Is CBD an Endocannabinoid Reuptake Inhibitor?

05 Oct Is CBD an Endocannabinoid Reuptake Inhibitor?

Transcript

Project CBD: Welcome to another edition of Cannabis Conversations. I’m Martin Lee with Project CBD, and today we’re going to be speaking with Matt Elmes. Matt is the director of new product development at CannaCraft, a major cannabis company in California. Matt heads up the science team there, and CannaCraft has been a supporter of Project CBD for several years. Matt holds a PhD in molecular and cellular biology from the State University of New York at Stony Brook, where he also did his post-doc work. And much of that work focused on the endocannabinoid system. And that’s what we’re going to talk about today.

Let’s s roll back the clock for a moment to the 1990s – the decade of the brain. There were several discoveries about the endocannabinoid system and certain components that comprise what scientists would refer to now as the “canonical cannabinoid system” – the cannabinoid receptors in the brain and the body, CB1 and CB2, and also the endocannabinoids that bind to these receptors. And then there was the identification of certain proteins that were involved in the biosynthesis and the breakdown of these endocannabinoids. Your group at Stony Brook, Matt, added a whole other dimension to understanding the endocannabinoid system. You were involved in the discovery of what’s known as “transport molecules.” Maybe you could explain what a transport molecule is and what it has to do with the endocannabinoid system.

Elmes: The transfer molecules we’re talking about are the fatty acid binding proteins, or I’ll call them the FABPs. First they have a canonical role in transporting fatty acids throughout the body, and that’s why they got their name. However, my group at Stony Brook, particularly my mentors Dale Deutsch and Martin Kaczocha, led the discovery that these molecules are also transporting the endocannabinoids – namely 2-AG (2-arachidonoylglycerol) or anandamide.

Project CBD: Why would they need to be transported? Why don’t they just sort of go in the blood, wherever they need to go?

Elmes: That’s because endocannabinoids, and cannabinoids in general, are highly lipophilic, so they are like oil in water. They will sequester to the oil phase and stay away from water. Now remember, all the cells in our body are essentially a bubble of oil where the water is in the inside, that’s the cytoplasm. So, we knew the endocannabinoids are made on the outside of the cell [membrane] and they’ll stick to that lipid layer. However, the enzyme that breaks them [the cannabinoids] down, particularly we’re talking about the anandamide breakdown enzyme which is known as fatty acid amide hydrolase or FAAH – that’s found on the endoplasmic reticulum.

Project CBD: So that’s inside the cell.

Elmes: Essentially in the middle of that bubble of oil. We knew the endocannabinoids somehow got from the outside to the inside, but no one ever knew what that process actually was, and how that happened. There were a lot of theories out there … So about 10 years ago, our group found that the FABPs in the brain, the few specific isoforms that are found in the brain, essentially pick up those endocannabinoids from the outside of the cell, carry them inside the cell, and pass it off to that enzyme [FAAH] or other areas too. Because these endocannabinoids are also interacting with nuclear receptors such as the PPAR receptors. So, they’re essentially a shuttle protein, they’re picking up cannabinoids and transporting them all throughout the cell.

Project CBD: So these transport molecules, these fatty acid binding proteins you referred to, what do the phytocannabinoids, CBD and THC, if anything, what do they have to do with this?

Elmes: It’s actually where my whole PhD project came in at Stony Brook. So, as I mentioned, my mentor had discovered this class of proteins being responsible for endocannabinoid transport. Phytocannabinoids are sort of a similar size, they’re also very lipophilic, so they have to overcome that same barrier of how to cross these aqueous layers in the body. I focused on [the thesis that] maybe FABPs are also transporting THC and CBD or other phytocannabinoids. We did some testing. I found that in vitro these things are actually binding. The FABPs have an affinity for THC and CBD. Then we did that a step further, and showed that this is actually happening in the body. THC and CBD can compete for anandamide uptake.

Project CBD: What does that mean? What are the implications of that? If the endogenous cannabinoids, like anandamide and 2-AG that you mentioned, they’re hopping on these transport molecules and getting through the cell and doing their thing, what does it mean then that CBD and THC can do the same thing, on the same fatty acid binding proteins?

Elmes: I think there’s potential that they are modulating the endocannabinoid tone in their own right. But again, as I mentioned, FABPs are picking up the endocannabinoid anandamide to be broken down. So, if we block that transport step, there’s going to be less anandamide broken down, and hence more anandamide in your body that’s able to signal and hit cannabinoid receptors.

Project CBD: And what would be the implication of that, for example, of an enhanced signaling from the endocannabinoids?

Elmes: Exactly. So now if we have CBD, say, competing with anandamide for binding to that protein, less anandamide is going to be able to bind and get broken down. So, the fact that CBD is around and present might actually lead to an increased levels of anandamide and increased endocannabinoid signaling.

Project CBD: So that would have potentially significant health benefits.

Elmes: Certainly. So this is all very new work. And we are still learning more about what this is doing and how this is interacting between the phytocannabinoid and the endocannabinoid systems. But I certainly think there is potential, strong potential, for CBD, a partial mechanism of action for CBD, to be modulating the endocannabinoid tone by decreasing the rate of anandamide breakdown in the brain.

Project CBD: So, in essence, the implication would be that CBD boosts our own endocannabinoid signaling, which might be sort of like a natural high, you might say.

Elmes: Yes. Again, we are still working some of the pieces out and we can’t definitively say this for sure. But I think it’s certainly a partial mechanism of action.

Project CBD: One of the knocks on cannabis use medicinally is that – okay you smoke a joint or you eat an edible, you swallow a gel cap or something, take a tincture – it has a global effect. It affects receptors all over the body and brain. Whereas, if you’ve got a problem in one place, what do you need all the rest of it going on? What about the fatty acid binding proteins? Is it still the same problem here, if CBD or THC or some other – maybe a synthetic ligand – was targeting these fatty acid binding proteins, would you still have the same global effect and would that be a detriment as far as a pharmaceutical company or pharmaceutical development was concerned?

Elmes: That’s a great point, Martin. And FAAH inhibitors have been developed in the past. Now again, that’s the enzyme that breaks down anandamide.

Project CBD: So that would also be kind of a global thing. It would break down everywhere.

Elmes: Exactly. And the FAAH you find in the brain is also the FAAH in the liver, the FAAH in the kidney, the FAAH everywhere in the body. Now, the FABPs are 10 different isoforms found in mammals. So, in humans there are 10 different types of FABPs, and they have tissue-specific expression patterns. The one you find in the brain, it might not be expressed in the liver or any other part of the body. So, what our group started doing, and we’re in the process of doing, is developing these endocannabinoid transport inhibitor compounds. And we’re still in the pre-clinical drug development phase, but pushing it along. We’re trying to target just the FABP isoforms that are found in the peripheral nervous system and in the brain. That would have anti-inflammatory and anti-pain effects by modulating our own endocannabinoid system.

Project CBD: But also very specific effect, because if there are these different FABPs in different parts of the body and the brain, by hitting one of them and not the other is you could have a very specific effect unlike –

Elmes: Exactly right. So that’s why we’re trying to target just those few isoforms that are found in the brain. We can have this anti-pain effect without shutting down our FAAH enzyme in the liver – where we need that enzyme to process other phyto-functions in the body. It gives us a bit of more finesse in a precise way of targeting just where you want it to be targeted, just to modulate the endocannabinoid system in these specific parts of the body.

Project CBD: That’s something I would presume pharmaceutical companies might be interested in, as part of their drug development.

Elmes: Certainly. We had some IT around this whole idea and some of our early chemical compounds at Stony Brook. A company called Artelo Biosciences, it’s a small biotech company, had licensed these patents from us and they actually had funded my post-doctoral work doing some preclinical drug development toward these endocannabinoid modulating drugs. There’s certainly interest. And we’re trying to push this into Phase 1 clinical trials to learn more about how these are working.

Project CBD: Last question: What is it like to go from this setting in academia, where you’re working at a high-powered lab doing this hard science [with a] testing program for drug development – what is it like going from that environment into the cannabis industry, the heart of it in California, at CannaCraft where you’re focusing presumably on product development, but different sort of work. What’s the transition been like for you?

Elmes: Well, I don’t want to say the stress goes away! There’s certainly a lot of that. But the work’s very interesting. The pay is certainly better, I’ll say that much. So I think my transition might have been a bit easier because I’m moving from sort of a hard science lab into an R&D environment, where your scientific knowledge is still valued and we’re still doing experiments and things like that. But there’s less of a focus, obviously, on grant writing and where to find that next grant money that keeps funding your research and funding your own payroll. Now it’s more about making the best quality product we possibly can – and ultimately money of course. But the goals are a bit different. It’s more of a typical 8:30 to 5:30 weekdays, whereas in my old lab it was also weekends, nights, you never stop thinking about it. You can kind of turn it off when it’s more of a 9 to 5 job. But so far, I’ve been loving it. It’s been great.

Project CBD: Thank you very much, Matt Elmes for sharing your perspective. This has been another edition of Cannabis Conversations.

(This transcript has been slightly edited for linguistic clarity)