YC-SCAN2 November 2025 Webinar

Transcript

• 00:04We should get started.
• 00:05It's my,
• 00:07pleasure to introduce,
• 00:08Ryan Wandre.
• 00:10Ryan is a professor of
• 00:11behavior of psychiatry,
• 00:14at Johns Hopkins.
• 00:16He works on the behavioral
• 00:17pharmacology
• 00:19research unit.
• 00:20I I think of Ryan
• 00:21as being, really one of
• 00:23the leading experts
• 00:25in human cannabis,
• 00:27pharmacology.
• 00:29His work has defined
• 00:31how product composition,
• 00:33dose, and route of administration
• 00:36shapes cannabis effects and pharmacokinetics.
• 00:40Some of his more notable
• 00:43contributions to the field include,
• 00:46a very important from a
• 00:47public health perspective
• 00:49that, most commercial cannabis edibles
• 00:52are often inaccurately
• 00:54labeled,
• 00:55and that's influenced,
• 00:57you know, regulatory policy nationwide.
• 01:01He has conducted landmark studies
• 01:03in cannabis withdrawal,
• 01:05and as it I can
• 01:07tell you personally influenced
• 01:08influenced my own work
• 01:10in in this space,
• 01:12and he has advanced the
• 01:13understanding of the variability and
• 01:15intoxication,
• 01:16impairment, and therapeutic response
• 01:19across smoking,
• 01:21vaporization,
• 01:22and,
• 01:23oral
• 01:24ingestion.
• 01:26His research extends
• 01:28to CBD,
• 01:29minor cannabinoids,
• 01:30effects on sleep,
• 01:33product testing, and cannabis drug
• 01:35interactions.
• 01:36I think, collectively,
• 01:38his work has significantly
• 01:40impacted public health
• 01:41clinical practice and regulatory practice.
• 01:43So,
• 01:44without further ado, Ryan.
• 01:50Thank you, Sarah. That was
• 01:51a a very
• 01:53welcome and touching introduction. I
• 01:55appreciate that, and, it's my
• 01:57pleasure to be here and
• 01:58to share some of our
• 01:59newer stuff with you.
• 02:01So I'm gonna focus,
• 02:03on
• 02:04two recent
• 02:06experiments. Actually, if you look
• 02:08at it, four recent experiments
• 02:09that we've, completed over the
• 02:11last two and a half
• 02:12years here at Hopkins,
• 02:15evaluating,
• 02:16oral and inhaled delta eight
• 02:18THC,
• 02:20and comparing it with delta
• 02:21nine THC. So,
• 02:24just as a a quick
• 02:26mention of disclosures,
• 02:27the research was funded by,
• 02:29the substance abuse and mental
• 02:31health service administration with material
• 02:33support from Storz and Nicholl,
• 02:35and that I do have
• 02:36paid consultantships
• 02:38with,
• 02:39some industry, but it's unrelated
• 02:41to this work here.
• 02:44So just to kind of
• 02:45orient us to
• 02:47the question here,
• 02:49delta eight THC is a
• 02:51an isomer of delta nine
• 02:53THC.
• 02:54And the
• 02:56from a, you know, chemical
• 02:58perspective, the difference between the
• 03:00two is a counterclockwise
• 03:02rotation of this double bond
• 03:04here from the nine position
• 03:05to the eight position.
• 03:07So
• 03:08almost chemically
• 03:09ident
• 03:10identical entities, and and both
• 03:13substances
• 03:14are naturally occurring in the
• 03:16cannabis
• 03:17plant. Although delta nine THC
• 03:19is typically much more abundant
• 03:21than delta eight THC.
• 03:24Now we are not the
• 03:25first people to do this
• 03:27work.
• 03:28So I often find myself
• 03:33following the pioneering work of
• 03:34Leo Hollister,
• 03:36in the nineteen seventies who
• 03:38did just an astounding,
• 03:42program of research on cannabinoids.
• 03:46And in nineteen seventy three,
• 03:48published a couple papers
• 03:51on oral and IV delta
• 03:53eight THC compared with delta
• 03:55nine THC at multiple doses.
• 03:58By their estimate, delta eight
• 04:00THC was about two thirds
• 04:02as potent as delta nine
• 04:03THC.
• 04:04And while I would love
• 04:06for that just to be
• 04:07the end of the story,
• 04:08you know, the challenge in
• 04:10in utilizing
• 04:11the data from back then
• 04:12is that
• 04:14the product,
• 04:16characteristics and routes of administration
• 04:19don't often translate to their
• 04:21current retail
• 04:22environment.
• 04:23And so we don't have
• 04:25many people using IV THC
• 04:27these days, but we do
• 04:28have a lot of people
• 04:29vaporizing it and inhaling it.
• 04:32And then just the limitations
• 04:34of their experimental model, back
• 04:36then was that
• 04:38they relied
• 04:39on
• 04:40observer reports and ratings
• 04:43of drug effects.
• 04:45And so we lacked the
• 04:46interoceptive
• 04:48effects that the the participants
• 04:50experienced of the drug exposure.
• 04:53We lacked,
• 04:55assessments of cognitive performance
• 04:57and and cognitive abilities and
• 04:59functioning,
• 05:00as well as pharmacokinetic
• 05:02assessments. And so what we've
• 05:04tried to do is with
• 05:05full acknowledgment
• 05:06of of what they did,
• 05:09in that pioneering work was
• 05:10rather to to extend that
• 05:13and and to see if
• 05:14we could add on to
• 05:15the story that they started
• 05:16to build
• 05:17fifty years ago.
• 05:20The other thing that led
• 05:21us to,
• 05:23studying this particular question,
• 05:26is that five years ago,
• 05:28the language in the twenty
• 05:30eighteen farm bill
• 05:32removed hemp and all derivative
• 05:34products from the Controlled Substances
• 05:36Act. So while there was
• 05:38specific language
• 05:39that exempted delta nine THC
• 05:43from that removal of the
• 05:44Controlled Substances Act, it did
• 05:46not extend to delta eight
• 05:48THC.
• 05:49And because delta eight THC
• 05:51is naturally occurring in the
• 05:52cannabis plant and in hemp
• 05:54plants even in trace amounts,
• 05:57it was argued by the
• 05:59hemp industry that delta eight
• 06:01is a legal byproduct
• 06:04of the hemp plant.
• 06:06And so over the last
• 06:07four years, really,
• 06:09there's been an explosion of
• 06:11delta eight and other kind
• 06:13of analog THC products that
• 06:16have emerged in a quasi
• 06:18label marketplace
• 06:20where these products are being
• 06:21sold without any regulatory control
• 06:24in gas stations and,
• 06:26head shops and,
• 06:29a number of other kind
• 06:30of CBD specific or hemp
• 06:32specific store environment retail environments.
• 06:35And we have,
• 06:36flower products. We've got vape
• 06:38cartridges, oral dose products, usually
• 06:40gummies,
• 06:42kind of representing
• 06:43the majority of the of
• 06:45that industry.
• 06:47But there's not much known
• 06:49about what's actually in those
• 06:50products, and and I'm happy
• 06:52that Cyril mentioned,
• 06:53some of our work with
• 06:55product surveillance analysis.
• 06:58We're in the process of
• 07:00finalizing
• 07:01a surveillance product testing study
• 07:04on these THC analog products.
• 07:07And what's interesting is delta
• 07:09eight THC is one of
• 07:11about a dozen different
• 07:13novel cannabinoids
• 07:15that have kind of emerged
• 07:16in this,
• 07:17quote, unquote, hemp marketplace,
• 07:20but it's by far the
• 07:21most predominant.
• 07:23And when we've analyzed both
• 07:26oral dose products and vaporized
• 07:28dose products, we see that
• 07:30indeed,
• 07:32most of the products do
• 07:33contain delta eight THC. So
• 07:35this is showing the detection
• 07:36of delta eight THC in
• 07:38thirty two of forty three
• 07:39samples,
• 07:40purchased in the Baltimore area
• 07:42from retail stores.
• 07:44But the other thing to
• 07:45highlight is just the range
• 07:47of milligrams
• 07:48per serving that we found.
• 07:50So everywhere from zero or
• 07:52near zero all the way
• 07:53up to two hundred and
• 07:54fifty milligrams per serving.
• 07:57So just keep that in
• 07:58mind. This is oral dose
• 08:00products
• 08:01as we go through and
• 08:02I show you the data
• 08:03from our laboratory studies.
• 08:05When we look at vape
• 08:07dose products, these are mostly
• 08:08the vape cartridges
• 08:10rather than flower products.
• 08:12But, again,
• 08:13forty three out of forty
• 08:14six THC analog products purchased
• 08:17in the Baltimore area contained
• 08:19delta eight THC
• 08:21at an average concentration of
• 08:22about sixty percent, but a
• 08:24range of just above zero
• 08:26all the way up to
• 08:28ninety percent.
• 08:30So
• 08:32what we've tried to do
• 08:33is take that data and
• 08:35this emergence
• 08:36of of of, an industry
• 08:40where people are really grappling
• 08:41with, well, what does this
• 08:43mean? What do these products
• 08:44do?
• 08:45At the anecdotal
• 08:47level, people often
• 08:49advertise or talk about delta
• 08:51eight as being, like,
• 08:53a safer,
• 08:55better version of delta nine
• 08:56THC. It's, they call people
• 08:59call it THC light or,
• 09:02diet weed or some stuff
• 09:03like that.
• 09:05Really kind of confusing
• 09:07names, but all of them
• 09:09seem to indicate it's a
• 09:10little bit safer. It's a
• 09:11little less worrisome.
• 09:13So our bread and butter,
• 09:17work here at at at
• 09:18Hopkins is to do controlled
• 09:20human laboratory studies with healthy
• 09:22adults,
• 09:24and we recruit folks who
• 09:26have prior,
• 09:27exposure to cannabis, but no
• 09:29use in the last thirty
• 09:30days. We're kind of eliminating
• 09:31the folks that have high
• 09:33daily use behavior with a
• 09:35high threshold of tolerance.
• 09:37We use a within subjects
• 09:39crossover design to the extent
• 09:41we can because we wanna
• 09:42minimize interindividual
• 09:44variability
• 09:45in our evaluation of of
• 09:47the drug product under scrutiny.
• 09:50And in this case, because
• 09:51there's both oral and inhaled
• 09:53dose products that predominate the
• 09:56market, we wanted to look
• 09:56at both routes of administration.
• 09:59So in this case, in
• 10:00in this the case of
• 10:01the studies that I'm gonna
• 10:02show you is we have
• 10:04a placebo control as well
• 10:05as an active control of
• 10:07delta nine THC because we're
• 10:08interested in how it relates.
• 10:11So I'm gonna show you
• 10:13data from four studies, and
• 10:14they're gonna be clustered into
• 10:16two,
• 10:17kind of pairs.
• 10:19So studies one and two,
• 10:22evaluated,
• 10:24ten, twenty, and forty milligram
• 10:26doses of delta eight THC
• 10:28and a twenty milligram dose
• 10:29of delta nine THC
• 10:31administered with both oral and
• 10:34vaporized routes of administration.
• 10:36Now these studies were recently
• 10:38published in the journal drug
• 10:40and alcohol dependence, and so
• 10:41this is kind of out
• 10:42in the world. It's not
• 10:43brand new data,
• 10:45but these things were just,
• 10:47hit press, over the summer.
• 10:50And,
• 10:51in the vaporization
• 10:53study, we used a a
• 10:54handheld vaporizer made by Storz
• 10:56and Bickel.
• 10:58The product was heated to
• 10:59two hundred and four degrees
• 11:01Celsius,
• 11:02and participants exhaled
• 11:04the the drug through a
• 11:05carbon filter to help mask
• 11:07and preserve the blinding.
• 11:09For the oral dose study,
• 11:11we baked pure delta eight
• 11:12THC or pure delta nine
• 11:14THC into a can
• 11:16an infused brownie format.
• 11:19And so in both of
• 11:20these cases across both all
• 11:21these studies, we're using pure
• 11:23delta eight THC and pure
• 11:25delta nine THC that were
• 11:26synthetically
• 11:28us for these experiments.
• 11:30Now in these first two
• 11:32studies,
• 11:33we had nineteen participants complete
• 11:36the oral dose study and
• 11:37twenty participants complete the vaporized
• 11:39study.
• 11:40We had a pretty good
• 11:41balance of,
• 11:43males and females in the
• 11:44study and good diversity in
• 11:46terms of racial profiling,
• 11:48and our average age was
• 11:49around thirty years old.
• 11:51These people had no past
• 11:53month cannabis use, no tobacco
• 11:54use, and light to moderate
• 11:56alcohol use.
• 11:58In studies three and four,
• 12:01these were sequential studies. So
• 12:03after the first two studies
• 12:04were done, we saw a
• 12:05couple interesting outcomes.
• 12:08One was that
• 12:09our max doses weren't
• 12:12quite producing maximal drug effects
• 12:14relative to what we've seen
• 12:16in other experiments we've done,
• 12:18in our laboratory.
• 12:19So we wanted to push
• 12:20the dose a little bit
• 12:21and fill out our dose
• 12:23response curves. We added,
• 12:25basically replicated those first two
• 12:27studies with oral and vaporized
• 12:28dosing at thirty and sixty
• 12:30milligrams of delta eight THC
• 12:33and thirty milligrams of delta
• 12:34nine THC.
• 12:36In addition to our traditional
• 12:38self report assessments and and
• 12:40pharmacodynamic
• 12:41assessments and pharmacokinetic assessments,
• 12:43we also added simulated driving,
• 12:46and standard field sobriety tests.
• 12:48We were really interested in
• 12:50assessing
• 12:51what did the effect of
• 12:53delta A THC look on
• 12:55driving
• 12:56performance. Again, we, for oral
• 12:58dosing, we, baked pure compounds
• 13:01into a brownie format. For
• 13:03inhalation, we used a different
• 13:05vaporizer made by the same
• 13:06company. So it's the same
• 13:07vaporization technology,
• 13:09but we moved to the
• 13:10volcano, which is a desktop
• 13:12vaporizer
• 13:13simply because the dosing pad
• 13:15and the handheld,
• 13:17vaporizer was too small to
• 13:19hold the amount of liquid
• 13:21required to get that sixty
• 13:23milligram dose. It was leaking
• 13:25through. So we went to
• 13:26the volcano, which had a
• 13:27bigger dosing pad just for
• 13:29feasibility.
• 13:31In this these two experiments,
• 13:33we again had twenty participants
• 13:35in each study,
• 13:37a decent,
• 13:38ratio of, males to females,
• 13:41again, a mean age of
• 13:42about thirty and good racial
• 13:43diversity,
• 13:44no tobacco use, no past
• 13:46month cannabis use, and light
• 13:47to moderate alcohol use.
• 13:50So the assessments that we're
• 13:51looking at across all four
• 13:53studies,
• 13:54included subjective assessments of drug
• 13:56effects on a hundred point
• 13:58visual analog scale,
• 14:00cognitive performance tests that included
• 14:03a,
• 14:04paced, serial addition task where
• 14:06participants had to,
• 14:08were presented with a number,
• 14:10one,
• 14:12single,
• 14:13digit integer at a time,
• 14:15and they had to add
• 14:16sequential numbers and select the
• 14:18sum of the last two
• 14:19numbers viewed at the bottom
• 14:20of the screen. And that
• 14:21went on and on for
• 14:22ninety trials.
• 14:23We did a computerized version
• 14:25of the digit symbol substitution
• 14:27task where patterns were presented
• 14:29and had to be replicated
• 14:30using
• 14:44We use the Druid,
• 14:46app, which is a two
• 14:48and a half minute test
• 14:49of multiple aspects of cognitive
• 14:51functioning,
• 14:52including,
• 14:53divided attention,
• 14:55working memory, and and higher
• 14:56order cognitive processing.
• 14:59Here's a picture of our,
• 15:01high level driving,
• 15:02simulator, which is a a
• 15:04proper sit down modeling a
• 15:06car, hundred and thirty five
• 15:08degree view with three monitors,
• 15:10big steering wheel, seat belt,
• 15:12the whole nine.
• 15:14We had our staff trained
• 15:15by Maryland State Police in
• 15:18administering
• 15:19field sobriety tests.
• 15:21Our staff went through the
• 15:22same training as police cadets
• 15:24do. It was a three
• 15:25day course,
• 15:26and then we had a,
• 15:28Maryland State Police officer
• 15:30who was a trainer come
• 15:32in and do fidelity testing
• 15:33throughout the experiments
• 15:35on ten percent of all
• 15:37assessments.
• 15:39And then we collected vital
• 15:40signs and collected blood and,
• 15:42for biomarkers to look at
• 15:44pharmacokinetics.
• 15:46So what I'm gonna do
• 15:47is I'll show you results
• 15:49for the first two experiments
• 15:51side by side, oral dosing
• 15:52in the left hand panel
• 15:54and vaporization on the right
• 15:55hand panel.
• 15:57So you can just kinda
• 15:58see side by side what
• 15:59oral dosing looks like versus
• 16:01vaporized dosing and,
• 16:03the difference,
• 16:04between delta eight doses and
• 16:06and and the comparison delta
• 16:08nine and placebo doses.
• 16:11So for this first slide,
• 16:12you're seeing subjective
• 16:14overall drug effect ratings.
• 16:16And you can see on
• 16:17the left hand panel with
• 16:18oral dosing, really nice dose
• 16:20orderliness in terms of overall
• 16:22subjective drug effect.
• 16:24The delta nine THC dose
• 16:26was qualitatively
• 16:28the highest rate rated,
• 16:30drug effect,
• 16:31and maxing out at about
• 16:33a fifty out of a
• 16:34hundred,
• 16:35on our overall drug effect
• 16:37scale.
• 16:38With vaporization,
• 16:40we got a qualitatively
• 16:42higher
• 16:43peak magnitude compared with oral
• 16:45dosing.
• 16:46The thirty mill the twenty
• 16:47milligram delta nine dose was,
• 16:49again, qualitatively the highest dose.
• 16:52The delta eight doses were
• 16:53dosed orderly, but we got
• 16:54much less separation
• 16:56between the ten milligram dose
• 16:58and the forty milligram dose.
• 17:01And I believe that is
• 17:02a route of administration
• 17:04specific
• 17:05effect
• 17:06where we're getting differential metabolism
• 17:09with oral dosing and we're
• 17:11getting kind of bolus dosing
• 17:13with inhalation
• 17:14that minimizes that,
• 17:16difference in in metabolism, and
• 17:18I'll show you some pharmacokinetic
• 17:20data that supports that.
• 17:22And, again, probably some titration
• 17:24in terms of how the
• 17:26the drug is being administered.
• 17:29So, again, overall, we're getting
• 17:31moderate
• 17:32to mild drug effects at
• 17:33these doses.
• 17:35But what's interesting is that
• 17:36across the subjective drug effects,
• 17:38and I'll show you how
• 17:39high people reported,
• 17:42feeling,
• 17:43again, a little bit more,
• 17:45spread with the delta doses
• 17:47on this rating, but by
• 17:48and large,
• 17:49not as much,
• 17:51dose difference in the vapes
• 17:53compared with the oral dosing.
• 17:55Again,
• 17:56at the peak level, the
• 17:57delta nine THC comparison doses
• 17:59is qualitatively
• 18:01higher, but it's about the
• 18:02same as that forty milligram
• 18:04delta eight THC dose,
• 18:06at the peak amount with,
• 18:09both ratings.
• 18:11And then
• 18:13by and large with the
• 18:14delta eight drugs up to
• 18:15forty milligrams, we'd see much
• 18:17in the way of unpleasant
• 18:19or unwanted drug effects. So
• 18:21very little side effects
• 18:23and also very few side
• 18:24effects of this twenty milligram
• 18:25delta nine THC dose.
• 18:28So, again, these are experienced
• 18:29but not acutely tolerant cannabis
• 18:31users. And so this is
• 18:32a little not really terribly
• 18:34surprising.
• 18:36But what we do see
• 18:37is we see
• 18:39the subjective
• 18:40perception of impairment of cognitive
• 18:42function.
• 18:43So it's not aversive,
• 18:45but they do feel impaired.
• 18:47And you can see here
• 18:49and this is self ratings
• 18:50in their confidence and their
• 18:52ability to go drive a
• 18:53vehicle at that moment.
• 18:55As you can see with
• 18:56oral dosing, that kinda kicks
• 18:58in about one hour post
• 18:59dosing.
• 19:00They remain less confident up
• 19:02until about four hours, and
• 19:03then it doesn't return back
• 19:05to baseline till about eight
• 19:06hours after dosing.
• 19:08With inhalation,
• 19:09the peak is is almost
• 19:11immediate
• 19:12and is sustained for about
• 19:14an hour and a half
• 19:15to two hours post dosing.
• 19:18And, again, not much difference
• 19:20between twenty and forty milligrams
• 19:22of delta eight with a
• 19:23vaporization, but we do see
• 19:25that
• 19:26bigger separation of dose with
• 19:27oral dose.
• 19:30When we look at our
• 19:32objective
• 19:32measures of cognitive performance starting
• 19:35with the the DRUID global
• 19:37impairment score,
• 19:39what's interesting is while subjective
• 19:42drug effect ratings were qualitatively
• 19:45higher for vaporization
• 19:46than they were for oral
• 19:48dosing,
• 19:51we see kind of
• 19:53they they get a little
• 19:54more equaled out. I do
• 19:56wanna mention that there's a
• 19:58lot of the same participants
• 20:00participated in both oral and
• 20:02vaporized
• 20:03studies.
• 20:04It's not the same people.
• 20:06So I think in this
• 20:08these first two experiments,
• 20:10I think thirteen
• 20:12of the nineteen to twenty,
• 20:15participants were identical in in
• 20:17both sub both experiments,
• 20:19but we had five or
• 20:21six people who were unique
• 20:23to each experiment. That may
• 20:24explain the difference in in
• 20:26the peak magnitude across these
• 20:28things.
• 20:29But, again,
• 20:30really nice dose orderliness
• 20:32with the oral dosing and
• 20:34no difference from placebo and
• 20:36cognitive performance
• 20:38with the ten or twenty
• 20:39milligram doses of delta eight.
• 20:42But the forty milligram dose
• 20:44of delta eight was comparable
• 20:46to the twenty milligram dose
• 20:48of delta nine and was
• 20:49significantly
• 20:50different from placebo.
• 20:52Same thing with the vaporization.
• 20:55Although, we do see a
• 20:56little bit more difference
• 20:58with the lower doses of
• 20:59delta eight. So, again,
• 21:01that subjective ratings where they're
• 21:03feeling more a higher drug
• 21:05effect, they're also showing
• 21:06impairment at lower doses with
• 21:08vaporization.
• 21:10When we look at the
• 21:11PACE serial addition task, again,
• 21:13this is a an evaluation
• 21:14of of working memory performance.
• 21:17With oral dosing, again, ten
• 21:19and twenty milligrams of delta
• 21:21eight are not showing much
• 21:22difference from placebo,
• 21:24but the forty milligrams of
• 21:25delta eight is really showing
• 21:26the same level of impairment
• 21:28as the twenty milligrams of
• 21:29delta nine, and that's different
• 21:31from placebo.
• 21:33With vaporization,
• 21:34less impairment is being noted.
• 21:36And, actually, here,
• 21:38qualitatively,
• 21:39we're seeing a a qualitatively
• 21:41greater impairment of functioning with
• 21:43the forty milligrams of delta
• 21:45eight than the twenty milligrams
• 21:46of delta nine THC.
• 21:50Cardiovascular
• 21:51effects,
• 21:52are are interesting and follow
• 21:54a similar pattern
• 21:56to,
• 21:57the cognitive performance effects
• 22:00in that,
• 22:02the forty milligrams of delta
• 22:04eight show a significant change
• 22:06from baseline and are comparable
• 22:08to,
• 22:09twenty milligrams of delta nine
• 22:11THC
• 22:12across these two. And then,
• 22:14again,
• 22:15a stronger
• 22:17cardiovascular effect with vaporization
• 22:19versus oral dosing where the
• 22:21two lower doses of delta
• 22:22A THC
• 22:23really aren't different from placebo.
• 22:28Now where things get really
• 22:30interesting and where we try
• 22:31to start to understand so
• 22:33on the pharmacodynamic
• 22:35side, we're seeing things that
• 22:37look to show that
• 22:39delta eight THC is about
• 22:41half as potent as delta
• 22:43nine THC.
• 22:45And so when you look
• 22:45at preclinical,
• 22:47CB one receptor binding data,
• 22:50there's a little bit of
• 22:51a signal that delta nine
• 22:53THC
• 22:54can bind a little bit
• 22:55more
• 22:56effectively at CB one than
• 22:58delta eight THC, but the
• 23:00the KIs are not terribly
• 23:02different.
• 23:03And so
• 23:04what else could,
• 23:06be driving this differential potency
• 23:09at the pharmacodynamic
• 23:11level?
• 23:12And,
• 23:13when you look at parent
• 23:15concentrations of these two molecules,
• 23:18so is it a differential
• 23:20absorption
• 23:21of the drug?
• 23:22So with oral dosing,
• 23:25we're looking at ten milligrams,
• 23:30twenty milligrams, and forty milligrams
• 23:32of delta eight THC in
• 23:33whole blood on the left
• 23:35hand panel. And this is
• 23:36just delta eight THC
• 23:38concentration in nanograms per milliliter.
• 23:41This is beautifully dose orderly.
• 23:43So, again, pharmacodynamically,
• 23:45we had beautiful dose orderliness
• 23:48with the delta eight THC
• 23:49pharmacodynamic
• 23:50response, and that maps on
• 23:52perfectly to what we're seeing
• 23:53with the parent drug in
• 23:56blood. Importantly,
• 23:57with placebo
• 23:58and delta nine THC dosing,
• 24:00we're not seeing any conversion.
• 24:02So when we're giving the
• 24:03delta nine THC dose, we
• 24:05don't see delta eight THC.
• 24:06And similarly,
• 24:08in the right hand panel,
• 24:09when you were looking and
• 24:10detecting delta nine THC,
• 24:12we're not seeing any delta
• 24:14eight. So there's no contamination
• 24:15of our drug products.
• 24:17We got good purity.
• 24:20And then when we look,
• 24:21these are two twenty milligram
• 24:22doses, and the peak
• 24:24is about five nanograms per
• 24:26milliliter for delta eight and
• 24:28about three and a half
• 24:29to four for delta nine.
• 24:31So we're seeing qualitatively
• 24:33stronger drug effects with delta
• 24:35nine
• 24:36about the same parent drug
• 24:38concentration, maybe a little bit
• 24:40less.
• 24:42Where things get fascinating is
• 24:43when we look at the
• 24:44eleven hydroxy metabolite. So, again,
• 24:46this is oral dosing only.
• 24:50We see a little bit
• 24:51less dose orderliness here for
• 24:53delta eight. So from ten
• 24:55to twenty milligrams, we see
• 24:56that doubling of the concentration
• 24:59curve, but we don't see
• 25:00it double again going from
• 25:02twenty to forty milligrams. We
• 25:04only see a fifty percent
• 25:05increase in the peak,
• 25:07and the peak gets pushed
• 25:08over
• 25:09to the right by one
• 25:11hour.
• 25:12So the metabolic curve is
• 25:14changing with dose.
• 25:16And when you look at
• 25:17the concentration
• 25:18of delta nine eleven hydroxy,
• 25:21it's double
• 25:23what you have for the
• 25:24eleven hydroxy delta eight at
• 25:26the same dose.
• 25:28So twenty milligrams of delta
• 25:30e is resulting in half
• 25:32the concentration
• 25:33of the eleven hydroxy delta
• 25:35nine at twenty milligrams.
• 25:37And as you know, eleven
• 25:39hydroxy
• 25:40is a psychoactive
• 25:41metabolite of the parent molecule
• 25:43for both delta eight and
• 25:44delta nine,
• 25:46and this is likely where
• 25:47we're getting that differential pharmaco
• 25:49pharmacodynamic effect between the two
• 25:51drugs.
• 25:52And, similarly,
• 25:54we're getting,
• 25:56double
• 25:57the carboxy
• 25:59inactive metabolite for delta eight
• 26:01than we are for delta
• 26:02nine.
• 26:03So,
• 26:04on a pharmacokinetic
• 26:06level,
• 26:08the liver is metabolizing
• 26:10these two drugs differently even
• 26:12though they're chemically nearly identical,
• 26:16and that's resulting
• 26:17most likely in in is
• 26:19the main driver of these
• 26:20differential pharmacodynamic
• 26:22effects.
• 26:23When we look at,
• 26:25vaporization,
• 26:27what's interesting here is a
• 26:28couple things of note.
• 26:30Again,
• 26:31two twenty milligram doses
• 26:34are resulting in identical
• 26:37time course and peak concentrations
• 26:39in whole blood of the
• 26:40parent drug.
• 26:42But, again,
• 26:43we're not seeing what what's
• 26:45a little bit different from
• 26:47the oral dosing is we
• 26:48see
• 26:49almost doubling from ten to
• 26:51twenty milligrams of of parent
• 26:53delta eight with inhalation.
• 26:55We don't see it quite
• 26:57there for, twenty to forty.
• 26:59So, again, this suggests that
• 27:01there's a little bit of
• 27:02a titration,
• 27:03maybe a little bit of
• 27:04a faster metabolism,
• 27:07but something with the drug
• 27:08absorption and and and clearance
• 27:10of of the parent drug
• 27:12with vaporization that explains that
• 27:14difference.
• 27:15We're also seeing much higher
• 27:16peak concentration.
• 27:18So, you know,
• 27:20twenty five to fifty milligrams
• 27:22of delta eight in whole
• 27:24blood versus with oral dosing,
• 27:27our peak drug
• 27:28plasma concentrations were at, like,
• 27:31five.
• 27:32So, again, those higher pharmacodynamical
• 27:35levels likely driven by higher
• 27:37bolus exposure to the parent
• 27:39drug in blood.
• 27:41When we look at the
• 27:42eleven hydroxy metabolite,
• 27:46we see that doubling at
• 27:48the same twenty milligram dose.
• 27:50It's about one
• 27:51nanogram per mil with vaporization.
• 27:54It's about two for,
• 27:56the delta nine.
• 27:58So
• 27:59twenty milligrams of delta nine
• 28:01gives you equal drug concentrations
• 28:02as forty milligrams of delta
• 28:04eight.
• 28:05The time course is a
• 28:06little bit different too. So
• 28:08you can see the delta
• 28:09nine eleven hydroxy metabolite
• 28:12lingering a little bit longer
• 28:13than the delta eight where
• 28:14you see a more rapid
• 28:16reduction.
• 28:17And so, again, that's likely
• 28:18contributing to the stronger or
• 28:20longer lasting pharmacodynamic
• 28:22effects.
• 28:23And then similar to the
• 28:24oral dosing, we see higher
• 28:26levels the carboxymetabolite
• 28:27with delta eight versus delta
• 28:29nine.
• 28:31So
• 28:32I mentioned a little bit,
• 28:33are they titrating? What do
• 28:35we see there?
• 28:37Tori Spindle, who's a colleague
• 28:39of mine here at Hopkins,
• 28:40trained under Tom Eisenberg at
• 28:42Virginia Commonwealth
• 28:43University.
• 28:44And while they were there,
• 28:45they established a collaboration with,
• 28:48some scientists over at the
• 28:49American University of Beirut
• 28:52and
• 28:53worked on developing puff topography,
• 28:57equipment that is flexible across
• 28:59different methods of inhalation.
• 29:01And so what we were
• 29:02able to do in that
• 29:03first experiment where we use
• 29:05the handheld vaporizers, we're able
• 29:07to capture detailed puff topography
• 29:10metrics,
• 29:11while people were using,
• 29:13these,
• 29:14drugs.
• 29:15And what you can see
• 29:16is as the dose of
• 29:18delta eight THC
• 29:20increased,
• 29:21the average puff duration decreased.
• 29:25The flow rate remained the
• 29:27same.
• 29:29The
• 29:30total number of puffs increased,
• 29:33and the volume of air
• 29:35inhaled
• 29:36decreased.
• 29:37So what people are doing
• 29:38is they're exhibiting
• 29:40a little bit of titration
• 29:41based on dose.
• 29:43So they're taking
• 29:45shorter,
• 29:46kind of less intense puffs
• 29:48and a
• 29:49a lower overall total volume
• 29:51of air being,
• 29:53inhaled. So probably stretching out
• 29:55the exposure to the drug
• 29:57over that period of time,
• 29:59which may also explain why
• 30:00we see a little bit,
• 30:02more of a concentration,
• 30:04a less
• 30:05dose orderliness
• 30:07or less distance between doses
• 30:09on both the pharmacokinetic
• 30:11and pharmacodynamic
• 30:12measures.
• 30:13And at the twenty milligram
• 30:15dose, we're seeing really no
• 30:17difference between delta eight and
• 30:19delta nine on that puff
• 30:20duration
• 30:21or on the inner puff,
• 30:25duration.
• 30:26We see a higher number
• 30:28of puffs for delta eight
• 30:29versus delta nine,
• 30:31and we see greater total
• 30:33inhaled volume for delta eight
• 30:35versus delta nine. So, again,
• 30:36a little bit of a
• 30:37titration
• 30:38based on the potency of
• 30:40the drug that's being administered.
• 30:43So moving on to,
• 30:46our next set of experiments.
• 30:48So, again, this followed sequentially.
• 30:50Right after we finished those
• 30:51first two experiments, we were
• 30:53interested because
• 30:54we didn't quite see the
• 30:56overall peak magnitude. We didn't
• 30:58see a a lot of
• 30:59very robust impairment of functioning
• 31:01at the even the forty
• 31:02milligram dose of delta eight.
• 31:05We were looking at those,
• 31:07products that we purchased it
• 31:08and evaluated, and we saw
• 31:09doses as high as two
• 31:11hundred, two hundred fifty milligrams
• 31:13of of delta eight.
• 31:14Now
• 31:15given that that first experiment,
• 31:17we knew delta eight was
• 31:18about half as potent as
• 31:20delta
• 31:21nine. I
• 31:22didn't feel very comfortable trying
• 31:24to give people
• 31:25four hundred, you know,
• 31:27two hundred milligrams of delta
• 31:28eight thinking that it was
• 31:30equivalent to a hundred milligrams
• 31:32of delta nine THC,
• 31:34to nontolerant
• 31:35users. So
• 31:37we thought filling in the
• 31:38dose response curve to thirty
• 31:40and sixty, so pushing that
• 31:42upper dose up twenty milligrams.
• 31:44And we had just finished
• 31:45an experiment where we had
• 31:46given thirty milligrams of delta
• 31:48nine t c acutely in
• 31:50the same vaporizer.
• 31:52So we felt we could
• 31:53do that safely in this
• 31:55population,
• 31:56and we felt pretty confident
• 31:57we'd get people pretty high
• 31:59and pretty intoxicated.
• 32:01And so what you can
• 32:02see here is this is
• 32:03subjective drug effect ratings again,
• 32:06and that's exactly what we
• 32:07did is is we pushed
• 32:09the dose up to the
• 32:10point where we're starting to
• 32:11hit the ceiling on overall
• 32:12magnitude of drug effects.
• 32:14We in all of our
• 32:16experiments, we've really not get
• 32:18an aggregate score of higher
• 32:19than eighty. There's always someone
• 32:21who's like, I've
• 32:22been higher before, but
• 32:24about half of our participants
• 32:26are capped out at a
• 32:27a rating of a hundred
• 32:28out of a hundred on
• 32:29this scale, and we're starting
• 32:30to see
• 32:31the emergence of unpleasant adverse
• 32:33effects. Remember, in those first
• 32:35two experiments, we didn't see
• 32:36anything higher than a total
• 32:38magnitude of about a five
• 32:40on this unpleasantness scale. Now
• 32:42we're getting up to about
• 32:43thirty with a thirty milligram
• 32:45dose of delta nine and
• 32:46a sixty milligram dose of
• 32:47delta eight. So that's kinda
• 32:49somewhere between twenty and thirty
• 32:51milligrams of delta nine, and
• 32:53forty and sixty milligrams of
• 32:54delta eight is where you
• 32:55push past the comfort level
• 32:57of most participants,
• 32:59most healthy adults.
• 33:02In terms of cognitive performance,
• 33:04we're seeing substantially more,
• 33:06robust impairment on the Druid
• 33:09application.
• 33:10Again,
• 33:11we're seeing that it's more
• 33:13sustained and a little bit
• 33:14more
• 33:15greater magnitude with oral dosing
• 33:17than with vaporization
• 33:19even though, subjectively,
• 33:21they reported stronger peak drug
• 33:23effects with vaporization than the
• 33:25oral dosing.
• 33:26I still don't quite
• 33:28understand that disconnect between the
• 33:30subjective
• 33:32intoxication
• 33:33and the impairment of functioning
• 33:35being kind of flipped between
• 33:36vape and and oral dosing,
• 33:39but it may relate to
• 33:40that
• 33:42pharmacokinetic
• 33:43difference and that higher level
• 33:45of the
• 33:46or different amount of the
• 33:48eleven hydroxy metabolite.
• 33:53Subjectively,
• 33:54they reported being very impaired
• 33:56and having low confidence in
• 33:57their ability to drive across
• 33:59all three doses.
• 34:00Definitely different from placebo
• 34:03in in all cases here.
• 34:05And then when we looked
• 34:06at actual simulated driving performance
• 34:08in that fancy driving simulator,
• 34:11I'm gonna show a couple
• 34:12things to you on on
• 34:14this slide that I think
• 34:15are important.
• 34:17One is that,
• 34:20this is a composite drive
• 34:22score that was developed by
• 34:23Austin Zamarripa and Tori Spindle,
• 34:25my colleagues here at Hopkins,
• 34:27based on a number of
• 34:29metrics that
• 34:30relate to overall driving performance.
• 34:34Included in this overall score
• 34:36is,
• 34:38deviation of lane position.
• 34:40It's the latency
• 34:42to break in a yellow
• 34:43light dilemma or in the
• 34:45instance of an object going
• 34:46out in front of the
• 34:47road.
• 34:48It's,
• 34:49the ability
• 34:50to follow a vehicle in
• 34:52front of you and keep
• 34:53the distance
• 34:54constant even though the vehicle
• 34:56in front is accelerating and
• 34:58decelerating.
• 34:59And so when they kinda
• 35:01rope all of those
• 35:02kinda key features together,
• 35:05this composite drive score
• 35:08is a numerical,
• 35:11reference of
• 35:12standard deviation
• 35:14change from the baseline
• 35:16performance for that particular driving
• 35:18session.
• 35:19So when you see a
• 35:20score of two here,
• 35:23that indicates that the performance
• 35:25for that person on the
• 35:27post drug exposure drive
• 35:30was two standard deviations
• 35:32worse than that per particular
• 35:34person
• 35:35on that day before they
• 35:37were given a drug.
• 35:39And so
• 35:40what I've highlighted here is
• 35:42this dotted line
• 35:44is
• 35:46using this metric on this
• 35:48driving simulator and these simulated
• 35:51drives.
• 35:52This is the
• 35:54rate of performance and the
• 35:56level of impairment
• 35:57that healthy adults showed when
• 35:59given alcohol to a point
• 36:01o eight blood
• 36:03alcohol concentration or breath alcohol
• 36:05concentration.
• 36:07And so with a thirty
• 36:08milligram dose of delta eight
• 36:09THC orally administered,
• 36:12we get about that same
• 36:14level of impairment.
• 36:15With sixty milligrams of delta
• 36:17eight, we get about double
• 36:19that.
• 36:19And with thirty milligrams of
• 36:21delta nine THC,
• 36:23we almost triple that in
• 36:26seventeen healthy adults.
• 36:29With vaporization,
• 36:32all three doses
• 36:34are approximate
• 36:35the amount of a point
• 36:37o eight BAC.
• 36:39So, again, we're seeing
• 36:42much stronger impairment of performance
• 36:44with oral dosing compared with
• 36:46VAPED.
• 36:47And I will point out
• 36:49that the timing of the
• 36:50simulated driving performance
• 36:53was tailored to the expected
• 36:55peak drug effect level
• 36:57based on the route of
• 36:58administration.
• 36:59So in the oral dose
• 37:01study, the simulated driving occurred
• 37:03two hours after exposure.
• 37:05With a vaped driving
• 37:06administration, it happened fifteen minutes
• 37:08after drug exposure.
• 37:13When we did field sobriety
• 37:15testing,
• 37:16and this again is very
• 37:17consistent
• 37:18with other experiments in our
• 37:20laboratory,
• 37:22we
• 37:23see very
• 37:25poor detection of impairment,
• 37:28in these overall field sobriety
• 37:30tests.
• 37:31So on average,
• 37:33detection of about three out
• 37:35of twenty eight possible clues
• 37:37on the walk and turn,
• 37:39touching your nose, modified Romberg,
• 37:42balance test.
• 37:45And the same thing for
• 37:47vaporization,
• 37:48an average of about three
• 37:49clues being detected, maybe two.
• 37:52And really no difference between
• 37:54delta eight or delta nine
• 37:56simply because
• 37:57standard field sobriety tests are
• 37:59not sensitive
• 38:01to impairment after exposure to
• 38:03either delta eight or delta
• 38:04nine THC.
• 38:06And I wish I should
• 38:07have added a column here
• 38:08to show you that when
• 38:09we dose people to a
• 38:10point o eight, it's somewhere
• 38:12up here around ten to
• 38:13fourteen, I think, on average.
• 38:17So,
• 38:19what I wanna
• 38:20hopefully convey
• 38:22through these experiments and and
• 38:24and my talk today is
• 38:25that
• 38:26when we look at the
• 38:28bigger picture,
• 38:29delta eight THC
• 38:31produces
• 38:32nearly
• 38:33identical
• 38:34effects to delta nine THC
• 38:37with regards to the type
• 38:38of subjective effects that people
• 38:41experience
• 38:42as well as the magnitude
• 38:43of effects
• 38:44at double the dose.
• 38:46So when we're thinking about
• 38:49the
• 38:50regulatory
• 38:51environment up until last week
• 38:54and even now continuing for
• 38:55the next year, and that's
• 38:57my next slide,
• 38:58is that delta A THC
• 39:01products were unregulated,
• 39:02sold in
• 39:04retail environments that are readily
• 39:06and easily accessible
• 39:08to most people
• 39:10nationwide
• 39:11and were considered
• 39:13an unscheduled drug,
• 39:16which is
• 39:17crazy.
• 39:19We did see stronger
• 39:22and shorter subjective effects
• 39:24and titration when it was
• 39:26vaporized in terms of subjective
• 39:28and, drug effect.
• 39:30But with oral dosing, we
• 39:32saw saw more impairment
• 39:34compared with vaporization.
• 39:36And that when we looked
• 39:37at the pharmacokinetic
• 39:38data
• 39:39in terms of blood concentrations,
• 39:42the difference
• 39:43in potency is most likely
• 39:45related to a combination of,
• 39:48the metabolism
• 39:49differential metabolism of the two
• 39:51drugs, the eleven hydroxy psychoactive
• 39:53metabolite,
• 39:54and some probably minor but
• 39:57potentially relevant
• 39:58differences between the two in
• 40:00terms of CB one receptor
• 40:01affinity.
• 40:03And that we do see
• 40:05significant impairment of driving performance
• 40:08that is not detected by
• 40:09standard field sobriety tests. And
• 40:11so that becomes really important
• 40:13from a policy perspective
• 40:16because in the
• 40:17roadside
• 40:18law enforcement
• 40:19setting,
• 40:20if someone is pulled over
• 40:21for erratic driving,
• 40:23they're given a breathalyzer,
• 40:25they pass it. They're given
• 40:27field sobriety tests, they pass
• 40:29that. They're taken to the
• 40:30emergency department and blood is
• 40:32drawn and tested for delta
• 40:33nine THC,
• 40:35it may be completely negative,
• 40:37and that person may be
• 40:39significantly impaired due to delta
• 40:41eight THC exposure.
• 40:43Because, again, we're not seeing
• 40:44cross reactivity
• 40:46at a mass spectrometer analysis
• 40:48of delta eight versus delta
• 40:50nine THC in blood.
• 40:53So and, again, I'm gonna
• 40:54highlight
• 40:55that last week for anybody
• 40:57who's not aware.
• 40:59In the bill that reopened
• 41:01the government, there was language
• 41:02added at the eleventh hour
• 41:05that was,
• 41:08intended to close this hemp
• 41:10loophole
• 41:11by banning,
• 41:13any intoxicating
• 41:15products derived from hemp, including
• 41:17delta eight THC.
• 41:19Now
• 41:20the question becomes
• 41:23is what's gonna happen to
• 41:24this industry?
• 41:27There the language in the
• 41:29bill says that this bill,
• 41:30even though it's signed into
• 41:32law currently,
• 41:33will not be enforced for
• 41:35one calendar year.
• 41:37So this large industry,
• 41:39according to the Washington Post,
• 41:41that's worth thirty billion dollars
• 41:43now has a year to
• 41:45advocate for some change
• 41:47to alter the packaging or
• 41:49the formulation of their products
• 41:51to somehow meet the new
• 41:53definition,
• 41:55or to move into a
• 41:56different industry altogether. So it's
• 41:59it's it's gonna be interesting
• 42:00to see if delta eight
• 42:02emerges
• 42:03as a product
• 42:05of choice
• 42:06within current state legal
• 42:09cannabis markets
• 42:11or if it gets pushed
• 42:12into an underground black market
• 42:14that's sustained.
• 42:15So we have,
• 42:17clear demand for these products
• 42:20when they were unregulated
• 42:21and unscheduled. The question is
• 42:23whether they
• 42:25remain
• 42:26a viable
• 42:28product and industry
• 42:29after it becomes scheduled again.
• 42:33So
• 42:34more to be seen,
• 42:36with time on that.
• 42:38So where we're going from
• 42:39from here
• 42:41is that we're,
• 42:44interested in looking at, generally
• 42:47speaking, the impact of oral
• 42:49dose formulation.
• 42:50So,
• 42:51in our experiments, I showed
• 42:53you that our oral dosing
• 42:55was in a,
• 42:56THC infused brownie.
• 42:59My colleague, Tori Spindle here,
• 43:00is doing a really fascinating
• 43:02study right now,
• 43:04comparing delta nine THC
• 43:06in a gummy versus a
• 43:08brownie versus a nano infused,
• 43:12beverage
• 43:13and showing that the nanoemulsion,
• 43:15which is essentially,
• 43:17converts a lipophilic
• 43:19THC
• 43:20substance and makes it water
• 43:21soluble,
• 43:23is showing substantially
• 43:24faster onset of drug effects,
• 43:26greater absorption,
• 43:28and stronger drug effects.
• 43:30So that even though we're
• 43:32doing that experiment with delta
• 43:33nine THC, there's every reason
• 43:35to believe that it would
• 43:36extend to delta eight THC
• 43:37products and other cannabinoids as
• 43:39well.
• 43:40And we're also interested in
• 43:41in doing studies of other
• 43:43novel cannabinoids. So we have
• 43:44a protocol going through review
• 43:46right now,
• 43:47to start to basically do
• 43:49the same experiments
• 43:51with hexahydrocannabinol
• 43:52and other minor cannabinoids like
• 43:54cannabinol.
• 43:55And so we'll see where
• 43:56things go with that.
• 43:58So thanks for your time.
• 44:00Happy to, touch base and
• 44:02answer questions.
• 44:04And I also do wanna
• 44:05just point out if we
• 44:06run out of time and
• 44:07people have other questions or
• 44:08don't feel comfortable asking them
• 44:10to this forum,
• 44:11my contact information
• 44:13is here. Feel free to
• 44:14reach out via email.
• 44:19Brian, that was great.
• 44:21Your your slides and your
• 44:23data is so clear.
• 44:25Questions?
• 44:27Folks, please,
• 44:28unmute yourself. I see someone's
• 44:30hand up there.
• 44:34Go ahead and unmute and
• 44:36ask your question.
• 44:37Oh, okay. I think that's
• 44:38my hand. Oh,
• 44:40Godfrey.
• 44:41Yeah. This is Godfrey. So
• 44:42the as Cyril said, this
• 44:44is very thoughtful and exceptionally
• 44:46thorough research, so thank you
• 44:48so much.
• 44:50And I know that you
• 44:52showed us that
• 44:54subjective effects as you measure
• 44:55them were not different between
• 44:58the delta eight and delta
• 45:00nine. I just wondered
• 45:02if you asked your subjects
• 45:03whether they use delta eight
• 45:05recreationally,
• 45:06just to give you the
• 45:08opportunity to say,
• 45:10with them being blinded, what
• 45:12do you think you got
• 45:13today
• 45:13to see if they could
• 45:14tell the difference?
• 45:15So we had a mixed
• 45:18bag of folks who had
• 45:19used a c b a
• 45:21delta eight product
• 45:22prior to being in the
• 45:24experiment. It wasn't a requirement
• 45:26because we weren't sure we
• 45:27could find enough people who'd
• 45:28use these products,
• 45:31to come into our our
• 45:32our studies. We knew we
• 45:33could find people who'd use
• 45:34delta nine.
• 45:37We
• 45:37we we we discussed this
• 45:39actually just last week.
• 45:41So what we we didn't
• 45:42formally assess that, but we
• 45:44had volunteers
• 45:46tell us,
• 45:48verbally,
• 45:49oh, I think I got
• 45:50delta eight this week, or
• 45:51that that was definitely a
• 45:52delta nine. That was different.
• 45:54We made notes of all
• 45:56of those instances,
• 45:58and we're actually in the
• 45:59process right now of going
• 46:01back through
• 46:02and trying to see if
• 46:03they were right or wrong,
• 46:05in those cases.
• 46:07Yeah. Love to know what
• 46:08you find with that.
• 46:09Yeah. Yeah.
• 46:11Thanks.
• 46:14Ko, you have a question?
• 46:15Do you wanna
• 46:18do you wanna go ahead
• 46:19and ask?
• 46:20I'm
• 46:21just curious. Have you,
• 46:24observed
• 46:25some, like, psychotic effect or
• 46:28mood effect for delta eight?
• 46:32We haven't seen anything
• 46:34where I would say it
• 46:35was a psychotic or any
• 46:37hallucinations or anything like that.
• 46:39We
• 46:40when we did see adverse
• 46:42effects and adverse events, it
• 46:44was in these experiments, usually
• 46:46the delta nine THC dose,
• 46:48especially when we pushed it
• 46:49to thirty milligrams.
• 46:51We did see some adverse
• 46:53events at the higher doses
• 46:55of delta eight THC,
• 46:57and they were the same
• 46:58kinds of things that we
• 46:59see with delta nine. It
• 47:00was usually a little bit
• 47:01of anxiety, a little bit
• 47:02of paranoia,
• 47:03some upset stomach or nausea.
• 47:05But, again,
• 47:07out of
• 47:08if
• 47:09out of every ten AEs,
• 47:11one was probably a delta
• 47:13eight dose and nine were
• 47:14a delta nine THC dose.
• 47:22Other questions? If not, I
• 47:24have a question. So, Ryan,
• 47:26can you say a little
• 47:27more about the
• 47:30the affinity of delta eight,
• 47:33relative to delta nine at
• 47:34the c b one receptor?
• 47:37Yeah.
• 47:38So and I I wish
• 47:39I had that
• 47:41data right in front of
• 47:42me. I've looked at it
• 47:44a couple different times, and
• 47:46that's really I I mean,
• 47:49it's an area of pharmacology
• 47:49that I know a little
• 47:49bit, but I don't know
• 47:49a lot. I can't say
• 47:49that I'm an expert there.
• 47:53Expert there at all. When
• 47:54you look at the KI
• 47:55values for the two, they're
• 47:57look more similar than different
• 47:59to me.
• 48:02What I don't know is
• 48:04whether there's, you know, a
• 48:05concentration dependent
• 48:07effect there. You know, with
• 48:09some cannabinoids,
• 48:10you can have slightly different
• 48:12pharmacological
• 48:13effects based on the concentration
• 48:16of the cannabinoids at the
• 48:17receptor, and I don't know
• 48:18if there's something there.
• 48:20But in terms of just
• 48:21receptor affinity,
• 48:23when I've looked looked it
• 48:25up, they look pretty similar,
• 48:26but I think delta nine
• 48:28is slightly
• 48:29has a slightly better affinity
• 48:30than delta eight. And so
• 48:32that's why, you know, it
• 48:33might be some combination of
• 48:34receptor affinity as well as
• 48:36the metap differential metabolism that
• 48:38drives the difference in potency.
• 48:40Thanks. And and just to
• 48:41follow that up, is delta
• 48:43eight also a partial agonist
• 48:46like delta nine?
• 48:48I believe it is. It
• 48:49is. Yes.
• 48:51We have someone I'm pretty
• 48:52sure there's preclinical pharmacology
• 48:54that shows that that eleven
• 48:56hydroxy
• 48:56delta eight metabolite
• 48:58is also a psychoactive
• 49:00compound
• 49:01similar to the delta nine.
• 49:04Great.
• 49:05We have someone at at
• 49:06Yale who's actually doing some
• 49:07work preclinical work with that
• 49:09delta eight, and that's Al
• 49:11k. Al, are you on
• 49:12the call?
• 49:15Thought I saw his name,
• 49:17on the call. Anyway,
• 49:19I have some methods questions
• 49:21for you if you don't
• 49:21mind. And one is,
• 49:25do you use a some
• 49:26kind of paste
• 49:29smoking procedure in your experiments?
• 49:32So we do not use
• 49:33a paste smoking procedure, and
• 49:35we tried that
• 49:37early on in our lab.
• 49:39And we found that when
• 49:40we did, like, the Fulton
• 49:42paste puff procedure,
• 49:45more often than not, it
• 49:47was aversive to the participants,
• 49:49and they would start coughing
• 49:50and choking. And then they
• 49:52couldn't take the next puff.
• 49:54And we also had a
• 49:55couple instances where people started
• 49:57hyperventilating.
• 49:59And
• 50:00we
• 50:02we abandoned that and moved
• 50:04to a a bottle where
• 50:06we have a defined period
• 50:08of time that the participants
• 50:09have to consume the entire
• 50:11dose, but they could do
• 50:12it at their own pace.
• 50:14Okay. But they still have
• 50:15some,
• 50:16they they still window,
• 50:18a temporal window by which
• 50:20they have to consume the
• 50:21drug.
• 50:22And we do kind of
• 50:24model
• 50:25dosing
• 50:26prior to experiments
• 50:27to figure out, well, okay.
• 50:29We use a plunger to
• 50:31kind of pull,
• 50:33pull doses,
• 50:35to see about how many
• 50:36puffs we think it's gonna
• 50:37take the average person
• 50:39to,
• 50:40deplete the drug.
• 50:41And then the other thing
• 50:42that we do is because
• 50:44individuals
• 50:45take different,
• 50:46you know, volumes of of
• 50:48puffs,
• 50:49We have that filter to
• 50:51ensure
• 50:52that, you know, they're
• 50:53we're blinding
• 50:54the placebo versus the active
• 50:56drug to the extent possible.
• 50:58And so we'll ballpark and
• 50:59we'll say, okay. We think
• 51:01most people should deplete this
• 51:02dose by fifteen puffs. So
• 51:04So we tell everybody, alright.
• 51:06You've got ten minutes to
• 51:07take fifteen puffs off of
• 51:08this thing.
• 51:10And then the last puff,
• 51:11they exhale into ambient air.
• 51:13And if the study participant
• 51:16sees any exhausted
• 51:18vapor, they tell them to
• 51:19take a few more puffs.
• 51:21If they don't see any
• 51:22exhausted vapor, then they say,
• 51:24alright. Dosing's done. We move
• 51:25on to the next, thing.
• 51:28Great.
• 51:31Other questions?
• 51:32Yeah. I had a question.
• 51:33This is Mohini Ranganathan. Thank
• 51:35you. That was, such an,
• 51:36such an interesting talk.
• 51:39Two questions, actually. One is
• 51:42given that
• 51:43maybe
• 51:44overlapping,
• 51:46pharmacodynamic
• 51:47effects,
• 51:49do do you expect
• 51:51people just to have cross
• 51:53tolerance, you know, if they
• 51:53are regularly using t h
• 51:55delta nine t h c
• 51:56that they would have different
• 51:57effects with delta eight, or
• 51:59have you seen any,
• 52:01pattern like that? I I
• 52:02think you said most of
• 52:04your participants were
• 52:06very infrequent users, but just
• 52:07what what you're thinking around
• 52:09that is. And the second
• 52:10is whether you're seeing any,
• 52:12saturated differences.
• 52:14Yeah. So I would full
• 52:16based on the data we
• 52:17collected, I would fully expect,
• 52:20if you have tolerance to
• 52:21delta nine, you'd have tolerance
• 52:23to delta eight. So everything
• 52:24that I've seen preclinically
• 52:26and in our lab is
• 52:27that it's all CB one
• 52:30receptor mediated.
• 52:31I don't think there's any
• 52:33unique pharmacology to delta eight
• 52:34through another
• 52:35neurotransmitter
• 52:36system or receptor system.
• 52:39And, again, qualitatively,
• 52:41the types of drug effects
• 52:43that they report
• 52:44are the same. So that
• 52:45we didn't and we our,
• 52:47you know, I showed you
• 52:48a representative
• 52:50few,
• 52:51subjective
• 52:52effect,
• 52:53categories, but
• 52:54our visual analog scale
• 52:57consists of twenty five different,
• 53:00adjectives.
• 53:01Do you feel anxious? Do
• 53:02you feel sad? Do you
• 53:03feel happy? Do you feel
• 53:05invigorated?
• 53:05Do you feel sedated?
• 53:08And
• 53:08there
• 53:09was none of those items
• 53:11across twenty five different things
• 53:14where we saw people consistently
• 53:16saying, I feel this for
• 53:18this one, but not that
• 53:19one. It was all
• 53:22relatively
• 53:23the same kind of experience.
• 53:25And we really didn't have
• 53:26anybody say, oh, this feels
• 53:28different. This is definitely blah
• 53:29blah blah blah blah.
• 53:31Now what we did have
• 53:32is people say, oh, that
• 53:34felt hotter or that felt
• 53:36harsher. That must be different.
• 53:40Or that but
• 53:41we we we're like I
• 53:42said, we're still going back
• 53:45in response to Godfrey's comment.
• 53:47We're still going back and
• 53:48looking to see if there
• 53:49was actually any,
• 53:52consistency
• 53:53in terms of people saying
• 53:54something was different to the
• 53:56actual drug that was delivered
• 53:57on those particular session days.
• 54:01I think Mohini also asked
• 54:03you about sex differences.
• 54:04Ah, yes.
• 54:06So I don't recall
• 54:08what we have in terms
• 54:09of sex differences for the
• 54:11delta eight,
• 54:12experiments,
• 54:13and I apologize for that.
• 54:15So,
• 54:16we didn't have large enough
• 54:18sample sizes in the first
• 54:20two studies to do those
• 54:22analyses,
• 54:24in
• 54:25in our our initial papers.
• 54:27Now that we have two
• 54:28experiments
• 54:29by
• 54:30route each route of administration
• 54:32and four studies total,
• 54:34we should have a large
• 54:35enough sample size to go
• 54:36back and look at sex
• 54:37differences, and that will probably
• 54:39be a secondary analysis that
• 54:40we'll do with this dataset.
• 54:43Thank you.
• 54:45And I fully expect to
• 54:46see sex differences
• 54:47because we see it every
• 54:48time that we've looked for
• 54:50them in our other cannabis
• 54:51and delta nine work.
• 54:52And what direction are you
• 54:54expecting? We usually see,
• 54:56higher levels of eleven hydroxy
• 54:58in females and stronger drug
• 55:00effects.
• 55:03One,
• 55:04can I Sorry? Can I
• 55:06add one? Okay. In I
• 55:07just wanna add in normally
• 55:08cycling females. Is that right?
• 55:10Is that is that what
• 55:11we usually see that in?
• 55:13Yes.
• 55:15Thanks for the clarification.
• 55:18So, Ryan, one question
• 55:20about the implications of this
• 55:21new,
• 55:24bill,
• 55:25from a few days ago.
• 55:27You said something like you
• 55:28think that this could migrate
• 55:29into the black market. And
• 55:31so my question for you
• 55:32would be,
• 55:34why would anyone
• 55:36wanna,
• 55:37spend money selling delta eight
• 55:40if there if then really
• 55:42no differences between the two?
• 55:46Cost.
• 55:47Cost. I see. Yeah. So,
• 55:49again, I think it's one
• 55:51of those things where
• 55:53we
• 55:54have a process here where,
• 55:57CBD,
• 55:58which is abundant and very,
• 56:00very cheap,
• 56:01there's a a relatively
• 56:04simple from what I've been
• 56:05told by smarter people than
• 56:07me and people who know
• 56:08analytical chemistry.
• 56:10There's a relatively
• 56:11simple process of of synthetically
• 56:14converting CBD to delta A
• 56:15THC.
• 56:17And CBD is cheap, and
• 56:19the process in of converting
• 56:21it is cheap and relatively
• 56:22straightforward. So
• 56:24while most of the US
• 56:26has
• 56:27legal
• 56:28cannabis markets for adult use,
• 56:31the products can be quite
• 56:33costly. And and a delta
• 56:34eight,
• 56:36market exists in Europe where
• 56:38that doesn't exist now. It's
• 56:40not very robust,
• 56:42but they also never had
• 56:44a robust market.
• 56:45And so I think right
• 56:47now,
• 56:49you're and it'll it'll be
• 56:50curious to see what happens,
• 56:52but I'm the way I'm
• 56:53looking at it right now
• 56:54is that there is a
• 56:56sizable industry
• 56:57that already knows how to
• 56:59do this.
• 57:00There's a
• 57:01sizable
• 57:02market in terms of consumers
• 57:04that have kind of grown
• 57:06accustomed to using these products.
• 57:08The infrastructure for making them
• 57:10is in place, and these
• 57:11companies
• 57:12are facing going out of
• 57:14business
• 57:14if they follow the the
• 57:16the law.
• 57:17So the question for me
• 57:18becomes
• 57:19a year from now, if
• 57:21the language in the bill
• 57:22stays the same,
• 57:24do those companies find something
• 57:26else to make?
• 57:27Do they keep making what
• 57:28they're making and
• 57:30challenge whether or not the
• 57:32DEA is going to enforce
• 57:34the law? Because if you
• 57:35think about it, right, at
• 57:37the federal level,
• 57:39all of the state legal
• 57:41programs
• 57:42are
• 57:43against federal law and are
• 57:45not being enforced. It's it
• 57:47so it really becomes a
• 57:48question of allocation of DEA
• 57:50resources
• 57:51and whether this is an
• 57:52industry they're going to go
• 57:54after.
• 57:56And and, again, it it
• 57:57may be that these
• 57:59businesses then apply for licenses
• 58:01to
• 58:02legally do it at the
• 58:03state level.
• 58:04I mean, that's another possibility
• 58:06here.
• 58:07I I really don't know
• 58:09which direction it's gonna go,
• 58:10but I'd be shocked if
• 58:13delta eight THC simply just
• 58:15goes away.
• 58:16Great.
• 58:20Thank you very much for
• 58:21a great talk. I'm sure
• 58:22people are gonna reach out
• 58:23to you. I will also
• 58:24reach out to you about
• 58:25some questions I have about
• 58:26methodology. But thanks again, Ryan.
• 58:28This is great. Really appreciate
• 58:29it, Sarah. Thanks for the
• 58:31invitation, and happy, rest of
• 58:33the afternoon, everybody.
• 58:35Thank you very much.