September 7, 2023 — Dr. Kelly Diehl sits down with Dr. Al Chicoine to learn more about CBD and its potential to treat diseases in dogs and cats. The pair discuss the basics of how CBD interacts with receptors in the body, what we know from published studies, what we don't know (yet) and what's on the research horizon.
Resources:
CBD-a promising-tool for companion animals
Cannabidiol (CBD) use in dogs and cats
High times - Marijuana, cannabidiol and synthetic cannabinoids toxicity in pets
0:00:09.6 Kelly Diehl: Welcome to Fresh Scoop, Episode 60, CBD Use and Companion Animals, What We know And What We Don't Know. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation, Senior Director of Science Communication. And today we'll be talking with Dr. Al Chicoine. Dr. Chicoine is Assistant Professor, department of Veterinary Biomedical Sciences at Western College of Veterinary Medicine at the University of Saskatchewan, Canada. Welcome, Al.
0:00:38.4 Dr. Al Chicoine: Hi, Kelly. Thanks for having me.
0:00:41.3 KD: Yeah. Before we get started, I always ask everyone to tell us a little bit about themselves, kind of what led you to become a veterinarian and then in your case, to be interested in pharmacology.
0:00:52.3 DC: Wow. Well, so I think, like most veterinarians, I grew up, really liked animals, particularly dogs and cats, but then certainly learned to appreciate particularly, farm animals, food animal production. But what really kind of got me into veterinary medicine was the diversity within the profession and within a typical day in the life of veterinarian as opposed to maybe some of the other medical specialties, which I was also interested in growing up. But you're kind of doing maybe the same thing all the time in those specialties, whether it's dentistry or surgery or what have you, whereas veterinarians seem to do a lot of different things on a lot of different species every day, and there just seemed to be lots of different skills required, and I found that pretty appealing.
0:01:42.8 DC: When I went through veterinary school, the interest in pharmacology is a little bit more abstract, but I kind of naturally gravitated towards physiology and how the body works. And what I really liked about pharmacology was it's essentially just applied physiology. You're taking some sort of body process and you're introducing some type of drug or chemical that is going to change that process in a way, whether it's opening up some sort of a channel or an antibiotic acting on a bacteria, but it's just, it's basically applied physiology. I find it very analogous to a lot of veterinary students, they really like surgery, and I kind of viewed surgery as applied anatomy, right? You're taking anatomy that's sort of broken, and then you're trying to surgically correct it. I hated anatomy as a vet student, still don't like it. So, surgery was never really in the cards for me, but I really liked pharmacology, how the drugs were working and modulating the physiology. So, I ended up coming back after a few years in practice and speaking with our clinical pharmacologist at the time, and started a residency in clinical pharmacology. And really appreciate how it really incorporates so many different aspects of veterinary medicine, the diagnostics, medicine, pathology, all of the different infectious disease components, and it's all kind of part of pharmacology.
0:03:18.9 KD: Well, that was a great explanation, I think, of pharmacology and a great lead-in to my next question. As we start out, I know everybody's here to hear about CBD, but I get really confused about the terminology because I think we hear about hemp, cannabis, cannabinoids, synthetic cannabinoids, and all of that. So, marijuana, can you maybe sort out, Al, what you think is important for us as scientists, veterinarians, pet owners to know about these terms?
0:03:53.8 DC: Well, first off, Kelly, and to answer your question briefly, no, I can't sort it out because I get confused all the time with these as well. It's been a quite the steep learning curve just for the terminology, and I still get them confused. The term that I prefer is cannabis, and specifically, if we're talking about like the plants, the cannabis type of plants. Now you get into the agricultural, the growing of the plants and things, and that's a whole nother world as well in terms of hemp and what's the distinction between them and the concentration of the various elements within them. But I think it's helpful, we talk about cannabis as sort of the overarching family of the plants, but where it's... Why we care about those plants is because of the cannabinoids.
0:04:40.6 DC: So those are the compounds within the cannabis plants. And why we care about the cannabinoids is because they are acting on specific receptors in the body, and they've been termed cannabinoid receptors. And it's probably a whole bunch more that we don't know, but the ones that are most well-known are what's called the CB1 and CB2 receptors. So, the cannabinoids are this family of compounds that act on these specific receptors. But where I find it really complicated is that there's endogenous substances produced in the body that also act on those cannabinoid receptors. So that's called the endocannabinoid system. And the body has its own chemicals that are produced innately that act on those receptors. But what we are sort of talking about in the cannabis world are the cannabinoid substances, exogenous substances, not produced within the body but are taken from these plant-derived sources that then act on those same cannabinoid receptors within the body. So, if you're not confused already, it's going to get worse. But the cannabinoids of interest, the one everybody has heard about before is THC. So technically, it's delta-9 THC, or tetrahydrocannabinol.
0:06:14.2 DC: That one is what's known as sort of the psychoactive THC, right? That's the marijuana that everybody kind of assume, we... It's synonymous with sort of the recreational use of cannabis, so getting high. As veterinarians, that's not the cannabinoid that we are particularly interested in for pretty obvious reasons. However, historically veterinarians have had a lot of experience with intoxication cases, unfortunately, and that's typically THC. And we've actually, some of my colleagues and I have done a study looking at cannabinoid intoxication cases and have demonstrated that yes, the THC is the predominant cannabinoid in those cases. We'll maybe get into a little bit later. THC does have a role, even in small quantities when we're talking about the other cannabinoids. But the big one, the focus of our talk today is CBD. Cannabidiol and we'll talk of why that is.
0:07:20.5 DC: The key thing right now is CBD is thought to not have the psychoactive components that THC does, but it does act on the cannabinoid receptors, CB1 CB2 throughout the body. But it's thought that it produces other types of effects, either anti-inflammatory effects or potentially analgesic effects. It's going to be a lot more complicated than that, but that's sort of the gist of what CBD might do. And make it more confusing, there's lots of other cannabinoids as well, things like cannabinol CBN, cannabigerol CBG, and then metabolites of all of the different cannabinoids as well, some of which are active on cannabinoid receptors, some of them less so. So, I still get confused with the cannabinoid pharmacology. When you really dive into it, the key message is it's not simple, it's not a straightforward process, but that's what kind of exciting about it. There's lots of things to learn and lots of potential avenues for their use.
0:08:34.8 KD: Right. And I think you brought up a good point there that when I started to learn more, I think as people, we think of THC and CBD, but there's so much more, especially in the plants, right? That a lot more cannabinoids than I ever had any idea were in there.
0:08:54.2 DC: Oh my goodness. And the chemistry, Kelly, behind this, it's pretty crazy. And it's beyond sort of my scope as a veterinarian, as a pharmacologist, but apparently the proponents, again, this is where the agricultural side comes in, but what they call the hemp terpenes, a lot of the chemicals that are within the plants. No, they're not cannabinoids per se. They're not active on say, cannabinoid receptors in the body, but yet they appear to have some impact on the activity of the true cannabinoids, let's say THC and CBD. But that also depends on the formulation of the plant material and how it's going to be administered to the animal or the person. And this is where and I am not into the cannabis world per se, of the different strains, and as veterinarians, we don't really think about inhalational products. That's not a route that we're going to be using for our patients.
0:09:55.7 DC: But there's a lot of important aspects for the plants when they are consumed via inhalation that maybe it's not the same effect when they are consumed orally and will or won't be absorbed through the gastrointestinal tract. And this is a real eye-opener for me. As a pharmacologist, I'm used to dealing with pharmaceuticals, drugs, and we think of cannabis as a drug, but it's really kind of straddles the line between the plant-based nutraceuticals and pharmaceuticals. There are some cannabinoid products, things like Epidiolex, which is a pure CBD formulation approved in the United States for people, not for animals right now, which is a pharmaceutical, and it meets pharmaceutical standards. But when clients typically talk about CBD products or cannabis products, they're not pharmaceuticals per se, and they can have lots of differences in those other cannabinoids or in the terpenes or the oil bases that they're put in. Those differences can have a real impact potentially on clinical application, but we don't see that in the pharmaceutical world where it's a very consistent formulation, a consistent product, and the drug manufacturer has to make it that way. So, I hope the viewers aren't completely confused already, but it's a wildly confusing area.
0:11:31.5 KD: It is kind of wild. And before we dive into CBD, you actually, what you just said reminded me of something that I've heard before. Maybe this is a good time to bring it up, which is something called the entourage effect.
0:11:43.0 DC: Yeah.
0:11:44.6 KD: And it's not a television show. It's not your like gang. But tell us a little bit, because you kind of just alluded to it, right? Which is these complex plants with lots of stuff in them and what the entourage effect is.
0:12:00.8 DC: First, I love that term. The entourage effect. I think, to be honest, it's a bit misleading though. So, the entourage effect, the idea behind this was when you have multiple cannabinoids or multiple chemicals in the formulation, the product, that the end result may be somewhat different because of that entourage, that whole hangers on, group, others associated with the one of interest, whether it's THC or CBD. And where I find it interesting is because from a pharmacological perspective, there's a number of different ways with which those entourage chemicals, moieties, could be impacting the cannabinoid of interest, whether it's THC or CBD. And so, my kind of interest, I like the sort of the pharmacokinetics, which is the time course of the drug in the body. How does it get absorbed? Where's it going? How long does it stay there? How does it get metabolized? How does it get excreted in a nutshell? Well, the entourage effect can have an impact on things like where that cannabinoid is actually being distributed and how is it... Is it staying in the central nervous system?
0:13:20.5 DC: How that might happen is some of those other chemical moieties, we'll use example of say THC and CBD put together in the same formulation. If both of those cannabinoids are in the plasma, you can imagine them kind of both trying to get through the same transporter protein. And they need that transporter protein to either get in somewhere or to be pumped out of a part of the body. And the best example I can think of is in the central nervous system today, the brain, protected by the blood brain barrier. There's lots of these transporters that it's their job to get rid of foreign substances like cannabinoids. But if you got CBD along with THC, this kind of entourage effect is, well, if they both kind of are fighting or the transporters get, trying to get rid of both of them, but it's only got room to get rid of one of them or it has a greater affinity from one of the cannabinoids, it might mean that the other one is hanging around a little bit longer in the brain or the central nervous system.
0:14:34.0 DC: So, it's sort of a fancy way of saying that the presence of multiple cannabinoids can impact the activity or the pharmacokinetics of the other products, the other cannabinoids in that formulation. But there's a whole bunch we don't know about this, Kelly, in terms of like what ratios, what combinations, do they all have that same sort of effect? Things like CBG and CBN and the metabolites. Are they all part and process of this entourage or is it really only just a couple of them? We do know, however, clinically it does make a really, really big impact. And there's some good published evidence on this, it came out just a couple years ago, authors who had looked at a CBD formulation, a THC formulation and then CBD plus THC at lower concentrations and they were giving these dogs increasing doses and, look, it was a toxicity type of study to see when toxicity would occur. Well, the combination of CBD and THC elicited toxicity at much much lower doses and the plasma concentrations were much much higher than dogs that were getting whopping high THC doses. And it was like, wow, you look at these numbers and you go, that's the type of thing veterinarians and owners really need to be aware of that, even like THC by itself was not nearly as toxic as this combination with lower concentrations of CBD and THC.
0:16:19.4 KD: Okay. Yeah, it's pretty interesting and I think it goes to plant. But I think it's what causes confusion. You probably hear this all the time. Like people are like, well this product worked with this product. And then you get into, I live in Colorado, you live in Canada, we have a lot of, like, you can go anywhere in Colorado and get all kinds of formulations of different, CBD, THC, same thing. So, it gets I think, pretty confusing really fast. You talked about receptors earlier in the body. Tell us a little bit more, because I think it's really fascinating the different types of cannabinoid receptors and where they are, because that gives you a clue of what they do. So, I know it's big subject, but see if you can walk us through it.
0:17:07.6 DC: Well, I can't give you a deep dive on it, Kelly, because it said this is, I'm aware of it, but this is where you get to the real pharmacology experts, specifically in cannabinoids. Long story short, the CB1, CB2 receptors are dispersed throughout the body. And again, if we go, I think I find it helpful to go back to the, we think of cannabis and the sort of getting high. Everybody assumes that the central nervous system and the effect of THC, and obviously that's a pretty critical component of this. But when scientists started looking for the presence of these receptors in other tissues, all of a sudden they found them, both CB1 and CB2. And as far as I'm aware, and I may be mistaken about this, but it's not like one specific cannabinoid and one specific receptor, that would make it a lot easier. It's not the way it is though. It seems that each of the cannabinoids has certain affinity for the different types of CB receptors, now varying levels of affinity.
0:18:12.7 DC: But they do seem to bind to these receptors. What I find really cool from a mechanism of action standpoint, what's a little bit different about these cannabinoid receptors versus lots of other receptors in the body, is that they work in a, what's called a retrograde fashion, meaning for the viewers that are familiar with say, neurons and neurophysiology in the body, if you think of like an electrical signal going down one neuron, called the pre-synaptic neuron, reaches the end of the line, that's the message. It's got to get that message to the next neuron, the post-synaptic cell, might be a neuron, might be a muscle cell, might be a gland, and it sends a message through a chemical signal called a neurotransmitter. And that's a pretty standard way we've known about that for well over a hundred years, how that works. But what's interesting with the CB receptors is at least many of them are found on the post-synaptic cell. And what they do when activated is they go back to the pre-synaptic neuron and modulate what gets released as neurotransmitters, which mechanistically is still a little bit beyond me, how exactly all this is happening...
0:19:36.1 DC: But at least in terms of the central nervous system and neural control of peripheral organs gives a glimpse into how the cannabinoids might be having some of the activity. Again, there's compounds within the body produced naturally, these endogenous substances that act on those receptors and help fine tune some of that, that transmission. But getting into the other uses of cannabinoids, I said, well, wait a minute though. There's lots of these CB receptors in lots of other tissues. It's not just all about psychoactive effects or neurological effects, what happens if those receptors get activated in, say, peripheral tissues or in liver or throughout the body? And that's where the In vitro testing showed some promising results for specifically CBD, that it might decrease some of the inflammatory processes the inflammations of wildly complicated topic on its own. So, there's lots of different paths through which that could happen. Long story short, it's typically through modulating how the immune system is getting ramped up or the immune or the inflammatory molecules, mediators, how they get produced. But that's where the other uses for cannabinoids for things like CBD as an anti-inflammatory or as an analgesic. But wait a minute, maybe there's a role for some of these substances as well. It's not just about THC and the psychoactive effects in the brain.
0:21:16.3 KD: Okay. Yeah. Tell us a little bit about the history of CBD. I mean, I'm old enough to have never heard of it before. And certainly, I saw marijuana toxicity in practice, but then you start hearing and THC, right? We all knew about THC. If you grew up in the '60s and '70s, like me, you knew exactly what it was, [laughter], but CBD is kind of new things. So, can you explain a little about the history, like when it started to gain in popularity and, you talked about the receptors, but can you take us back to like when this stuff first got popular?
0:21:55.7 DC: Sure. And I can only give Kelly my impression from the veterinary side of this. I suspect there was a lot more of a knowledge base, maybe not clinical application, but on the human side, I think they've known scientifically about CBD for a very long time. You go back through some of the published literature, and there's papers certainly from the 1970s where they talked about cannabis and they had identified CBD, they had quantified it in various strains of the products. But those papers, from what I have seen typically were focused on the on THC as their endpoint and either as potentially therapeutic uses for cannabis in the context of THC or maybe diagnostics for detecting as a drug of abuse, something like that.
0:22:52.3 DC: Cannabis usage and metabolism of the various cannabinoids. But you could go back a long way in the scientific literature. They've known about CBD, some of the other cannabinoids as well, although they, you really didn't see things like CBG and CBN start being reported more until closer to the 2000s. I think that the chemistry side they were known, but the clinical side, I don't think anybody gave them a whole lot of thought. But what was interesting when I kind of dug into this from the veterinary side, we really needed to know a little bit about the specific cannabinoids and how they get metabolized. Because when we were developing assays, my colleagues that were doing the analytical work, they couldn't just assume that say the dogs or the cats, which we were doing these studies, that they would produce the same metabolites for CBD or THC that humans did.
0:23:51.9 DC: And it turns out there's a lot of similarities, but there are some differences there. Same general principles, what they're doing, but the chemicals that are produced as metabolites are subtly different. But looking back to see whether or not scientists knew about this, the answer was they knew a lot, maybe not everything, but they would do studies in rats. And they knew that yes, you administered THC, you'd get these sort of metabolites. You gave THC to dogs you'd get this sort of metabolites. And then they started branching into some of the other cannabinoids as well. Again, the, those initial studies, they really didn't seem to have much, if any, clinical application. It didn't even really seem to be on the radar of many of the authors. It was, again, mostly an analytical type of a thing or chemistry type of thing.
0:24:46.3 DC: And then somewhere, and I want to say in the '90s you started to see, and this was I think more on the human side to begin with, CBD, there were some In vitro work being done showing, wait a minute, in these kind of cell culture media, maybe less inflammation or the mechanism potentially leading to decreased inflammatory production. And people thought maybe there's a clinical application for this. 2000s, it really kind of started going, seemed much much more the interest here. And then in the 2010s, again, more and more interest, particularly on CBD. And in the last five years, I'm going to attribute this in large part due to legalization of cannabis products in many states, in the United States, in Canada, many areas of Europe as well.
0:25:48.1 DC: Whole boom in the research specifically for clinical applications in animals. But it's not like this was, oh, a scientist discovered CBD in 2009 and we just started getting into this. They've known about the compounds for a long time, but from what I can tell the clinical usage really has only been the last decade, 20 years at the most on the veterinary side, maybe in the human side there, I assume there's lots of people dabbling in cannabinoid pharmacology whether legally or not at the time for a variety of conditions. But in the vet side, really only seeing clinical applications in the last 10 years.
0:26:33.0 KD: Okay. And do... This is hard because I know that you've talked about this. Before we get into your Foundation grant, what do we know or don't know about how CBD works in dogs and cats?
0:26:51.1 DC: So, I think we've got to define, Kelly, when we say CBD working. And for me, that's always what I struggle when, when talking with this, when teaching my students about this. How do you know that a drug works or a product, an intervention works? Does it work in terms of the molecular aspect, binding to the receptor that it needs to bind to? Okay. Does it work in terms of you administer a particular formulation and it gets to where it needs to go and then binds to that receptor and does what it needs to? Yeah, that's kind of the next step. Does it work in terms of it actually does the clinical job that you want it to? As veterinarians I think that's where we gravitate. Is it doing and I'll be quite honest, I mean, I find the hardcore molecular pharmacology, it's kind of interesting, but it's not in my wheelhouse.
0:27:43.4 DC: I'm a veterinarian first and foremost, and I want to develop therapies or evaluate therapies that are going to improve standard of care. So, when we say works, that's the context with which I'm looking at it. Does it improve something in terms of the care of that animal, whether it's analgesia or functional abilities or a behavioral change or what have you. So what do we know about particularly CBD and does it work? Well, the biggest area of research right now, and I think for a good reason is osteoarthritis. And osteoarthritis affects most dogs as they get older to some degree. Of course, certain breeds, large breed dogs, dogs that are overweight, really, really a critical problem in terms of quality of life, the functional ability of those animals. And veterinarians didn't think of this by themselves. In human medicine, a lot of people had said, I take these CBD supplements and they help. And that's very debatable. I think there's some good evidence, but there's some not so good evidence as well.
0:28:58.0 DC: But veterinarians started thinking, wait a minute, arthritis, osteoarthritis, musculoskeletal issues, really big issue in veterinary medicine, and maybe there's a role for CBD there. So, by my count of, actually, I was discussing this with my summer student, my grad student. I can see on the board there, it's all backwards. We had been doing a literature review on uses of cannabinoids, specifically CBD for arthritis. And there was five papers at least published in the last five years, evaluating CBD for arthritis. They're all relatively small scale. Each of them is unique and they all have their own kind of pros and cons and aspects to them. Long story short is it looks promising, but it also looks like it's not a panacea, it's certainly not going be the be-all and end-all of this. And I think any of the issues with arthritis and locomotion and pain, really tough to do a well-designed study because there's lots of confounding factors and there's a ton of placebo effect. And we found that firsthand when we did a real small study with some of our cats in our vet college. The placebo effect is absolutely real.
0:30:27.7 DC: Other researchers in this area I've discussed it with them and they're like, "Oh my God, especially with cats, it's so hard to tell what's happening in terms of their movement and their pain, whether or not arthritis is impacting them." So, long story short, for arthritis, a lot of research in that area for the companies that make these products, I think that's their holy grail because there's a big market and it's chronic administration of these products. So, in terms of sales potential, I think they see that as kind of where they'd like to go and I think the jury's still out on that. It's very promising, but there's so much we don't know, most appropriate dose, most appropriate formulation. And I think there's really big differences there subpopulations where this is likely to be helpful with CBD or cannabinoids. And for me as a veterinarian is I don't think I would ever recommend to a client that they not use established pharmaceuticals and they go to a cannabinoid.
0:31:31.6 DC: I think that would be, frankly, that would be irresponsible. But adding cannabinoids in as a supplementary therapy or as an adjunctive therapy to established interventions, things like non-steroidal anti-inflammatories that all veterinarians are very, very familiar with, where's the role of cannabinoids in something like that? There's some newer therapeutic modalities, monoclonal antibodies just released in Europe, United States, Canada, what's the role of cannabinoid products with those substances?
0:32:07.7 DC: So, my best guess, it's only a guess right now, is that for arthritis, I think cannabinoid products will have a role, but I don't think we've elucidated what that role is. I'm a little hesitant when some of the proponents are, point to the published studies as if it's a slam dunk. I don't think it is. But I also don't think it's appropriate to say, oh yeah, it's just snake oil, they don't work. Some of the studies have shown some very interesting findings, and it's definitely worth exploring further.
0:32:39.6 DC: The other big area, Kelly, that I think that CBD may have a very, very helpful role is in animals with epilepsy. We know for people, especially pediatric, kids with epilepsy, and being in Colorado, Colorado is at the forefront of treating pediatric epilepsy with cannabinoid products. There's some research at our university here, in our human hospital, looking at using actually the same formulation that we're using in our dog study for the Morris grants, exact same formulation, same company, for kids with epilepsy. Really promising results. The folks at Colorado State, Dr. Stephanie McGrath and her group, they're using CBD formulations.
0:33:28.1 DC: Again, not conclusive evidence, but it looks really promising. If I had to guess, and it's just a guess, I would say that epilepsy would probably be the usage of CBD that is most likely to have a significant positive effect. I don't think we know enough about it yet, but we certainly know there's subsets of epileptic patients that are just extremely difficult to treat, refractory to the common medications that we use right now. I think CBD will have a role, again, probably not by itself, but in conjunction with those other medications, there's probably going to be a benefit there, but that's, it's not fully ironed out yet. I know some of the folks down in Auburn, Dr. Tom Jukier and the group there, and Dr. Dawn Boothe's lab, looking at some other CBD formulations in cats with neurological conditions.
0:34:24.5 DC: So, I think that's another big area as well. So, when you ask me, does CBD work? That's a really long-winded way of saying there's some good evidence for epilepsy and some pretty decent evidence for arthritis. In neither case is it the be-all and end-all, but it looks like there's some promising areas there. Other people have proposed using CBD for a variety of other conditions, as a sedative product or to alter animal movement for hyperactive animals, as a generalized anti-inflammatory. I haven't seen evidence that really stands out demonstrating it's likely to be effective for those cases.
0:35:08.9 DC: It doesn't mean it won't work, but I haven't seen any evidence that says, yeah, this is a really promising area. Originally, we had planned on using CBD as an antiemetic product, so a product that stops vomiting. I think there could potentially be a role there, but that's one where it's probably a real niche area. And we have some really good antiemetic medications in veterinary medicine, drugs like Cerenia that are already approved. Really unlikely that CBD would be as effective or more effective than those guys. Probably didn't make a lot of sense to study it. And from an animal welfare point of view, we can induce vomiting in dogs and cats, but it's not the nicest thing to do and it's just. For certain types of drug studies, you kind of have to do those things, but that's one where it didn't make a whole lot of sense. So that kind of let those areas, the one area I left out is the area that we chose to study here at our institution, which was post-surgical use of CBD.
0:36:18.5 KD: Yeah go ahead and tell us about your grant, because this is a really cool grant that we're funding.
0:36:24.1 DC: Yeah. First off, thanks so much to Morris Animal Foundation for helping out with this one and for providing the funding. We certainly can't do this study without that support, so I need to get that out of the way right at the beginning. When we were deciding about cannabinoid projects in veterinary medicine, and we had been doing this in consultation with other cannabinoid researchers at our university, in the medical college and in the School of Pharmacy in particular, I said, well, what are the areas in veterinary medicine?
0:37:01.8 DC: And I always laugh about this, because the human scientists, whether there be medical doctors or the pharmacy people, they always just go, oh, yeah, veterinary medicine, you guys just are an afterthought. They don't really think about it. But our dean of the pharmacy college at the University of Saskatchewan is actually a veterinarian. And she went on and did a PhD in the area of pharmaceutical sciences and is now the dean of the College of Pharmacy. So, has a real good understanding of veterinary applications, and she had contacted me and said, we think there's got to be some usage of CBD in particular in animals. And even just as an experimental model, if not as a clinical application for veterinarians. So, okay, well, we knew there was lots and lots of work going on with osteoarthritis, lots of different research institutions, universities, private institutions studying this, didn't think that we needed to reinvent the wheel there. We knew the folks in Colorado State were looking at for epilepsy and neurological usages of CBD. Okay. That's really and we don't have the caseload to really dive into that.
0:38:19.0 DC: What we thought we could contribute into this area was what about after surgery? , as an analgesic, as an anti-inflammatory and as a general I don't want to use the word sedative, that's not the correct term but just calming agent. We did see that in some of our preclinical studies with CBD. Would that be helpful? The next question was, okay, what type of surgery are we talking about? And the obvious answer is something like spays and neuters. But to be honest, we've got really good analgesia for spays and neuters. And not to minimize in terms of a spay especially in a large dog it's not an insignificant procedure by any stretch but it's incredibly routine and the vast majority of the cases it... We have good analgesia for that. So, there's probably not a whole lot of room for cannabinoids to improve those outcomes for some of those surgeries.
0:39:21.9 DC: But in discussion with our surgeons where do you think maybe there is room for improvement? And they had thought, well, some of the more invasive orthopedic surgeries. And the one that kept cropping up is a surgery for cruciate ligament rupture called the TPLO procedure, tibial plateau leveling osteotomy, which was again, I was never a surgeon and that's a pretty specialized type of surgical procedure that most veterinary practices are not performing but it is sort of the gold standard at least the last... Historically it has been for cruciate ligament repair but it's pretty invasive. And while we have very good analgesics that are used currently for dogs undergoing this TPLO surgery is well, maybe there's some room for improvements in terms of analgesia. And that's where we thought, CBD might augment the analgesia in those cases. But we also think there might be some other benefits there as well. The anti-inflammatory action and again this is, it's easy to demonstrate that in vitro that's really hard to show in a live animal and particularly in a clinical setting. What are we looking for? So, a clinical improvements regarding inflammation. So, things like swelling, things like pain at the surgical site. Can we... Would we see an improvement if these dogs getting this orthopedic surgery were administered CBD in terms of their function, how are they moving?
0:41:04.4 DC: Is there an inflammatory component to that? And then finally the last little bit was the behavioral aspect of it. Because many of the owners, anybody who's had a dog that's ruptured their cruciate ligament, it's often dogs that are extremely active and just going nonstop all the time. Of course, the first thing a veterinarian says is, well you need to have cage rest, you need to minimize the activity. And for many of these dogs it's incredibly difficult. Well, we could just take the edge off a little bit and again we have medications to help with that but perhaps CBD, cannabinoids could also help make those animals a little bit calmer in that immediate postoperative period when they're most likely to damage themselves with inappropriate activity. So that's how we decided on this particular study so will be administering CBD in addition to the standard analgesic protocol and then trying to assess does it improve analgesia? Does it improve functional ability?
0:42:10.2 DC: So, bearing weight on that limb or movement of that limb, how much can it flex or extend, swelling around the limb, and then does it make the animals any calmer, the versus sort of the standard analgesia that they would receive. So that's a nutshell. That's how we came up with this particular study. At the time we had lots and lots of cases of this particular type of surgery. Unfortunately for our dogs it's really common that they tear their cruciate ligaments. It's not a great thing. But it meant a really big caseload at the time. And it's, we thought this was a good model to assess whether or not cannabinoids might be beneficial.
0:42:55.7 DC: So, and I just want to make clear that when we chose that model I mean I don't have a particular interest in cruciate ligaments or cruciate ligament rupture repair but it was just the surgical model that we thought was most appropriate for assessing cannabinoids in that postoperative period.
0:43:19.5 KD: Right. And I think it's a surgery also that has a very standard procedure, right? It's very consistent. One dog I mean Everybody's different but and so talk a little bit about the methodology because basically as you mentioned in this study there's a control group, it's blinded and some get standard pain medication, right? And then some get standard plus CBD but nobody knows, right? So, talk about that.
0:43:45.4 DC: Right. Actually, the way Kelly and I described this to the clients, when we go to the clients to see whether they'd like to enroll their dog in the study. At its heart, this is actually a really, basic study design. I joke but it's sort of like high school level science in terms of the study design. It's all the dogs get the standard procedure, standard surgery, standard analgesic anesthesia during the surgery, all that kind of stuff. So that doesn't change for anybody. But then we have three groups in the study, those that get all the standard stuff plus a placebo, and that's just an olive oil base with a chicken flavoring agent in it. I'll get into why we need that placebo group in a second. And then two different treatment groups and they're basically the cannabinoid formulation, so the CBD oil, at one of two different doses. So, we did some preclinical studies with our colony of beagle dogs. And we had... Initially, we didn't know what doses to use in these dogs. And when we first started this we had, we were basing this off some of the human literature.
0:44:52.3 DC: There was very little published at the time in the vet world about some of these doses and the highest dose that we had used had caused some neurological issues and I don't want the joke around the vet college was, "Oh, you got the dogs all stoned". Right? And that wasn't it. I don't think it's that terminology but it certainly did cause some neurological changes, predominantly something called hyperesthesia. So, the dogs would be a little bit slow to react to a stimuli but then when they reacted, they overreacted. So, whether it was somebody like waving their hand in front of the dog's face or a noise the dogs would it was a little bit of a delay and then they would overreact to an otherwise normal stimulus and it was pretty obvious in the dogs at that highest dose and we didn't think it was going to, it didn't cause any other issues for the dogs in terms of other health effects.
0:45:56.7 DC: But we didn't think this was something that owners would be willing to accept. And it was certainly getting to the point where it was beyond our comfort zone for the dosing. We had used two other smaller doses and in those cases, the dogs had not shown the same degree of neurological issues. Some of the dogs had very, very, had minor neurological changes but they were very subtle and that required a really trained eye to notice that. So that's how we kind of picked our doses for this study and before we could perform the study. So, it took a little while before Health Canada gave us approval to run this study in client-owned animals. And we had to demonstrate safety of these dose regimens that we proposed which was two weeks of CBD therapy given twice a day and we had to administer that same dose regimen to our beagle dogs that we have at the Vet College. And we had to assess them every day, physical exams, neurological exams blood work a few times over the two-week period to assess whether or not there were significant health concerns.
0:47:15.1 DC: That was a relatively small sample size. It was only 16 dogs but it was sufficient that we were pretty comfortable. Health Canada was comfortable that this was relatively safe and they were willing to let us proceed with client-owned animals. So that's how we got into the doses used in the study. So, we have a two milligram per kilogram CBD dose group and a five milligram per kilogram CBD dose group. So, three dogs come in, all of them get the standard analgesic protocol that consists of some non-steroidal anti-inflammatories which consists of a drug called Gabapentin. Typically, they will receive an antimicrobial for at least a couple of days after surgery as well. And then they either receive all of oil placebo or one of the two doses of the CBD product.
0:48:08.5 KD: And then they're... Remind everyone and remind me how they're evaluated, right? Because these guys go home and then they're evaluated by they the owners fill out something, right? And then their veterinarians.
0:48:24.6 DC: And Kelly, that was, to be quite honest, that was the hardest part of designing the study. And as we're performing the study, that's what where we're really seeing the challenge is that fundamental question of how do we know if this is working, right? So what outcomes are we going to look for? One of the reasons why we had gravitated to this orthopedic surgery model was our rehabilitation service at our vet college is phenomenal, and our rehabilitation veterinarians have the equipment and the familiarity for assessing the physical impacts of some of these changes in their patients. So, one way to saying it what's called kinematics or what is a pressure sensing walkway? So, the dogs walk across it's just a glorified mat. It's a really, really expensive mat with all kinds of sensors underneath it. And as the dogs walk across it they put pressure on it and that pressure is quantified.
0:49:22.5 DC: And then the computer captures all of this and we can go and see how much weight are they bearing on their limbs. Again, I'm a pharmacologist, this is way outside my area, but it's really interesting in terms of quantifying how the dogs are moving and what we're looking for then in terms of does CBD health is, are these dogs bearing more weight on that affected hind limb? So, it's always a cruciate ligament. In this case it's the hind limb, the right hind or left hind. And we do measurements at three times. We'll do it the day of the surgery before they get their pre-medication. So, these dogs are all lame but at varying degrees of lameness, we just use that as a way to kind of assess where they're at right before they have the surgery. So, some of the dogs actually move pretty well, all things considered other dogs they're hardly bearing any weight on that limb whatsoever. So, we just get that first measurement. It also helps acclimate the dog to the rehabilitation area and going on the pressure sensing walkway.
0:50:34.2 DC: They have the surgery that day. So that's all for the surgeons to deal with. The next day before the dog is released back to the owner, we will take the dog down to the rehabilitation area again. And that's where we really do our measurements. So, they'll go across the pressure sensing walkway again and remember this is the day after surgery. So, they're in pretty rough shape at this point in time. Say why would you want to test them the day after their surgery? You've just started giving them the CBD literally an hour or two before you walk them it can't have any effect then. No. But again what we're trying to do is figure out where they're at. Right? So, what's their lowest point after that surgery?
0:51:24.3 DC: But we don't just walk them across the walkway, the rehabilitation veterinarians. And now my graduate student will also do what's called goniometry which is flexing and extending the limbs to see how much movement there is. And after the surgery, I mean, these dogs are pretty sore and there's a lot of swelling inflammation. Now note they may not have a very good range of motion but that's to be expected. They just had surgery like literally the day before. We'll measure the swelling around the surgical site. So that's basically their stifle joint or their knee, measure the circumference of their stifle so how much muscle mass is there? How big is that leg? And then we of course, we weigh the dog. So, we're getting sort of a suite of physical measurements right after the surgery. That doesn't tell us anything about whether or not CBD is effective.
0:52:20.1 DC: But when those dogs come back in after two weeks and why we chose two weeks, because that's when they come back, the surgeons want to check the incision site, make sure the dog's doing okay, talk to the clients. It's just a convenient time for us to reassess them. We repeat all of those measures and what we're really interested in, what is the improvements from that day after surgery to 14 days after surgery? And do the dogs treated with CBD have more of an improvements versus the dogs that just had the standard analgesic regimen and the placebo. So, they all improve which is pure great news, right? Our surgeons do a great job, the other analgesics do a great job. So, all of the dogs improve. And to be honest with you I mean, I'm not a surgeon and seeing these cases come in, I'm like, wow, it's really dramatic how much they all improve but do the dogs that receive the CBD, do they improve more?
0:53:20.7 DC: So that's kind of our veterinary assessment. But the clients are a really critical part of this puzzle as well because what we miss on the veterinary side is, we don't see those dogs at home. We don't see what's going on. And it could very well be if CBD does have an effect maybe it's only within the first couple of days or maybe it's in the last week. And we can't really get that assessment because we don't see the dogs every day at the teaching hospital but the owners do. And so the owners do a scoring assessment. We modified it from arthritis studies and we had to modify it specifically for post-surgical orthopedic studies. But essentially the owners are looking for the severity of the pain and the interference of pain in sort of general day-to-day activities within the context of what the dog is allowed to do.
0:54:17.9 DC: So, following the surgeon's instructions. You don't expect these dogs to go to the dog park at seven days after major orthopedic surgery but how are they improving? Are there any adverse events that are occurring either due to the cannabinoids or just adverse events in general in that post-surgical period? And if I had to guess and it's far too early to say with any certainty but if I had to guess if there is going to be a difference between the cannabis group or CBD group and the placebo group it'll be the owner assessment where we see it. Maybe very well we will see a physical difference in force production and things like that. But if it is I suspect it's going to be fairly minor. The owners are going to be a critical part of the assessment of this study. But that introduces a whole host of other challenges. Anybody who's ever done owner-involved research is aware of but it can't be left out. I think it's really an important element of assessments whether or not the cannabinoids are helpful.
0:55:24.0 KD: Yeah, it's tough. I mean we've done a few things here and in Golden Retriever Lifetime Study, right? We rely really heavily on the owners and their evaluation. Well, I am looking at the time and we have had so much fun talking. So, two questions for you to finish up. First, when do you think your study is going be done based on how enrollment and things are going right now?
0:55:48.9 DC: We were hoping originally to be, we started enrolling in December of 2022. It was a long time with all the regulatory challenges and then getting all the funding mechanisms in place. But we just got our first cases in December of 2022. We were hoping that it would be about 18 months. And initially in our Morris grant application, we had estimated about 180 cases. Unfortunately, in the veterinary profession as a whole right now, a real shortage of veterinarians and our surgeons are just so slammed like every other vet clinic it seems, we haven't had the opportunity to cut as many of these cases as we had, especially before the pandemic. So, we're not enrolling as many cases as we had kind of liked to enroll. There's other factors as well. Some we had predicted some, some less so. This week we had a case just on Monday, thought great, it's a local case.
0:56:45.0 DC: The owners were really excited about the surgery. We thought for sure they were going to enroll. Turns out it was a dog that nearly ate the attending surgeon and couldn't be handled unless the owner was in the room. I don't think our liability insurance covers that if my grad student gets mauled. So, unfortunately, that one with temperament was not a great fit for our study. We've had a few instances like that or owners from out of town who couldn't come back for a recheck. But hopefully, if we can keep ramping up the enrollment we're thinking, mid 2024 or late 2024. And if we don't get the full 180 cases that we had originally planned, at least do a preliminary assessment, see where this is going. And if it's worth continuing the trial beyond that point. But a two-year window is what we had originally envisioned. So, end of 2024.
0:57:38.3 KD: Sounds... That sounds great. So, as we finish up, what's your kind of take home message for people listening which again is going to be our donors, supporters, veterinarians, vet techs, et cetera.
0:57:51.5 DC: So, I guess there's a couple take home messages I had specifically for the broader veterinary community and not so much about my particular study. I love talking about it but honestly it's just a small piece in the broader cannabinoid puzzle. The bigger things are, I, there's some good evidence for CBD usage but in my estimation it's not conclusive. And I don't I get really reticent when I hear veterinarians or owners jumping on the bandwagon, so to speak. For CBD I think we need to be still a little bit skeptical on this but I also don't want to go, it's just all snake oil. I think there is some really promising areas for its usage but we need to know more specifically about dosages and product formulations. That leads to my second big take home message, which is looking at some of the literature, some of the groups doing these studies, a number of us have found very consistent results. And I want to say a shout out to the groups at Colorado State, some of the groups in Florida, Cornell University, working with things like Ellevet, folks in Auburn. We've got generally comparable kinds of results.
0:59:00.2 DC: I think Washington State as well. And for the products that were used in those studies, I think there's some consistency and clients maybe have, would have more confidence in those products. We've seen other studies published with results all over the map in terms of plasma concentrations, in terms of effects. And where that take home message is you can't be switching between products or dosages willy-nilly because some products required whopping high doses to get plasma concentrations that we observed at relatively low dosages. And you'd hate to have somebody switch to a, for lack of a better term, more potent formulation and then find out that their dog has 10 times higher cannabinoid levels simply due to differences in product formulation. There's other factors that go into that as well.
1:00:00.1 DC: Things like feeding status. So, for owners, administering the medication consistently either if it's in a fed state that's fine or a fasting state but there's big differences in bioavailability in terms of how much drug gets absorbed. In the fed State it's usually a lot higher so don't be kind of going back and forth. These everybody's, oh, it's CBD, it's all kind of the same. It's not the same. They're not interchangeable in terms of the products or the doses or the dose regimens. So really try and keep it consistent. And for the clients, it's you know talk to your veterinarians about this. They're not going to be prescribing it per se but they can give you some good advice on usage of cannabinoids.
1:00:45.1 KD: Well, that is really, really helpful. Well, thanks so much. And that does it for this episode of Fresh Scoop. Once again, I'm going hopefully get your last name right. Because we had a big discussion about this before we start. So, Al Chicoine. Yes?
1:01:00.9 DC: Yes.
1:01:01.5 KD: Yeah. We had a really fun time talking about this, and thanks Al again for joining us. We'll be back with another episode next month that we hope you'll find just as informative, the science of animal health is ever changing and we need cutting edge research information whether we're treating patients as veterinary caregivers or as pet parents. And that's why we're here. You can find us on iTunes, Spotify, Google Podcast, and Stitcher. And if you like today's episode, we sure appreciate it. If you could take a moment to rate us, because that will help others find our podcast. To learn more about Morris Animal Foundation's work, go to morrisanimalfoundation.org. There you'll see just how we bridge science and resources to advance the health of animals. You can also follow us on Facebook and Instagram. And I'm Dr. Kelly Diehl, and we'll talk soon.
