Ethan Russo, Neurologist and Medical Scientist

23:06

PROJECT CBD:DR. ETHAN RUSSO: CBD &

CLINICAL ENDOCANNABINOID DEFICIENCY
Our video series Cannabis Conversations interviews Dr. Ethan Russo on clinical endocannabinoid
de ciency and ways to target the endocannabinoid system for therapeutic bene t.
BY CANNABIS CONVERSATIONS (/SEARCH/NODE/CANNABIS%2BCONVERSATIONS) ON JUNE 21, 2016

Dr. Ethan Russo, neurologist and medical scientist, discusses CBD, clinical endocannabinoid de ciency, and various ways to target the
endocannabinoid system for therapeutic bene t. 

Transcript
Project CBD: Today we’re talking with Dr. Ethan Russo. Dr. Russo, a board certi ed neurologist, is the medical research director at
Phytecs, a biotechnology company that specializes in developing di erent ways of targeting the endocannabinoid system for
therapeutic bene t. Dr. Russo was formerly the senior medical advisor to GW Pharmaceuticals and a widely published author in
many scienti c journals, as well as a contributor and editor of several books. He has also been a faculty member at the University
of Washington, a guest teacher at Harvard Medical School, and other academic institutions. Welcome to Cannabis Conversations.

Russo: Thank you for having me.

Project CBD: Ethan, you’ve been way ahead of the curve with respect to cannabidiol, years before most people in the medical
marijuana community had ever heard of it, you were emphasizing its signi cance. Tell us brie y, what is the signi cance of CBD?

Russo: Well I think we need a little background rst to indicate that cannabidiol has always been part of the capabilities of
cannabis. Its just that it’s been pushed into the background through selective breeding, basically another byproduct of prohibition
where the emphasis has been on maximum psychoactivity to the exclusion, for the most part, of medicinal bene ts that might go
beyond that. But, clearly, this is a substance that has a lot to o er on many levels.
Firstly, it synergizes with THC, so it complements the ability of THC to treat pain while in its own right it’s an excellent anti-
in ammatory without the liabilities that we say get from non-steroidal anti-in ammatory drugs with their tendencies to
produce serious side e ects like ulcers, heart attacks, and strokes, these just aren’t a liability with cannabidiol.

So cannabidiol, on the one hand, can counteract some of the less desirable e ects of THC such as this tendency to produce anxiety
and rapid heart rate. But at the same time, cannabidiol on its own has many properties that THC doesn’t – as an anti-anxiety
agent, as an anti-psychotic, and doing all this without producing intoxication, if you will, that can happen with too much THC. So
this is just a few of the things.

Project CBD: You mentioned CBD in the context of it being combined with THC; you also mention it as an isolate. And GW
Pharmaceuticals, when you were involved with the company, has done extensive clinical trials focusing on CBD in combination
with THC for Sativex. It’s been approved in a couple of dozen countries as a sublingual spray. But also GW has been focusing more
recently on Epidiolex, which is more like a single molecule formula. I realize there are some other things in there, but it’s mainly
CBD.

Russo: That’s true.

Project CBD: So what are the advantages and disadvantages of both ways of looking at it, both as an isolate or as a whole
plant mixture?

Russo: So in Sativex, basically it’s a 1:1 mixture of THC and CBD, plus some other terpenoid components. That turned out to be the
best approach for treating a large variety of symptoms such as spasticity in MS, some pain conditions, particularly neuropathic
pain, and worked out quite well. In the early days, the company looked at di erent ratios and di erent modes of administration
and the oral mucosa spray with Sativex with this 1:1 mixture turned out to be a good balance of e cacy and safety, meaning fewer
side e ects.

On the other hand, cannabidiol alone, again, would be very good in treating a variety of other conditions. One is epilepsy. CBD as
an anticonvulsant has a broad spectrum of activity. In other words, it works on many di erent kinds of seizures and has the
possibility, again, of doing this without any of the liability that THC might produce, both in terms of side e ects but also legal
constraints. So that’s a big advantage. Additionally, as an anti-psychotic, say to treat schizophrenia, there’s already been a Phase
2 clinical trial with Epidiolex, in essence, with good success apparently. That hasn’t been published yet. But the preliminary
results were announced online.

Project CBD: So I’ve heard it described that CBD is like THC without the psychoactivity. Is that accurate? Or is that sort of a blunt
description that really doesn’t get at what’s going on here? Are there other conditions that really CBD seems more suitable than
THC?

Russo: More the latter. It is really distinct. Something I haven’t mentioned is that in its own right cannabidiol is an
endocannabinoid modulator, in other words, when given chronically it actually increases the gain of system, which is, at its core,
a homeostatic regulator. To explain that: homeostasis is a state of balance. Many diseases interfere with a balance in a given
system and if we can bring that balance back to where it should be there’ll be improvement in the overall condition. This is one
reason that cannabidiol is such a versatile medicine because so many disorders operate on that kind of level. So, if there’s too
much activity in a system homeostasis requires that it be brought back down. If there’s too little, it’s got to come up. And that’s
what cannabidiol can do as a promoter of endocannabinoid tone, we call it.

Project CBD: Well usually when we think of a drug, it goes in one direction or the other. But you’re suggesting that CBD really has
a bi-directional e ect. It can balance either excess or de ciency. Can you explain how that works? Or would that require a kind of
in-depth scienti c …

Russo: It would but, looking at the endocannabinoid system, it is sort of a bu er. So CBD can be thought of as a bu er as well – a
bu er is something that will work both ways as need be. So, for example, in the endocannabinoid system one of its main roles in
the brain is to regulate neurotransmitter function and again, if there’s too much of one kind of neurotransmitter it will bring it
down, if there’s too little it will bring it up. Without diagrams, that’s probably as well as we’re going to do this evening.

Project CBD: Now does THC do something similar, but in a di erent way?

Russo: Yes. Okay, we can think of THC as acting directly on the cannabinoid receptors. In contrast, CBD is quite distinct. It doesn’t
tend to bind directly, what’s called the orthosteric site where THC binds. Rather, it binds on what’s called an allosteric site,
another site on the receptor, and it so it alters the binding of both THC and the endogenous cannabinoids, the endocannabinoids.
So, cannabidiol is what’s called the negative allosteric modulator, which is a fancy way of saying that when THC is present it
interferes with its activity – which is a good thing in terms of wanting too much psychoactivity and again limiting side e ects
like anxiety or rapid heart rate that can be a problem if someone has too much THC.
Project CBD: So the idea that CBD is a negative allosteric modulator of the cannabinoid receptor, that would suggest – if it’s
impeding or reducing the signaling of a particular receptor – that it might be helpful for diseases that are an expression of an
excess, because you want then a limit, and the opposite would be if you had some kind of allosteric modulator, unlike CBD, that
would have a enhancing e ect on a receptor that would then perhaps be helpful for disease of de ciency of the endocannabinoid
system. Now you’ve written a very important paper, I think it was published back in 2001, on clinical endocannabinoid de ciency,
maybe you can explain the thesis of that?

Russo: It was a concept I introduced then, I had a larger review paper in 2004, and just this year 2016, I submitted further review
that’s currently under consideration for publication. Basically it occurred to me that many diseases a ect neurotransmitter levels.
A couple of examples: We know one of the primary problems in Alzheimer’s disease or other dementias is a lack of Acetylcholine,
the memory molecule in the brain; similarly in Parkinson’s disease there’s not enough dopamine and you try to replace that with
a medicine with a medicine call L-Dopa. So what would a de ciency of endocannabinoid function look like? Well, we already knew
that. If you don’t have enough endocannabinoids you have pain where there shouldn’t be pain. You would be sick, meaning
nauseated. You would have a lowered seizure threshold. And just a whole litany of other problems. It occurred to me that a
number of very common diseases seem to t a pattern that would be consistent with an endocannabinoid de ciency, specially
these are migraine, irritable bowel syndrome, and bromyalgia. They have some things in common. They’re all hyper-algesic
syndromes, meaning that there’s seems to be pain out of proportion to what should be going on, in other words you can look at
the tissues they look okay, but there’s biochemically something that’s driving the pain.

Additionally, they occur in the same individuals. If someone has a chronic problem with migraine there’s a high likelihood they’re
going to have bromyalgia at some point in their life; similarly, with the irritable bowel syndrome. Previously there wasn’t a lot
of genetic linkage, but we’re still looking for evidence of that and there seems to be a possibility that there’s some linkages there.
But again, the theory as it started out was that they would have in common an endocannabinoid de ciency. Subsequently to the
review paper in 2004, there’s been a great deal of work done both clinically and experimentally that supports the concept. I’ll just
give one example: Some years ago in Italy a group Sarchielli, et al, measured the anandamide levels in the cerebrospinal uid.
They did lumbar punctures, spinal taps –

Project CBD: Anandamide being one of the endocannabinoids.

Russo: Exactly. They showed in people with migraine that the levels were vastly lower than in normal people that didn’t have
migraine headaches. So this was the rst strong objective proof, if you will, behind the theory. There have been other examples
that have tried to document the new paper.

Project CBD: Given just the notion of measuring of the levels of one’s own endocannabinoids, if there was a technology that was
relatively inexpensive and accessible that would seem like a very, very valuable diagnostic. Is there such a thing in the works as
far as you know?

Russo: Well, in development – we’re not there yet. There are direct measurements, hopefully we’d have a technology that didn’t
require an invasive procedure like a lumbar puncture to gure these things out. There are also physiological scans like PET scans
and to a lesser extent functional MRI scans that could look at that, but we’re still in early stages of trying to harness the kind of
technology that would give us these answers particularly without resorting to more invasive techniques.

Project CBD: Phytecs, the company that you’re working with now, as far as I know has been involved with developing techniques,
possibly drugs or herbs or combinations thereof (maybe other techniques, you’ll have to ll us in) that target the
endocannabinoid system in a way to restore balance if it’s de ciencies as you’ve just described of migraines and other things –
presumably that would somehow enhance the endocannabinoid functioning in the body. Or if it was an excess disease, perhaps
something like obesity you’d want to bring it down. Tell us a little bit about what’s in the works with Phytecs? Is the focus just on
cannabis or are they looking beyond cannabis to other herbs or other techniques.

Russo: Cannabis is certainly in the mix. We’re interested in developing more focused chemovars that would be chemical varieties
of cannabis that would work better on certain diseases that maybe haven’t had as much attention heretofore. But yes, you’re
right, we’re also interested in non-drug approaches. This would include herbal approaches that would a ect the endocannabinoid
system with agents that aren’t intoxicating. Additionally, it would include lifestyle and dietary approaches. And there’s a large
body of evidence now to show that diet can positively in uence the endocannabinoid system and its balance.

Project CBD: Presumably bad diet, negatively in uenced.

Russo: I’m afraid that’s true too.

Project CBD: So, when we talk about the endocannabinoid system, at least when I was rst hearing that term several years ago, a
kind of simplistic notion was that there’s these compounds in cannabis, they bind to these receptors, and that’s what it’s all
about. But when you talk about other herbs, are you suggesting that there are other herbs, other plants, which can also interact
directly – or maybe indirectly – with the endocannabinoid system? What would be some examples?

Russo: There’s an example we need to learn a little bit more about, a thing called the New Zealand Liverwort. It’s recently been
shown to have a cannabinoid agent that works at CB1, the same receptor where THC binds. I’m afraid the paper isn’t out yet. I’ve
just had a tantalizing hint from our colleague Jurg Gertsch about this. A couple of years ago there was an agent called yangonin
that was isolated from kava, the south sea beverage, that also works on the CB1 receptor, and it could certainly have something to
do with the relaxing properties of that drink. So this is just two examples.

Project CBD: And what about the compounds from the cannabis plant? Do they only bind to the cannabinoid receptors or are there
other interactions going on that we might not be thinking about?

Russo: Sure. Let me give a couple of examples: again, CBD is what’s called an agonist, a stimulator of serotonin 1A receptor. This
is something that I had hypothesized and with colleagues of the University of Montana back about 2005 we described this. And it
turns out to be an important mechanism of a lot of the activity of cannabidiol, seemingly independent of the cannabinoid
receptors. Another example is, another component of cannabis that’s chemically wasn’t thought to be cannabinoid turns out to
be, that is the sesquiterpenoid called beta-caryophellene.

Project CBD: When you say terpenoid or sesquiterpenoid, what do you mean by that?

Russo: Well, this is a 15-carbon molecule, it’s quite distinct in its appearance from the cannabinoids we think of normally in
cannabis, but as it turns out this is a strong selective agonist at the CB2 receptor.

Project CBD: That’s more in the periphery compared to CB1 tends to be more in the center?

Russo: This is thought of, this is a non-psychoactive receptor. It is more important in in ammatory mechanisms and also in
pain. So the advantage of an agent that would act on CB2 would be reducing in ammation, reducing pain, but without
psychoactive side e ects. Now as it turns out this caryophellene is very selective there. It’s a very safe agent. This, for example, is
in black pepper. It’s called GRAS by the government – not that kind of grass – rather GRAS, Generally Recognized As Safe as a food
additive. So this is something with the government’s seal of approval. It’s in our diet. But more of this would certainly have a
positive in uence on health, particularly for people with arthritis or other kinds of chronic pain. And again, without any liability
in terms of having unwanted side e ects.

Project CBD: So beta-caryophellene, this sesquiterpene that you refer to, this is actually present in some cannabis strains and
therefore would have presumably an additive e ect combined with the synergy with the cannabinoids like CBD and THC could
enhance the painkilling or anti-in ammatory e ect.

Russo: Yes, that certainly would be the case. It’s going to be present to some degree in almost all cannabis strains. However, if
you have, say in a dispensary the ability to have a good assay for the cannabinoid content and we’re able to select for one that was
high in caryophellene we would expect that to be much better at treating pain and in ammation.

Project CBD: So if you have a situation where the cannabinoids like CBD and THC from the plant are binding not only to the
cannabinoid receptors but other receptors, and then we have other herbs – you mentioned kava, there’s others as well – that are
interacting with the cannabinoid receptors, what does this mean in terms of our conception of what the endocannabinoid system
is? I remember years ago when I was fumbling around as a non-scientist trying to get a handle on some of these concepts, the
idea was I think maybe somewhat narrow: you have compounds in the plant, they bind with these receptors, great, and good
things happen. Is that too narrow a conception when we say the endocannabinoid system in that classic way, do we need to
expand our idea of it?

Russo: Well it’s a great question because it highlights the problem that we have. First and foremost, we need to better understand
the role of the endocannabinoids in our lives and our health status. That’s been ignored, possibly because of its name – having
cannabis in the name of this pejorative connation has impeded education, even in medical school. Basically, it hardly exists. Let’s
consider this. There are more cannabinoid receptors in the brain than there are for all of the neurotransmitters put together. That
being true – and it is – recognizing that fact, why would one ignore this system? Why isn’t this being taught? Our public needs to
know about this and how lifestyle and diet a ect this system, and how it could be brought to bear to improve their life condition.

Project CBD: We want to thank you Dr. Ethan Russo for bringing this type of information to our attention. You’ve been a pioneer
in this area and it’s been greatly helpful to all of us. Thank you.

Russo: My pleasure.

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