>> [Inaudible]. Thanks, Chad. So yes, today I'll talk
a bit about the use of cannabinoids to treat pain. And I have no financial
disclosures that relate to this. And before I get into
the scientific background of how we actually use
cannabinoids to treat pain, I think we just need to acknowledge what a
mess this situation is; so [laughter] we have
fairly few states with legal medical cannabis. This slide as of a couple
days ago is outdated because Illinois just passed
adult use recreational law, so we now have 11 states
with adult use cannabis. And this is despite
it being schedule one so under the Controlled
Substances Act, it has no accepted medical use,
and a high potential for abuse. So this has created such a
mismatch for so many clinicians who want to know how to
adjust the use of cannabis in their patients,
and how to do this in a safe and effective way. And so to this point
a little bit -- we just published a paper little
while ago, we see the conditions for which people are
actually using cannabis. Far and away, the most
prevalent qualifying condition for your cannabis
license is chronic pain. It's about two-thirds
of the total number of qualifying conditions, and
about 80% of the total patients. So what does this look
like then in Michigan? We're one of the biggest
states in terms of the number of medical cannabis patients. We have about 270,000
patients as of 2017. And we've had medical
cannabis -- a medical cannabis
law since 2008. But because of this mismatch,
we have a lot of uncertainty about how to actually
interface with patients. A lot of physicians are
uncomfortable regarding certifications for
their patients. They're not actually saying,
"This is the prescription, and this is how you
should go use cannabis." Instead, what they're doing
when they sign an application for your medical cannabis
license is they're saying, "Yes, you have a condition
that qualifies you under the state law to
possess cannabis up to two and a half ounces and 12 plants, and go and figure it
out for yourself." And so because so many
physicians are uncomfortable with this, there's also a lot
of clinics that have popped up where all they do is
medical cannabis certifications. You can go in, get a five-minute
appointment, pay 100 bucks or something, and voila,
you have a license, but still no idea of
what necessarily to do. So we have that mess
on that side. And then of course, as
everybody's been talking about today, we're in the
midst of an opioid crisis. And there's a lot of interest in
using cannabis or cannabinoids, the active compounds
in the cannabis plant, to treat both opioid
addiction, but then some of the undergoing chronic pain that has driven this
opioid crisis. And there is some support
of this being plausible. So we know from a lot
of preclinical studies, as well as like there
are some clinical trial that there does seem to be
some synergism between THC, one of the compounds in
cannabis, and opioids. So in this recent
clinical trial, they gave people Oxycodone, as
well as [inaudible]cannabis. And they found with
sub-threshold dose of the cannabis and
Oxycodone together, they got the same
pain relief with -- as they saw with a
higher dose of the opioid. So there's some interest
there, and might be a way that people are able to reduce
their opioid consumption when they start using cannabis. But then we also see statewide
analyses where people have shown that states with medical
cannabis legislation have lower rates of opioid overdose,
lower opioid prescribing than the states without. And having active operating
dispensaries is really important for these effects. We then also see numerous --
dozens of studies at this point in the US, in Israel, in
Canada, where people say, "Yes, I've substituted
cannabis for opioids, and I do so for better
symptom management, and I do so because there's
fewer adverse side effects." So, again, schedule
one substance, not much clinical guidance,
widespread availability. You can see why we're
in quite a mess. So I think that what we need
to do next is then figure out where the evidence
lies for chronic pain, how we can use this in a
safe of a way as possible, and how to conceptualize
cannabis in the correct way, which, at least in my view,
is rather than thinking of it as a panacea or a poison, which
are really the extended -- the dichotomist use that are
really out there at this point, and think of it, "Well, this is
potentially one pain medication that people could use,
and this is the way in which they could do so." So with that, let's drum
into some of the science, so in terms of definition
and background, then I'll go into some of the risks that
are known about cannabinoids, their role in pain
management, looking at some of the clinical trials, and
then some practical tips and guidelines on how
of use these compounds. So and much of this comes
from the National Academies of Sciences 27 through --
report on the health effects of cannabis and cannabinoids. There is some stuff that's
been updated since this time, but this is a really
good place to start. It's available to
anybody online, so I would suggest looking
into it if you would like. In terms of definitions, so I'm
going to use "cannabis" instead of "marijuana", just because "cannabis" is the botanical
name, and "marijuana" has, you know, [inaudible]
xenophobic history to the word, so I'll just avoid
using that for now. And so there's subspecies
[inaudible]. And then we also
have cannabinoids, which is active compounds,
both in the cannabis plant, but also we -- our
body makes its own endo or endogenous cannabinoids. And then there's also
synthetic cannabinoids, which either are replicas
of the phytocannabinoids that are synthesized
in the labs, or novel cannabinoid
compounds that we think of as having potential
therapeutic uses. These compounds all
interface with the endogenous or endocannabinoid system,
which is the set of receptors from your naturally
recurring ligands and enzymes regulating control. And this system is so ancient,
so widespread, and involved in so many functions including
memory, analgesia, stress, appetite, sleep that
there's a lot of excitement about targeting it for
clinical applications. I guess I can't tell
if it shows up nicely. The two most common
receptors in this system, the ones that are the
most widely studied, are cannabinoid receptors
one and two. CB1 is one of the
most common receptors in the central nervous system. And it is -- when
it's activated, it tends to be more involved in the sleep memory analgesia
appetite, those responses. By contrast, CBQ is found
more in the immune system. And when it's activated, it
doesn't seem to have any kind of psychoactive effects in the
same way as the CB1 receptor, so there's a lot of
interest in targeting that immune system-related
conditions. So next let's go into
some of these cannabinoids and what we know about them. At this point, I'm just
going to touch on two, even though there's over 100
which have been discovered. But the most commonly studied
is THC or tetrahydrocannabinol. It's analgesic, it's
mood-altering, and appetite-stimulating, and it partially binds
to both CB1 and CB2. I will note that even though
there's a lot of concern about the psychoactive
effects and all of that of THC when in smoked cannabis,
that synthetic THC as dronabinol has
been legal for decades for treating chemotherapy
induced nausea and vomiting, and AIDS-related anorexia. So there is a known
therapeutic use. It's FDA-approved. It's a schedule-free substance, while herbal cannabis
is schedule one, further muddying
confusion in the waters about what's going on with this. Hot on the scene is
CBD or cannabidiol. We've known about this
compound as long as we've known about THC, but there's so
much more excitement about it at this point because
it is non-intoxicating. It seems to protect against some of the psychoactive
effects of THC. And then in a lot of
preclinical studies, it has anti-inflammatory
effects, it has effects on pain, and most excitedly, is a
very potent anticonvulsant. In fact, the FDA just approved
a CBD-based drug last -- I think it was last June
in 2018 called "Epidiolex" for childhood epileptic
disorders. And it is schedule five, so
very low abuse potential. I would be remiss if I didn't
mention the other cannabinoids. I'm not going to go into
them much, except to say that there's over 100 of them. And there's a big dispute in the
medical and scientific community at this point about how
to account for them, because classically
pharmaceuticals will try to find the active ingredient
and synthesize that and give that in isolation and say,
"Okay, that's a good -- that's the effect that we want." But because there are so many
terpenes responsible for aroma and taste, et cetera, as well
as these other cannabinoids and herbal [inaudible],
people want to know, "Should we use a
full spectrum product or should we use an isolate?" So I'm not going to
go anymore into that, but just to say that
it's out there. In terms of photos, you
can see that there -- it's a close-up of
a cannabis bud, and then a cannabis
oil [inaudible]. And you can -- now that
CBD is so exciting and hot on the scene, you
can buy it anywhere. You can buy it on Amazon, you
can buy it at gas stations, you can but it at CVS. And to the frustration
of scientists who want to actually do studies on
this stuff, but you have to get a scheduling license
to do so, you can buy it for your dog [laughter] in
case your buddy has anxiety or joint pain, or
something like that. You can get this in BarkBox
delivered to your house. [Laughter] So we also see that this situation is
evolving quite quickly. So in 2018 -- at
the end of 2018, President Trump signed
the 2018 Farm Bill that legalized industrial
hemp, and thus opened the door for the availability for many
hemp derived CBD products; so they have less
than .3% THC in them. But there's not a
lot of uncertainty about how the FDA is
going to regulate that, so there are concerns about
products that have heavy metals because hemp is a
bioaccumulator. There's also a lot of shady,
you know, companies out there who don't have good processes in
place that remove the solvents that are used to extract these
compounds, or they use a lot of pesticides and then
don't do anything about that when they're actually
doing the extraction. So it's really important
to go to -- ideally to go to a place that has third-party
independent testing for metals, for solvents, for
pesticides, and then also so you'll actually know
what is in the product that your patients
might be using. One such place, there's a
nonprofit called [inaudible] that has collaborated
with places like Johns Hopkins University. And they've done much of this
safety and potency testing, and have a list of product
that they verify as being safe and actually accurately labeled. And then lastly,
in this definitions and background section,
I just want to talk about how these compounds
work a little bit in the body, because this will come in later
when we're talking about how to use them and the
effectiveness. So pharmacokinetically, you
can see from this slide the way that THC shows up in
the blood [inaudible] administration groups. If anybody knows of anybody
who's injected cannabinoids, please let me know so that,
one, that injection one, it looks almost the
same as smoking. So you can just go with that. But if you [laughter] actually
ingest the compounds orally, you have less of a spike of
THC in the bloodstream and less of a fast taper, and instead
you have an extended -- it takes a while to hit
and then an extended taper. So you can think about slow and fast release
administration groups for using these compounds,
especially knowing that the feeling of high maps onto those pharmakinetics
really nicely. And then lastly, about how
these interact in the body; we do seem to see a
u-shaped curve for cannabis and cannabinoid effects. So with that in mind, what
this means is there's a kind of sweet spot above which if
you go above a certain point, you can end up overshooting
your medical dose, and then just get higher, in
fact maybe even get worse pain. So if you look at the Y axis, you see a green plus
and a red minus. The curve shows where
somebody's pain relief is. So maybe you have a low dose
and you get a little bit of pain relief, you'd
find that sweet spot up at the top of that curve. But if you go past that, people
could have increased anxiety, they could have increased pain. So trying to figure
out how to do that safely is something
that's really important when using these compounds. All right; so next let's
move into cannabinoid risks. I feel like this is
really important to go into because there's so
much concern about this, just given that cannabis is
still a schedule one drug. And actually, this is where the
bulk of the research funding from the National Institutes
of Health has gone in the past. And we don't have that much info
on the medical risks of cannabis and cannabinoids because these
studies have typically looked at recreational users. But because many of these folks who are using it recreationally
would be considered the chronic heavy users, they're
smoking a lot daily, and tend to be younger,
we can say, "Well, these are probably -- this
is the worst case scenario of what this might look like, at
least as a surrogate right now." We know that smoking,
not really good. So the respiratory effects
of that, those are some of most widely known
risks of cannabinoids, but there's also risk of
dependence and addiction. About nine percent of people who use cannabis develop some
kind of dependency issue. There's also increased rates
of psychotic illness developed by people, especially using
cannabis under the age of 25. I also need to addend the point
on dependence and addiction. People who use cannabis at a
younger age have about a double of that risk of addiction, so
important to note that as well. And that's a particularly
vulnerable population. And we see some long-term
effects on memory and brain structure in
cannabis users as well. In terms of in the acute phase,
we see dizziness, somnolence, euphoria, although some
people might not say that that is a risk, lightheadedness,
anxiety, and others. Less commonly, but
especially seen in people who take way too much in
terms of an edible dose, you'll see some vomiting,
paranoia, occasionally seizures and hallucinations, although
those are more associated with the synthetic cannabinoids
like spice that people can buy on the street, not typically
cannabis itself; and then, vehicle accidents, of
course, and then lastly, as with the CBD products
that you can buy on Amazon, there's an uncertain
quality of many of the herbal [inaudible]
as well. So in states that don't have
good regulatory statutes in place about testing
for safety and potency, you can end up with things with
bud mold on them like you see in that -- in the upper picture. And if somebody's
immunocompromised and smoking that, it can be
really serious and problematic if they get some kind of
systemic fungal infection. So in terms of the risks
of medical cannabinoid use, as I said, we have much
fewer data on this. The best study that I've
seen came out of Canada on McGill called
the "COMPASS Study" and what they did was they
followed folks using 12.5% THC smokable cannabis for a
year, and what they -- and compared to people
who were not using it in a chronic pain setting. And what they found is about
a double direct increase in minor adverse effects in
people who were using cannabis, compared to those who were
not, but also increases -- or improvements in pain
and quality of life. So definitely a mixed
profile there, but in a place, excuse me, that needs a lot more
work, especially given that, you know, there are so many
people using cannabis medically and we just don't really
have a good sense of what that looks like risk wise. A couple studies that
did come out of Israel where they have more regimented
titration regimes have found that there's a pretty low risk
profile in elderly adults. They would be looking
in a population of mixed cancer patients
and they found with this titration regimen that they saw very
few adverse events. Okay; so going into the
role of cannabinoids and pain management,
we've talked a lot today about the mechanisms of
pain so I'm going to skip over this a little bit,
except to remind you that there's the
peripheral neuropathic and centralized pain states,
and that people can have any of these in combination. In terms of preclinical models
of pain, we know that CB1 and CB2 agonists are quite
effective in many of these types of pain, but people
are really concerned about the CB1 acting compounds because of the off-target
central nervous system activity, the types of effects
that we'd associate with the cannabis high. While CB2 agonists
there's a lot of excitement about at this point because as
I said, they don't really seem to produce that effect. And there's actually a company
making a compound called [inaudible] that
they're testing in a lot of inflammatory disorders that doesn't really
appear to bind to CB1. And so there's some
potential there to maybe in the future see some
CB2-specific compounds on the market. In terms of clinical
trials with chronic pain, the most recent meta-analysis
that looked at all of the clinical trials noted,
as with all the other studies that have done this, that
these are short-length studies, they have small sample size, they have unrepresentative
dosing of what people actually use. And they typically find a
modest decrease in pain, compared to placebo
across pain states. But most of this effect
size is driven by the data in neuropathic pain, using the
combination of THC plus CBT -- CBD excuse me, called "sativex", which is a sublingual
[inaudible], it's a one-to-one
ratio of the two. It would be really nice, if
I could give you more data about how CBD alone is effective
in different types of pain, but unfortunately, I've only
seen one study that has looked at that in any kind
of long-term setting, and that has just been
published as an abstract, as opposed to a published paper. They did find decreases in pain
and improvement in function, but mostly in men with
knee osteoarthritis. I will say also that there's
a pretty clear mismatch between these clinical trials
and the observational studies in which many people using
cannabis who have been followed over time they say that they've
great success, they've been able to taper off opioids,
whatever it might be. But that uncontrolled nature of their dosing makes
it really unclear about how exactly they're doing
that, and how to translate that into a more
clinical setting. Because we've talked
about -- oops, excuse me; because we've talked about
surgical pain a little bit as well, I'll just
touch on that briefly. There's only been about seven
studies that have been done in the acute or surgical
pain setting, and unlike in the
chronic pain space, there's pretty much no
evidence that cannabinoids that have been tested thus far
are effective in this setting. But similarly to the
chronic pain studies, fairly limited in length. Many of them actually use
novel cannabinoid compounds that have CB1 intoxication
psychoactive effects. And none of these
studies used CBD. And given that there's actually
a CBD clinical trial that came out in the last week, that there
was a lot of excitement about it because it seemed to decrease
-- what am I trying to say, it seemed to decrease
cravings and anxiety related to heroin addiction
and recovery in people who were ex-heroin users. There's a lot of excitement
about using it potentially as an opioid sparing medication,
potentially in a surgical space, or as an opioid substitute,
again just CBD alone. Okay. So in summary, then,
we know that cannabinoids and chronic pain, that
they do that plausibility for therapeutic value. We know that dosing
is really important, and we know that using them in the right people
is also important. We need to consider how much to
use, because we want to figure out that sweet spot
on that u-shaped curve so we don't overshoot
an effective dose. We want to know about
cannabinoid content, THC versus CBD, and then the
administration groups as well, because smoking all day
every day probably is not an effective strategy. But it's possible
that you could think of using a long-acting
form of a cannabis compound like an edible, and then have -- or a capsule, and
then having something for short-term great
for pain relief. So actually I was just talking to Evan Latinas [assumed
spelling], my colleague at [inaudible] Medicine,
and something that they do is they give people
CBD alone for the daytime, and if people have
issues with sleeping, they give them a little bit
of THC with CBD at nighttime to help with that, as well
as the CBD [inaudible] for your pain, starting
at very low doses so that people can avoid
getting too high, incidentally, by taking a product that they
don't know what's in it or one that has too much THC. So I guess along
those lines, then, some practical tips would then
be to start low and go slow; so again, those low doses
so you don't overshoot, using a verifiable source with
credible third-party testing so you know what you're getting and you're avoiding heavy
metals, pesticides, et cetera. And then because we know that smoking is really
not probably a good way to ingest medicine
if you can avoid it, using other administration
groups that are available, tinctures, capsules, vaporizing
if somebody absolutely feels that they have to inhale,
things of that nature. And using a combination
of CBD and THC, because using just
THC alone seems to have a much lower toxic
threshold for psychosis and potentially other
adverse events, than using that combination
together. And actually, Dan and I
published a paper in "Annals of Internal Medicine"
with a commentary of how we think people should be
using these compounds from more of a harm reduction standpoint
and on a safety standpoint. And if anybody's
interested in that, I'm happy to send it your way. So with that, I know I'm at the
end of my time, I'd be happy to take any questions. "And thanks so much for
your kind attention. [ Applause ]
