The Need for Research on Cannabinoids, Chronic Pain, and Opioid Use Disorder

Transcript

• 00:06Started.
• 00:08Everybody, you're in the right
• 00:09place. Thank you for joining.
• 00:12This is our
• 00:13next in a series of
• 00:14talks designed to
• 00:16address issues and the overlap
• 00:18between
• 00:19chronic pain, opioid misuse, and
• 00:22opioid use disorder.
• 00:24And we're really excited to
• 00:26focus on issues related to,
• 00:29cannabinoids
• 00:30today.
• 00:31We have an expert speaker,
• 00:33who I will introduce and
• 00:34then go ahead and let
• 00:36him talk. So our speaker
• 00:37today is Cyril D'Souza.
• 00:39He's the Vikram Soddy,
• 00:42professor of psychiatry here at
• 00:44the Yale School of Medicine
• 00:45and a psychiatrist at the
• 00:47VA Connecticut health care system.
• 00:49He directs the schizophrenia
• 00:52neuropharmacology
• 00:54research group at Yale, the
• 00:56neurobiologic
• 00:57studies unit at the VA
• 00:58Connecticut,
• 01:00the VA Schizophrenia
• 01:02Research Clinic, and also the
• 01:03Yale Center for the Science
• 01:05of Cannabis
• 01:06and Cannabinoids.
• 01:08This research is funded by
• 01:09the National Institutes on Drug
• 01:11Abuse, the National Institutes on
• 01:13Mental Health,
• 01:14the National Institute on Alcoholism
• 01:16and Alcohol Abuse,
• 01:18the VA Research and Development,
• 01:20and several foundations.
• 01:22And he's principal editor of
• 01:24the Journal of Pharmacology.
• 01:27Really excited to have doctor
• 01:29D'Souza today to speak to
• 01:31you about the need for
• 01:32research on cannabinoids and pain.
• 01:34Thank you, Cyril.
• 01:36Thanks for the invitation.
• 01:38And,
• 01:39I'm I'm I'm a psychiatrist
• 01:41as David mentioned, and my,
• 01:44focus over the last maybe
• 01:45twenty five years or so
• 01:46has been on cannabis and
• 01:48and cannabinoids.
• 01:50In the spirit of full
• 01:51disclosure, I'm not an expert
• 01:54on pain. There I see
• 01:55there are other experts
• 01:57attending here,
• 01:58but I, hopefully provide,
• 02:02an overview of, cannabis,
• 02:04cannabinoids,
• 02:05and pain. So,
• 02:08let me see if I
• 02:09can move my slides.
• 02:11Yeah.
• 02:13So why,
• 02:14is it even interesting to
• 02:16talk about cannabis, cannabinoids, and
• 02:18and pain? It's because this
• 02:20is one of the most
• 02:21common reasons that people use
• 02:23for using,
• 02:24gift for using cannabis or
• 02:26cannabinoids.
• 02:29I'm gonna give you an
• 02:30overview of
• 02:31the of cannabis and and
• 02:33cannabinoid pharmacology,
• 02:35tell you about the endocannabinoid
• 02:37system,
• 02:38tell you about
• 02:40the products that are currently
• 02:41available and those in pipeline,
• 02:43and cover some information about
• 02:45the efficacy of cannabinoids in
• 02:47acute
• 02:48and chronic pain,
• 02:49and then,
• 02:51find the clothes with gaps
• 02:53in information
• 02:54and, therefore, opportunities for research,
• 02:57on this topic. So
• 03:00everyone knows,
• 03:01about cannabinoids. Cannabis
• 03:03is ubiquitous now. It's available
• 03:05all over the place.
• 03:07But for those who of
• 03:08you are not familiar,
• 03:10most of the, interesting chemical
• 03:12compounds present in cannabis reside
• 03:14in these hair like trichomes,
• 03:17that are magnified here.
• 03:19And, cannabis contains
• 03:21about five hundred chemicals, including
• 03:23about a hundred cannabinoids.
• 03:25The ones that have, gotten
• 03:28most of our attention include
• 03:29delta nine tetrahydrocannabinol,
• 03:31which I'll refer to as
• 03:33THC from now on,
• 03:35and cannabidiol
• 03:36or CBD as I referred
• 03:37to. But beyond that, there
• 03:39are a number of other,
• 03:42minor cannabinoids
• 03:43present in the cannabis plant
• 03:45and then four hundred other,
• 03:47chemical constituents, including terpenes,
• 03:51and flavonoids.
• 03:52But the ones that are
• 03:54clearly of greatest interest, especially
• 03:55to this topic, is, RTHC
• 03:57and cannabidiol.
• 03:59So
• 04:01just to make this clear,
• 04:03the intoxicating or the psychoactive
• 04:05effects of cannabis
• 04:07can be attributed to THC.
• 04:09THC alters perception,
• 04:11produces euphoria, alters cognition,
• 04:14and also produces,
• 04:15some cardiovascular
• 04:16effects, including tachycardia,
• 04:19hypotension, and hypotension. In contrast,
• 04:21CBD
• 04:22does not produce any of
• 04:24those effects.
• 04:26CBD is not known to
• 04:28be a psychoactive
• 04:30cannabinoid. However, there's some data
• 04:32suggesting that on its own,
• 04:34at certain doses, it may
• 04:35have anxiolytic effects.
• 04:37And at certain doses, it
• 04:39might offset
• 04:40some of the less desirable
• 04:42effects of THC. And hopefully,
• 04:44we may get a chance
• 04:45to talk about it,
• 04:47later on.
• 04:48So
• 04:52that THC is a principal
• 04:54active constituent of cannabis was
• 04:56discovered in nineteen sixty three.
• 04:59But then for the next
• 04:59twenty five years or so,
• 05:01we really didn't know exactly
• 05:03how THC produced its effects
• 05:05until the late nineteen eighties
• 05:07when,
• 05:09when the first component
• 05:11of the endocannabinoid
• 05:12system was discovered.
• 05:14We now know a lot
• 05:15about that. I'm gonna spend
• 05:16quite a bit of time
• 05:17talking about the endocannabinoid system.
• 05:21There are two receptors. One
• 05:23is a mostly brain receptor,
• 05:25the c v one receptor,
• 05:27which mediates the
• 05:28psychoactive effects of of, cannabis
• 05:30and THC,
• 05:32and the other is the
• 05:33c v two receptor, which
• 05:34is mainly peripheral on immune
• 05:36cells and and may play
• 05:38a much more important role
• 05:40in in inflammation and immune
• 05:42responses rather than psychoactive effects.
• 05:47The distribution of cannabinoid receptors
• 05:50is in exactly those areas
• 05:52that we know,
• 05:54cannabis to produce
• 05:56its effects. So,
• 05:58cannabis can impair,
• 06:00attention, memory, and executive functions.
• 06:02There are higher densities of
• 06:04cannabinoid receptors in the in
• 06:06the prefrontal cortex.
• 06:09Cannabis can impair,
• 06:10memory, and we have there
• 06:12are high densities of cannabinoid
• 06:13receptors in the hippocampus.
• 06:16Cannabis can, can alter anxiety
• 06:18and produce fear and paranoia.
• 06:20We know there are high
• 06:21densities of cannabinoid receptors
• 06:23in the amygdala.
• 06:25Cannabis can alter appetite and
• 06:27sleep, and there are high
• 06:28densities of cannabinoids in the
• 06:30hypothalamus.
• 06:32And then
• 06:34cannabis and THC can impair
• 06:35coordination,
• 06:36reaction time, and balance. And
• 06:38there are very high densities
• 06:39of cannabinoid receptors in the
• 06:41cerebellum
• 06:42and the cerebellar cortex.
• 06:44There are some receptors in
• 06:45the brain stem,
• 06:47though the density of cannabinoid
• 06:48receptors in the brain stem
• 06:49is is relatively low compared
• 06:52to other areas of the
• 06:53brain.
• 06:54We now have the capacity,
• 06:56to actually image
• 06:58cannabinoid receptors in in in
• 07:00vivo
• 07:01in in humans, and this
• 07:02is data from my lab
• 07:04looking at the distribution of
• 07:06cannabinoid receptors using positron emission
• 07:08tomography.
• 07:09And, again, what you see
• 07:11here is the distribution of
• 07:12these receptors, the highest densities
• 07:14on
• 07:14those areas that are shown
• 07:16in red seem to overlap
• 07:17with what we know from
• 07:19from,
• 07:20from,
• 07:22from postmortem studies,
• 07:24and from the known effects
• 07:26of of,
• 07:27cannabinoids.
• 07:30So
• 07:33with the discovery of the
• 07:34cannabinoid receptors in the late
• 07:35nineteen eighties, the next logical
• 07:37question was,
• 07:38are there endogenous,
• 07:41compounds acting in these cannabinoid
• 07:43receptors? So just as endorphins
• 07:45were discovered as the
• 07:47endogenous,
• 07:48ligands for, opioid receptors,
• 07:51we now know that there
• 07:52are at least two,
• 07:54endocannabinoids
• 07:55that have been discovered.
• 07:57The first one
• 07:58is anandamide
• 08:00and named after the Sanskrit
• 08:01word meaning bliss or anand,
• 08:03and the second is two
• 08:04AG. So these are the
• 08:06two endocannabinoids
• 08:08that have been, that are
• 08:09known to be part of
• 08:10the endocannabinoid machinery.
• 08:15We know a lot more
• 08:16now about this endocannabinoid
• 08:18system, and I'm I'm not
• 08:20going to go into all
• 08:21of the details, but I
• 08:22wanna point out some some
• 08:24really important things about the
• 08:25endocannabinoid
• 08:26system.
• 08:27We know the enzymes that
• 08:28are responsible
• 08:29for the
• 08:30synthesis of these endocannabinoids,
• 08:32and we know the enzymes
• 08:34that are responsible for the
• 08:35degradation
• 08:36of these endocannabinoids.
• 08:38And pharmaceutical companies have
• 08:40have seen these as targets
• 08:42and have developed drugs that
• 08:43have now been used in
• 08:44humans
• 08:45to,
• 08:46to modulate the endocannabinoid
• 08:49system. So
• 08:50the enzyme
• 08:51fatty acid amide hydrolase or
• 08:53far,
• 08:55is what's,
• 08:56responsible for breaking down anonamide
• 08:59to ethanolamine.
• 09:00And a number of companies,
• 09:02including Pfizer, developed inhibitors of
• 09:05these compounds that were that
• 09:07have been tested in humans
• 09:08and used for a number
• 09:09of indications, including, and I'll
• 09:11talk about that later on,
• 09:13pain.
• 09:15We know the enzyme that's
• 09:16responsible
• 09:18for the
• 09:19for the
• 09:21synthesis and degradation of the
• 09:23the other endocannabinoid two AG.
• 09:25Now what's peculiar about the
• 09:27endocannabinoid
• 09:27system
• 09:28is that unlike most other
• 09:30neurotransmitter
• 09:31systems,
• 09:32it is a retrograde
• 09:34messenger system. So let me
• 09:35try and explain this. So
• 09:37shown here in green is
• 09:38the presynaptic
• 09:39neuron,
• 09:41and shown here in pink
• 09:42is the postsynaptic
• 09:44neuron, and there's a synaptic
• 09:46cleft that's between them.
• 09:48So let's say there's a
• 09:49nerve impulse that comes down
• 09:50this presynaptic neuron resulting in
• 09:53the release of, let's say,
• 09:54these,
• 09:55glutamate,
• 09:58this this neurotransmitter glutamate shown
• 10:00here in these orange
• 10:02circles, and glutamate binds
• 10:05to a glutamate receptor on
• 10:07the postsynaptic neuron.
• 10:08What then happens is that
• 10:10it triggers
• 10:12the on demand synthesis
• 10:15of anandamide
• 10:16and two AG. So
• 10:18anandamide and two AG are
• 10:20not stored in vesicles. They
• 10:22are produced on demand, and
• 10:24they are produced on demand
• 10:26in response to,
• 10:28activation of postsynaptic receptors. In
• 10:31this case, I'm giving the
• 10:32example of glutamate.
• 10:33What happens once they are
• 10:35produced and released is they
• 10:37travel back
• 10:39to bind to cannabinoid receptors
• 10:41that are present on the
• 10:43presynaptic neuron.
• 10:44So it's a retrograde
• 10:47messenger system.
• 10:48And what that does is
• 10:50when the c b one
• 10:51receptor shown here is activated
• 10:54or shown here is activated,
• 10:56it basically
• 10:57prevents
• 10:58or inhibits the further release
• 11:00of the initial neurotransmitter, in
• 11:02this case, glutamate.
• 11:04So
• 11:05what is happening is, in
• 11:06in essence, is that the
• 11:08endocannabinoid
• 11:09system serves as a breaking
• 11:11function,
• 11:13preventing the release or inhibiting
• 11:15the release of further neurotransmitters.
• 11:18So this is something really
• 11:20important to keep in mind
• 11:21as we think about the
• 11:22physiology
• 11:23of the endocannabinoid
• 11:24system.
• 11:27Something else that's really important
• 11:29to keep in mind is
• 11:30that
• 11:31once these endocannabinoids
• 11:33are released and they bind
• 11:34to cannabinoid receptors,
• 11:36they are inactivated
• 11:38almost immediately within milliseconds.
• 11:42That's one important point to
• 11:43keep in mind. Second is
• 11:44that the release of these
• 11:45endocannabinoids
• 11:47is very discreet.
• 11:49They are they only release
• 11:51in very, very small spaces.
• 11:53And why am I want
• 11:54to emphasize this is in
• 11:56contrast,
• 11:57when
• 11:58someone smokes marijuana or weed,
• 12:01first thing is that THC
• 12:03floods the entire brain.
• 12:06THC does not just act
• 12:07on very discrete areas of
• 12:09the brain. It floods the
• 12:10entire brain and therefore activates
• 12:13c b one receptors all
• 12:15over the brain. That's number
• 12:16one. Second is that unlike
• 12:18endocannabinoids
• 12:19that are that are
• 12:22destroyed almost immediately after activating
• 12:24c b one receptors,
• 12:26THC
• 12:27will continue to activate c
• 12:29b one receptors.
• 12:31So the point here is
• 12:33that THC's effects are nonphysiological.
• 12:35They are different
• 12:37from the from the effects
• 12:39of the endocannabinoid system. By
• 12:40the way, please stop me
• 12:41at any time if you'd
• 12:43like to ask questions or
• 12:44if I'm if I'm not
• 12:45clear about,
• 12:46about, what I'm trying to
• 12:48trying to say. So, again,
• 12:50this is what we know
• 12:51about the this is a
• 12:52basic idea about about the
• 12:54endocannabinoid
• 12:55machinery.
• 12:59Another point to keep in
• 13:00mind is the idea that
• 13:02THC is a partial agonist
• 13:04at c b one receptors,
• 13:06and I'll try try and
• 13:07illustrate this. So,
• 13:10if a
• 13:11the endogenous
• 13:12of full agonist, which is
• 13:14a, anandamide or two AG
• 13:17is shown here in blue.
• 13:18And as you increase the
• 13:20dose
• 13:21of, say, anandamide or two
• 13:22AG, you get increasing
• 13:24effects that plateau off at
• 13:26around, let's say, hundred percent.
• 13:29What you may get with
• 13:30the with THC, which is
• 13:31a partial agonist,
• 13:33is that even at the
• 13:34highest dose of THC, it
• 13:35will never produce the same
• 13:37degree of efficacy or effects
• 13:40as the endogenous agonist.
• 13:43So what what we mean
• 13:44to say here is that
• 13:45THC is a partial agonist.
• 13:47And in contrast,
• 13:49synthetic cannabinoids,
• 13:50and we'll talk about that
• 13:51later on, can produce,
• 13:54supranormal
• 13:54effects, effects that are higher
• 13:56than the endogenous agonist.
• 14:00So, again, this is just
• 14:01to show that
• 14:03the effects that you get
• 14:04with the full agonist
• 14:06is more than what you
• 14:07would get with THC, which
• 14:09is a partial agonist.
• 14:12And likewise,
• 14:13when you talk about efficacy
• 14:15and side effects,
• 14:16you see a difference
• 14:18between full agonists or synthetic
• 14:20agonists and, THC shown here.
• 14:23These are the clinical implications.
• 14:26Excuse me.
• 14:29Okay. So,
• 14:32something important to remember about
• 14:34the endocannabinoid
• 14:35system is that it's a
• 14:36highly dynamic system.
• 14:38What do I mean by
• 14:39that?
• 14:40With repeated exposure to THC
• 14:42or cannabis,
• 14:44there is
• 14:45a there is a remarkable
• 14:49downregulation
• 14:50and desensitization
• 14:51of the CB one receptor.
• 14:53It was previously only
• 14:55shown in animal studies, but,
• 14:57we again, because we have
• 14:58positron emission tomography available at
• 15:01Yale with a highly selective
• 15:03ligand for CB one receptors
• 15:05that allows us to actually
• 15:06look at the impact of
• 15:07repeated cannabis exposure
• 15:09on the endocannabinoid
• 15:11system.
• 15:12Shown here on in the
• 15:13top row,
• 15:15is CB one receptor binding
• 15:17or availability
• 15:18using measured using positron and
• 15:20sheet tomography
• 15:22and, and a ligand highly
• 15:24specific for the c v
• 15:25one receptor.
• 15:26And the middle panel shows
• 15:29you daily cannabis users. And,
• 15:31hopefully, to the naked eye,
• 15:32you can see that
• 15:34in response to repeated
• 15:36exposure to cannabis as in
• 15:37daily cannabis use,
• 15:39there is a reduction
• 15:41in the numbers of cannabinoid
• 15:43receptors,
• 15:45as as a consequence.
• 15:48What accompanies this is obviously
• 15:51tolerance. That is to say
• 15:52with repeated exposure to cannabis,
• 15:55there will be the develop
• 15:56there there is a development
• 15:57of tolerance
• 15:59to the effects of cannabis,
• 16:01and the underlying biological
• 16:03basis for that is downregulation
• 16:06of the CB one receptors,
• 16:07which we can see now
• 16:08using PEC,
• 16:10and also desensitization
• 16:12of these receptors.
• 16:14Of course, there are clinical
• 16:15implications for that.
• 16:17Based on on this biological
• 16:20data, one would expect that
• 16:22if you wanna target,
• 16:24a symptom
• 16:25or a tree or a
• 16:27condition,
• 16:28with THC or cannabinoids,
• 16:30with repeated administration,
• 16:32you could expect
• 16:34that there would be some
• 16:35degree of loss of efficacy
• 16:37because of the development of
• 16:38tolerance.
• 16:40Okay. Now what's also interesting
• 16:43about this downregulation
• 16:44desensitization,
• 16:46is that
• 16:48this system is a highly
• 16:49dynamic system.
• 16:51So if you take heavy
• 16:52cannabis users and you ask
• 16:54them to stop using cannabis
• 16:57and you confirm that, you
• 16:59can see that within a
• 17:00fairly short period of time,
• 17:02there is recovery
• 17:04of c v one receptors.
• 17:06Again, this is data from
• 17:07my lab using,
• 17:09PET and the c v
• 17:10one receptor,
• 17:11highly specific c v one
• 17:13receptor ligand. That is within
• 17:15four weeks or so, there
• 17:16is a pretty remarkable
• 17:18recovery
• 17:19of c v one receptors.
• 17:21And the clinical implications would
• 17:23be that,
• 17:25if you were to,
• 17:28to
• 17:28devise a treatment,
• 17:30it might be important
• 17:33to give breaks in that
• 17:34treatment so there's recovery of
• 17:36that c of the of
• 17:38the system,
• 17:40or you may have to
• 17:41continue to increase the dose
• 17:42as we see with a
• 17:43number of other drugs that
• 17:44we use to treat
• 17:46pain, including opioids.
• 17:49Okay. So what do we
• 17:50know about the endocannabinoid system,
• 17:53and what you should you
• 17:54know about it? Because if
• 17:55you plan to use,
• 17:58cannabinoids in the treatment of
• 17:59a condition,
• 18:00if you understand
• 18:02the scope of its effects
• 18:03on other systems,
• 18:05you might be able to
• 18:06anticipate
• 18:07what side effects and other
• 18:08effects you might expect
• 18:10with repeated administration. We now
• 18:12know that the c v
• 18:13one system or the endocannabinoid
• 18:15system
• 18:16is plays an important role
• 18:18in stress regulation, in the
• 18:20in in regulating mood,
• 18:22in reward and reinforcement,
• 18:24in learning and memory,
• 18:27in sleep and appetite,
• 18:29pain modulation. We've talked about
• 18:32psychomotor control
• 18:34and
• 18:35neurodevelopment,
• 18:36especially during adolescence
• 18:37and in utero.
• 18:41Peripherally,
• 18:42we are CB two receptors
• 18:43residing on immune cells.
• 18:46The endocannabinoid
• 18:47system may play a role
• 18:48in inflammation and immune cell
• 18:50signaling.
• 18:51And we also know that
• 18:52that there are,
• 18:55effects of the endocannabinoid
• 18:56system on energy balance and
• 18:58and glucosin glucose and lipid
• 19:00metabolism.
• 19:04So,
• 19:07I wanna point out and
• 19:09contrast the effects
• 19:10of the known
• 19:13endocannabinoid
• 19:14function and how that might
• 19:16differ from the effects of,
• 19:18cannabis and THC. If you
• 19:20recall, I mentioned to you
• 19:21that endocannabinoids
• 19:23are destroyed almost immediately,
• 19:25and are released in a
• 19:27very small area. In contrast,
• 19:29cannabis and THC present in
• 19:31cannabis
• 19:32floods the entire brain,
• 19:33in an indiscriminate
• 19:35way,
• 19:36and continues to activate receptors,
• 19:39for, minutes and up to
• 19:41hours.
• 19:43So
• 19:44what that means is
• 19:46that THC
• 19:47may actually convert a precise
• 19:49feedback system
• 19:51into a diffuse sustained signal,
• 19:53or THC is producing nonphysiological
• 19:56effects
• 19:57via via,
• 19:59the endocannabinoid
• 20:00system.
• 20:04So
• 20:05what else would be interesting
• 20:06from the perspective of pain
• 20:08and the endocannabinoid
• 20:09system?
• 20:10We know of a peculiar
• 20:12polymorphism,
• 20:14of,
• 20:15the enzyme
• 20:16that's involved in the in
• 20:18the degradation
• 20:19of,
• 20:20of anandamide, the principal endogenous
• 20:22cannabinoid.
• 20:24This polymorphism is associated with
• 20:26a reduction in the activity
• 20:28of that enzyme. So if
• 20:30the enzyme is responsive
• 20:31responsible for breaking down anonamide,
• 20:34a
• 20:36reduction in the activity of
• 20:37the enzyme
• 20:38results in an increase in
• 20:39anandamide
• 20:40present and increase in c
• 20:42b one receptor signaling.
• 20:44What they found is that
• 20:45individuals with this polymorphism
• 20:47seem to have a an
• 20:49unusually high pain tolerance.
• 20:52So this is really interesting
• 20:55clinical data
• 20:56supporting
• 20:58a role of the endocannabinoid
• 20:59system
• 21:00in pain signaling
• 21:02given the fact that,
• 21:04a polymorphism
• 21:05for the for, the
• 21:08of the far gene, which
• 21:10is which, results in a
• 21:12reduction in far activity and
• 21:13increased endocannabinoid
• 21:15tone is associated with higher
• 21:17pain, tolerance.
• 21:19And and, obviously, there are
• 21:21some pharmacological
• 21:22implications
• 21:23as I'll talk about later.
• 21:26There have been studies
• 21:27using a fine inhibitor in
• 21:29the treatment of pain.
• 21:31We'll talk about that,
• 21:32later.
• 21:34So what would higher endocannabinoid
• 21:37tone do?
• 21:39It may reduce
• 21:40nociceptor
• 21:41firing.
• 21:42It may reduce glutamate and
• 21:43substance p release in the
• 21:45spinal cord.
• 21:46And at the central level,
• 21:48at the level of the
• 21:48brain, it might reduce pain
• 21:50savings.
• 21:53So
• 21:56how might THC modulate pain?
• 21:59Just going back to the
• 22:00earlier slide, THC may modulate
• 22:02pain
• 22:03by reducing the firing of
• 22:05nociceptors,
• 22:07by reducing inflammation that may
• 22:09be contributing to pain. So
• 22:11at a very peripheral level,
• 22:12at the spinal cord level,
• 22:13it could,
• 22:15THC can,
• 22:16reduce glutamate release
• 22:18and reduce signal transmission. And
• 22:20then at the level of
• 22:21the brain,
• 22:22THC may reduce pain salience
• 22:26and increase descending inhibition. So
• 22:29it is at these multiple
• 22:30levels that one might hypothesize,
• 22:33THC to modulate,
• 22:35pain.
• 22:38So
• 22:39I've spoken a lot about
• 22:41THC, but cannabis is a
• 22:42lot more than THC. As
• 22:43I mentioned earlier, there are
• 22:45at least hundred cannabinoids,
• 22:47present in cannabis and at
• 22:49least four hundred other,
• 22:51chemical
• 22:52constituents of cannabinoids, and some
• 22:54of those include terpenoids and
• 22:56flavonoids.
• 22:57We know that terpenoids are
• 22:59what impart
• 23:00the distinct aroma
• 23:02of cannabis,
• 23:04and there's some interest now
• 23:06in looking at these at
• 23:07pharmacological
• 23:08doses.
• 23:09We acknowledge
• 23:10that THC is the dominant
• 23:13driver of the psychoactive effects
• 23:15of cannabis,
• 23:16and THC,
• 23:18together with CBD,
• 23:19seem to account for the
• 23:20majority of the known clinically
• 23:23relevant effects of, cannabis.
• 23:25And these other compounds, these
• 23:27terpenoids and flavonoids,
• 23:29play a mostly secondary or
• 23:30modulatory
• 23:31role.
• 23:34Some have argued
• 23:35that
• 23:36these other constituents
• 23:38of cannabis, including terpenes,
• 23:41flavonoids, and the minor cannabinoids,
• 23:44play something of an entourage
• 23:46effect.
• 23:48This is the idea of,
• 23:50let's say, illustrating here a
• 23:53a movie stars
• 23:54surrounded by an entourage
• 23:56where the entourage themselves may
• 23:58not have effects,
• 24:00but,
• 24:01they
• 24:02embellish,
• 24:03the aura
• 24:04of,
• 24:05of the, of the superstar.
• 24:08There's some data suggesting that
• 24:11some of the minor cannabinoids
• 24:13including cannabidural,
• 24:15cannabinol,
• 24:16and terpenes may modulate
• 24:18some of the effects of
• 24:20THC,
• 24:21and contribute in a subtle
• 24:23and context dependent way on
• 24:25the overall
• 24:26effects or the net effects
• 24:28of of cannabis. However,
• 24:32on their own,
• 24:34that is independently,
• 24:36there is not that much
• 24:37data
• 24:39and and very, very inconsistent
• 24:42data. So this concept of
• 24:44the entourage effect, which you
• 24:45might hear about a lot
• 24:47in the cannabinoid field,
• 24:49is not universally accepted and
• 24:51remains
• 24:51incompletely proven
• 24:53in humans.
• 24:56So,
• 25:00two minor cannabinoids that I,
• 25:03I want to point out,
• 25:04one is,
• 25:06cannabidural
• 25:07and the other is cannabinol.
• 25:09One is a very weak
• 25:11potentially,
• 25:12c b one antagonist and
• 25:14the other is a weak
• 25:15partial agonist.
• 25:16They may reduce anxiety,
• 25:20and may have minimal sedating
• 25:22effects.
• 25:23The net effect on THC
• 25:25may be that cannabagiol
• 25:26might attenuate its effects, and
• 25:28cannabinol might slightly enhance the
• 25:31sedating effects of THC.
• 25:35Something else that you'd hear
• 25:36from your patients
• 25:38is this distinction between cannabis
• 25:41indica and can cannabis sativa.
• 25:44And I would argue,
• 25:46that we are struggling still
• 25:48struggling with whether this is
• 25:49science or or myth.
• 25:51The idea is that,
• 25:53that,
• 25:55if that that
• 25:57cannabis indica,
• 25:59may be more of a
• 26:01downer,
• 26:02whereas cannabis sativa might be
• 26:04more of an upper.
• 26:06The problem with this is
• 26:08that most of the cannabis
• 26:10that's available
• 26:12is highly mixed.
• 26:13It's not distinctly indica or
• 26:15sativa.
• 26:17And if you talk to,
• 26:20folks who, do research in
• 26:22this space,
• 26:23they are extremely skeptic skeptical
• 26:25of this,
• 26:27of this distinction.
• 26:29There's a feeling in in
• 26:31amongst researchers that this is
• 26:33really
• 26:34something that is exploited for
• 26:35marketing purposes,
• 26:37rather than pharmacological
• 26:39purposes.
• 26:42So
• 26:43how do we think about
• 26:44cannabis then?
• 26:46Many would argue that we
• 26:47might divide cannabis into three
• 26:50distinct types.
• 26:52One is THC dominant, the
• 26:54other CBD dominant,
• 26:56and the third is a
• 26:57balance between THC and CBD.
• 27:01As the names would suggest,
• 27:03the THC dominant has a
• 27:04very high THC content, low
• 27:06CBD content,
• 27:08and,
• 27:09has a variable content of
• 27:11other cannabinoids.
• 27:13Its typical effects include significant
• 27:15intoxication,
• 27:16euphoria,
• 27:17maybe analgesia as we talk
• 27:19about,
• 27:20but there's also a risk
• 27:22for more unpleasant effects, including
• 27:24anxiety, paranoia,
• 27:26psychosis.
• 27:27In contrast,
• 27:29CBD dominant cannabis
• 27:31produces minimal intoxication
• 27:34and
• 27:35is generally
• 27:37well tolerated relative to THC
• 27:39dominant cannabis.
• 27:41Also, THC dominant cannabis
• 27:43may
• 27:45be more abuse liable relative
• 27:48to CBD dominant cannabis,
• 27:50and the balanced version
• 27:51is falls somewhere in between.
• 27:57So what has changed over
• 27:59the last maybe three decades
• 28:01or so is that the
• 28:02THC content of cannabis
• 28:04continues to increase.
• 28:06This is, data from University
• 28:09of Mississippi,
• 28:11which has been tasked
• 28:12for the last forty years
• 28:14to
• 28:15to test the THC and
• 28:16CBD content
• 28:18of cannabis that's been seized
• 28:20by the Drug Enforcement Agency.
• 28:22And you can see here
• 28:23that,
• 28:24in nineteen ninety five, the
• 28:26average THC content was about
• 28:28four percent.
• 28:29In twenty twenty two, it
• 28:30was closer to sixteen percent,
• 28:33and it continues to grow.
• 28:34In contrast, the CBD content
• 28:36of cannabis has remained relatively
• 28:39stable over time.
• 28:42Now cannabis is only one
• 28:45of the many ways that
• 28:46people can use cannabinoids, and
• 28:48then a staggering array of
• 28:49other products derived from cannabis
• 28:51that you should be aware
• 28:53of.
• 28:55And to put that in
• 28:56perspective,
• 28:58the
• 28:59the THC content of cannabis,
• 29:02for example, in the state
• 29:03of Connecticut that's shown in
• 29:05dispensaries,
• 29:06has a cap at thirty
• 29:08five percent THC. So this
• 29:10is cannabis that you can
• 29:11buy at a dispensary in
• 29:13the state of Connecticut. In
• 29:14other states,
• 29:16other states do allow the
• 29:18THC content of cannabis to
• 29:19be even higher than thirty
• 29:21five percent.
• 29:22And to put that in
• 29:23perspective, that's about ten ten
• 29:25times higher than what the
• 29:27average THC content was in
• 29:29cannabis in nineteen ninety five.
• 29:31And beyond that, we now
• 29:33have a number of,
• 29:35products that we refer to
• 29:36as concentrates
• 29:38that may have a THC
• 29:39content of ninety percent. So
• 29:42that's,
• 29:43almost twenty times twenty to
• 29:45thirty times more than the
• 29:46THC content of cannabis,
• 29:49in the nineteen nineties.
• 29:51Why is that important? It's
• 29:52important because for from a
• 29:54number of different perspectives. That
• 29:55is that if we believe
• 29:57that the effects of cannabis
• 29:59THC are dose related,
• 30:01then as,
• 30:02people use these more potent
• 30:04products, you might expect,
• 30:06greater effects. That's number one.
• 30:09The second
• 30:10important issue to keep in
• 30:12mind is that
• 30:13studies would that were done
• 30:15on the
• 30:16consequences
• 30:17of cannabis use from the
• 30:19nineteen eighties and nineteen nineties
• 30:21may not extrapolate
• 30:22to the current landscape of
• 30:24cannabis where cannabis is much
• 30:26more potent than it was
• 30:27back in the eighties and
• 30:28nineties,
• 30:29and we have these really
• 30:31potent products available, which have
• 30:33about ninety percent THC content.
• 30:37And and and the
• 30:38another consequence of that is
• 30:40that
• 30:41studies that were done back
• 30:43in the seventies and eighties,
• 30:45that showed that only one
• 30:47in ten people who use
• 30:48cannabis developed cannabis use disorder.
• 30:52The the more recent studies
• 30:54looking at the current landscape
• 30:55of cannabis would suggest that
• 30:58one in three people who
• 30:59use cannabis will develop cannabis
• 31:01use disorder.
• 31:02And that's,
• 31:03I think, directly related to
• 31:05the THC content
• 31:07of Canvas.
• 31:08So these are some of
• 31:10the products that are available
• 31:11with unusual names like, shatter,
• 31:14and DHL.
• 31:16The basic idea behind these
• 31:18studies these products is that,
• 31:20they use different techniques, including
• 31:23using butane
• 31:24to leach out all the
• 31:25THC from herbal cannabis material
• 31:28and to extract this wax
• 31:29like substance.
• 31:31The way that,
• 31:33these compounds are used is
• 31:35either in a,
• 31:36in a in a a
• 31:37vaping cartridge
• 31:39or by heating up a
• 31:40glass rod,
• 31:41dipping it in there, and
• 31:43inhaling the vapors.
• 31:44Again,
• 31:45these products contain
• 31:48up to ninety five percent,
• 31:49THC and so are really
• 31:51potent, and we are seeing
• 31:52some negative consequences,
• 31:54associated with the use of
• 31:55these products.
• 31:58So
• 32:00route of administration is really
• 32:02important, and I'll get to
• 32:03to that in a in
• 32:05a minute, especially if you're
• 32:06thinking about designing studies.
• 32:08Of course, you know, the
• 32:09typical the most common way
• 32:10that people use consume cannabis
• 32:12is by inhalation,
• 32:14and why that might be
• 32:15important for you for you
• 32:16all if you're thinking about
• 32:18doing,
• 32:20you know,
• 32:21conducting clinical trials is that
• 32:23it's unlikely the that the
• 32:25FDA will ever approve
• 32:27any product that needs to
• 32:28be in smoke.
• 32:30So that's clearly off the
• 32:31table.
• 32:33Another more common way of
• 32:35of using,
• 32:36cannabis products is,
• 32:38by by using it orally,
• 32:40especially amongst older individuals,
• 32:43who prefer using edibles,
• 32:45that are sold in in
• 32:47doses of anywhere from five,
• 32:49ten
• 32:50milligram increments.
• 32:52But
• 32:53but,
• 32:54there are a number of
• 32:55other oral products
• 32:57available.
• 32:58There are topical products that
• 33:00are also available. I don't
• 33:01really know too much about
• 33:02them. And then, of course,
• 33:03there are also some rectal
• 33:05and vaginal support suppositories that
• 33:07are available, and that's pretty,
• 33:09the use of this product
• 33:11is pretty,
• 33:12rare.
• 33:13So what are the implications
• 33:14of this from a drug
• 33:16development point of view or
• 33:17from the point of view
• 33:18of treating,
• 33:20treating pain? I'm gonna skip
• 33:21this slide since I've already
• 33:23told you about it.
• 33:24Is that the pharmacokinetics
• 33:28of palminal and oral THC
• 33:30are quite different.
• 33:31So when someone smokes or
• 33:34vapes,
• 33:35THC,
• 33:37the time to peak plasma
• 33:39levels is within minutes, three
• 33:41to ten minutes,
• 33:44And so people experience the
• 33:45effects
• 33:46fairly quickly,
• 33:48the psychotropic effects fairly quickly.
• 33:50The effects usually peak about
• 33:52fifteen to thirty minutes later
• 33:54and last for a hundred
• 33:56and twenty two two hours
• 33:57to two to three hours.
• 33:59And the bioavailability
• 34:01of THC when smoked or
• 34:02vaped is fairly high.
• 34:04The other important piece of
• 34:06this is that when a
• 34:07person smokes or in or
• 34:08vapes,
• 34:09they have the capacity to
• 34:12titrate the dose with exquisite
• 34:14precision
• 34:15in real time. Because
• 34:17if someone hasn't had too
• 34:18much of an effect, they
• 34:19can take another hit
• 34:21and get to that desired
• 34:23effect. If someone has had
• 34:24too much
• 34:26if the effects are too
• 34:27intense,
• 34:28they just hold off on
• 34:29when their next hit is.
• 34:31In contrast,
• 34:32when someone consumes an edible
• 34:34shown here in red,
• 34:36the effects only emerge about
• 34:38two to three hours later.
• 34:42The peak effects are two
• 34:43to three hours later. The
• 34:45onset of psychotropic effects is
• 34:47an hour to an hour
• 34:48and a half later,
• 34:50and the duration of effects
• 34:51is highly variable, anywhere from
• 34:54four
• 34:56to six
• 34:58to to to more than,
• 35:01eight hours,
• 35:02depending on the
• 35:04the metabolism
• 35:05of the of the drug.
• 35:07And, again, here, the bioavailability
• 35:09of THC when consumed orally
• 35:10is is quite slow.
• 35:13So
• 35:14there are some pros and
• 35:15cons to,
• 35:17the route of administration.
• 35:20When smoked or vape,
• 35:22people feel in control of
• 35:24the effects, and they can
• 35:25control it with exquisite precision.
• 35:29When people consume an edible,
• 35:31they don't have control.
• 35:33On the other hand, the
• 35:34effects of the edible last
• 35:36for much longer.
• 35:37The onset and the slope
• 35:39of the or the rise
• 35:40in the in effects
• 35:42also tends to be, much
• 35:44slower. And so, therefore, it's
• 35:46not by accident that
• 35:48in in general, people
• 35:50don't abuse
• 35:51edibles to the same extent
• 35:54as they may have used
• 35:55smoked or baked products.
• 36:00Okay. So what are the
• 36:02cannabinoids that are currently
• 36:04in use on in, in
• 36:06or in the pipeline?
• 36:09So,
• 36:10these
• 36:12the three columns show drugs
• 36:13that are
• 36:14already approved and marketed,
• 36:16those that are in clinical
• 36:18development, and those that are
• 36:19in preclinical development. So there
• 36:21are a number of c
• 36:22d one are agonists that
• 36:24are available.
• 36:26They include dronabinol, which is
• 36:28THC,
• 36:29and nabilone, which is a
• 36:31synthetic analog
• 36:32of THC.
• 36:34Both those drugs are FDA
• 36:35approved,
• 36:36and the primary indication is
• 36:38for
• 36:38chemotherapy induced nausea and vomiting.
• 36:41There's another product,
• 36:43that's available but outside the
• 36:45US and Canada, Mexico, and
• 36:46and Europe,
• 36:49known under the brand name
• 36:50Sativex or nabiximans.
• 36:52This is a balance
• 36:54of one of near one
• 36:55to one ratio of THC
• 36:57and CBD,
• 36:59sold as a as
• 37:01a as a spray,
• 37:03as an oral mucosal spray.
• 37:05And it seems like
• 37:07from reports it's better tolerated
• 37:10than THC alone.
• 37:12Now in what's in clinical
• 37:14development include a number of
• 37:15other THC rich formulations,
• 37:18and historically,
• 37:20there have been a number
• 37:21of other drugs that were
• 37:22developed that were abandoned,
• 37:24including the drug levonantrodal.
• 37:26It was developed by Pfizer.
• 37:28It was found to
• 37:30be a very potent analgesic,
• 37:32but was dropped from further
• 37:33development because of an unacceptably
• 37:36high,
• 37:37level of,
• 37:39psychotropic
• 37:39side effects, including psychosis and
• 37:41paranoia.
• 37:43Of course, what's interesting is
• 37:44at the time that levonantradiol
• 37:46was developed,
• 37:47the CB one receptor had
• 37:49not been discovered. It's only
• 37:50later that they discovered that
• 37:52this drug,
• 37:53bound produced its effects by,
• 37:55by by, activating CB one
• 37:57receptors.
• 37:59There are a number of,
• 38:01endocannabinoid
• 38:03modulators.
• 38:04If you recall, I spoke
• 38:05to you about the enzymes
• 38:06that are involved in the
• 38:08synthesis and degradation of,
• 38:10of anandamide in two AG.
• 38:12One of those enzymes is
• 38:14fatty acid amide hydrolase.
• 38:16A number of fatty acid
• 38:17amide hydrolase inhibitors had been
• 38:19developed.
• 38:20Pfizer tested,
• 38:22fatty acid amide hydrolase inhibitor
• 38:24for the treatment of pain
• 38:26associated with osteoarthritis,
• 38:28and we'll come to that,
• 38:29in a minute now.
• 38:31Companies are trying to develop
• 38:32a second generation, a new
• 38:34generation of, five inhibitors,
• 38:36and I believe there are
• 38:37also MagLytease inhibitors that have
• 38:39been administered to humans.
• 38:42There are also drugs that
• 38:43have been
• 38:44developed as
• 38:45only peripheral c v one
• 38:47agonists, so they only have
• 38:49effects on c v one
• 38:50receptors
• 38:51peripherally
• 38:52and not centrally.
• 38:53The advantage of that would
• 38:55be that these drugs, in
• 38:56theory, should not produce psychoactive
• 38:58effects, which tend to be
• 39:00the rate limiting, side effects,
• 39:02in using these drugs to,
• 39:05as as potential treatments.
• 39:07There are also c v
• 39:08two
• 39:10agonists. And as you may
• 39:11recall, c v two receptors
• 39:13are mostly present on immune
• 39:15cells in the periphery
• 39:16and may contribute,
• 39:19to reducing pain by modulating
• 39:21inflammation.
• 39:23And then there are CB
• 39:24one r and antagonists.
• 39:28You some of you may
• 39:29recall from the from the
• 39:30early two thousand drug called
• 39:32rimonovant
• 39:32that
• 39:33was,
• 39:34that became commercially available. It
• 39:36was used in the treatment
• 39:38of,
• 39:39of obesity.
• 39:41The
• 39:42simple
• 39:43messages,
• 39:44if cannabis gives you the
• 39:45munchies,
• 39:46a CB1R
• 39:47antagonist
• 39:48will, will reduce appetite. And
• 39:50indeed, it did reduce appetite
• 39:51and people did lose weight.
• 39:53Unfortunately,
• 39:55some patients,
• 39:56developed
• 39:57suicidal
• 39:58ideation and depression, and that's
• 39:59what really killed the rimono
• 40:01band program. There are a
• 40:03couple of other CB one,
• 40:04CB one receptor antagonists
• 40:07that are in development. These
• 40:09are drugs that are
• 40:10basically being developed to reverse
• 40:15cannabis intoxication or THC intoxication
• 40:18and to reverse, say, acute
• 40:20paranoia and panic attacks, that
• 40:22often lead people to go
• 40:23to the emergency room.
• 40:26So
• 40:27the the current philosophy in
• 40:29terms of drug development,
• 40:31involving,
• 40:33cannabinoids is not for stronger
• 40:36cannabinoids, but to make them
• 40:37more selective.
• 40:40And so that's that's the
• 40:42general,
• 40:43direction that these drugs are
• 40:45being developed.
• 40:48There are also some
• 40:50minor cannabinoids that are receiving
• 40:53some
• 40:54attention, including cannabagirals,
• 40:57and, and a few others,
• 40:59these are fairly early on
• 41:02in,
• 41:02in in development.
• 41:04They have not yet been
• 41:06established, and they are mostly,
• 41:07as I mentioned,
• 41:09in early translational work.
• 41:13So,
• 41:15in terms of acute pain,
• 41:17what is the evidence
• 41:19for,
• 41:20cannabinoids in acute pain?
• 41:22And I make this distinction
• 41:23between acute pain and chronic
• 41:25pain,
• 41:26and I'm sure there are
• 41:27others on this call who
• 41:28who probably know a lot
• 41:29more about this. But
• 41:31in terms of acute pain,
• 41:32what is the data? I'm
• 41:33gonna draw your attention to
• 41:35a study that that I
• 41:36did in my lab in
• 41:38in collaboration
• 41:39with,
• 41:40with colleagues in anesthesia and
• 41:42neurology.
• 41:43And this was a study,
• 41:46where we tested,
• 41:50it was a double blind,
• 41:51randomized,
• 41:52placebo controlled crossover study, so
• 41:54each subject served as
• 41:56his or her own control.
• 41:58This was done in healthy
• 42:00volunteers,
• 42:01and we used, we tested
• 42:03placebo,
• 42:04low and medium dose of
• 42:06THC, and we inflicted
• 42:08five different kinds of experimental
• 42:10pain, including
• 42:12heat and cold pain using
• 42:13a thermode.
• 42:15We injected
• 42:16capsaicin,
• 42:18into,
• 42:19subcutaneously
• 42:20and that,
• 42:22intradermally, sorry, and that induces
• 42:24a,
• 42:25reliable zone of hyper hyperalgesia.
• 42:29We also had,
• 42:30we looked at mechanical and
• 42:32electrical pain.
• 42:34This was the basic design
• 42:35of the study. There was
• 42:36a baseline phase. We did
• 42:38some pace pain assessments at
• 42:40baseline,
• 42:41and then we administered,
• 42:43THC,
• 42:46have the pain paradigms, and
• 42:47then we looked at pain
• 42:50at the peak of THC
• 42:51effects
• 42:52and sometime later during the,
• 42:55the study.
• 42:57And what we found was
• 42:58that at these doses, THC
• 43:00produced effects that are consistent
• 43:03with the known effects of
• 43:04cannabis, as in they made
• 43:05a person feel high, the
• 43:07people felt more calm and
• 43:08relaxed.
• 43:10They had some alteration in
• 43:11cognitive test performance,
• 43:14and heart had an increase
• 43:16in heart rate. But
• 43:18at none of these doses
• 43:19did THC have any significant
• 43:21effects
• 43:22on experimentally induced
• 43:24chemical, mechanical, thermal,
• 43:27electrical,
• 43:28pain, or capsaicin induced hyperalgesia.
• 43:31So at least in our
• 43:33hands,
• 43:33we did not find,
• 43:35that THC in this,
• 43:37highly controlled, double blind, randomized,
• 43:40placebo controlled study,
• 43:43have any effects on acute
• 43:44pain in healthy individuals.
• 43:48There have been a couple
• 43:49of other,
• 43:51meta analyses done, systematic reviews
• 43:54and meta analyses that have
• 43:55been done,
• 43:56which have shown that,
• 43:59there may be a small
• 44:00increase in pain threshold,
• 44:03a small to medium increase
• 44:05in pain tolerance,
• 44:07and a small to medium
• 44:08reduction in the unpleasantness
• 44:11of ongoing experiment pain in
• 44:13these experimental studies.
• 44:15But,
• 44:16cannabinoids did not decrease experimental
• 44:19pain or mechanical hyperalgesia.
• 44:22So,
• 44:24I draw your attention to
• 44:25the last line of their
• 44:26conclusions, which is that they
• 44:28see that cannabis induced improvements
• 44:30in pain related negative affect
• 44:32may underlie the widely held
• 44:34belief that cannabis relieves pain.
• 44:38This was followed by a
• 44:39more recent
• 44:40systematic review,
• 44:42which,
• 44:43which concluded that
• 44:45the evidence was all over
• 44:46the place
• 44:47and not consistent,
• 44:50of,
• 44:51efficacy of cannabinoids as an
• 44:53analgesic agent for acute,
• 44:55acute pain.
• 44:58So
• 44:59just to summarize the data
• 45:01on acute pain with THC
• 45:02and CBD,
• 45:04there may be some evidence
• 45:05to suggest that there's an
• 45:06increase in threshold
• 45:08pain threshold and a decrease
• 45:09in pain unpleasantness.
• 45:12There's some questionable evidence about
• 45:14of hyper hyperalgesia
• 45:16at higher doses,
• 45:17and there may be biphasic
• 45:19effects that is at at
• 45:21low doses.
• 45:22THC may have effects going
• 45:23in one direction and a
• 45:24higher dose is a different
• 45:26direction.
• 45:27But they are limiting
• 45:28if,
• 45:29the limiting factor is that
• 45:30at doses that might produce
• 45:32some of these effects on
• 45:33pain threshold,
• 45:35they may also produce,
• 45:37psychoactive adverse events.
• 45:39In fact, the psychoactive adverse
• 45:41events may emerge
• 45:43at at or below
• 45:45analgesic,
• 45:46doses, suggesting a very narrow
• 45:48therapeutic
• 45:49window.
• 45:50And then in terms of
• 45:51CBD,
• 45:52at least in acute pain,
• 45:54there's very little, if any,
• 45:55data to suggest that CBD
• 45:57has any effects on acute
• 45:59pain.
• 46:02Now what about the effects
• 46:03of, cannabinoids
• 46:04and chronic pain?
• 46:07There's a lot more research
• 46:08that has been done on
• 46:09chronic pain,
• 46:11and I'm not going to
• 46:12review all that literature.
• 46:14If you're interested, I would
• 46:16point you to a very
• 46:17interesting collaboration between the Department
• 46:19of Veterans Affairs
• 46:21and,
• 46:22Oregon Health Sciences University,
• 46:24where they have a program
• 46:26called systematically
• 46:27testing the evidence on marijuana.
• 46:29And they published,
• 46:31they published,
• 46:34live reviews. These are ongoing
• 46:36reviews of different topics such
• 46:38as cannabis and pain, cannabis
• 46:40and PTSD, cannabis and pregnancy,
• 46:42and they're basically one page
• 46:44summaries that
• 46:45make it easy for people
• 46:47who are not familiar with
• 46:48the the cannabis field
• 46:50to understand
• 46:51exactly what the evidence is
• 46:53out there, and it's really
• 46:54also useful for patients
• 46:55in addition to clinicians.
• 46:57This is,
• 46:58this is their summary
• 47:01of the evidence of cannabis,
• 47:03for pain.
• 47:05And,
• 47:07they look at
• 47:08both benefits,
• 47:09and they look at harms.
• 47:12And they've looked at, this
• 47:14in a in an ongoing
• 47:15fashion. I think this review
• 47:16was from maybe last year.
• 47:19And I'll just read out
• 47:20the bottom line, which is
• 47:21there's moderate certainty evidence that
• 47:23a product come with compact
• 47:25comparable THC to CBD ratios
• 47:28probably improves pain but not
• 47:30functioning,
• 47:32and that oral CBD alone
• 47:33probably does not affect pain
• 47:35or function.
• 47:36Some formulations
• 47:38increase the risk of side
• 47:39effects,
• 47:40and several formulations
• 47:42remain understudied.
• 47:44So there you have it.
• 47:48So oral t h oral
• 47:50CBD doesn't affect,
• 47:51the strength of the evidence
• 47:53for all other benefits is
• 47:54low or insufficient.
• 47:57Compared to placebo, cannabis related
• 47:59interventions
• 48:00result in greater
• 48:02risk of common
• 48:03side effects, but not severe
• 48:06adverse events,
• 48:08and there's little data on
• 48:11the effects of these compounds
• 48:13in children or adolescents.
• 48:18The International Association for the
• 48:20Study of Pain presidential
• 48:22task for force had a
• 48:24consent statement,
• 48:25and they basically concluded that
• 48:28there was a lack of
• 48:29high quality clinical evidence
• 48:31and that they do not
• 48:33currently endorse the general use
• 48:34of cannabis or cannabinoids for
• 48:36pain relief.
• 48:37And they further go on
• 48:38to say there is a
• 48:39pressing need for preclinical
• 48:41and clinical studies to fill
• 48:43this gap.
• 48:44Now some of you may
• 48:45also be aware
• 48:47of a recent study that
• 48:48received quite a bit of
• 48:49attention.
• 48:50This was a very large
• 48:52study,
• 48:53staggeringly large
• 48:55study that had more than
• 48:56eight hundred adults
• 48:57enrolled. This is far bigger
• 48:59than any other study that's
• 49:00ever been done where they
• 49:02used an oral full spectrum
• 49:04cannabis extract,
• 49:06versus placebo in a in
• 49:08a in a study that
• 49:10was quite complicated. I'll just
• 49:11focus on the first twelve
• 49:13weeks of treatment.
• 49:15And in that study,
• 49:16they showed that there was
• 49:17a two to three point,
• 49:20reduction in pain versus baseline
• 49:23in the group that received
• 49:24the cannabis
• 49:25extract,
• 49:27and the primary outcome measure
• 49:28here was NRS.
• 49:31In addition
• 49:32to improvements in pain, they
• 49:34saw improvements in function and
• 49:36sleep, which has not been
• 49:37shown in previous studies,
• 49:39and these effects were sustained
• 49:41over time.
• 49:42And while these effects were
• 49:43modest, they were clinically,
• 49:45meaningful.
• 49:46Now what caught my attention
• 49:47was that
• 49:49at the time that,
• 49:52at least until recently,
• 49:54the one kind of pain
• 49:55that was seemed most likely
• 49:57to benefit from cannabis or
• 50:00cannabinoids was neuropathic pain.
• 50:03When we did a literature
• 50:04review several years ago,
• 50:06in thinking about designing a
• 50:08study to address pain, we,
• 50:10one of our first tasks
• 50:12was what kind of pain
• 50:13would we want to target?
• 50:15And it became clear that
• 50:18even though there was limited
• 50:19evidence, that limited evidence suggested
• 50:21that the kind of pain
• 50:23that was most likely to
• 50:24respond to cannabinoids
• 50:25was chronic neuropathic pain.
• 50:28So I was surprised
• 50:30by the results of this
• 50:31study that was published in,
• 50:33in Nature Medicine.
• 50:38So I think that
• 50:40we still
• 50:42don't have a good idea
• 50:43about the risk benefit ratio
• 50:45of, cannabinoids and the treatment
• 50:47of pain.
• 50:49We have,
• 50:51I just wanna point out
• 50:52one study that was done
• 50:54several years ago with the
• 50:55inhibitor.
• 50:57There was quite a bit
• 50:58of excitement because, of the
• 51:00mechanism of action of fine
• 51:02inhibition increasing
• 51:04endocannabinoid
• 51:05levels in the brain without
• 51:06producing intoxication.
• 51:08Unfortunately, this drug did not,
• 51:11did not produce pain in,
• 51:13in osteoarthritis,
• 51:15though it was very well
• 51:16tolerated. And then drug was
• 51:17abandoned by Pfizer,
• 51:20at the time.
• 51:22So,
• 51:24there are a number of
• 51:25research gaps and opportunities for
• 51:27cannabinoids. I know we have
• 51:28a few minutes left.
• 51:30I just want to summarize
• 51:31some of the limitations
• 51:32as some of you may
• 51:34be thinking about designing studies
• 51:35to look at the effects
• 51:37of cannabis or cannabinoids with
• 51:39pain. The first is sample
• 51:41sizes. Most of the studies
• 51:42had very small sample sizes.
• 51:44Blinding is a big issue.
• 51:46If you use doses that
• 51:47are clearly psychotropic, you really
• 51:49need to think about using
• 51:50a dose that is on
• 51:52the
• 51:53on the threshold of psychotropic
• 51:55effects.
• 51:57Many of these studies, and
• 51:58it's so important in pain
• 52:00and depression and PTSD research
• 52:02to measure expectancy and take
• 52:04that into account in studies.
• 52:07Many studies do not take
• 52:08into account previous cannabis exposure
• 52:11as I showed you in
• 52:12we have pet data showing
• 52:13that there's down regulation and
• 52:15desensitization
• 52:16of c b one receptors.
• 52:18Most of the studies have
• 52:20relied almost exclusively on subjective
• 52:22effects,
• 52:23and did not look at
• 52:24other measures, including functioning.
• 52:28The literature is a mess
• 52:29because there's so many different
• 52:31compounds that have been tested,
• 52:32that have been administered.
• 52:33We
• 52:34we have different routes of
• 52:35administration
• 52:36and different doses.
• 52:39And, and most studies looked
• 52:41at isolated cannabinoids
• 52:43with one exception. That is
• 52:44the last study published from,
• 52:46in Germany in nature,
• 52:49nature medicine
• 52:50that used whole plant cannabis
• 52:52that contained,
• 52:54not just THC, but many
• 52:55other cannabinoids, terpenes, and flavonoids.
• 52:58So,
• 52:59we are actually trying to
• 53:01address many of these limitations
• 53:03in
• 53:04what is the first VA
• 53:05funded study,
• 53:06that,
• 53:07Don McGarry and I are
• 53:09are are
• 53:10leading,
• 53:12involving five VAs. We are
• 53:14going to study a very
• 53:15large number of subjects larger
• 53:17the sample size is larger
• 53:18than
• 53:19any other study that's been
• 53:20done recently.
• 53:22We are gonna study chronic
• 53:24neuropathic pain, and we are
• 53:26testing
• 53:27THC,
• 53:28CBD,
• 53:29the combination of the t
• 53:30of the two and placebo,
• 53:32in an eight week long
• 53:33trial. We're looking at a
• 53:34number of measures, including
• 53:36measures of pain, measures of
• 53:38function, and measures of mood,
• 53:40and, of course, side effects.
• 53:42The study is ongoing. We
• 53:44are about a third of
• 53:45the way through.
• 53:46Hopefully, we have results,
• 53:49in in a couple of
• 53:50years.
• 53:52So thank you for your
• 53:53attention. I'm happy to take
• 53:54questions if you have any.
• 54:01I think you're muted.
• 54:04Oh, I can't hear you.
• 54:12I can't hear you. I
• 54:13don't know if anyone else
• 54:14can.
• 54:47I can definitely see the
• 54:48chat.
• 54:49So if you have questions,
• 54:50happy to answer questions.
• 54:58Oh, can you hear me?
• 55:00Yeah. Yeah.
• 55:02Oh, great talk. You mentioned
• 55:04that
• 55:05edibles
• 55:06are
• 55:08are good but less potent
• 55:10than smoking.
• 55:12Did you also mention edibles
• 55:13are good for pain but
• 55:15not function?
• 55:17Did I get that right?
• 55:18So I I I I
• 55:19would not say good or
• 55:20bad. I I try and
• 55:22steal care from using those
• 55:24kinds of adjectives.
• 55:25I I would I would
• 55:26say that,
• 55:31that there are differences,
• 55:32pharmacokinetic
• 55:33differences between
• 55:35edibles
• 55:36and, of course, smoke and
• 55:37vape, which and there are
• 55:38some advantages and disadvantages
• 55:40to to both.
• 55:42When one consumes an edible,
• 55:44the
• 55:46the duration of exposure is
• 55:48a lot longer
• 55:49than,
• 55:50when one smokes or vapes.
• 55:52Also, the
• 55:53the
• 55:54the effects emerge a lot
• 55:56slower, but then, of course,
• 55:57last a lot longer.
• 55:59The disadvantages
• 56:00of of consuming
• 56:02these products,
• 56:03orally
• 56:04is that there's there's a
• 56:05lot
• 56:06of variability
• 56:08in the bioavailability
• 56:10of the of of THC.
• 56:13Also, when you consume
• 56:15THC
• 56:15orally or cannabis products orally,
• 56:18there is
• 56:20a greater
• 56:26synthesis of an active metabolite
• 56:28of THC,
• 56:30and that active metabolite of
• 56:32THC tends to be more
• 56:34potent than THC itself.
• 56:36So some people might experience,
• 56:41more negative psychotropic effects in
• 56:43theory,
• 56:44when they consume edibles.
• 56:47I don't think there's been
• 56:48any study to my knowledge
• 56:50that has compared oral versus,
• 56:53vague to smoked
• 56:54THC,
• 56:55for pain.
• 56:59And the study that you're
• 57:01proposing will do that?
• 57:04The study that we are
• 57:05proposing,
• 57:07the THC
• 57:08is in an oral form.
• 57:11Like I mentioned to you
• 57:11earlier, it's very unlikely the
• 57:13that the FDA is going
• 57:15to approve of any drug
• 57:17that's going that would that
• 57:18needs to be smoked.
• 57:19That's just not gonna happen.
• 57:22And so that's one of
• 57:23the one of the interesting
• 57:24things about this space that,
• 57:27people who are using cannabis
• 57:28are mostly using it by
• 57:30smoking,
• 57:31but research that's being done
• 57:32on cannabis and smoking
• 57:34cannot use smoking as a
• 57:36way of delivering cannabis. So
• 57:38there's always going to be
• 57:39this mismatch between
• 57:41the real world evidence
• 57:43and what we as clinical
• 57:45scientists are trying to
• 57:47to determine.
• 57:53Yeah. For the last study,
• 57:54was it oral? Which, the
• 57:56study in Germany with the
• 57:57eight hundred subjects? Yes. That
• 57:59was oral.
• 58:01And they call their product
• 58:03VER one.
• 58:07I I I'm you I'm
• 58:08happy to send the paper
• 58:10to you. It's in nature
• 58:11and, medicine, so it's easily
• 58:13accessible.
• 58:23Are there any more questions?
• 58:27Thank you so much, doctor
• 58:29D'Souza and everyone for joining.
• 58:31Have a wonderful
• 58:32day. Bye.
• 58:34Bye.