21:56tell us after they put
21:57their hand in ice cold
21:58water at what point does
22:00that cold water feel painful,
22:02and how long can they
22:03keep their hand in the
22:04ice cold water. It says
22:05pain tolerance. What we see
22:07here is pain threshold.
22:08And what you could see,
22:10with the dotted line is
22:12the
22:13percent
22:14of the participants'
22:15baseline threshold. So before they
22:17got the drug,
22:19how much did their
22:21pain threshold change? So the
22:23higher
22:24the threshold, the more
22:26they can withstand the pain.
22:28And we captured this effect
22:30over the course of six
22:32hours of a session. And
22:33what you could see is
22:33that when participants received placebo,
22:35we did not see any
22:36fluctuation
22:37in pain threshold.
22:39But when participants
22:40smoked cannabis with THC in
22:42it, we saw immediate increase
22:44in pain threshold as expect
22:46as expected based off of
22:47pharmacokinetics.
22:49And it quickly came back
22:50down to baseline. And with
22:51oral THC,
22:53we saw a slow onset
22:54of that analgesic effect, but
22:57it was longer lasting than
22:58with the inhaled,
23:00as one would expect.
23:02And when we
23:04look to see, you know,
23:05the adverse effects associated with
23:07both routes of administration, similarly,
23:09when we ask people to
23:10rate how high they felt
23:11on a scale of zero
23:12to one hundred, zero meaning
23:14not high at all, a
23:15hundred being very, very high,
23:16maximally high,
23:18we saw that the smoked,
23:19cannabis with THC produced intoxicating
23:22effects that were immediate
23:24and of high magnitude.
23:26The oral THC
23:28produced slower onset of effect,
23:29and the magnitude was not
23:31as,
23:32significant.
23:33And then we asked participant
23:35abuse liability.
23:37One of the areas of
23:39research that I've been engaged
23:41in for the last twenty
23:42years is related to the
23:43abuse related effects of psychoactive
23:46substances. And so this is
23:47something that we do in
23:48our laboratory.
23:50And we ask people how
23:51good of a drug effect
23:52they feel, how much they
23:53like it, how much they're
23:54willing to take it again.
23:56Now, of course, keep in
23:56mind that these people are
23:58they do use cannabis, so
24:00it would be very surprising
24:01if they did not experience
24:03a good effect,
24:04from our cannabis. But what
24:05we can see here is
24:06that the good effect rating
24:09was different between the oral
24:10administration,
24:12relative to the smoked administration.
24:14Smoked had a a higher
24:16magnitude of effect than oral,
24:18and, actually, oral didn't really
24:19look any different than than
24:21a placebo.
24:23And so what we could
24:23see here is a separation
24:25between
24:26the different effects of THC
24:29based specifically on route of
24:30administration.
24:31We saw,
24:33analgesic effects with two routes
24:35of administration,
24:36but intoxication
24:37and abuse liability ratings were
24:39much lower with the oral
24:40THC relative to the smoked.
24:42And so this was oh,
24:44yeah. Sorry. Yeah. Sorry if
24:45I'm, interrupting you. But Please.
24:47In the pre like, in
24:48this study that you just
24:49showed the results,
24:51they were cannabis. You're like
24:52healthy individuals who use cannabis
24:54frequently. Right?
24:57Yes. So these were people
24:58who are not who are
24:59tolerant
25:00probably, to some degree.
25:02And so the twenty milligrams
25:03of THC
25:04is a pretty hefty dose,
25:06for people relative, you know,
25:07to doses that for people
25:09who are not experienced.
25:11So this was a these
25:12these were people who were
25:13pretty tolerant to to THC's
25:15effects Mhmm. I I would
25:17say.
25:18And they preferred
25:20the route of administration that
25:22use cannabis use was smoking
25:24or they you had both
25:25subjects who had edibles or
25:28smoking?
25:29These participants were smokers.
25:31Smokers. Yeah. Yeah. Yeah. These
25:34participants were smokers.
25:36Had they been using orally,
25:38we might have seen a
25:40a different response.
25:41This,
25:42study was also using a
25:44double dummy design. So every
25:45single session this was repeated
25:48repeated measure, so everybody got
25:49all drug conditions.
25:51During every session, participants smoked
25:53a cannabis cigarette that had
25:55THC in it or did
25:56not, and they also got
25:57a capsule that either had
25:58the THC in it or
25:59did not. And so they
26:01didn't know which one had
26:02the THC, if it had
26:04THC, and the experimenters didn't
26:06know either.
26:07Mhmm. Mhmm. That's what we
26:09used to Yeah. Yeah. Thank
26:10you. Thank you for the
26:11question. Happy to answer any
26:12questions along the way.
26:15What this
26:16study demonstrates to us is
26:17that even though, you know,
26:18we're using healthy participants,
26:20we were able to
26:22test
26:23and understand
26:24signals
26:25with respect to cannabinoid induced
26:27analgesia
26:29and understand in tandem some
26:30of the adverse effects that
26:32are interesting to me
26:34as a scientist that started
26:35off studying substance use disorders
26:37as well,
26:38as the public with respect
26:40to the public health relevance.
26:41And we knew from the
26:42study I only showed a
26:44couple of figures from this,
26:45but we knew that
26:46we can reliably induce these
26:48effects and that it was
26:50dependent on route of administration,
26:52dependent on and dependent on
26:54dose. And so we were
26:55able to test these effects
26:56in humans, again,
26:58in healthy participants and use
27:00this cold presser test. And
27:01I'll talk a little bit
27:02more about the cold presser
27:03test in a minute. So
27:04other phytocannabinoids
27:06that I know you've heard
27:06of, of course, is cannabidiol.
27:08Unlike THC, cannabidiol is not
27:10intoxicating. It does not have
27:12abuse liability
27:13at very high doses given,
27:15every day
27:16if there is a cessation
27:19of that drug being administered.
27:21To our knowledge, we have
27:23not seen the literature has
27:24not seen any type of
27:25withdrawal from cannabidiol. So it's
27:28very different than THC
27:30even though molecularly it's quite
27:32similar.
27:32We know that it has
27:33therapeutic effects. It was FDA
27:35approved for pediatric seizure disorders
27:37back in two thousand eighteen.
27:38There's a hypothesis that it
27:40might be helpful for certain
27:41types of anxiety. We know
27:43that pain is one of
27:43the primary reasons why people
27:45use CBD.
27:46But at this point in
27:47time, the overwhelming evidence of
27:49CBD by itself and exclusion
27:51without any THC,
27:53it's
27:55the evidence is is sparse,
27:57and
27:58the the field is working
28:00in that area.
28:02In addition to CBD and
28:04THC, there's many other minor
28:05cannabinoids that are of interest,
28:07Cannabinol, which people think it
28:08might be helpful for sleep,
28:10CBDV,
28:11and then, of course, CBG,
28:13which is the minor cannabinoid
28:14that I'm gonna be talking
28:15about today.
28:17We're doing some work with
28:18some other minor cannabinoids as
28:20well.
28:21CBG is interesting,
28:22because when we started working
28:24on this, there was really
28:25only animal studies related to
28:27CBG, and it was
28:29clear from those few animal
28:30studies,
28:31as I'll show you in
28:32a minute, is that it
28:33did not have the same
28:34type of THC related effects,
28:37the cadavermetic
28:38effects that are prototypical
28:40of
28:41cannabinoids that act specifically at
28:43that c v one receptor.
28:44So it looked very different
28:46than THC.
28:48And there was interest,
28:50in the preclinical
28:51literature as well as, you
28:53know, the industry
28:55and people who are using
28:56CBG,
28:57for its potential helpfulness for
28:59reducing pain,
29:03helping with, appetite, antidepressant like
29:06effects. And then also now
29:07there's this,
29:09part of the literature that
29:10looks at immune function and,
29:13and as well as anxiety.
29:16So as I mentioned before,
29:18we're seeing a booming trend
29:19and interest into these, minor
29:21cannabinoids probably in part because
29:23similar to c b CBD,
29:25there isn't that acute intoxication,
29:28acute cognitive impairing effects, and
29:30there's also hint in the
29:31preclinical literature suggesting that they
29:33might be therapeutic.
29:34And the big question is,
29:35you know, what are the
29:36effects of these types of
29:37products?
29:38Are they even safe? At
29:40what dose are they safe?
29:41You know, at what mode
29:42of administration? And, also, of
29:43course, are they therapeutic for
29:45the indications for which they're
29:46given?
29:47And if you look at
29:48the holistic interest in the
29:50cannabis plant with all these
29:51different chemicals that exist in
29:53the cannabis plant, there's been
29:55great interest in understanding how
29:56these constituents might work together.
29:58And as you know, at
30:00at Yale, you know, there's
30:01been a lot of work
30:02in this area that there
30:03is evidence that CBD might
30:05reduce some of THC's negative
30:06effects, although there's a lot
30:08of work coming out now
30:09about the pharmacokinetic
30:10interaction of the two.
30:12And here, we are interested
30:13in specifically looking at CBG.
30:15Is it is there a
30:16potential here for CBG to
30:18reduce some of the adverse
30:19effects of
30:20THC?
30:21CBG reduce the adverse effects
30:23of THC while also improving
30:24the, therapeutic profile of THC
30:27by enhancing the therapeutic effects.
30:29And so here's cannabagiol and
30:31delta nine THC. I'm not
30:32gonna go into the medicinal
30:33chemistry of this because I
30:34am definitely not a chemist.
30:36But for those in the
30:37audience, hopefully, you appreciate that
30:39I put the structures here.
30:41When we look at the
30:42preclinical evidence related to CBG,
30:44I
30:46I mentioned before,
30:47the literature demonstrating that CBG
30:49lacks this THC like cycle
30:52activity in animal models, and
30:53so this is an example.
30:55Catalypsy is a prototypical
30:57behave behavior
30:59of THC and other drugs
31:01that act similarly at the
31:02CB1 receptor at THC. And
31:04you can see in the
31:05blue line with CBG that
31:07CBG does not produce catalepsy,
31:09but THC in the black
31:10well, THC and a THC
31:12like substance, c p five
31:13five nine four zero, which
31:14is this THC like substance,
31:16does produce catalepsy.
31:19And when you look at
31:20the antinociceptive
31:21effects, so that's
31:23code for saying the pain
31:24relieving effects in animal models.
31:27Again, you could see that
31:28THC like substance in the
31:30black circle.
31:31And the blue there in
31:33this particular assay, they demonstrated
31:35that
31:36CBG does have modest antinociceptive
31:39effects. It doesn't reach the
31:41magnitude of the CP compound,
31:43but it does have,
31:45it does have modest effects
31:46there.
31:47There's also been,
31:48literature in the animal model
31:50showing that it can improve
31:51appetite. And remember, what we're
31:53interested in here is a
31:55potential
31:56cannabinoid based therapeutic that can
31:58both improve appetite as well
31:59as improve pain without the
32:01adverse effects. And so here
32:02in animal models, it seems
32:04like CBG might be one
32:05of those.
32:06And
32:07then even though we weren't
32:08looking at this initially,
32:10there's evidence demonstrating that CBG
32:12might have anxiolytic effects. And
32:13so this was demonstrated
32:15in a recent study in
32:17the elevated plus maze, which
32:18is a animal model that
32:20can measure,
32:21anxiogenic and anxiolytic effects of
32:23drugs. And what you can
32:24see here
32:25with increasing doses of CBG,
32:27there was a anxiolytic
32:29response,
32:30demonstrating a signal that potentially
32:33CBG might be helpful in
32:35reducing anxiety in humans if
32:37it was if it's translated
32:38as such. I won't get
32:39much into mechanism of action,
32:41but I will say that
32:42CBG has a very different
32:43pharmacology
32:44than THC, and we can
32:46talk a little bit about
32:46that if there are audience
32:47members who are interested in
32:49that.
32:50When we first started out
32:51this study, and this was
32:53a grant that we wrote
32:54in twenty
32:56twenty twenty, and I think
32:58it was in twenty twenty
32:59one, we got funding, and
33:00then it took forever as
33:01you'll see to to get
33:03off the ground.
33:04At that time, there was
33:05really
33:06nothing in humans,
33:09very little in humans, I
33:10should say, that
33:12investigated the effects of CBG.
33:15But we knew at the
33:16time that CBG naturally occurred
33:17in cannabis at
33:19at measurable levels that we
33:22thought concentrations would be high
33:23enough to likely have some
33:25effect.
33:27And the doses that we
33:28chose for this study were
33:29really guided based off of
33:31what people are exposed to.
33:32Because, again, this was a
33:34study that was
33:35developed,
33:36before we knew about any,
33:39safety profile of CBG in
33:41humans. And so when we
33:42submitted the protocol to the
33:44FDA, what we did was
33:45we demonstrated that we were
33:46going to be exposing participants
33:48to CBG concentrations
33:50that they would normally be
33:51exposed to when they're using
33:53cannabis.
33:55So we did this study.
33:56It was a controlled environment,
33:58double blind placebo controlled. Again,
34:00we recruited people who use
34:01cannabis. Although they were occasional
34:04they used cannabis occasionally, so
34:06they weren't using cannabis every
34:07day. It was usually about
34:08once a week. I think
34:10I have the data here.
34:11And we were interested in
34:12looking at the therapeutic
34:13and adverse effects. And so
34:15what we did here, again,
34:16because this was the path
34:17of least resistance, people are
34:19usually exposed to CBG when
34:20they're inhaling cannabis. Most people
34:22inhale their cannabis.
34:24And so we were recruiting
34:25people who were using cannabis.
34:26And so we use inhaled
34:28mode of administration using this
34:30vaporizer here, the stores at
34:32Embecol Vaporizer.
34:34And so as many of
34:35you know who are working
34:36with THC and other other
34:37types of products, you know,
34:39the study was is these
34:41studies are a regulatory nightmare
34:42regardless of whether or not
34:44cannabis becomes marijuana becomes schedule
34:46three. It's still very difficult,
34:49for a number of reasons,
34:50but we got through it.
34:52And so the primary goal
34:54here, again, was to look
34:55specifically at the potential analgesic
34:57effects as well as appetite
34:59stimulating effects based off of
35:01how we built this study.
35:02This is we were interested
35:04in understanding, does CBG alone,
35:06like the preclinical work, could
35:08it help to reduce pain
35:09and improve appetite, and might
35:11it interact with THC in
35:13a beneficial way?
35:18Cognitive impairing effects of THC.
35:20And, also, does CBG have
35:21any intoxicating effects on its
35:23own? Right? Based off of
35:24the preclinical literature, it would
35:26suggest not. But, you know,
35:27we we really wanted to
35:28test that.
35:30So while we were doing
35:31this study, and I see
35:32that Carrie, doctor Cutler is
35:34here,
35:35there was a survey that
35:36was launched of people who
35:37were using CBG.
35:39And the number one reason
35:41why people were using CBG
35:42was for anxiety
35:44followed by chronic
35:45pain. And so following that
35:47survey,
35:48doctor Cutler did a field
35:50study where she compared oral
35:51CBG, and I'm hoping I'm
35:52getting these doses right, twenty
35:54milligrams
35:55versus placebo.
35:57And
35:57the study our study launched,
35:59but the field was evolving.
36:01And what that study particularly
36:03found
36:04was that in a naturalist
36:05semi naturalistic setting, when people
36:08were exposed to a stressor,
36:10what you can see is
36:11that CBG, the red line,
36:13reduced anxiety ratings compared to
36:15placebo.
36:16And so this kind of
36:18shifted our
36:20somewhat shifted our focus, and
36:21you'll see a little bit
36:22why it really helped to
36:23shift shift our focus.
36:25But we decided to look
36:26at well, we were already
36:27looking at, anxiety related behaviors,
36:30just because we always ask
36:31about mood ratings. And so
36:32we always include a a
36:34couple of questions related to
36:36whether or not people feel
36:37anxious.
36:38Okay? So we included anxiety
36:40ratings.
36:41For here here, this is
36:42an example of the cold
36:43presser test. Again, one of
36:44our primary outcomes was looking
36:46at pain response, and we
36:47use a cold presser test
36:48here. I describe pain threshold
36:50and pain tolerance. We see
36:51here that the experimenter is
36:52the same sex as the
36:54participant,
36:55which is helpful in controlling
36:56for,
36:57gender or sex specific responses.
37:00And the reason why we
37:02use the cold pressor test
37:03is because it has predictive
37:04validity specific for specifically for
37:07therapeutics that are helpful for
37:08chronic pain. So even though
37:10it's an acute painful stimulus,
37:12therapeutics that work specifically for
37:14acute pain don't necessarily provide
37:15a signal here. And what's
37:17also nice about this test
37:18is that every person is
37:20their own control. So, for
37:21example, people have very different
37:23ranges of pain tolerance, but
37:24we're really comparing every human
37:26being
37:27to their pre drug administration
37:29pain special and pain tolerance
37:30to their post drug administration
37:32pain special and pain tolerance.
37:33And we're also comparing their
37:34response to a placebo condition
37:36as well as different doses
37:38of CBG and THC.
37:40And during the course of
37:41these sessions, we just ask
37:42people on a visual analog
37:43scale,
37:44please rate how high you
37:45feel. Please tell us how
37:47good of a drug effect
37:48you feel from not at
37:49all too extremely.
37:50Tell us how hungry you
37:52are because we were interested
37:53in appetite, and tell us
37:54how anxious you feel from
37:56not at all too extremely.
37:58We were interested in in,
38:00appetite, and so we measured,
38:03caloric intake and macronutrients,
38:06and everything like that and
38:07associated with, subjective ratings of
38:09hunger.
38:10So this was a nine
38:11session study. It was a
38:12little bit of a beast
38:13to do in Los Angeles
38:15where public transportation isn't that
38:16great.
38:17But we had participants come
38:19in for eight hour sessions.
38:21And across,
38:22nine different sessions, the dose
38:24order was randomized, but we,
38:26had people who are exposed
38:28to everybody was exposed to
38:29a low dose of CBG,
38:31five milligrams, a higher dose
38:32of CBG, fifteen milligrams,
38:34a low dose of THC,
38:35a higher dose of THC,
38:36and then the combinations. Again,
38:38this was all done, through,
38:41through the sores and bicl
38:42vaporizer.
38:43And we looked at appetite.
38:45We looked at pain, anxiety,
38:46intoxication, and abuse liability.
38:48And today, I'll be talking
38:49about cardiovascular
38:51effects, which I don't necessarily
38:53always talk about, but, is
38:54relevant here. And we also
38:56collected blood to look at
38:57pharmacokinetics
38:58to see if there's a
38:59pharmacokinetic
39:00interaction between the two.
39:02And so the question here
39:03was, does CBG
39:04alone,
39:05does it decrease
39:06pain and increase appetite?
39:09Might it enhance THC analgesic
39:11effects, or might it reduce
39:12THC's adverse effects?
39:14And here specifically related to
39:16abuse liability.
39:17And then,
39:19we decided to also look
39:20at anxiety. And so here's
39:21a picture of doctor Pabon.
39:23Many of you know her,
39:24and she's a postdoc who
39:25really spearheaded this study.
39:27So we had nineteen participants
39:29who who completed all sessions
39:30and pretty evenly split between
39:32males and females, and you
39:33can see that they were
39:34on the lighter end of
39:35cannabis use.
39:36Happy to answer any questions
39:38if there are any. I
39:39see that Laura. Okay.
39:42Okay.
39:43So,
39:44again, we wanted to understand
39:46CBG's effects by itself as
39:48well as with THC.
39:49So the first question is,
39:51are people high? When you
39:53expose somebody to CBG, do
39:55they get high?
39:56This is a hallmark sign
39:58of THC as you'll see
39:59in a minute. And you'll
40:01see that on a scale
40:02of zero to one hundred,
40:03this just goes up to
40:04seventy five. CBG did not
40:06make people high. Okay? So
40:08didn't really didn't have an
40:09effect there, whereas THC did.
40:11THC alone,
40:13increased ratings of intoxication.
40:15And the question was, would
40:16CBG reduce it,
40:19because of some other,
40:21mechanism of action that's not
40:22at the c v one
40:23receptor necessarily.
40:25We found that CBG did
40:27not change,
40:28THC induced intoxication.
40:30Next, we want to know
40:31about abuse liability. Does THC
40:33have any abuse liability? Do
40:35people like the CBG?
40:37What we found was that
40:38people
40:39had no
40:41no subjective ratings associated with
40:44abuse liability of CBG at
40:46all. And so, similarly, for
40:48drug liking, take again, good
40:49effect. We really did not
40:50find a signal for the
40:51low dose of CBG or
40:53for this high dose of
40:53CBG.
40:54Unlike THC,
40:56where, again, even though these
40:57are occasional users, we found
40:59that people did report having
41:01a good effect from THC,
41:03and CBGs did not, mitigate
41:05that effect.
41:06So next, we wanted to
41:07understand if CBG would impact
41:09THC's analgesic effects.
41:11We found that CBG did
41:12not have any effect on
41:13its own, nor did it
41:15impact THC's effects. So we
41:17did not
41:18our hypothesis did not come
41:20out as planned for this
41:21particular endpoint.
41:22What about appetite related effects?
41:25What we found is that
41:26when we asked people how
41:27hungry they felt before they
41:29had access to food, so
41:31there was a period of
41:32time where they did not
41:32have access to food, and
41:34we found that ratings of
41:35hunger increased
41:36as they would under the
41:38placebo conditions, but ratings of
41:39hunger,
41:40increased a little further with
41:42CBG.
41:43And it's expected with five
41:44milligrams of THC. The lower
41:46strength of THC, we found
41:48further increases in hunger.
41:49Interestingly, with the highest dose
41:51of THC, we actually found
41:52that it reduced hunger and
41:54increased
41:55feelings of nausea. I think
41:56they got too much of
41:57a drug effect.
41:59But the combination of THC
42:00and CBG did not further
42:02increase ratings of hunger.
42:04So next, we looked at
42:05this anxiogenic
42:06effect.
42:07And so what Alisa found,
42:09doctor Pabon found, was that
42:11compared to how
42:12people rated their feelings of
42:14anxiety, you know, they come
42:15into lab. It's a strange
42:17environment.
42:17They're inhaling THC in a
42:20at nine AM on a
42:21Monday morning. You know, it's
42:22it's a very different type
42:23of experience than what people
42:25are used to. So there
42:26is some low levels of
42:27subjective ratings of anxiety. And
42:29what we found was that
42:30relative to placebo, CBG
42:32reduced these subjective ratings of
42:34anxiety.
42:35Unlike
42:36THC, the fifteen milligram,
42:38dose of THC increased ratings
42:40of anxiety.
42:41The combination, though, with THC
42:43and CBG
42:44reduced these ratings of THC
42:47by itself,
42:48which was interesting and aligned
42:50with, what others and doctor
42:51Kuller have found before.
42:53We were interested in looking
42:54at heart rate.
42:56Heart rate is one of
42:57the hallmark signs of THC
42:59exposure.
43:00Those of you who work
43:01in the in these labs
43:03will know it's like a
43:03telltale sign that somebody
43:05somebody's more reliable than intoxication.
43:08CBG did not increase heart
43:09rate, but THC did. And
43:12CBG did not augment these
43:13effects at all.
43:15But we ask people,
43:17to tell us about how
43:19they feel about their their
43:21heart. They feel like their
43:22heart is racing.
43:24And what's been found before
43:25is that with THC induced
43:27anxiety,
43:28usually, it's associated with this
43:30increased subjective ratings of heart
43:32racing.
43:33CBG,
43:35did not have this effect.
43:36In fact, it was lower
43:37than placebo,
43:39but THC did have a
43:41pronounced,
43:42increase in ratings of, heart
43:45racing,
43:45and CBG
43:47reduced these effects in orange.
43:49So it was interesting because
43:51we found that,
43:53CBG reduced anxiety
43:55subjective
43:56ratings of anxiety did not
43:58actually augment the cardiovascular
44:00effects of THC,
44:01but reduced the subjective
44:03feeling
44:05that people's hearts were racing
44:07that participants' hearts were racing.
44:09So to summarize,
44:11you know, this was kind
44:12of a mixed bag of
44:12a study.
44:14CBG didn't have abuse liability,
44:16and no analgesic effects. In
44:18fact,
44:19we wondered if CBG had
44:20had any effects at at
44:22all, really, but we did
44:24find this, modest reduction in
44:26in anxiety.
44:28But CBG did not impact
44:29THC induced appetite or pain
44:31effects, but the t the
44:33relationship between CBG and anxiety
44:35was definitely interesting. So
44:37THC shows potential for pain
44:39and appetite.
44:40There are adverse effects that
44:41might limit,
44:43its utility,
44:44and preclinical studies point to
44:46the fact that CBG might
44:47have this potential.
44:50But it seems like angiogenic
44:51effects of THC might be
44:53the target for this type
44:55of, THC sparing effect, not
44:57necessarily the abuse liability component.
45:00And so rigorous studies of
45:01CBG's effects alone and THC
45:03sparing effects are definitely needed.
45:05So so just to summarize,
45:08cannabis constituents, I hope I
45:10can I've convinced you that
45:11cannabis constituents have potential to
45:13reduce harms,
45:15and improve outcomes.
45:17It could also
45:18exacerbate, you know, some some
45:20of the harms associated with
45:21THC and certain combinations.
45:24We have an expanding cannabis
45:26market, and I'm sure that
45:27this isn't going to slow
45:28down,
45:29especially with the with the
45:30with the news. We know
45:32that THC concentrations are increasing
45:34across products, and there are
45:35many novel cannabinoids. So we're
45:37starting to study CBC now,
45:39as well as terpenes.
45:40And these controlled studies that
45:42are getting signals from the
45:43preclinical literature as well as
45:45signals from what types of
45:47offerings there are in dispensaries
45:49and what people are are
45:50using are really very important
45:52to understand,
45:53how they might act together
45:55to either improve the safety
45:56profile or actually
45:58perhaps make these,
45:59products even more risky.
46:01And with that, I'd like
46:02to thank, the funding and
46:04the collaborators,
46:06and the participants.
46:08And I'm happy to take
46:09questions.
46:12Thank you so much, Ziva.
46:14This was really
46:15interesting, and, I'm sure this
46:17was a very hard study
46:19to do. You had so
46:20many multiple sessions
46:22in like, I know that
46:23regulator issues are always an
46:25issue, but also you had
46:26a very, like, every dose
46:28three times, and
46:30that was a lot for,
46:31also two
46:33compounds. But thank you.
46:35This is really wonderful. And
46:37if anyone has any question,
46:39please either type it in
46:41the chat or raise hands.
46:43But I'd like to start
46:44with one question that I'm
46:45sure you had looked at
46:47that. Although the sample size
46:49might be small, but any
46:50sex differences?
46:54The sample size is very
46:55small for this.
46:57We're looking at,
46:58some sex dependent effects for
47:00THC specifically across a range
47:02of studies that use similar
47:03doses. But for CBG at
47:05this point, it's it's really
47:06small. Yeah. Yeah. But the
47:11males and females didn't differ
47:12in their in their baseline
47:14demographics, which was nice, but
47:15that that will be for
47:16a larger study.
47:18Yeah. Next one.
47:21I'm sorry.
47:22So there is one question
47:24in the chat.
47:26I'm sorry.
47:28I'm coming off a cold.
47:29That was a great presentation.
47:31I might have missed it,
47:32but any changes with pharmacokinetic
47:35and cognitive changes?
47:37Really good question.
47:39So the bloods are
47:41are being analyzed,
47:44as we speak.
47:46And then with respect to
47:47cognitive impairment, we we did
47:50we did look at,
47:52those effects. They weren't our
47:53primary outcome, so we haven't
47:55delved into the into
47:57that data quite yet.
47:59But that will be important
48:00as well because we know
48:01that THC has effects on
48:02that endpoint.
48:04Thank you.
48:06Doctor Mizrahi has a question.
48:07Romina.
48:08Hi.
48:09Excellent presentation. Thank you.
48:12So I I I I
48:14will ask you a difficult
48:15question,
48:17really because I don't know
48:18the answer to this question.
48:19So I thought maybe you
48:20have a better,
48:22you know, you can help
48:23with this. So what I
48:24what I think all all
48:25the time when,
48:27I,
48:28I think about,
48:30cannabinoids
48:31is the the mechanism of
48:32action.
48:34Right? And so and and
48:36I was thinking, oh, how
48:37great it would be, this,
48:40this,
48:41slide with the mechanism of
48:42action of every one of
48:44these, compounds.
48:47I don't have it.
48:50Do you have any sense
48:51of what we would say?
48:52I mean, I know a
48:53bit I mean, I know,
48:54I guess, for,
48:56THC,
48:57but not even for CBD,
48:59we know.
49:00Not fully even for THC.
49:02No clue, at least for
49:04me, for the other compounds.
49:06Do you have a better
49:08understanding,
49:09or can you shed some
49:10light on this,
49:11or we
49:12we keep trying? You know,
49:14I I
49:16frequently, I think, you know,
49:17people talk about how the
49:19cannabis plan is like this,
49:21you know,
49:22so many different chemicals that
49:24might be helpful.
49:25We're a pharmacologist.
49:26I really think it's a
49:27total nightmare.
49:28I don't you know? I
49:30I mean,
49:31I'm seeing that realizing that
49:33it's not restricted
49:35to cannabinoids or natural products.
49:36I mean, we know that
49:38even the therapeutics that are
49:40used today for, you know,
49:41mental illness, like, it's some
49:43it's really hard to pinpoint
49:44the mechanism of action. But
49:46But I think, Romina,
49:48I grew up I grew
49:49up studying opioids, and I
49:51loved the pharmacology,
49:54back then. It seemed simple.
49:56You have the delta opioid
49:57kappa. You had different agonists,
49:59different antagonists that, you know,
50:01were had different efficacy, different
50:04potencies. It was such a
50:05beautiful model.
50:06And I think I was
50:07turned on to the cannabinoid
50:08system because I thought the
50:10pharmacology
50:11would be as equally fun
50:12and meaningful.
50:14But the cannabis plant is
50:16like you know, we call
50:17them cannabinoids, but as you
50:18said, like, CBD has
50:20hundreds of different mechanism of
50:22action and whether or not
50:23actually acts in a meaningful
50:24way at the endocannabinoid system
50:25is like a huge question
50:27mark.
50:28So how to make sense
50:30of the pharmacology of each
50:31one of these chemical constituents
50:33and how they interact
50:35together and whether that's, like,
50:36a pharmacodynamic
50:38effect.
50:39Is it? Or is it
50:40really chalked up to just
50:42pharmacokinetics,
50:43which in my head is
50:44really important,
50:45but a lot more boring
50:47than the pharmacodynamic
50:49interaction.
50:50And so I don't you
50:51know, we don't know. If
50:52you look at the preclinical
50:53literature, it seems like CBG's
50:55action at the serotonin system
50:57is probably
50:59responsible for a lot of
51:00these effects. And, you know,
51:01how does THC
51:03and CBG interact at that
51:04system, you know, I think
51:06is a question mark.
51:07You know, there's some good
51:08preclinical behavioral pharmacologists
51:10who we have in common.
51:12A lot of them are
51:12in Canada,
51:14who are really trying to
51:15work out this pharmacology.
51:16But I think
51:18I think it's exciting. I
51:20think it is very confusing.
51:21It's not like the opioid
51:23field as much as I
51:24kind of, like, hoped it
51:25would be.
51:27But there might be some
51:28unique combination of mechanisms
51:30there that might produce
51:33a clinically relevant
51:34positive outcome for specific populations
51:37across different doses and different
51:39modes of administration. But it
51:40is a big puzzle. And
51:41I think one
51:42I think one that, like,
51:43we have to work on
51:44just given the proliferation of
51:46products and the popularity. Right?
51:48They're, like, not going away.
51:49It's not like, you know,
51:50the old antipsychotics that we
51:51don't know, like, how they
51:52work, but they somehow work.
51:54But we moved on, and
51:55we can get get rid
51:56of them. So
51:58so it will be a
51:58fun puzzle to figure out.
52:00I agree. Thank you. Carrie
52:02Cutler. So much. Yes. Go
52:04ahead.
52:05Hey, Ziva. It's really great
52:08talk. It's really fun to
52:10hear all your Eva's findings,
52:12especially about CVG.
52:14I was super excited to
52:16see that you were able
52:18to mitigate the THC
52:19induced anxiety to some extent
52:21in CBG.
52:23We also just replicated that
52:25finding that
52:27CBG reduces anxiety, but not
52:29with that very cool THC
52:31aspect to it.
52:33In our most recent data
52:35from our lab study, we
52:37also did not find,
52:38any evidence of analgesia.
52:41And we used a cold
52:42presser as well and found
52:44that did absolutely nothing to,
52:48latency to withdraw the hand
52:50or pain ratings or anything
52:51like that.
52:52And I'm just curious if
52:54you think that we are
52:55just hitting the wrong kind
52:57of pain
52:57because so many people are
52:59reporting using for pain, the
53:01reporting beneficial effects. You see
53:03that evidence in the rodent
53:04literature.
53:06I'm not sure if you're
53:07aware of what kind of
53:09pain they're looking at in
53:10that rodent literature. They're also
53:11getting massive doses, but I'm
53:13just wondering if maybe we're
53:14going at the wrong kind
53:15of pain.
53:19So thank you so much
53:20for coming, Carrie. It's great
53:22to hear you, and to
53:23hear about your your recent
53:25study.
53:26I mean, the CPT is
53:28really just,
53:29it's supposed to have predictive
53:30validity for for
53:33therapeutics that are for chronic
53:34pain, whatever chronic pain means.
53:37A lot of people use
53:38QST
53:39to try and look at,
53:40you know, whether or not
53:41cannabinoids can have a signal
53:43there. So across a range
53:44of sensory modalities, you know,
53:46is there a signal? And
53:48THC has not been shown
53:50to have a signal there
53:52in that in that type
53:53of in that type of,
53:55series of of pain tests.
53:57CBG might.
53:59I'm I'm not sure.
54:01I think
54:04it's hard to study pain
54:06in people, both patient populations
54:08and healthy participants.
54:10CPT is just one way
54:12to get at it. But,
54:15you know, there's all kinds
54:16of there's anxiety induced pain,
54:19that can be looked at
54:20compounded with a cold presser
54:21test. There is
54:24inflammatory
54:25types of pain, so capsaicin,
54:27which is done at Yale,
54:29if I remember correctly.
54:31So which is very difficult,
54:33as difficult as it is
54:34to do these studies. Looking
54:35at capsaicin induced pain is
54:37a whole another
54:38ball of wax.
54:40So there's definitely different avenues.
54:41With respect to the preclinical
54:43literature,
54:44there hasn't been as much
54:45with CBG as there has
54:47been with THC and and
54:48CBD even at this point.
54:51So I think there's some
54:52question marks,
54:53and some different thoughts about
54:54that.
54:56Thank you. Thanks again for
54:57a fantastic talk and wonderful
54:59research, Ziva.
55:00Thank you, Carrie.
55:01Thank you so much. We
55:02have one question from doctor
55:04Omari.
55:05Doctor Omari, do you, if
55:07you have if you can
55:08ask your questions or I
55:10can read it.
55:13I'm gonna read it.
55:14I read that this wasn't
55:15the focus of your research,
55:17but do you have any
55:18opinion about,
55:20like, in literature that suggests
55:23about the effects of CBN
55:24on pain and intoxication?
55:27Interesting. I haven't we usually
55:29think about CBN with respect
55:31to the
55:32the, quote, unquote, like, sleep
55:34inducing effects of CBN. I
55:35haven't I haven't necessarily thought
55:37about it, with respect to
55:38pain.
55:40I don't expect it to
55:43be intoxicating.
55:46It's it's been shown you
55:48know, it doesn't with a
55:49few studies that have been
55:50done, it doesn't in humans
55:52with high high much higher
55:54doses than what we usually
55:55give a THC. It doesn't
55:57really have that THC, like,
55:58profile, and there's, you know,
56:00questions about whether or not
56:01it is it is helpful
56:02for sleep.
56:03But for pain, I I
56:05don't know.
56:06I'm trying to, like in
56:07in the back of my
56:07head, I'm trying to scroll
56:08through the preclinical literature that
56:10I can think of in
56:10the back of my head
56:11as as CBN shown
56:14an interesting signal for pain.
56:15I can't it it doesn't
56:17come up for me,
56:19that it would. But at
56:20the same time, you know,
56:22as I said, there is
56:23a positive association
56:25between,
56:27between pain and,
56:29reductions in appetite. That feels
56:31like a
56:32positive red there's an association
56:35between reductions in appetite and,
56:37severe pain. Right? And so
56:38one would think we know
56:40that sleep also goes hand
56:41in hand with pain, also
56:42with appetite.
56:43So one one might think
56:45that if there is an
56:46agent that can help with
56:47sleep, it might also be
56:48helpful for for pain and
56:49vice versa. So there might
56:51be that potential there similar
56:52with THC with CBG.
56:55Thank you so much.
56:58Oh, I oh, that's just
56:59the thanks. Okay. So,
57:02if there is any other
57:03question,
57:04we have, like, two minutes,
57:07but if there is no
57:09other question,
57:10I have general questions about
57:12pain. And I know that
57:14we use different models of
57:15acute pain when we want
57:17to, investigate the effects of,
57:20cannabinoids.
57:21But it seems that chronic
57:22pain might really have very
57:24different mechanism or different components
57:26to it compared to acute
57:28pain. Do you what do
57:29you think about that?
57:30I think this is a
57:31really important point that we
57:33have to include in the
57:34conversation. So, for example, I
57:35always say CPT this the
57:37colorectal test has predictive validity
57:39for therapeutics for chronic pain.
57:41But when we think about
57:42chronic pain and the neurobiological
57:44adaptations that likely occur
57:46over the months that people
57:48are experiencing the chronic pain,
57:49we know based off of
57:51animal studies, based off of
57:52pet imaging studies, that there
57:54are
57:55changes in in people's neurobiology.
57:58And so
58:00how do
58:02how does pharmacology
58:03change then? We know that
58:05pharmacology changes in preclinical literature.
58:07You know, we talked about
58:08opioids before.
58:09It's been nicely fleshed out.
58:11So
58:12is that the same for
58:12cannabinoids? You know, we know
58:14that the that the CB1
58:15receptor changes
58:17in response
58:18to chronic pain, at least,
58:20again, in animal models. I'm
58:21I'm trying to think about
58:22human, but this is a
58:23really important question. You know,
58:25we have these assays.
58:27Maybe they can potentially provide
58:28a signal for the
58:30therapeutic effects of of an
58:32agent
58:33that might be helpful for
58:34pain so we can move
58:35into a into a pain
58:36population. But it is hard.
58:38At a certain point, you
58:39gotta move on. You gotta
58:41move on to a phase
58:42two study and be able
58:43to understand the effects in
58:45the pain population. The question
58:46is, though, is like, oh
58:47my gosh. What type of
58:48pain are you gonna
58:51look at? I can't be
58:52what's chronic pain? Chronic pain's
58:52a million different things. So
58:52you gotta figure out and
58:53hone in on
58:55what what is the hypothesized,
58:59analgesic potential
59:01with respect to pain pathology.
59:03And so it's it's hard.
59:05Yeah. It's a hard thing
59:06to study. Yeah. Totally get
59:07it. Yeah. We have one
59:08final question. I know we
59:10are out of time, but,
59:12Lola,
59:14do you want to ask
59:15a question? Sure. Hi, Ziva.
59:17Fantastic presentation. Thank you so
59:18much. I have so many
59:19questions, but I'll follow-up
59:21on all of them with
59:22you separately.
59:24Question here is next minor
59:26cannabinoids that you might study.
59:28What are they gonna be?
59:31So we're we're working on
59:32finishing some terpene stuff.
59:41The terpenes are very interesting.
59:43Some of the most interest
59:44in terpenes terpene profiles that
59:48you might be sending? But
59:49to the ones the ones
59:50we're finishing right now, we
59:51have preclinical
59:52counterparts to them is myrcene
59:54and beta caryophyllene.
59:56Mhmm. But there are some
59:56other ones that are popping
59:58up, like Humalene,
59:59that are interesting.
01:00:04There's
01:00:05a lot of opportunity.
01:00:07You know, the the plan
01:00:08has a lot of different
01:00:09chemicals. I think
01:00:11part of what part of
01:00:12this is really guided based
01:00:14off of, like, survey data,
01:00:16based off of what people
01:00:17are using, you know, when
01:00:18you go to the dispensaries.
01:00:19Like, what's the next hot
01:00:21thing? You know? CBDs got
01:00:23you know, might be getting
01:00:24out of favor.
01:00:26So
01:00:28I'll
01:00:29I'll have to think about
01:00:30what's what's next. We do
01:00:32we do have a study
01:00:33with CPC
01:00:36lined up.
01:00:39So, you know, that that's
01:00:40exciting.
01:00:43But, yeah, there's a lot
01:00:44of different possibilities.
01:00:46Alright. Thank you. Thank you,
01:00:48Lola. So much. It was
01:00:50wonderful having you today, Ziva,
01:00:53and I hope to see
01:00:54you again soon. Yeah. I'll
01:00:56see you in New York
01:00:57Running around Central Park.
01:01:00Take care. Have a nice
01:01:01day. Thank you, everybody. Thank
01:01:03you very much, everyone.
01:01:04Okay. Bye. Bye.