It is truly humbling to read or hear about a human who totally defines an
area of life that their biography is indistinguishable from a discipline,
that their history is also the history of an art.
Dr. Raphael, Ms. Shula is one such person. Dr.
Ms Shula was a titan of cannabis research,
and his breakthroughs were breakthroughs for all of us.
His setbacks set all of cannabis science back,
and his successes were to the benefit of all humanity.
Today's episode is unique on shaping fire.
We don't do company profiles or product profiles,
or cannabis personality profiles. We always focus on a topic,
and then I curate a guest who is an expert in that area.
Shaping fire is always in service of education instead of cannabis business,
but today is different. Today we're going to look back on the life's work of Dr.
Raphael Ulum. And in doing so,
you will not only get an idea of the expansive work and discoveries of Dr. Ulum,
but at the same time,
you will get a really engaging history of the last 60 years of cannabis
research. Even if you don't fancy yourself someone who listens to biographies,
you'll likely find that your interest in cannabis medicine and the history of
our favorite plant is plenty to engage you in the scientific work of Dr.
Raphael Ulum,
who passed away last week on March 9th, 2023 at the age of 92.
Today's episode creates a portrait of a man whose curiosity and unbreakable
stamina for research open the doors for all of us interested in cannabis
medicine,
and made whatever cannabis normalization we are experiencing now possible.
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and technique efficiently and with good cheer,
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You are listening to Shaping Fire, and I'm your host, Chango Los.
My guest today is Dr. Ethan Russo.
Ethan Russo is a board certified neurologist and former senior medical advisor
to GW Pharmaceuticals.
He's served as study physician to GW Pharmaceuticals for three phase three
clinical trials, OFS effects.
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, of the International Cannabinoid Research Society,
and his former chairman of the International Association for Cannabinoid
Medicines. In 1995,
he pursued a three month sabbatical doing ethno botanical 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.
Dr. Russo has joined us before on shaping Fire,
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,
and episode number 67 about treating migraines with mushrooms and cannabis,
episode 80 on cannabis hyperemesis syndrome,
episode 83 on Canero, C B G, and of course,
the shaping fire sessions on the Shaping Fire YouTube channel. Today, Dr.
Russo joins us to talk about the life's work of his good friend, Dr.
Raphael Meshulum. Welcome back to Shaping Fire, Ethan.
Thanks, uh, unfortunate that, uh,
this has to come up due to this event,
but I I hope that the message that we impart today will be valuable to people.
Yeah, I think so too. I think, I think that making sure that this story is, uh,
preserved for people coming up behind us is, is important, and it's, um,
it's important to show the, the respect for Dr. Ulum too. So,
so thanks for joining me today, um, for this very special topic.
I know you and Dr. Ulum were very close. Um,
so to get us started for context,
would you give us a little bit about your relationship with him before we get
started looking at his career? Um, just so people know, uh,
from what perspective you're, you're speaking.
Uh, sure. So, I, I knew of him by reputation a long time before,
but we actually met for the first time in 1999
at the International Cannabinoid Research Society meeting in
Acapulco, Mexico. Um,
so this is the first time we had to the opportunity to meet one-on-one,
uh, and, you know, uh, chit Chat, uh,
he recognized my name as one that, uh, uh,
could be an Israeli name. Um, and, uh,
I knew that he had been born to a Sephardic Jewish family in
Bulgaria and pointed out to him that my, uh,
father's family had come from nearby, uh,
in what is now North Macedonia, uh, town called, uh, Monae,
then currently called tk. Uh, so there was an immediate, uh,
rapport there. Also, I was afforded, uh,
some respect beyond that, which I had earned at that time mm-hmm. ,
um, by virtue of being a physician who was interested in
cannabis in the endocannabinoid system.
So that was a bit of a rarity then. Um, and,
uh, it,
it gave me a little bit of an edge in people taking me seriously.
So, um, I know that, um, you know, I'm gonna ask you a lot of questions today,
um, kind of asking you what Dr. Ulum thought of this or that,
and I know it's like, like it's a hard thing to speak for somebody else,
but you worked with him so much over the years and, and were also, you know,
kind of social, even even family friends. I, I think it's fair to say that, um,
you were pretty familiar with his thoughts on both medicine and,
you know, the, the world wri large. So,
so I know that some of the questions are gonna,
will be more challenging for others cuz it kind of asks you to say what Dr.
Ulum thought. Um, so,
so I appreciate the extra effort you need to put into that,
and I also appreciate that, um, you know, you're speaking for somebody else.
And so, um, if, if I come across something that you're like, you know, uh,
I don't, I don't think I, I would know what he would have to say, uh,
feel free to just move me on.
Sure. So it's a responsibility,
but [inaudible] take on willingly.
Excellent. Good. Thank you. So, so let's start, um, what initially inspired Dr.
Ulum to study cannabis and its compounds and,
and how did he become interested in the field? Well.
I think he nicely explained this in a resource.
I think all your listeners would, uh, be, uh,
very find very worthwhile to take an hour and see the film online
at YouTube called The Scientist.
So if they enter the scientist and Raphael Meshulum, they'll find this.
Um, but, uh, to answer your question, uh,
it was pretty clear to him. He, he seemed to be the kind of person that,
uh, wanted to do something novel and important. Um,
because of his good education,
he was well aware of the fact that cannabis had remained
a mystery, uh, for at least 150 years. Um,
for example, uh,
morphine was isolated from the opium poppies circa 1804.
Similarly, cocaine, uh,
was identified from coca leaves in the 19th century, but, uh,
try as a may, uh,
scientists around the world were unable to really get isolation of the
quote, active ingredient of cannabis. Uh,
in the 19th century, there was some isolation of a red oil,
they called cannabinol, but it wasn't quite, uh, right.
So he wanted to try to figure out what cannabis had
in it. Um, and, uh,
it just wasn't something that people were paying attention to in the early
1960s. Uh, so that was it. Um,
uh, and it wasn't an easy thing to do. Um, you know,
there were some real challenges that he faced.
Yeah, I I can imagine not only, you know, you're describing how, um, how this,
you know, scientists around the world were having a hard time isolating things,
but of course it was all, it was all, you know, very much, uh,
illegal internationally too. And,
and comparatively it's relatively easy to research cannabis during, you know,
this kind of creeping normalization that we're experiencing right now, uh,
a lot different than when Dr. Ulum began his research in the 1960s. So,
so what were those challenges that Dr.
Mac Schulman faced in his research due to the fact that it was, you know,
not only not legal most places,
but it was also demonized worldwide at the behest of the United States?
Yes, absolutely. So at the time, um,
cannabis was by no means widespread in Israel. In fact, early,
uh, supply, uh, came from Lebanon. Uh,
the way I understand it, uh,
people on the Lebanese side would come to the edge of the border and, uh,
throw the parcel of hashish ch the barbed wire, uh,
to someone on the other side, presumably with an exchange of cash. Um,
but there were seizures of hashish. And so that's where he got his supply.
It was initially from the police. Uh, he tell,
used to tell a very funny story about, uh,
uh, getting help to, uh, go to the police and,
uh, requesting five kilos of hash,
which he put in his briefcase and got on a public bus . Um, and,
uh, became quite o different apparently and root. But at the time,
people just didn't recognize the smell. He figured out subsequently,
uh, that what he had done was illegal on both sides. And that, uh,
in future he had to go through, uh, the police to get a supply of Hashish.
Um, but basically from their first five kilos of, of Hashish,
they used the latest, uh,
techniques to get a separation of different components. And, uh, uh,
found isolated, uh,
identified the structure of T and also synthesized it in Novo.
Uh, that was in 1964. Prior to that, in 1963,
um, they had found, uh, cannabidiol.
So cannabidiol was actually first. Um, but uh,
shortly thereafter, we can go through a whole list of other discoveries,
uh, that came, uh, from those initial investigations.
Um, before we move forward, I have a, a side question on, uh, him getting his,
uh, research supply of hash from the police. Um, you know, I,
I have seen how traditional hash is made in Lebanon, and,
and you described them, you know, chucking it over the fence. Um,
I imagine that, you know,
the hash that was being gotten from the police was, you know,
was dirty and maybe had other, you know,
items and hairs and straw from wherever it was made or whatever.
Did did that really matter with this kind of molecular research because you're,
you're gonna do an isolation and just pull out the parts anyway? Or, or, well,
was that, was it harder to work with that kind of, uh, product? Oh.
Yeah, no, you're right. It absolutely had to be,
there'd be all these impurities in one way or another. Um, you'd have to,
uh,
get through the crudity of the initial material to get
down to the isol isolates of the compounds of interest.
So I have no doubt it was more technically difficult.
Yeah, I can believe that. So, so in 1963, Dr.
Ulum started researching tetrahydrocannabinol, A K T H C specifically,
would you explain how he suspected it was present and the process
by which he discovered and isolated it?
Um, yeah, basically they used separation columns, but, you know,
in terms of, it was well, well known that, uh,
hashish and cannabis were psychoactive,
and it was a matter of identifying which compound or
compounds were responsible. And that includes, um,
uh, a series of steps of fractionation and then, uh,
fractionation again to get down to the, uh,
pure compound hopefully that, uh,
really is responsible for the activity. Um, you know, at that time,
uh, testing would have to be done in animals,
and they used monkeys for better or worse, for a lot of the initial work.
Um, but, uh, you know, they, they found so many things.
It wasn't just thc. Uh, also in 1964,
they isolated cannabigerol. Um, they published on that,
uh, with his, his partner, ya G. Um,
and, um, even at the time, I, you know,
in reading Professor UL's old work,
I'm just struck with the presence that he had, uh,
his predictions about things, uh,
very quickly they identified the cannabigerol had to be the parent
compound, um, to THC and C B D. Um,
but that same year they identified the, uh, acid cannabinoids,
which ultimately were identified later as the,
the actual parent compounds, um,
in the fresh plant before Decarboxylation. And then in, uh,
66, they found Cannavaro.
And then there were a whole bunch of miners like Canna Cylo, uh,
but they didn't stop there.
And this is one of the things I would always appreciated about RAI was he
was a chemist. Most chemists are happy to stay in their lane.
That was never enough for him. Mm-hmm. ,
he always wanted to knew more what was the biological function?
How can we figure out what this does? So by 1970,
they had tested, uh,
all of these compounds and basically found that, um,
uh, t h C was mostly responsible,
and they made an important distinction. Even today, uh,
you know, some 60 years later, almost, um,
people make the mistake of saying that C B D or C B G are not
psychoactive. This is absolutely wrong. Both of them are,
what they should say is they're not intoxicating. But back in 1970,
professor Ullo knew that,
and he said that these other substances were not Picato Memetic,
which was a fancy way of saying that they didn't make you crazy when you
took them. Um, and that was true throughout his career.
Um, again,
he did not confine himself to the lab and was heavily involved
in clinical pursuits, uh, with his discoveries.
Um, you said that he discovered, um,
cannabidiol before thc, when he started looking at cannabidiol,
was his first thought that that might be, uh,
the substance that was ta causing in intoxication, and it wasn't?
Yeah, I, I don't think so.
There had been some prior work actually done in the United States by a
German refugee named Lowe. Um,
and cannabidiol had been, um,
identified almost perfectly in 1940. Um,
but, uh,
they didn't kneel down the actual three-dimensional structure until Professor
Ulum in 1963. Um, so, you know,
they're in science, they're often these incremental developments,
and we'd have to say that that was one of them.
So from the timeline that you set up of, of the different labs, uh,
discovering the different cannabinoids and,
and figuring out their structure and isolating them, it sounds like, um,
you know, this time between, you know, 1960 and the early seventies,
it was like bang, bang, bang, one cannabinoid after another . And,
you know,
that must have been not only like an exciting time to be doing this initial
research to finally kind of like crack the, you know, cannabis secret. Um,
but also, you know, THC was something that,
that people could immediately tell there was going to be medicinal use for.
What was the, the significance, like both in science,
but also perhaps in society wri large? Um,
what was the significance of the discovery of THC and impact at that time?
Well, uh, I'd like to take this on a couple of levels. Mm-hmm. ,
I mean, the, it's first notoriety came as an intoxicant.
Um, certainly, um, again,
being an extremely educated and well-read person,
professor Ulum was very familiar with medicinal uses of
cannabis throughout the ages.
And I'm sure that the wheels were turning with him, uh, very,
uh, very quickly. But, um,
people have to understand how earth shattering, um,
these discoveries were. For example, most,
uh,
most psychoactive drugs prior to this time were alkaloids.
So there were water soluble substances.
The cannabinoids were absolutely a different kettle of fish, um,
because they were lipid soluble and not alkaloids. Um, you know,
they had no nitrogen in them. Um,
so this really was a bit strange,
and it made the material very hard to handle. Um, you know,
we usually dissolve things in water and, um, you know,
instead you have these lipid soluble sticky substances that are
sticking onto the glassware and everything else.
It's never been easy to work with this stuff. Um,
yeah. Uh, but, and again, he,
he quickly pivoted into looking at, uh,
clinical indications.
And probably the first one that really came to the fore,
um, was, uh,
the idea of cannabidiol as an anticonvulsant. Uh, so,
you know, at this time, um,
he was isolating these different components from Hashish
and sharing them with other scientists. And, uh,
there was a great collaboration between the Israelis and the Brazilian
scientists, um, uh, doctors Kuya and Carlini. Uh,
in 1980,
they published the first clinical study of cannabidiols and
Anticonvulsant, um, in nine patients. And, uh,
very successful. And, you know, I,
I would point out that these were all people that, um,
had failed treatment with, uh, available drugs at that time.
Um, now people may be really struck by the fact that was 1980.
We didn't get approval of cannabidiol as an anticonvulsant,
as Epidiolex in this country until 2018. Um,
so there was this huge gap of time, uh, that he was very,
uh, surprised and outraged by, uh,
that this work had gone on, had shown such great promise,
and yet got ignored. Uh, for all that time.
This might be as much of a question about the scientific method as it is about
Dr. Ulum, but, um, what about cannabidiol?
Um, co caused Dr. Meshulum to air quotes,
suspect that cannabidiol was an anti-convulsant.
Was there something in the nature or something that he had seen in people who,
who used hashish or, or was it the,
the structure of the molecule itself that he could look at and
envision how that would interact with the human body?
No, I'm really gonna attribute to his open-mindedness.
What I mean by that was he was, uh,
very aware of historical references to
cannabis, uh, as an anticonvulsant coming from the Arab world. Um,
um, and these dated back many centuries. Um,
so there was a suspicion that Hashish, um,
could work as an anti-convulsant,
and then it was a matter of seeing what component or components
might be responsible mm-hmm. . Um,
and why he honed in on cannabidiol probably was because,
um, uh, they were aware at that time that it wouldn't be intoxicating.
Uh, and, uh, so it would have an advantage if it worked. Uh,
it wouldn't have the liability that can be attached to th h c Yeah.
We, we, we still experience that difference even today. Sure. Um,
so I talk with a lot of research scientists, uh,
on shaping fire. And more or less, they fall into three different groups, um,
scientists that study and intoxicating substance. Um, but they,
they never touch it themselves because they are,
they are not the kind of person who enjoys I intoxicants.
And then in the middle, you've, you've got scientists that, you know,
don't use whatever it is regularly, um,
but they have used it to understand what the human experience is.
And then you've got researchers that research drugs and they like using them
as well. Um, did Dr.
Meshulum use cannabis or have any personal appreciation for it?
Uh, I'm gonna have to equivocate a bit. Mm-hmm. , um,
he would tell a story of, uh,
first human experiences in, in trying th c um,
and it went something like this. They had invited friends and colleagues,
uh, to a dinner party, and his wife, Dahlia, who was a,
is a wonderful person, um, had made a cake.
Um, and, uh,
there were portions of 10 milligrams of th h c I think that there were 10 people
involved. Um,
five didn't show any obvious effects. Uh,
five did one in anxiety reaction. The others, um,
felt something or felt different, um, in ways that you might imagine.
Uh, one, um, said nothing had happened,
but was laughing outrageously every few minutes. And another one said,
nothing happened, but never stopped talking. So ,
you can draw your own conclusions.
What he did say in relating this story was whether he was one of the 10,
but I imagine he was,
I can attest to the fact that he was not a regular user of cannabis.
Right on. Thank you for that story. That's great. So, um,
another key cannabinoid that, uh, Dr.
Michel mis credited for and we haven't brought up yet is,
is actually one of my favorites, uh, anandamide. And he discovered it in 1992.
Right. Um,
would you tell us about the discovery of anandamide and what it meant for
endo cannabinoid science and kind of patient health generally?
Sure. Yeah. I think we just have to back up a little bit mm-hmm.
to 2018. Um, so at that time, uh,
William Deva in the lab of Alin Howlet at St. Louis University,
um, had discovered, uh, cannabinoid receptor. So,
uh, and I'm gonna back up a little more. Prior to that time, uh,
people had no idea how T h C worked.
The working theory was that it somehow,
um,
disrupted the membranes of the neurons and the way that alcohol
ethanol does. Um, but there, uh,
were synthetic cannabinoids that were being made, and, uh,
these were stereo elective. That's a way of saying that, um,
if the molecule had one configuration in three-dimensional space,
it, it worked, it was intoxicating. However, if it didn't have the right one,
it didn't work.
That implied that there must be a receptor where the thing was working.
So the search was on for a cannabinoid receptor.
And again, that was found in 2018,
subsequently known to us now as CB one, the, uh,
the cannabinoid one receptor. Um, so,
uh, after that,
there was an all hands on deck search for endogenous
ligands.
That's a way of saying that people were looking for molecules within
us endogenous cannabinoids now called endocannabinoids that would
bind with this receptor. Um, but, uh, again,
it was super difficult. Um,
the thing that set Professor Ulum apart was he thought
the endogenous molecules, rather than being peptides, um, you know,
short amino acid, uh, molecules, uh,
rather would have to be a lipid, um, to, uh,
lodge on this receptor. Um, so analogous to th h c.
Um, and then things get really interesting because there they were in Israel,
uh, this is in the lab again with William Deva and Lumir Hanush,
um, his associates at that time. And, um,
they looked for these endogenous cannabinoids in pig brains.
Now, again, that's anachronistic for sure. Um,
I can tell you that Jerusalem, where the work was done, is a very kosher city.
Um, but, um, there was a place in Tel Aviv that, uh,
they could get the pig brains, uh, and they said each time they went back,
the price went up. Uh,
but after painstaking work over a couple of years,
they had a tiny fraction of this material that they
identified chemically, um,
as Erika Donal Ethan Olamide. Uh,
then they had fund deciding what the common name of the molecule should be.
Uh, as it turned out, William de Vain was a Sanskrit scholar. Um,
and, um, he knew that the Sanskrit word for bliss was ananda.
So they called it anandamide, uh, which is a, a great name,
a beautiful coinage. Um, and, uh, they kept looking,
they found other related molecules. And in 1994,
they uh, discovered another called two Erika Donal Glycerol,
uh, less flashy name, just two HG for short. Uh,
that was in 95. Yeah. Uh, but, uh,
then again, didn't stop there.
They found hundreds of related molecules that seemingly didn't do a lot
on their own. Um, but in putting these together in different combinations,
by 1998,
they figured out that there was synergy when you had the main players,
uh, with these less active or inactive, uh, related molecules.
Uh, hence the concept of the entourage effect. Mm-hmm.
was born in 1998.
So, um, so far we have discussed, um,
you know, maybe even a dozen or at least 10 different, uh,
cannabinoids and, you know,
functioning aspects of the endocannabinoid system that Dr. Ulum is credited for.
Um, to round out this group, is there, is there anything of significance,
um, any other cannabinoids or that,
that he discovered that we should make sure we mention at this time that we
haven't so far?
Well, again, just, uh, to make sure we do justice to his work, uh,
his discoveries included C B D T, H C C B G C,
bbc, um, the acid cannabinoid, C B N A,
C B D A, C B G A, uh, Canna. Cyclo,
and likely a few more. Um.
That's a great answer. I couldn't have asked for anything better. Thank you.
. So, so I know kind of like, you know, as we,
as we wrap up the first set here, you know, I,
I know the entirety of the first set has been how, you know,
we've been talking about how Dr. Chu's research, you know, um,
changed our understanding, uh, uh,
very specifically of cannabis and the endocannabinoid system
on a, on a level of perspective, kind of like one level of magnitude up,
like what impact did this entire body of
research have on both the scientific, I don't know,
acceptance and interest in cannabis and in the
attraction of more scientists to dive in?
Because Dr. UL's research opened up the area.
Yeah, I, in a word, it affected it profoundly. Um,
what we see a few track,
the number of publications on cannabinoids and the endocannabinoid
system, there was a huge growth, um,
in the early nineties, uh, which has continued for, for some time.
You know, once these molecules, particularly endocannabinoids were identified,
it then was a matter of experimenting them to see where they are and what they
do.
And the fascinating thing in retrospect is every organ
system, every type of, uh, physiological function that was examined,
there was a role for the endocannabinoid system. Mm-hmm. .
So again, we had, uh,
discovery of cannabinoid compounds,
then the endogenous cannabinoids. Uh, they had to figure out,
uh,
how they were made and broken down the metabolic and catabolic enzymes,
how they were regulated. Um,
so you can see how there was this expansion,
sort of a pyramid, uh, effect of, uh,
research opportunities and, uh, they were pursued around the world. Now,
unfortunately,
that is not extended to enlightenment on the political side.
Um, nor, um,
did it totally break down the barriers to research which still remain in this
country. Admittedly,
it's easier to study cannabis now than it was then,
but it still remains very difficult.
Yeah. Um, that is certainly the case. Uh, I,
I can imagine after Dr. Mali's, um, you know,
earliest discoveries, he never, um,
he never wanted for funding though, uh, during his career. Like, cuz he,
it sounds like he would an earliest celebrity, and,
and I just assumed that well, he was well funded at that point. Is that,
is that accurate?
Uh, up to a point, but it only after a certain point,
his first, uh, application of the National Institutes of Health,
which then has now has been the main funder of biomedical research domestically
and internationally.
But his first application was turned down with the explanation that nobody uses
cannabis here. Yeah. You know, this is circa 1963. Um,
then the tune changed, um,
partly was because of this discovery, uh,
but additionally there seemed to be a political, uh, rationale,
um, uh, uh,
something to the effect that a senator's son was busted for,
quote, marijuana unquote, um,
and wanted to know if it was gonna make him per permanently crazy. Oh man.
Um, all of a sudden,
n i h was more interested in cannabis and cannabinoids.
And for the subsequent 40 years, uh, professor Ulum, uh,
had n NIH funding annually.
, that's a good story. All right. So,
so we're gonna take a short break and be right back.
You are listening to Shaping Fire, and my guest today is Dr. Ethan Russo.
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That's Gas Lamp seeds. Welcome back. You are listening to Shaping Fire.
I am your host, Shang Golos, and my guest today is Dr. Ethan Russo.
So during the first set, we talked, you know, uh, mostly about the,
the timeline of Dr.
Ms Shula's discoveries and clearly how it impacted not only
the, the research of cannabis itself as a drug, but in a,
in a larger form, the endocannabinoid system,
and then the impacts that it had on medical research for humans as a whole.
Where I wanna start out here in second set is that, you know, how has Dr.
Ms Shula's research impacted the development of,
of cannabis based medicines, um,
and what potential therapeutic applications have derived from his work
so far? Um, you know, contemporarily?
Yeah, that's a great question. I mean, the first obvious ones are, uh,
you know, the classic cannabinoids,
phyto cannabinoids from the plant. So at this time,
uh, in terms of cannabis-based medicines, uh,
we have synthetic THC as Marinol, which has never had big impact. But,
um,
CX is an extract of two different
chemovars of cannabis,
one rich in thc and one rich in C B D. Um,
and that's approved in 30 countries around the world for treatment of
spasticity in multiple sclerosis, but not in the us.
In the us Um, for the last few years, we have had,
uh,
98% pure cannabidiol as epidiolex for
treatment of severe epilepsy syndromes. But again,
um, we're looking at, uh,
future developments related to Cannabigerol,
Cannavaro and many others. And, uh,
I need to extend the conversation to talk about the, uh,
semisynthetic analogs that, uh, professor Michelle Maiden.
Um, perhaps we could run through those. Yeah, please do. I,
cause I'm not sure what those are. Okay. Well, uh,
you know, chemists like to take a molecule and see how it might be,
quote, improved meaning different,
meaning patentable or longer lasting or more potent.
So good example, there would be what's called U two 10.
So the HU medicines were, uh,
all discovered by Professor Ulum at Hebrew University.
So that's where the hu uh, derives. So U two 10,
um, was, um,
a dimethyl hep derivative of thc.
So instead of just a five carbon side chain,
it was a seven carbon side chain with two methyl groups on it.
And that made it more potent and longer lasting. So each U two 10,
um, is something I believe,
on the order of 50 to a hundred times more potent in thc.
And it's been a very important agent in laboratory studies of the
endocannabinoid system, but not a drug for clinical use.
Um, it has appeared occasionally and synthetic cannabinoids,
but it's not something I would ever recommend anybody taking. Uh,
I have a colleague who did and spent the whole weekend, um, uh,
with a very bad experience. , um, let's leave it at that.
Uh, I'll never tell . Um,
a closely related molecule was U two 11.
Now this one actually got into the clinics, um, but wasn't approved.
And it's a bit of a sad story.
This had the name Dexon Naval. Um,
this was investigated by a now defunct company called
FAR an Israeli company.
They developed this for treatment of severe head injuries.
The idea being that they would give this intravenously after someone had a
severe head injury, and hopefully it would help prevent damage, uh,
from the, the head trauma. Um, however,
after this was licensed to the company, um,
they never consulted Professor Ollom again. Um,
I think that they made a big mistake in that because the, again,
only used this once, um, after the onset of the head injury and,
and not subsequently it worked in phase two clinical trials.
But in phase three, nothing, uh, just didn't work.
Um, I wonder in retrospect whether they had given, uh,
administered it multiple times. The result could have been different,
but that's probably a done deal at this point. Mm-hmm.
And then there are a variety of agents he developed that yet could make it to
the clinics. Um,
professor Ulum was very active in research on
CB two,
the non psychoactive receptor that's important in pain and inflammation.
Um, he thought that, uh,
one of the things the endocannabinoid system did was
provide, uh,
protection from non-infectious insults or,
or non immunologic insults. Um,
it developed a medicine called a U 3 0 8,
which is very active at the CB two receptor, but not active.
It's CB one. Uh, so wouldn't be intoxicating.
And that's been investigated, uh, for arthritic conditions.
Um, and then more recently in 2018, um,
he came out with, uh, HU five 80. Um,
so what this is, is they took the cannabidiol acid molecule,
which is unstable C B D A, and, uh,
they made it a methyl Esther. Um,
what that means is they put this group on it that made it shelf
stable and, uh, it could be a pro-drug. In other words,
when taken into the body,
it would break down spontaneously into C B D A, uh,
which in testing has shown, um,
very powerful activity on the serotonin one,
A receptor where C B D also works,
but it's somewhere between a hundred and a thousand times more potent.
So this may have the application in treating nausea of
different causes, um, among other things, uh, also might have a,
a role in treating anxiety. Um, but, uh,
that really hasn't gotten to the clinic yet. There's still, um, could be,
could be developments there. Mm-hmm.
So I have a, um, a two part question. It is a, uh,
it's a request for a vocabulary cl clarification, uh,
but then also I would like you to explain its use in the lab. And,
and here's here is what it is. Um,
you began the answer talking about the cannabis analogs that Dr.
Ulum had created. And so when you said that, I'm like, all right, uh,
that sounds like synthetic cannabinoids, uh, to me. And we've discussed, uh,
both you and I and then,
and then on other episodes about how synthetic cannabinoids can be useful in the
lab, but, um, it,
it's not as great when they get out of the lab and people try to take them as if
they're from nature and they're not. But, so you started by describing these,
these analogs that Dr. Ulum was making,
and then you described these agents that Dr. Ulum was making,
and then you seem to contrast and say,
and also synthetic cannabinoids where if he made them,
it sounds like they're all synthetic cannabinoids. So,
so the first part of the answer, I'd like you to tease those apart,
but then second,
for people who have never thought about the use of synthetic cannabinoids
in, in research in the lab only,
but not actually used out in the real world, would you explain what that,
that lab tool is for.
Sure. Uh, so again, of the ones I mentioned,
h U two 10 was the only one that was a CB one agonist.
Um, so, you know, would cause intoxication.
So h U two 10 and related drugs in the lab would be used to look
at binding. Um,
so say you had an unknown substance,
you wanted to compare its activity to something,
it could be compared to U two 10. Uh, as, as one example,
uh, whether your new substance could displace U two 10
from the receptor, uh, compete with it. Uh, so it'd be, uh,
measure of potency. Mm-hmm. . Um, and, you know, you're correct.
I have decried the use of high potency CB one
agonists as, um, potentially quite dangerous. Uh,
but these other agents, h u 2 11 3 0 8 580, uh,
were all for entirely different purposes and really would have no activity on
the CB one receptor.
I see. So, so it,
it sounds like analog agent and synthetic synthetic cannabinoids are probably
in the same bucket,
but we delineate between them because some of them are for used
solely in the lab and, and, and should not be used outside by, by,
for people for either medicinal or recreational reasons.
But then the other ones are also synthetic,
but they're also promising as, as actual healthy medicines.
And so we, we just refer to them differently then.
Quite Right. Okay. Great. Quite right.
Cool. Thank you. Um, so, uh, while ,
while Dr. Ms. Shula's role was clearly set in pharmaceuticals, right,
you and I have spoken on this program often about our,
our both of ours belief in whole plant medicine, whole plant cannabis resin,
what were Dr. Ms.
Shula's personal thoughts about whole plant medicine and using the
whole resin instead of isolating compounds and then mixing,
matching them to make something patentable since he worked in the pharmaceutical
realm, but also his heart was in pure medicine.
Uh, and, you know, he straddled both worlds. Um,
part of, uh,
the time that we worked most closely together was between, um,
2003 and 2014. We were both, uh,
working actively, uh, with GW Pharmaceuticals.
Um, they would have an annual research meeting, uh, which, uh,
he attended. I attended, uh, as an, uh, scientific, uh,
senior medical advisor at that time to the company. Um,
so we worked with people at the company and also
with other cannabinoid scientists, mainly European, um,
and get together and talk about projects and plans. And,
um, a lot of what we know now about cannabidiol,
cannabigerol and the others came from that research.
So he absolutely understood and aided, uh,
the development of these whole plant medicines,
uhs effects and Epidiolex. Um,
at the same time he was working on the Semisynthetic analogs.
Um, I would highlight a point of difference, perhaps, uh,
he and I mm-hmm. , Um, I'm not so sure.
He was absolutely convinced, um,
of the role of the terpenoids, uh, in cannabis. Uh,
you may recall I pointed out in 1998, he had coined, uh,
the term with Professor Ben Shabbat, uh,
of the entourage fact initially applied to endogenous
cannabinoids. The next year. The same payer, uh,
published another article and pointed out that the same thing could apply to
cannabis, uh, the idea that, um,
plants might be better medicines than their single components. Well, I,
I already felt that way, and I really seized upon this.
And although some people have misattributed coining the term,
the entourage effect to me, I didn't,
I may have popularized it, um,
through my efforts to show the synergy between terpenoids and
cannabinoids, I think, um, he needed a little more convincing.
Uh, at the time, in 1999,
they pointed out that this idea that plants could be better medicine than,
uh, single compounds, uh, was a theory. Um,
but in the ensuing 24 years, um,
we've had a lot of proof for that theory . So, um,
you know, a good scientist, um,
is thinking about possibilities and also retaining, uh,
an ear of skepticism. I think that's necessary.
Sometimes you have to play devil's advocate with your colleagues or with
yourself.
Well, yeah, because the,
the whole point is that we're hypothesizing and we don't want to go into it
assuming we're right. So we have to, we have to be our own devil's advocate.
Sure. Yeah.
So much has changed in cannabis research in the last decade of Dr.
UL's life. Like, what was Dr.
UL's opinion on the current state of cannabis research and the
potential for new discoveries in the field? Well.
I, he never stopped working. Um, you know,
he continued, uh, throughout his career to find new things to do.
Uh, we've mentioned many of his accomplishments, but, uh,
in more recent decades, um, he worked, uh,
with the late EAI bob on, uh,
endocannabinoids and their role in treating osteoporosis. Um,
he did, uh,
some clinical work on cannabidiol for graft versus host disease,
um, that affects transplant patients. Um, and it, it,
it really never ended, uh, again, the more recent work, uh, on,
um,
making the methyl of the acid cannabinoids to make them more stable.
Um, and, uh, also the important work on, uh,
the CB two receptor done with Paul Paer, uh,
who's at the National Institutes of Health, and the idea that, uh,
the endocannabinoid system provided protection from non-infectious
insults. Um, so it, it never ended. Um.
So the, the, the wording of this question is, is kind of, um, I guess juvenile,
but, um, I, I think the point of it is good, uh, you know, as,
as cannabinoid research expanded here in the last, you know,
15 years or so, did, did Dr. Ulum,
was he at all annoyed that there were people who were not approaching
cannabis medicine properly in some way because there were so many people do it?
Or was he generally thinking that this was badass,
that there were all these different types of scientists looking into it?
Uh, you know, he was not prone to criticize,
uh, that often. However, he was quite, uh,
willing to decry the dearth of clinical work, um,
that had gone on in, in any number of areas.
Uh, you know, this is certainly manifest by the fact that, again,
here's a bench scientist, um, with, uh, uh,
lifetime record of accomplishment.
And when the International Association for Cannabinoid Medicines,
a clinical group was begun in 2001, he was right there at every meeting,
um, and, um, contributing, um,
and encouraging people to do more work. Uh, so that was another place that,
uh, we, we got together, uh, all told,
I tallied it up, um, after word of his demise.
And, um,
he and I were together at meetings or working together in at least
14 different countries, . So.
That actually must have been a pretty heartfelt list that you worked on after
his passing last week.
You bet. Yeah.
Um, to wrap up this set, I, I was curious, you know, we,
you told that great story about, about, you know, the cake. Uh, but how did Dr.
Ulum view the use of cannabis for recreational purposes, like in society?
Um, and, and has his research affected his stance over the years?
Um, yeah, A little bit of a tough one. It's not something he talked about a lot.
You know,
my impression would be that he thought that a lot of it was a
distraction. Um,
and he was laser focused on clinical applications, um,
for this system. Um, so he,
he wasn't a prohibitionist, um,
overtly in any kind of sense. Um, but I think,
you know,
far more interesting to him was how can we harness these substances,
uh, to treat disease. Mm-hmm.
. Yeah. I can see him being all, listen,
I'm trying to get the labs going.
I'm trying to get funding and you guys getting busted for illegal weed
is in the news that it's not helpful. . So not, not that he was.
Necessarily against, he was never, so, yeah. Right. He was,
he was never so overt about it,
but I I'm sure he may have harbored internal fe feelings of a similar nature.
Yeah.
I could follow that. All right. Thank you.
So we're gonna take another short break and be right back.
You're listening to Shaping Fire, and my guest today is Dr. Ethan Russo.
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Welcome back. You are listening to Shaping Fire. I am your host, Chango Lo,
and my guest today is Dr. Ethan Russo. So Ethan, how has Dr.
Ms Schlemm's work impacted the development of new drug therapies beyond
cannabis?
I can imagine that there are other areas of medicine that are benefiting from
his research.
Uh, again, um, the,
uh, endocannabinoid system is ubiquitous.
It is the major home aesthetic regulator of human physiology and that of
all higher animals. Um, so it's had a huge impact,
unfortunately,
that hasn't extended towards education of medical students
on the system and its importance. Um, so, uh,
again, you know,
this idea that there were these lipid molecules rather than
water sol soluble molecules. The cannabinoids, uh,
led to a real expansion. Um, you know,
the endocannabinoid system isn't really confined, uh,
to the two known cannabinoid receptors.
It's become a much broader concept and includes a number of the trip
receptors and even some of the, uh, serotonin receptors,
particularly serotonin one A, um, which I'm happy to say,
uh, was an extension of, uh,
work that I did with colleagues at the University of Montana back in
2005. Um, so it,
it's been an ever expanding,
it's like the tendrils of the plant have extended and all these areas
of science. Um, it's been an amazing thing to see, um,
o over the 30 years since the discovery of Theo Cannabinoid system. Mm-hmm.
.
Mm-hmm. , you know,
that's one of the reasons why some people are even skeptical or suspicious of
cannabis because they say, oh, you people talk about it like it's a panacea.
It's like, like as if it's gonna solve all these things. And,
and that's only comes from people who don't understand the endocannabinoid
system, because that is the whole point. It's everywhere.
And so by working with cannabinoids,
you can work on all these different ailments. And, um, I don't,
I don't think that the skepticism for that is going to be overcome until more
people are familiar with how the endocannabinoid system actually functions.
Quite right. You know, again, it,
it's important to say there really aren't a lot of things that cannabis
cures. However,
there are tremendous number of things that cannabis treats effectively.
Uh, at least as an adjunct, uh, if not directly.
So what was, what did Dr.
Ulum feel was like the most rewarding aspect of his, uh, career? I mean,
uh, his, his list of,
of recognitions and awards are, it's a long list, but,
but the list of what he achieved is different than the achievements that he
himself was most proud of.
Well, you know, that's a hard one for me to say. Um,
he was not the kind of guy that, uh,
rested on his proverbial laurels. Um,
there was always more work to do,
so I don't think it's something you'd dwell on. Mm-hmm. . Um,
you know,
when we look at this list of accomplishments over the course of six
decades, it's astounding,
but the obvious pattern is the guy never quit working,
uh, or thinking about what's next. Um, so, uh,
to me he was a role model in that regard. Um, you know, it's,
uh, to an extent, if I can compare myself,
it's the same thing when I get a paper accepted for publication.
I'm happy for a little while, but, um, thinking about what's next,
um.
Fair, fair, fair enough.
It's sort of the restless mind syndrome.
Well, Dr. Meshulum was, uh, involved, um,
in cannabis policy creation in Israel much more than ever in the United States.
Um, what advice do you think Dr.
Ulum would give to us policy makers and regulators regarding the regulation of
cannabis and cannabis BA based medicines?
I think it'd be really concise, and that would be to follow the science.
Um, again, I have no doubt that he had, uh,
pervasive, uh,
skepticism about the ability of politicians to incorporate
the kind of scientific knowledge, uh, that was going on in this area.
Um, but I,
I don't remember him wasting a lot of time with criticism of that.
Uh, there might be some remark in passing, but again, uh,
his concentration was always on advancement of the science. Mm-hmm.
. Mm-hmm. . Um, so, so looking forward, I mean,
clearly Dr. Meshulum, um, mentored so many, and,
and he even mentored so many people who never met him. Right. Who,
who knew him through his research and his interviews.
What advice do you think that Dr.
Ulum would give to young researchers interested in studying cannabis and its
compounds now?
Well, I think the first thing he'd say was, expect to work hard. Um,
it is a very deep and, uh, difficult field.
I mean, the thing that attracted me when I really got into it circa
1996, was, uh, boy, this is complex,
but it's also exciting. Um, and, uh, boy, I,
I became addicted to cannabinoid knowledge very
quickly and, uh, led to a career change.
And that's happened to plenty of other scientists and physicians. Um,
but, um, you know,
I have to really identify his personal role, uh,
in this because, um,
the thing that most people who met or, uh,
corresponded with Dr.
Lan will tell you was how availing he was of, um,
his time in helping them with whatever question they posed to him.
Um, so I've met hundreds of people,
not just scientists who said, you know,
I wrote to him and I was shocked. He got back to me. And, you know,
or even we talked on the phone or Zoom,
and he gave me all this time, and people are just blown away by that.
Um, but that's the way he was. Um, as he explained, he didn't,
didn't have a lot of hobbies,
but he was always willing to talk about this mm-hmm. .
Um, so it, it's,
it's kind of an amazing set of circumstances that Dr.
Ulum, you know, even got to be a researcher. His,
his family was persecuted by the Nazis.
His father was placed in a concentration camp and survived.
And eventually Dr. Micum found his way to Israel, where, you know,
we all know his research blossomed. Of course, as a Jewish person,
this would've been part of his culture and his awareness as an entire life.
In what ways do you think it influenced his life choices or even research
choices that, that his, his, he, he grew up in persecuted times?
Um, yeah. You know, because we had so much one-on-one time, uh,
these were things I got to talk to him about. You know, his,
his early experiences and what they went through in the war.
Um, you know, basically, um, Bulgaria, um,
was occupied by the Nazis early on. Um, and there was a certain, uh,
well definite level of, of collaboration,
of very strange situation, uh, developed. Um, in that,
king Boris in Bulgaria, uh,
decided that they would protect the Jews of Bulgaria to an extent,
but they had invaded Macedonia next door and
basically allowed, uh,
even collaborated with the Nazis in, um,
in sending the Jews of Macedonia to the death camps.
Tripa, uh, in most instances, uh, there went, uh,
all of my family on my father's side, uh, with the exception of my grandfather.
Um, so, um, you know, it was a difficult situation.
As he mentioned it. His, his father spent time in a concentration camp,
but when it burned down, and he helped, uh,
the people that were victims of that, uh, they decided to let him go.
Mm-hmm. . Um, but, uh, after the war, uh,
Bulgaria became a communist country. Uh, there was, again,
increase in antisemitism. And, um,
that's when he immigrated to Israel in 1949.
What came out of this, um, again,
it's not something he dwelled upon. However, I think that,
um, it probably caused him to take nothing for granted, uh, in life.
He was an extremely open-minded person. Um,
he also wasn't tainted by politics, which is,
is so easy to have happen. Um, you know, I can give,
uh, a lot of examples. Uh, in,
in 1999 when I met Professor Ulum, I also met, uh,
professor Mau Soli, uh, from the University of Mississippi,
uh, who was an Egyptian. And I wondered, geez,
how are these guys gonna get along? But in fact,
they've been colleagues forever and, um, you know, uh,
the politics of their, uh,
their nations, uh, never entered into their relationship.
Also,
when I went to do research on cannabis in Morocco in 2002,
um,
I was delighted with how curious people were
about Professor Ulum there and the reverence that they had for 'em.
So it really transcended politics. Uh, finally, uh,
professor Ulum had Palestinian researchers in his lab.
Um, you know, and again, there, uh, the business was science.
It wasn't politics.
It reminds me of, of how you referred to his,
his thought that he wasn't as interested in the, in the, you know,
he, he thought that science should inform regulations and policy.
I can imagine him having that same idea about politics and, and, and race,
and how he interacted with others where, where it's like the science was,
was the priority. And, and, and it,
it's better for us to all be all be friends and focus on the science than
letting the, that, the rest of the world into our lab to,
to slow us down.
You bet. Yeah.
So, I'd like to finish this episode, um, with, um, you know, a bit of a,
a personal question for you. I really appreciate, um,
the time that you've offered us, um, and, and sharing your,
your personal stories of Dr. Ulum. You know,
obviously the two of you were such good friends as to feel like family, and, uh,
I'm curious, what was Dr.
UL's impact on you as both, uh, cannabis researcher,
but also as a human being?
Uh, well, he was a role model in every respect.
He was a very magnanimous and magnetic guy. Uh,
very warm, um, funny, uh, you know,
I mentioned we had this, I immediate bond as, uh, fellow Sephardic Jew.
Um, I considered him like my surrogate uncle.
He was 22 years older than me. Uh,
he looked a little bit like my father. Um, you know, for all I know,
we could have been genetic cousins on some level, um, cuz there was interchange,
uh, during the Ottoman era between, it was a Bulgarian,
Macedonia we're all part of the Ottoman Empire at that time. But,
um, you know, it was a great relationship and, uh,
I miss him. I was really proud, um,
that he asked me to write the first chapter of his last book in 2005.
Um,
he thought that they needed an article on the history of cannabis and
that, um, should, uh,
begin with one of the oldest cannabis cultures in India. And as it,
uh, happened, I had this huge amount of data, it amassed with nowhere to go.
And here he asked me to write a book chapter. And so I,
I was very pleased with that also. Uh,
he provided me with what I think is one of the best compliments I've ever had in
my life. Hmm. Um, it was probably about 2008.
We were at a conference in London together and, uh,
he tried to introduce me to somebody already knew, uh, your garage,
the Swiss scientist.
And he said something to the effect that of, um, I'd like you to meet,
uh, my friend Ethan Russo. And then he said,
he has many crazy ideas, and I, I left like hell,
because if he knew Rafi, uh,
that was a great compliment and I certainly took it as such. Um,
yeah.
That's a, that's a beautiful story. And, um, I can imagine that, you know,
right now in this, this, you know, week or two after his passing, um,
tho those types of thoughts are, are, uh, are heavy, you know,
on your heart as, as you, you know, look back and appreciate your friendship.
So thank you Ethan, for, um, you know,
taking the time to discuss, uh, Dr.
Ulum with us and sharing your personal stories because, um, you know,
as we all know over time, um, you know, history changes and,
and people forget. And it's very important to, um,
to record these people who mean so much to us. So,
so that we can remember 'em as as, as they were. So thank you, Ethan.
Amen.
All right. So, uh, you dear listener, if you would like to, uh,
hear more from Dr. Russo, and I think you do, um,
I've got a bunch of places for you to check out. Um, at the top of the list is,
uh, you can go tuck out, uh, Dr. Russo's company where, um,
he does, uh, research that's, uh, credo Science and that's, uh,
credo-science.com. Um,
you can also find, uh, ethan russo.org,
and if you go to the library tab, um,
you can see all of Ethan's papers there under that tab,
and which is really convenient if you wanna, um, look at his work without,
you know, trying to find out, you know,
where the papers are online and trying to get permissions to download him and
all that kind of stuff. Ethan's a a big fan of, of, of having as,
as many of his papers available as possible. Um, if you would like to,
uh, reach out to Ethan, uh, directly, um,
he always offers his email address,
which is ethanRusso@comcast.net.
And, you know, I just wanna say that Ethan, you know,
I think get gets back to everybody, or at least tries to get back to everybody,
but also realize that he is an active everyday researcher still.
And so sometimes it takes him a while to get back with folks and, um, you know,
you might, you might not get the reply you want until he's, you know,
stuck in an airport somewhere for a couple hours. Um, and then, uh,
there's a great series on the Shaping Fire, uh, YouTube channel, uh,
the Ethan Russo Shaping Fire Sessions, which is a series of, uh, uh,
10 short videos on an array of topics that, um, I thought were being under,
uh, under considered in cannabis.
And so Ethan and I sat down in his front room and he addressed, um,
those various topics. And then finally, um, you know, I don't think anybody has,
uh, appeared on shaping fire as much as Ethan have has.
And there's, I think there's, uh, either six or seven just fantastic episodes,
um, where Ethan, uh, shares his research on, you know,
a range of topics from, uh, cannabis terpenes,
the endocannabinoid system, psilocybin migraines. I mean,
this is all like really juicy stuff. So I recommend you go back and,
and check out the, the, the Shaping Fire catalog of episodes. Um,
you get,
it's easily searchable if you just put Ethan Russo in and it'll pop 'em all up
for you.
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