It doesn't matter who you are really.
Modern life is stressful and causes various forms
of anxiety in all of us.
There are so many recommended actions we can
take to help reduce that stress.
Exercise, meditation,
eating whole foods to keep our gut biome
happy, and working directly to resolve the source
of stress are all proven to work.
Various pharmaceuticals come and go in popularity
and supposedly help, but most are either
or eventually debunked as ineffective.
And then there's cannabis.
Humans have been turning to cannabis for anxiety
relief for 1000 of years. And there are
several different ways that we can use cannabis
to relieve stress and we will discuss several
of them today.
Today, we're going to focus on a brand
new scientific study published just last week looking
at the cannabinoid, cannabagirl,
known as CBG,
to reduce anxiety.
And the results are truly remarkable and will
absolutely influence the direction of anxiety medicine research
going forward
and how we as cannabis enthusiasts avoid anxiety
too.
If you want to learn about cannabis health
cultivation and technique efficiently and with good cheer,
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You are listening to Shaping Fire, and I
am your host, Shango Los.
Welcome to episode 116.
My guest today is doctor Ethan Russo.
Ethan Russo is a board certified neurologist and
former senior medical advisor to GW Pharmaceuticals.
He has served as study physician to GW
Pharmaceuticals
for 3 phase three clinical trials of Sativex.
He has held faculty appointments in pharmaceutical sciences
at the University of Montana, in medicine at
the University of Washington,
and as visiting professor at the Chinese Academy
of Sciences.
He has been president of the International Cannabinoid
Research Society
and is former chairman of the International Association
For Cannabinoid Medicines.
In 1995,
he pursued a 3 month sabbatical doing ethnobotanical
research with indigenous people in Peru. He is
author of several books of cannabis medicine and
has published over 30 articles in neurology,
pain management, cannabis and ethnobotany.
He is presently founder of Kratoscience,
where he works to formulate cannabis therapeutics for
the good of all.
Doctor Russo has joined us before on shaping
fire several times.
Episode 22 on treating traumatic brain injury with
cannabis and mushrooms, and episodes 11 and 27
about his famous research papers on cannabinoids and
terpenoids.
Episode number 67 about treating migraines with mushrooms
and cannabis.
Episode 80 on cannabinoid hyperemesis
syndrome.
Episode 83 on the cannabinoid CBG,
episode
103 regarding the life's work of doctor Rafael
Mishulam,
episode 110,
taking a good look at Delta 8 THC,
and of course the Shaping Fire sessions on
the Shaping Fire YouTube channel.
During the 1st set today, we will review
what we know about CBG cannabigerol
and look at the results of prior CBG
studies.
We will also discuss using isolate versus whole
plant preparations during scientific research.
In the second set, we will review the
mechanics of the study and look pretty closely
at the various ways participants were made to
be anxious and the battery of skills test
participants were given while anxious and using CBG.
And during the 3rd set, we will look
at the groundbreaking
and really remarkable results from this study and
compare using CBG to other cannabinoids like CBD
and THC for reducing anxiety.
Welcome back to Shaping Fire, doctor Russo.
Well, it's good to be back with you.
Excellent. So, Ethan, you know, why don't we
do something new and why don't we start
with
giving some respect to your other co authors
on this paper?
Sure. Happy to do that.
Well, this was led by doctor Kerry Cutler
of Washington State University,
who's an associate professor professor of psychology there
and has done fantastic work
on cannabis over the last several years.
Also, her graduate student, Amanda Stuber,
did a lot of the interviewing,
for folks in the study.
And, then Ziva Cooper, who's a professor at
UCLA and heads the cannabis research program there.
Fantastic. Thank you. You know, the more and
more I get into the science side, in-depth
in cannabis, the more I realize how important
every single person on a paper is. And
so I think I like this, and I
think I'll I think we'll start plugging
those other co authors as going forward. So
thanks for that. So let's let's get started
by creating a little bit of context for
cannabagirl
for folks who are relatively new to CBG
as a cannabinoid.
Now clearly, throughout this entire show, we're going
to be talking about CBG in significant detail,
but for the moment, would you just give
us a general understanding of CBG as a
cannabinoid?
Yes. Happy to do that.
So, let's go back to 1964.
That was the year that Rafael Meshullam
and Yechiel Ghayoni
identified
finally,
THC, tetradrocannabinol,
as the main psychoactive ingredient
in cannabis. But that same year,
they also discovered cannabagiol
and were quite prescient
in identifying
it as a precursor
to all the other
major cannabinoids.
So it it started there.
Interestingly,
all the attention was focused on THC.
Cannabidiol,
had been discovered
or
identified
with clear
ideas to its structure only the prior year
in 1963.
But because
there was not this,
overt psychoactivity
to some of these other compounds,
they got much less attention, and that was
certainly the case
with kinaabegirl.
So there were some initial
studies looking at what it did in animals,
but,
it really didn't get the attention it deserved
for perhaps another
30 years or more.
What would have caused the interest in CBG
to increase?
Well, you know, along the line, people did
take a look at,
certain things.
In the seventies, it was shown that,
CBG
is an uptake inhibitor for GABA,
which is an inhibitory
neurotransmitter.
Why that is important is that it could
account for
muscle relaxant activity and certainly for some,
activity
as an antianxiety
agent, which we'll certainly be talking about more.
Additionally, in 2006,
it was shown that,
there was an antidepressant
effect
in tail suspension models
in in rodents.
Along the way,
it was shown that there is a mild
effect of CBG
to lower blood pressure
and also to lower intraocular
pressure the way THC
does, in glaucoma.
Subsequently,
during this interval,
in the early 2000,
there was a lot more investigation.
Some of this was
spearheaded,
through support
of GW Pharmaceuticals
where I was working at the time.
They had a
program of selective breeding for the so called
minor cannabinoids, and one of those
was cannabageral.
The chief breeder there,
Atienda Meyer, actually developed a CBG only plant.
And,
so that there was a good bit of
basic research going on.
Among other things, it was shown that,
CBG
stimulates,
several TRP channels,
especially TRPM8.
M is sort of like,
is named for menthol.
So this is a a temperature
sensitive receptor.
Trypmate is important because,
certain tumors, especially
prostate cancer
and some,
breast cancer lines,
would be targets for this.
Additionally,
there it was shown that there were antibiotic
effects,
strong effects
against
methicillin resistant
staphylococcus
aureus.
That was shown by Appendino et al.
This is an important result,
because at the time,
there were all these hospital acquired infections and
many deaths related to MRSA.
So this remains in the area of great
interest.
So 2 of the big things were this,
effect
on certain cancers.
And I should point out that CBG, like
just about all the other cannabinoids,
shows a a great selectivity
in its ability to kill cancer cells
while being preservative for normal cells.
This is an important distinction because
standard chemotherapy
agents tend to be toxic to cells in
general.
So it's always an issue of, can you
kill the tumor before you kill the patient
or at least
make them very sick in the process.
So anybody who's been through chemotherapy
or has a
family member or friend that has is familiar
with this concept.
So with
the cannabinoids, we have the prospect of
having much more selective
ability to kill cancer without producing
overt toxicity.
The study reminds us a couple of times
that there are nearly no CBG studies that
involve humans.
And yet we know, you know, quite a
bit about CBG and have pretty good ideas
about other things we want to research in
humans.
It gives me kind of a vibe
that there is a bit of a sea
change as far as human research into CBG.
You know, as somebody who is doing this
research on the front lines,
do you feel that as well that we're
at a transition point where
we're moving out of purely rodent studies and
moving more and more into CBG,
studies in humans?
Yes. Quite true.
So why is that?
Again,
for better or worse, there's been all this
attention
on THC. And then,
starting about 15 years ago,
CBD came to the fore mainly because of
its utility
in epilepsy,
which is well deserved. But,
I think people would understand
that,
CBD has sort of peaked in terms of
interest. That It it certainly is a very
versatile
therapeutic molecule,
but,
perhaps it hasn't
quite,
panned out,
from a business standpoint.
That's certainly true for many companies.
So it's pretty much everywhere, but,
again, lost in the shuffle were other candidates,
particularly CBG.
Now that has changed recently because certainly,
on the West Coast of the US,
there has been selective breeding again
leading to CBG
predominant or CBG
only
chemo bars of cannabis.
This really started in the northwest,
particularly with Oregon CBD.
And slowly,
CBG
interest and breeding has diffused
to the rest of the United States and
around the world.
So along the line,
along the way,
certainly, there've been a lot of people, particularly
in the northwest US that have been using
CBG
for some years now.
And so we have their what we'll call
what the scientists call anecdotal experience,
what
patients and consumers report,
but it's only recently that there have been
the formal clinical studies,
and we'd like to think that we've been
at the forefront of that,
with our survey
study
that was published in 2021.
And now
this, which was the first
study to
examine in a randomized controlled trial
the effect of CBG on anxiety.
I have to agree with you, Ethan, that
it is no small impact that the CBG
dominant cultivars from,
Seth and Eric Crawford there at Oregon CBD
down in Albany, Oregon has really made a
difference here in the Pacific Northwest because up
until their CBG dominant cultivar,
mostly, we were getting CBG
in,
THC dominant cultivars, and it's really hard to
tell
anything either in a controlled study or just
anecdotally
when THC is the primary ingredient. But when
you can
strip that out and make a CBG dominant
hemp cultivar where,
you know, it's nearly entirely CBG,
This opens up not only the ability for,
that plant material to find its way to
research scientists like you, but also it really
gives a lot of strength to
what, you know, some call anecdotal evidence, some
call citizen science.
The whole idea that it gets its hand,
CBG gets itself into the hands of caregivers
who are
who don't really have the same constraints as
legitimate science do. And so a lot of
the initial,
you know, grunt work about what we should
even look for can happen.
And I'm really grateful for
those, you know, single
cannabinoid dominant cultivars and hopefully, we'll continue to
be seeing more of them,
Doctor. Darrell Bock Yes. Certainly.
You know, this is the kind of selective
breeding that took place at,
GW Pharmaceuticals,
unfortunately,
because
there was a concentration
on development of Sativex and Epidiolex,
CBG, again, never got
into clinical trials,
despite the availability
of the CBG only chemo Var,
clear back, you know, in the early 2000.
So it's just one of those things that
got lost in the shuffle.
You
know, you may not be able to speak
to this, and and and my my
awareness might not even be true, but it
seems to me that there's probably a whole
bunch of really interesting cultivars at GW
that just like you said, kind of got
lost in the mix. And it isn't until
similar cultivars
are rebred in the public that we see
a lot of those because most of the
pharmaceutical companies
defend that cherished IP, I would assume.
Right.
So, you know, you've been researching CBG for
years and you and I have been talking
about it for years now. And this particular
study, though,
it seems like it's a direct follow-up to
another one that you did just a couple
years back again with Doctor. Kerry Cutler at
Washington State University.
A bit more of a general study but
it absolutely sets this one up. Would you
summarize that study and its results so that
we can all have a better picture of
what we're building on top of?
Sure. So at that time,
we weren't in in a position yet to
do a randomized controlled trial.
1st,
I thought that we really needed a survey,
a decent survey
of what people were reporting with CBG,
preparations,
to lend some credence to the idea
that, number 1, this could be used therapeutically.
Number 2, that there weren't any associated problems.
So we initiated
a survey study
and had a 127
folks
that,
the stipulation
was they had to be adults
and they had to be using a preparation
that was at least
50%
CBG.
So that was a mixed,
sort of sample. Some of the people were
using CBG only products,
but a a lot of them,
were
CBG with THC. And as you mentioned,
that creates
a few complications,
but, for the most part, we got some
very useful information.
So,
Yeah. Let's let's talk about what people saw.
Mhmm. 1st,
what I expected was,
something we did see that a lot of
people were using it for the big 3,
which are treatment of pain,
help with sleep, and,
mood, particularly,
anxiety.
So these are the same things for which
many people turn to cannabis,
of one type or another.
But when we started asking
about conditions that people were treating, we got
a list of 30 different conditions.
And what was really surprising was,
people reported that the CBG
preparations
were highly effective and often
much more so than conventional medicines that they'd
use for the same purposes.
And we got,
very highly
statistical
significance with claims of benefit on pain,
sleep,
anxiety,
but also for some hardcore
medical conditions
like,
inflammatory
bowel disease,
endometriosis.
Now some of the numbers weren't big on
those specifics,
but when
3 quarters of the people are saying that
this is the best medicine that they've ever
used,
for their condition,
you know,
it is creating a sync signal that deserves
attention.
Now at the same time,
people were really not
reporting side effects to speak of.
Some people reported dry mouth, sleepiness,
increased appetite, but
certainly that would suggest
that those were preparations that had some THC,
in them.
And this is borne out subsequently when we
looked
specifically
just a a CBG only preparation.
Similarly,
in this survey,
84%
reported no withdrawal symptoms when they stopped.
So, you know,
our conclusions were, first, this was the
first study that really looked at therapeutic use
of of CBG in humans.
Again,
anxiety, pain, depression, and insomnia were the most
commonly reported target symptoms,
and people reported a very high efficacy
with,
no adverse events to speak of.
And, you know, the the main thing was
we thought that this is a good indicator
that CBG would be safe for future randomized
controlled trials.
Now we were immediately interested in taking this
forward, but it it took a good long
time,
as these things often do.
Recruitment for the new study,
which was
again a randomized
controlled trial
of a CBG
only chemo Var extract,
and its effect on anxiety.
This took a while to recruit. It it
was confined to
people in Washington state because,
that's what the institutional
review board
wanted.
But
it it came together nicely.
So why don't I stop there for a
second and see if you have an interim
question because I could just go on and
on. Sure. Sure. Sure. So,
I find it interesting that it was
challenging
to recruit for this study. I mean, not
only were you limited to Washington, which has
got its own challenges as since you've got
a national audience,
but even more so after reading the study,
I can imagine
that it may have been challenging to find
people
who met your stipulations
because
in one hand, for somebody to be open
to participating in a cannabis study, they need
to be open to cannabis.
But then
the study required for them
to
not be using cannabis or any other
illicit drugs during, I think it was a
2 or 3 month window.
And so many people, you know, were they
may have had cannabis or they may have
been microdosing
or may have done a lot of things.
So
this actually continues to make the pool of
people possible much smaller, right? Well, that's a
problem in general. In this instance,
we ask that people
not use
cannabis,
for 24 hours. Oh, alright.
So, you know, in some studies, they're much
more stringent about that.
We also wanted people that were cannabis familiar,
but not
necessarily
heavy users.
So,
and That's that's walking a line right there.
Well, sure. You know,
there are always exclusion criteria.
We wanted to exclude people that might have
felt that they had used CBG before and
had a bad reaction.
They couldn't use,
harder drugs within 2 months.
They couldn't have a serious psychic psychiatric
condition like schizophrenia
or bipolarity.
They couldn't be pregnant or breastfeeding,
and they couldn't have any chronic
neurologic
disorder
or history of
a a serious head injury.
So, I mean, those were the
the kinds of things.
And,
oh, they also,
had to be fluent in English.
They had to have a smartphone because one
of the tests was
done on an app,
on a smartphone.
And as mentioned previously,
just in Washington state, so there were no
issues about
shipping product
over state lines,
that might have
attracted federal
interest, let's say. Yeah.
Well, there was,
I I found it interesting because, you know,
when you reached out that that you were
going to be working on this study, I
was excited to participate. And then I didn't
get through the first sifting process because
my association with cannabis and other influences were
far too high for the study. But I
am happy to say that we let Shaping
Fire users or not users, Shaping Fire listeners
know about the study and
you have some of them in your study.
So thanks to everybody
who chose to participate.
So
we talked about
the baseline study that you did with Doctor.
Cutler
over there at Washington State University that laid
down the base.
And so then you worked with Doctor. Cutler
to design this new study.
What were the objectives for this new study?
Doctor. Darrell Bock It was, again, to see
if
in a sort of manufactured
situation
creating anxiety that we could show that CPG
made a difference in compared to placebo.
And I I just wanted to go back,
for a second
to,
the demographics
of,
people's cannabis use,
because this is important.
A lot of studies,
you know, for instance, in the survey, obviously,
wanted people that had used CBG
before.
In this
one, it we hope that we'd get some
people that never used CBG and, because this
is really important.
What's the reaction of it to somebody that's
never had it before?
So as it turned out,
65%
of the people in the study, which was
34,
had no prior experience using cannabagiol.
Again, all had been cannabis users in the
past.
The average was about 3 and a half
days a week
or 18 days a month.
Okay. But with that in mind,
you know, again,
what were the
what was the premise of the study?
Well, I'll just read from the purpose.
To examine the acute effects of hemp derived
CBG
on anxiety,
stress, mood,
and memory, as well as positive and negative
subjective
drug effects in humans.
And the design is what's called a double
blind, meaning
patients and the administers
of,
this didn't know who was getting what at
the time.
Placebo controlled, that means that on one occasion,
people got the CBG
preparation.
On another occasion,
they got a placebo,
and it was called a crossover study because
they had to take both,
in separate trials.
And it's called a field trial because,
this is done
over Zoom
with patients in their home environment.
And
someone asking the questions on the other end
at Washington State University.
I can imagine that,
asking people their questions at home actually gets
rid of an entire
layer
of anxiety related questions
that that you don't have to do anymore
since people are often made to feel anxious
just by coming into a facility.
Right. That's called white coat anxiety.
Oh. And we use that to advantage. Wait.
Wait. Wait. Did you say white coat anxiety?
Yeah. That's so that's aptly named. Okay. Go
ahead. Sure. We use that to advantage though
because, part of the testing was I mean,
some of this is diabolical.
How did we make people anxious?
Well, one of the things was,
they were told that they had 5 minutes
to prepare,
to say,
what their ideal job would be and how
they were qualified for it.
And,
you know, they were expected to talk this
whole time. And if they stop talking,
they would
be prompted to continue.
And,
the examiner
did a thing of starting out in civilian
clothing and then coming back in a white
coat.
And then there was a thing of a
calculation.
Usually,
the usual calculation
when you're testing someone cognitively is to track
subtract
7 from 100.
This is much worse.
It started with a very high number subtracting
17,
and
every time a mistake was made, they were
told to go back to the beginning.
So these are the diabolical effective
they
effective they are for being so gentle, right?
Because you're not actually putting them under threat,
but it sure can feel like it. And
we'll be talking more about those in the
second set too because this battery of tests
that you gave people
were something else.
For this set, let's finish with this though.
You know, most studies
that are happening on cannabis nowadays,
they default to using isolate.
Even though I prefer whole resin,
most studies are using isolate because
it is
just one specific molecule instead of being the
cannabis resin which has got lots of components
in it.
And yet we know that
generally speaking,
using resin
offers better benefits
from isolate which has got its own problems.
Why did you choose to go with a
whole plant,
CBG
dominant
resin solution in the tincture for the study
instead of going with isolate,
which is probably more easily available and also
is
you know, what all your peers in pharmaceuticals
are doing?
Well, we wanted real world experience.
Now, again,
this the study
drug was a CPG extract that has been
used by a good number of people,
in the Pacific Northwest.
So we knew a little bit about what
to expect from it.
That was a big advantage.
We definitely wanted,
CBG only preparation
to the extent that there'd be no THC,
no significant
amount of CBD or other cannabinoids.
And in fact,
each milliliter of the study drug had 10
milligrams of CPG,
a little bit of CBGA.
There were barely any THC,
point
0 1 milligrams of THC,
and the only significant
was 0.35
milligrams of caryophylline,
which we don't expect to be overtly
psychoactive.
So each person
in the study drug,
set,
got 2 milliliters
of this material in a glass of water.
So that was 20 milligrams of CBG and
not a lot,
else.
Now it was a real challenge to figure
out a placebo.
So the placebo would be something that wouldn't
be psychoactive
to any great extent,
but it it should look like
the study drug and and have a taste,
that
might be hard to tell apart. So
I wracked my brain. This was
part of my contribution to this study.
What can we use that would have this
effect?
So
I wondered, how about an herbal preparation,
but one that wouldn't have cannabinoids in it?
And,
we want something that's sort of green,
like the the study drug.
So I I thought about the liqueur chartreuse.
Chartreuse.
For people who don't know chartreuse is,
from Europe,
100 of years old, originally made by monks,
said to be made,
with
somewhere between 50 a100 different herbs.
It has a distinct herbal taste
and it is green,
so we use that
as the placebo.
When I read that in the study, Ethan,
I just howled sitting in my living room
because
number 1,
it's really humorous to see chartreuse
so out of place and in the wild.
Like I was a bartender
in my 20s 30s, so I was, of
course, very familiar with Chartreuse, but I didn't
expect to see it in the study while
I was reading
it. And then it makes so much sense
because
even though Chartreuse has got a certain sweetness
to it, it is so herbal. And when
you watered it way down, I totally see
how it could become an effective,
placebo
that
looks and and and acts like a tincture
without
the active components.
Did you find that it worked out pretty
well? Because I would think that that would
be a home run.
Sure. You know, I
nobody said,
that I'm aware of,
that
we know this is the drug, and we
know that this one isn't.
So and, you know, again,
people were sent vials
and the person administering
didn't know what was what.
You know, this is a way to maintain
the blind, and we think it was quite
effective in this instance.
Right on. And since since the name of
the individual is in this study, we might
as well go ahead and mention who provided
the CBD tincture for this study. They might
find that novel.
Yes. This came from 1 Shango Los.
Oh, me.
Yeah. Well, I I was happy to do
my bit for science, Ethan. So I am
grateful to have participated.
So, all right. So let's go ahead and
take our 1st break. When we get back,
we're gonna talk a lot about the battery
of tests
that were given to
the research participants because
since this study is pointing specifically
to
how CBG
helps with anxiety,
it's going to be very interesting to look
at these different tests and figure out how
they tease at anxiety different ways.
So you are listening to Shaping Fire and
my guest today is neurologist, Doctor. Ethan Russo.
And you know, without these advertisers, Shaping Fire
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I'm your host, Shango Loos, and my guest
today is neurologist doctor Ethan Russo.
So before the break, we were talking about,
the study that this new study was based
on,
the various advantages that we're starting to see
teased out of CBG,
and specifically this study, how it looked
at the anxiety of patients and CBG's
ability to decrease that anxiety.
And how the study
is designed is remarkable because what it has
to do is is subtly push people's buttons
in different ways
and see whether or not
they can handle
having their anxiety buttons pushed
with the study drug versus the placebo, which
we now know was just very watered down
chartreuse.
So the study consisted of 2 interviews
between the research assistant and the participant
1 week apart via Zoom.
So before the interview, the research subject ingests
a vial of either 20 milligrams
of whole plant CBG tincture
or the watered down chartreuse placebo.
Then, when the interviewer starts, some baseline demographic
questions are asked just to kind of like
get them talking. But then a whole battery
of tests take place.
And I got to say, Ethan, reading about
them in the study, they really seem numerous
and varied and designed to stress like any
kind of person out in a way that
doesn't do any permanent damage.
So I know we've got, you know, a
handful of them and they all work in
slightly different ways. So I think I just
want to hand you the mic and let
you walk us through these battery as tests
and teach us what they are and what
their goal was.
Sure.
So,
at the zero point,
they had baseline assessments,
mood, anxiety,
stress, and drug effects.
It may seem strange to ask about drug
effect questions when nothing's on board, but
you you want to establish,
comparison,
before the drug is administered.
So at that time,
as you mentioned, they take the CBG
tincture
or the,
chartreuse placebo.
Then they take an online survey
using,
up some time,
and the first testing
was at the 20 minute mark. And I
wanna mention here,
we got a criticism,
from one reviewer about,
you know, why did you start then? Probably
wasn't doing anything, but
in the interim,
there was a pharmacokinetics
study done. Pharmacokinetics
is what are the effects,
how long does it take for certain effects
to appear, And we were able to show
that
when people took CBG orally,
that the effects begin
and are seemingly
well established
by the 20 minute mark.
So at the 20 minute mark, there were
tests of mood, anxiety, stress, and drug effect
ratings.
Then,
they take the thing called a trier social
stress test.
They beget more,
ratings of all those parameters
at 45 minutes.
And then,
between 45
60 minutes,
they'd have the California verbal learning test too,
which assesses
memory impairment,
and they'd have the Druid
application.
Druid is an app that's designed to assess
motor and reaction times and whether someone's impaired.
And, you know, this is something that's been
validated, and it's done on a smartphone.
And then,
at time 3, it's 60 minutes.
Again, the mood, anxiety, stress, and drug effect
ratings.
So there were different time points
and as you mentioned, these different types of
of testing,
to see,
what
would happen.
So in choosing these studies,
did you approach them as, okay, these are
the studies
that are always used by scientists
who study anxiety, like were this is a
preset
battery?
Or did you, as the designer of the
study,
have to go and choose these yourself off
the shelf,
because they're the ones that you respect and
the ones that were going to tease out
the kind of
data points that you wanted to look at.
I'm just trying to figure out whether or
not these are like boilerplate studies or whether
or not
that this is more of a custom ordeal?
Well, you know, there are always differences,
but, these are well accepted
types of studies to look at these parameters.
So
basically what I could say if you looked
at studies from Johns Hopkins
like the limonene and THC study we just
did, a lot of overlap in the tests
that were done,
and that's for a reason.
These are time tested measures,
that are well accepted,
in the scientific community.
When you look at these tests,
and,
they wanna come about this a different way.
We know that anxiety comes in a lot
of different forms.
And and, you know, people on Vashon Island
here where I live have been taking CBG
tincture
for a couple years,
and and the results that people speak back
anecdotally,
they they review different types of anxiety
that the tincture helps with.
As you were designing the study,
what were you looking to pull out of
the various
tests that you're giving folks. And and I'm
not asking you to necessarily go through them
all, but but so we can understand how
to scientifically think through these tests, would you
maybe compare 2 or 3 of them and
say,
well, this one is looking at this type
of anxiety versus this one's looking at the
different type of anxiety because unfortunately, most people
who who have anxiety, they just say, I'm
anxious
without the ever having had the opportunity to
think about what kind of
feeling anxious in general.
Situ situational anxiety would be I get
stressed when I have to go outside.
But,
again,
and I
although I was a psych major in college,
I'm not an expert on this, but I
can assure you that doctor Cutler and doctor
Cooper are,
but,
again,
one of the tests is called the stain
anxiety,
and
another is more specific for stress,
as as might
be precipitated
by subtracting
17 from a high number Mhmm. And having
to repeat it.
So I I don't think I've given you
a great answer, but,
what I can say is
that over time,
we saw these statistically
significant
differences
in the these folks tested twice
between
their,
experience
on the CBG
and their experience on the placebo.
And because, you know, it wasn't always one
before the other, it was random
as to which came first,
You can control,
so it's not a matter of
well, you know, I'm not stressed because they
I knew they were gonna subtract
have me subtract 17 from a high number,
and it wasn't as bad the second time.
In general,
these are set up in a way that,
there shouldn't be these big practice effects.
I wanna poke at that a little bit.
The the term practice effects is one I'm
unfamiliar with, so that might be what I'm
asking about. But, okay. So let's assume that
the tincture that is was the CBG tincture
presented a certain way, and then the chartreuse
presented a certain way. And they both seem
like they could have been the CBG tincture,
which was the goal. So that's great.
But we those of us who who do
use CBG regularly,
it really has
a huge effect
on anxiety. In my own personal experience, I've
experienced this.
So
do you have a data point that speaks
at all to,
to what degree
the test subjects were able to determine
which one was likely the study drug, not
based on presentation,
but based on based on, oh my God,
this works so much better than the one
other one I had. The other one must
have been the placebo.
Well,
you know, I we didn't
record
people's reaction
that way.
You don't want to
probe too
deeply
at this point when you're trying to get
2
sets of data points.
And,
again,
you might get varying degrees
of response in an individual,
but you need numbers. In this instance,
34 folks
to see what the overall
effect is and whether it has statistical
significance.
So my answer to your very pertinent question
is
we
rate the benefit
in terms of statistics,
and
now I need to give a little primer
on statistics.
Statistics,
the the lower the number is, the more
significant it is.
Something is considered medically
significant
if it has a probability or p value
under 0.05.
What that means is there's less than a
chance one chance in 20
that the results occurred due to chance,
meaning that
when it's 0.05
or less,
we consider that likely a real effect,
and then as the numbers are smaller, it's
more statistically
significant.
So in this instance,
in the subjective
anxiety,
ratios,
there was a moderately
large size
significant
effect of the condition, meaning one versus the
other.
That p value was 0.034,
so under the 0.05,
and
over time, it was very significant.
So,
p value of 0.001,
that means one chance in a thousand
that this could be just a chance occurrence.
That's a real effect.
Anytime there's one chance in a 1,000,
that, you know, this
it it it really
is highly statistically
significant.
Similarly, the stress ratings,
the effect over time,
p value of 0.001,
and
a large size simple effect of the condition
on the change in subjective
stress ratings again at 0.032.
It's under the 0.05.
But at the same time,
there were not major changes in in mood.
The thing called the state anxiety scores,
again, showed us large
statistically
significant main effect over time,
point
001.
Now if we were looking at the graphs
from the study,
you can see that there's a clear
demarcation.
There's space between the effects
on placebo
and the effects on CBG,
and the bigger the space between those, the
more significant it is.
In these, you can see that the differences
are pretty clear.
You know, again, this wasn't a situation where
we
asked people for a lot of introspection
on
what they thought was going on. It it
really had to be objective, meaning
what did the test show.
So,
you know, it would have been interesting to
ask people more about their reactions.
So that's
one thing. We showed these clear statistical
and
significant changes
looking at anxiety
and stress with these standardized
measures.
But,
at what cost?
In other words, were the people impaired
when this happened? I mean, you can
make someone
no longer anxious by sedating them.
So what would really be important is to
have benefit on anxiety
without sedation.
So we looked at other measures.
1 was a measure of intoxication.
So,
this is a
place where
if there were a lot of THC, you'd
expect you'd get significant difference
between that preparation
and placebo.
We also
had drug effect ratings, and this is
asking people about their reactions
and,
how much they like the drug.
So most often, cannabis users
in a clinical trial setting
will report that they liked a certain amount
of THC.
So three measures there,
but we saw no significant differences between the
cannabagiol
and the placebo
at any time point
with respect to intoxication
ratings,
they were almost straight lines.
Same with drug effect
and same with drug liking.
So no space between the lines
at the three time points, 20 minutes, 45
minutes, and 60 minutes.
This is really remarkable
because if you test any other drug
used for anxiety like a Benzodiazepine,
Valium,
diazepam,
almost always, there's gonna be significant sedation
or other complaints, and we just didn't see
that.
And then there's another
dimension
here.
I'm sorry. I wanna talk a little more
about,
subjective drug effects.
So these are rated
0 to,
0, not at all, to 10 extreme.
And again, there were no significant differences between
CBG
and placebo
at any of the three time points,
20 minutes, 45 minutes, or 60 minutes.
Then,
again,
if we have a drug
that's good for anxiety,
we
wanna make sure that it's not producing any
impairment.
So memory tests were part of the trials.
Then a very surprising and important thing happened,
which was
people on the CBG
actually did
better on memory tests, and this was
statistically
significant.
So there was a moderate
size significant effect
of the condition,
and that's at the
the probability
of point 0 5 level
and a large
statistically
significant effect over time.
It meaning looking at all the time points
and that p value
was point 001.
So that supports the idea
that on this verbal memory test
that
the performance was significantly
better on CBG than it was on placebo.
This is not what you
expect,
from most studies of this type. Especially on
cannabis.
Yeah, exactly.
But, again, lacking THC, CBG is a different
kettle of fish.
It really is distinctly different in what it
does.
And to me, this might be the
the most,
surprising
finding. Yeah. It was definitely surprising to me
reading it. It was actually kind of like
a plot twist in a book as I
was reading the study. I'm like, oh, I
I didn't know that was here and I
didn't certainly didn't expect it coming.
I I believe that this next question is
outside the scope of the study.
But as a neurologist and as somebody who
has spent their life studying cannabis, I bet
you have an opinion,
which is
do you think that the improved
memory
was more related to
something this something that CBG was doing to
actually
improve memory function?
Or do you think it was because,
memory was increased in the absence of the
anxiety which the CBG had solved for?
Right. Well, it's likely the latter,
that the reduction in anxiety in a test
situation
led to better performance. However,
that might not only be it.
There could be memory enhancing properties, and that
is gonna have to be teased out
in subsequent studies. So there's plenty more to
do.
I did wanna indicate that there was one
final thing
that we tested that was again very important,
and that was
the question of impairment of any type.
And,
in fact, again,
CBG
showed,
lack of impairment.
Participants
performed
significantly better,
in the
trial times 2 and 3
after,
taking CBG than they did on placebo.
So,
again,
something that may not really have been expected,
but
what I like to say is what the
world needs now
is an effective drug
for
anxiety
that doesn't produce impairment
or sedation or addiction, and we may have
it
in the form of cannabagiol.
Amen. Now that is a big statement that
I can get behind. My goodness. Alright. So,
unless you have anything else to add regarding
the conclusions of the study, I'm about to
go to break and we'll after after the
set break, we will we will talk about
ramifications and next steps. But do you have
anything else regarding the conclusions of the study
that you want
to tuck in here before we move on?
Well, I could summarize now or after the
break. Alright. Well, since you're going to summarize,
let's summarize after the break because we'll be
summarizing a couple different points. So,
you are listening to Shaping Fire and my
guest today is neurologist
Doctor. Ethan Russo.
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Welcome back. You are listening to Shaping Fire
and I am your host, Shango Los. And
my guest today is neurologist,
Doctor. Ethan Russo. So here we are in
the big 3rd set wrapping things up.
And, you know, Ethan, the
throughout our conversation, the thing that really send
tends to glow big in this study
is that 78%
of the participants
said that CBG works better than their pharmaceutical
or other traditional medication,
and that is a staggeringly
successful number in my eyes that nearly 80%
of people said that CBG was better than
whatever they normally use.
Does this stand out to you as a
research scientist too being like an oh my
god moment?
Yeah. It was a surprise to me that
it was that high, but
perhaps,
in retrospect with,
3 years since then, it's
less of a surprise to me because
in our formulation
work, we've been using CBG
extensively,
and,
the results
bear this out. It is an extremely
versatile medicine that,
really contributes
greatly to therapeutic effects.
And it just feeds into your, your statement
right before we went to commercial about how
how big the impact of this can be
in, you know, reducing human suffering from anxiety.
I mean, it's a big deal
Even even though you and I are becoming
increasingly
comfortable with it, right?
Yes.
Yeah. So
one of the attributes or one of the
aspects that I think is worthy of looking
at is that
so many people presently use CBD
and
or THC
for their anxiety
now.
And and CBD,
CBG,
and THC have all 3 of them got
different
modes of operation
approaching
anxiety. As you mentioned in the last set,
one of the magical things that not magical.
One of the impressive things that CBG does
is decrease anxiety
without intoxication,
which as most of us know is is
exactly the mode of operation for why THC
works. It sedates people and for many people
that handles, you know, their major type of
anxiety and it decreases. So would you please
do us the favor of comparing
CBG
versus
THC for anxiety
and then CBG versus CBD
so we can tease out a little bit
more what is unique about CBG compared to
these 2 which are very common commonly used
in the cannabis world?
Sure.
So
THC is a very strange one in this
regard. It's it's well known that,
it THC can be helpful or
hurt
anxiety, and it's really a matter of dose.
So very, very small doses
have an antianxiety
effect, whereas higher doses
can certainly induce anxiety or even panic.
And this is an effect that's been known
for 4000 years because it was in the
ancient Assyrian literature
on relation to cannabis that was said to
be for or against
panic,
And, again, a matter of dose.
Is is that the biphasic nature? Is that
the is that the vocabulary? It's called a
biphasic
dose response with THC.
Now if CBG induces
anxiety, I don't know what the dose is.
We know anecdotally
that people have taken very high doses and
not,
had this problem.
So I don't know what the upper limit
is.
In this instance,
CBG
probably
is a safer bet if the target is
anxiety because
we know that there's a dose range that
seems to be effective
and, without
the intoxication
that can occur if the THC dose gets
too high.
You know?
So how about the 2 together?
Well, again,
in our formulation work, we're using CBG with
low doses of THC, and,
seemingly, it's a really useful adjunctive
thing to add that
improves clinical response.
So there seem to be these at least
additive or even synergistic
benefits on pain,
sleep, and mood.
And having CBG aboard may increase what's called
the therapeutic index of THC,
meaning the amount that you can use without
producing side effects,
and making the overall effect that much
greater.
So the idea is that adding CBG to
your THC may relay may relieve
some of the negative outcomes of THC
and, therefore, helping THC do its job while
CBG is doing its job?
Quite. Right on. Right. And we're we're seeing
this where we have
situations of people rating their effects of different
chemoVARS,
and we know what the
certificates of analysis
tell us about the portions of the different
components, it's it's easy to see these patterns.
One of the things we're hearing consistently is
when there's a
consistently is when there's a significant amount of
CBG
in the preparation along with the THC, that
it's much better tolerated,
that people
have a
good experience
or benefit
on symptoms without
THC associated side effects.
We've seen some of that anecdotally as well
here on Vashon Island because,
since
the CBG dominant cultivar has been grown here
on the island for a few years,
people who
historically
had a strong anxious reaction,
dysphoric response to smoking cannabis,
even if they used, you know, edibles or
oils or things like that, some folks, you
know, they're just smoking doesn't work for them
because it it shoots them up really fast
and and some some folks don't like that.
People started
mixing CBG flour
in with their THC flour
and
and and a lot of those,
you know, sharp increases in anxiety were relieved.
And, you know, that those are those are
very small number of people, but again, shows
the potential for use for folks
who are also
needing THC
for some other issue that they're dealing with,
but CBG
can take the
the edge off.
Definitely.
Do you have, do do you have compare
similar comparisons of CBG versus
CBD use for anxiety?
Okay. So let's look at why people use
them. We've we've mentioned that,
the survey patients,
use CBG
to treat pain, anxiety, and aid sleep.
We often hear the same claims for CBD,
but we have to parse this out.
If we're talking about
CBD
as an isolate,
it actually is alerting at low and moderate
doses. It's only at extreme doses. Again, this
biphasic dose response
that CBD actually,
produces any kind of sedation.
With respect to anxiety,
we know now
after these studies that there's a distinct difference.
CBD was studied in this,
an article by Bergamaski
et al in Brazil
some years ago.
They looked at social anxiety, which is akin
to what we were doing here.
It required 400
milligrams of CBD
isolate
to produce a significant
antianxiety
effect.
We got the antianxiety
effect with 20 milligrams, so that's a 20
fold difference in dose,
meaning that
it appears that CBG is much more potent
as an antianxiety
agent.
400 milligrams of CBD is gonna be quite
expensive no matter what kind of preparation.
Whereas,
hopefully, with a CBG only ChemoVAR,
20 milligrams is is just not that much.
It should should be much more economical and
I suspect, more effective overall.
Do we know enough about the mode of
operation of CBD versus CBG to
know what they may be doing differently.
Certainly based on the size of dose,
it it suggests we should move in towards
CBG,
but but having used both
independently
for my anxiety, I just simply find CBG
to be wildly more effective than CBD,
which makes me think that it's doing something
different than the CBD.
Quite likely. And, again, some of this gets
into some really heavy
effects,
in different areas of the brain and and
neurotransmitters.
What I believe, and we'll need to have
subsequent studies like functional MRI
or,
PET scans to look at this, but,
this is likely
affecting,
the limbic system,
emotional areas of the brain.
And, yeah, that likely are a lot of
distinct differences, but
that's gonna require more investigation.
Yeah. That sounds like a great Shaping Fire
episode too. So
as soon as you got that research done,
make sure you let me know, Ethan.
Yeah, it might be a while.
Another thing that I wanna point out, you
just compared,
the 20 milligrams of whole plant CBD dominant
tincture
to 400 milligrams of CBD isolate. And we've
already talked a little bit, on other times
that we have spoken about the difference between
isolate and whole plant preparations.
One of the ideas that the paper puts
forward is that,
one way to tweak the study
to look for,
additional benefits
would be to increase the dosage of the
CBG from from the 20 milligrams that was
delivered
up to 25 to 50 milligrams
because some of the other science that is
being done at this time
are is using isolate up to 50 milligrams.
But to me, someone who's very much in
the whole plant medicine,
the efficacy
of isolate and whole resin aren't the same.
And time and time again, we see,
CBD isolate, for example, not showing the same
efficacy as whole plant.
How do you weigh for yourself,
you know, 20 milligrams
of whole plant tincture that was used in
your study versus 25 to 50 milligrams of
isolate being
used in a different study? It seems to
me like those are they would be very
hard to compare those because
they're not apples and apples.
Yeah. It's a problem, and this is why,
certainly when I'm reviewing,
acting as a peer reviewer
on other studies, I want
specification
on what's being utilized. In other words, we
wanna see studies where there actually is
a certificate of analysis
as we provided here.
In contrast, where you've got studies where,
let's say you're looking at pain,
and,
there are a whole bunch of different preparations.
They might
be THC predominant, or they might be type
twos with
THC and CBD, different doses, different modes of
administration.
It's very hard to parse out
what's doing what, and you come up with
generalities
like cannabis helps with pain.
That's
nice, but,
science really demands more specificity.
And that's why
I believe that studies of this type where
we have a defined,
preparation,
we can it's it's much easier to to
make these claims,
particularly since
we had so many significant results.
I think that a lot of citizen scientists
and caregivers
like myself,
we we find ourselves running into an issue
where,
the studies that are being done right now
are being used are being done with isolate
because isolate is just a single molecule
of the cannabinoid
and, it's very specific
and and and it's also those studies
transition very easily
to to pharmaceutical
research.
Your research on the other hand, I, Harold,
because you have the audacity to use the
plant
as it's grown and using a whole resin
and using it in ways that that actual
patients, actual humans have been using it for
1000 of years,
but I can see that since you choose
to not use isolate,
you might get some pushback from either people
who wanna use your work for pharmaceutical
applications
or folks who just think that a a
plant resin
is too wild, if you will. There's too
many variables because there's cannabinoids that don't even
show up in the COA.
But but those of us who are into
whole plant medicine, we we still hold on
that that's where the future of cannabis medicine
is.
So, you know, as somebody, you,
who has been a long time proponent of
the entourage effect and whole plant medicine,
how do you see it personally as as
why you choose to use whole plant medicine
versus isolate?
Well, the number one reason is I believe
in the synergy of the different components.
However, I've been on the other side of
the fence too. Keep in mind,
the study we just did with
limonene,
isolate with THC isolate.
Sometimes you require
a deconstruction and reconstruction
to understand
what the differences are. So I see a
a place for both in research.
When it comes to therapeutics,
I'm firmly in the camp that
you want an extract and not an isolate.
Right on. That sounds good for me, and
it seems to work best on, on the
things that we're trying to do with with
real people.
So, Ethan, do you have any, other,
summary or or impact that you would like
to share before we wrap up?
Doctor. Darrell Bock Sure. You know, going back
to the study,
that we did, I'd like to run through
some key points, if I may. Doctor. Darrell
Bock Please do. Yes. Doctor. Darrell Bock Okay.
So this was the first study of cannabagiol
looking at anxiety in humans.
So we're very pleased with that, and it's
often a race against time
to get these things published before
somebody else
does it. So,
we're pleased with that.
So can Abigirl
reduced anxiety and stress
in this
sort of manufactured
setting.
You had asked about the degree.
I have another figure that we can utilize
here.
So there was an average decrease in 0.95
out of 10.
That's a 26%
reduction
in the anxiety
and stress scores that were already low to
begin with.
So, you know, what does this mean to
somebody who has a clinical
anxiety disorder?
We can't say from this, but
you know and I know from people that
have utilized CBG preparations
that they're usually very pleased with the results.
Another point,
in this study, CBG actually enhanced
verbal memory,
and it did that with no significant impairments
either in memory
or motor functioning,
that's
psychomotor speed and balance. That was what the
Druid app looked at.
So the CBG
drew Druid score was lower
and comparable to placebo
and baseline.
Again, we saw no evidence that CBG was
intoxicating. Intoxicating.
The intoxication and drug effect ratings
were under 1 on a 10 point scale,
and drug liking
remained neutral throughout the study.
And in terms of side effects,
negative drug effect ratings like dry eyes,
rapid heart rate,
dry mouth,
those remain low and did not
differ from placebo.
So all of these really indicate that this
seems to be have an extremely
benign profile
at the same time that it's producing
significant effects
on stress and anxiety.
Well, that's a great summary. And, you know,
on a on a real human level, I
can only imagine that you and doctor Cutler
are pretty stoked with how this survey turned
out or how the research turned out.
Yes.
We're definitely going on from here. We have
immediate plans for 2 more studies.
One would be similar to this, but done
in the lab,
which allows for
greater objective measures,
you know, measuring
blood pressure, measuring
cortisol,
a stress hormone,
measuring reactions to pain on a thing called
the cold presser test.
So that'll be up,
coming up. And we also have plans for
a clinical study,
where,
CBG preparation
would be looked at,
in terms of
an actual disorder.
You mean like a what would like you'll
target 1? Yes. Exactly. I see. Good. Well,
doctor Russo, thank you so much for being
a guest today again on Shaping Fire. I
mean you've been on the show so many
times
over over the years now I think this
is gonna be a 115th episode 115
and every time you do, we learn we
learn something new and great and and usually
on the cusp of the science, so,
we really appreciate you taking your very valuable
time and joining us
and and letting us know what the latest
is and what it means to us.
Well, always a pleasure. I really welcome this
opportunity.
So, dear listener, if you would like to
follow along with doctor Russo's research, there are
2 good places to do that.
The first one is you can follow along
with Doctor. Russo's research organization, Kratoscientific.
So that's credo, c r e d o,
dashscience.com.
Or in even better places to
get familiar with doctor Russo's library of online
at ethanrusso.org.
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