Good evening, everybody, and welcome to tonight's webinar. My name is Bruce Stevenson, and I have the honour and privilege of chairing tonight's session. It promises to be a good one and I'm sure we are going to have some lively debates and questions afterwards.

So, little bit of a change of format tonight. We have 3 speakers on. The two main presenters, and then, we will have Michael on at the end, doing a little bit of legal stuff as well.

So our two speakers tonight. The first one is Steven Sitel. Steven originally started college to become a registered human nurse, but decided he much preferred working with pets than with humans.

So instead, Steven became an RVT and then obtained certification as a surgical research anaesthetist. Steven also holds a VTS credential in research anaesthesia. He's well recognised expert in the use of CBD and hemp-based cannabiid terpine products in veterinary medicine, speaking over 20 major conferences each year.

In April 2020, he has been invited to give several lectures at BSAVA. Steven is the director of education and development at Elit Sciences, which is a US based company that leads the way in hemp CBD research for companion animals. Elit was the first company to publish peer-reviewed safety, pharmacokinetic and efficiency studies using their unique hemp CBD extract in the dog and the cat.

So Steven is gonna start off for us and then he will hand over to Joseph. Doctor Joseph Westlack started his academic career receiving a BS and an MS from Montclair State University. He then attended Cornell College of Veterinary Medicine, graduating in 1998.

He continued his residency training in both pathology and nutrition, as well as receiving his PhD in pharmacology in 2005. He became a diplomat of the College of Veterinary Nutrition in 2008 and furthered his board certification as a diplomat in the College of Veterinary Sports Medicine and rehabilitation in 2010. He was an associate professor at the University of Florida in integrative medicine and nutritional Sciences.

And his background in sports medicine has produced many publications on working dogs, obesity, science, canine cancer cell biology, and arthritis management. He is currently the professor at Cornell University of Veterinary Medicine and recently joined the LA VET team as Chief Medical Officer to oversee their research and clinical trial programme. Gentlemen, welcome to the webinar vet.

And Steven, it's over to you. Thank you so much. I am so excited to be doing this webinar for everyone tonight.

I know this is a very hot topic, and to start that off, I think we need to kind of cover some of the bases and, and get a better understanding of this kind of panacea effect that we're seeing with people wanting to use cannabinoids from the hemp plant, in particular CBD. I think we've all encountered on social media, on our TVs, on the internet of, of, of some form, people wanting to use these chemicals, these molecules from the hemp plant for just about everything. And as Exciting as this, this research field is and this industry is, we do have to be careful because there can be indications where certain cannabinoids might not be the best option for some of our pets.

So at Elevet Sciences and through Elevan. We have really strived to be one of those companies to put science first and really prove the therapeutic value of some of these cannabinoids and certainly the safety that comes along with using different chemicals introduced into the body. I think this is a really interesting paper that came out not too many years ago looking at some of the research behind some of these, these molecules from the hemp plant, in particular CBD, and we see a large interest in CBC as well for all kinds of different conditions out there.

To understand where these molecules are working, we have to understand that there's this G protein coupled receptor system in our bodies that has been around for aeons. It's, it's evolved with us, from when we're single, single-cell organisms all the way to our, our mammalian friends today, and it's known as the endocannabinoid system, and the endocannabinoid system is comprised of two receptors known as the CB1 and the CB2 receptor. And as I mentioned earlier, these are G protein coupled receptors.

So these are the same type of receptor that we're familiar with, such as the opioid receptor, the serotonin receptor, the dopamine receptor, except our body as mammals has many more times, the amount of these types of receptors compared to the These other forms of G protein coupled receptors. The other thing that we have to understand when we're talking about the endocannabinoid system is we produce endogenous ligands, and we're going to cover that in just a second. But when we're talking about these molecules that come from the hemp plant, we have to understand that there's much more out There than CBD and THC.

In fact, there's over 100 different, what are called phytocannabinoids, meaning they come from the, the, a plant versus an endogenous cannabinoid that comes from the body. There's several different kinds of these cannabinoids, all with their own therapeutic benefits. And then we're also going to dive into a little bit.

Other sets of molecules known as terpines, which add the, the aromatic component to these types of products. Going back to the classic CB1 and CB2 receptor of our endokenabinoid system, we have to understand that our CB1 receptor is our most prolific receptor that we have. And it is mostly found in our CNS, so our central nervous system.

We see a lot of these types of receptors in the brain, in particular in the dog, especially compared to a human. That's why we see some of the sensitivity when those particular receptors are agonised by that famous psychotropic molecule known as THC. CB1 receptor is the only receptor that's really gonna produce this psychotropic effect when we have the introduction of THC, but that's largely not an issue when we're talking about the Eevans product because THC has been removed from this particular product.

When it comes to the CB2 receptor, we see this more in the periphery, and we certainly see this on certain immune cells, in particular glial cells, and it's a little bit of a more difficult target to hit with these phytocannabinoids, and that's really where the utility of these other molecules known as urines comes in and kind of saves the day for us. What's interesting about the endocannabinoid system is this is typically not a system that is taught in veterinary school and a veterinary nursing programmes, but there is a, a good body of evidence out there looking at these specific receptors and how these endogenous and exogenous. Molecules work on this particular system.

There are over 23,000 published papers looking at these different receptors and these, these different molecules on this particular recept on this particular receptor system, excuse me. And what's interesting about this is we are getting more and more data showing endocannabinoid system receptors in particular areas of interest for pharmaceutical or medicine or even supplement type products out there, in particular, the the dorsal root ganglia, which we know is a really important anatomical site for the modulation and, and first signalling before we go into the spinal cord for, in particular, pain signalling. What's also interesting about the endocannabinoid system is we used to think that this was a fairly a more simple system comprised of the CB1 and CB2 receptor, but we, what we now know is it's really this endocannaminoid home.

So this, this bigger picture when it comes to The affinity for these phytochemicals coming from the hemp plant and certainly our endogenous ligands on other receptors. Other receptors, as I mentioned earlier, other G protein-coupled receptors known as orphan receptors, we can see 3 of them labelled here. We have GPR 18, GPR.

5 and GPR 119, as, as well as our opioid system receptors. We also have other receptors outside of these G protein, type receptors known as our TRIP receptors. So we have TRIPV1.

We also have TRIPV3 through 5 where we see affinity of these phytocannabinoids. We also see affinity at our glycine receptor, which is particularly interesting not only for analgesia, but for some, seizure or epileptic type conditions as with our GPR 55. And then we have other receptors known as nuclear receptors, which are gonna be really important when it comes to other pharmacological and physiological actions, in particular, things like, cancer and immune expression.

Those are known as nuclear receptors, Part alpha, and gamma. So, if we have a set of G protein-coupled receptors, as mentioned, CB1, CB2, to validate the system, we hopefully have endogenous ligands, and we have it in the literature so far, at least 5 described to us as known as endogenous cannabinoids or endocannabinoids. And the two most popular.

Endocannabinoids that we are aware of and, and really have a lot of scientific research behind are known as anandamide and 2AG. 2 AG is our most dominant endocannabinoid that our body produces. It's, produced 200 times more compared to anandamide.

But anandamide seems to get a lot of the attention in the media, and I think it's because people can Actually pronounce this word. It's also a nice little, Sanskrit word for the word bliss. So if we think about what the endokenanoid system does and what happens when we, expose our bodies to things like THC in a controlled setting and appropriate dosages, we can kind of get that euphoric or that, that, psychotropic effect that people seek out at times.

So, Some really interesting discoveries and all of this is all kind of been discovered within the last 40 to 50 years. So it's still pretty new to us as medical professionals and certainly science. OK.

So when we start to hear people interested in using phytocannabinoids to alleviate, cure, do all kinds of crazy things in their bodies, whether there's scientific evidence to back that or not, what they're Really bringing this back to is this thing known as the endocannabinoid system tone. So I think we're all familiar with taking different supplements, different vitamins, eating, appropriate food to support the body and its healing process. What we have going on with the interest of using these phytochemicals are people feeling depleted or, or feeling that their endocannabinoid system may need this extra boost.

Maybe our body is not producing enough of these endogenous cannabinoids, things like a nanomide and 2 AG. Maybe our body is not producing enough of these enzymes that help break down these phytochemicals to turn into other molecules that our body uses for, different physiological processes. Or maybe we have kind of a mix of both, and we know that things like chronic stress, we know that things like chronic pain and other conditions can certainly put extra strain on the endocannabinoid system.

The end. The system in general is activated when the body is out of, out of balance. So by and large, when we're adding these phytochemicals into a patient, into ourselves, we're trying to bring the body back to homeostasis.

The body always wants to be balanced, and that's what these particular sets of molecules are doing for us. And that's known as the endocannabinoid system tone. One thing that we have to be familiar with when we're talking about these phytochemicals, the, the molecules from the plants such as CBD or THC, as, as this example shows is we don't have typical affinity for things like CBD the same way THC sits on these endocannabinoid system receptors.

THC will sit On the CB1 receptor, or rather I should say sit in the, the CB1 receptor, as a full fitting key. And when we have this full agonistic effect in the CB1 receptor is when we get those psychotropic effects. What's interesting about THC, again, not something that we're really worried about when it comes to the elements product cause it's been removed.

I THC is actually 11 times, has 11 times the affinity compared to our endogenous ligand. So it's a very, very powerful molecule at the CB1 receptor. Whereas CB1 does not necessarily sit in that receptor the same way THC does, but instead sits on the outside and does this, this type of modulation called allosteric modulation to turn on or stimulate the CB1 receptor.

And get more of the positive effects without that psychotropic effect that you can see with THC. What's interesting about these phytochemicals, in particular CBD. As we hear a lot about how CBD is anti-inflammatory.

When we think about anti-inflammatories, I think our general perception is the pharmacology or the MOA with non-steroidal anti-inflammatories. But when we actually look at the data and some of the COX inhibiting effects of CBD specifically, you can see in this chart that CBD is itself not very good at COX inhibiting effects, compared Compared to some of the other phytochemicals that are out there, in particular CBDA, which is about 50% of the, the solution that you find in Evans. And this is interesting because this actually is COX inhibiting, which may be beneficial for, more beneficial for some of our patients rather than just the homeostatic properties that we see with CBD itself.

You'll also note that, some of the, the little acronyms here. THC, THCA, CBDA, CBG, and CBGA, the A at the end of those acronyms means it's an acidic form. So that means that this molecule has not been decarboxylate.

So it's maintaining a carboxyl group. It's very, very similar to the, the, what I call the adult forms of these molecules, but does have that little extra tag on it that can make them work different and, and affect our physiology a little bit different than these mature forms. What does CB CBD do for us as far as anti-inflammatory effects or this perceived anti-inflammatory effect?

As I mentioned earlier, our body creates these endogenous ligands known as 2. And then to the arachedonic acid. I am so sorry.

I know we're not back in 2nd year of, of vet school or nursing school where we're having to learn this inflammatory cascade, but we see arachedonic acid, and we see these arrows pointing from 2 AG and anandamide. And under those little arrows, we see MAGL and we see fo, which is fatty acid amide hydrolase. And these are enzymes that actually break.

Take down these endogenous ligands, these endocannabinoids, and they turn them into a acheddonic acid. What CBD is doing for us and some of these other phytochemicals are actually preserving and slowing down the degradation of endogenous ligands, those those endocannabinoids from turning into a acheddonic acid. It doesn't take a huge leap of logic to understand if we can slow down the degradation of these endogenous ligands from turning into arachidonic acid, we are therefore slowing down and decreasing some of the inflammatory cascade that we see with the genesis of erectonic acid turning into these different prostaglandinnoids and acacinoids.

What's interesting about this is because these chemicals are working at such a high level in this inflammatory cascade, we see a much larger therapeutic index, so safety of these phytochemicals. This is one study looking at THCA. Compared to traditional non-steroidal anti-inflammatories, things like ketorofen, ibuprofen.

Obviously, this is a, a human study, and we shouldn't be using, things like ibuprofen in our small animal friends, but it does show the safety, the therapeutic index compared to some of our traditional non-steroidal anti-inflammatories. Joe will talk about this a little bit later, but we Also see really good effects when combining these phytochemical, CBD products with non-steroidal anti-inflammatories as well. And we don't have the same concerns with mixing two non-steroidal anti-inflammatories, together, because of the different mechanism of action with CBD and CBDA compared to our traditional non-steroidal anti-inflammatories.

What's important about all of these different receptors I'm talking about, all these different, inflammatory pathways I'm talking about is we understand veterinary medicine today that it's important to have multi-modal approaches. We understand that giving a huge dose of methadone or morphine or a huge dose of paracetamol. Might not benefit our patient as well as smaller dosages of multiple, different molecules, pharmaceuticals, such as non-steroidal anti-inflammatories, opioids, and whatnot.

What's interesting about these hemp products, especially when they're not an isolate product, which have been found to be less effective compared to complete spectrum products, is because we have a multi-dimensional, multi-molecular product. All in the same bottle, we are actually creating and giving a multimodal, approach to, to aiding in, different conditions for these animals. So I think it's a really interesting, not necessarily novel, but to us in the sense that it's, it's only become popular again, a way of helping our patients.

OK. Mentioned earlier, a term known as terpines, and terpines are these molecules that also come from the hemp plant, and they add the, the aroma, that you are going to experience when you try the Elevans product. And what these terpines do.

AKA essential oils, is, they not only add smell, they can add a little bit of flavour, but they also have their own therapeutic value. These terpines that are up on the slide are the most common terpines that we see in the Elevans product and certainly the elevate product in the United States. And you can see some of the pharmacological and therapeutic activity from these particular terpine.

Mersine is one of my favourite, terpine, not only because it comes from hops and hops makes beer, but we also see bursine come from mangoes, which happens to be one of my favourite fruits, but Merssine itself can actually be antagonised by naloxone and Yoheb. And so if something can be antagonised by naloxone, it is likely that this particular molecule is likely working at our opioid receptors. We also know that if it could be reversed with Yohembean, it is probably working at some of our alpha 1 and alpha 2 receptors, which we know can be associated to decreasing pain scores in animals.

Beta carophylline is a very common terpine, kind of a, a spicy smell. Beta carophylline is often found in black pepper. And beta carophylline is really interesting because it works very similarly to CBD.

It's actually known as a dietary cannabinoid, and also has some therapeutic benefits. Such as an anti-inflammatory. Usually, when you get beta caroline, you have heparin involved as well, which is also good for kind of helping, clean the liver and, and make the liver happy for us, which is important as we metabolise these certain sets of molecules.

And we have things like alpha pinine, which is also an anti-inflammatory, but also a bronchodilator. Other common urines that we've seen a lot of hemp pro products and certainly are dominant in the elements products are things like Liul. I think we're all familiar with the stress relieving or anxiety relieving effects of the lavender smell.

That's why we have lotions and face creams and candles and all kinds of things that smell like lavender. Because just by sniffing these things, by, by picking up these molecules, Through our mucosa in our, our nostrils and whatnot, we can actually get some of these therapeutic benefits from lavender. We also know that lavender, it's super high concentrations can actually be used as an organic pesticide, which is nice.

So it's super high concentrations. We know it can actually be, cleaning as well as with lemonine, which is, a very common terpine that we see in not only stress relieving or antidepressant type, products for us out there, but also a lot of our, our cleaning, supplies out there adding to that nice smell, and we know that this is a really safe turpine for us. That's why we see so many, companies advertising products filled with lemonine as safe to use around children and babies.

It's really interesting things coming from these turpines. What these turps help do is create this effect known as the entourage effect. And the entourage effect is essentially a potentiation or, or synergy between not only phytocannabinoids, things like CBD, CBDA, but also those terpines, and then certainly we have some interplay with our.

The ligans, known as our endocannabinoids, and certainly some of our enzymes. When we have all of these things put together, it creates a better effect. It creates this thing called the entourage effect.

And some people I know get a little bit weary about this term because they've never heard about it in their pharmacology, courses. They maybe you've never heard of it in general, but what we know is the entourage effect actually happens within our bodies, even without the addition of exogenous molecules, things like the urines and the phytocannabinoids. We know that our endocannabinoids, have other sets of molecules, things like, PEA and OEA with our endogenous, ligands can create this entourage effect itself, especially in inflamed tissues.

So, when we're talking about cannabinoid toxicosis, I, I think the first molecule that comes to mind is certainly THC. Again, this is not a concern when it comes to Elevans product because this has been removed, for UK standards. And what we have to understand that THC in general, if we were to come across, a THC product, is it is really, really Difficult to kill an animal with THC itself.

We have studies in the 60s and the 70s where they were giving greater than 3000 milligrammes per kilogramme of THC intravenously, so we're not worried about by first pass from the liver, intravenously to dogs, non-human primates, and other species, and it would not kill them. Where we do see toxicity and, and potential lethality. It's certainly when it is co-administered with other contaminants such as chocolate.

So when we have the the roaming toxicity with the TH the THC toxicity compounding each other, we can certainly see more room for concern and certainly death. And then we also have concern with other ingredients that might be used. In edible products that pet odours might have around the house, such as raisins or even Xylitol containing THC products.

So when it comes to the LD50 or the, the actual concern of these cannabinoids in killing something, we don't have an established LD50 for THC and we certainly don't have an LD50 for CBD at this point. One concern that we hear all the time from practitioners and certainly, pet owners is what are the long-term effects of Saying products like CBD or CBDA. And we do have some really critical, studies out there that have been published.

This particular paper was from 2017. It was actually, funded by GW Pharmaceuticals, for a product you guys might be familiar with, known as S C Tex. And what they did in this, in this particular study is this is a 56 week long study.

That's a long time for any veterinary study. Most veterinary Studies are anywhere from 12 to 28 weeks. This one's 56 weeks, where they were giving dogs and rats.

Our focus will be the dogs, almost 25 milligrammes per kilogramme of CBD and almost 25 milligrammes per kilogramme of THC. Those are extremely high dosages, probably not dosages we would use, in most clinical settings. But what they found over this 56 weeks after the 4 weeks.

Acclimation period is the animals, the dogs in particular that we're getting that much THC and certainly the CBD, we're certainly building a tolerance to the THC, which is something that is appreciated in human and animal models, which is not found with CBD. We don't see a tolerance built up to CBD so far in the literature. Is the animals did great, during the 56 weeks.

We didn't see any major physiological concerns with the animals getting these super high dosages for 56 weeks. It should also be noted that GWB Pharmaceutical also did a 39 week study with a CBD isolate product at 100 milligrammes per kilogramme for 39 weeks in dogs, and again, saw no serious detrimental effect to the animals getting those high dosages for such a long period of time. Joe, I'm gonna hand this over to you.

This is about our twelve-week study. Yeah, and I think that's always one of the major concerns for us as veterinarians. So thanks, Steven.

I think we have to get a little bit deeper into this, from the hemp perspective, and, this is a, a study that we did, basically through a contract research laboratory where we actually looked at the pharmacokinetics of our product, which is a, a, cannabinoid rich hemp product, primarily CBD and CBDA as Steven has said. And we found that if you look over, it's hard to see here, but in terms of the overall biochemistry, we found no changes over a twelve-week period of time in either dogs or cats. And so we feel that it's relatively safe, but we know that there is due diligence.

This is something that we probably should be following just like our typical non-steroidal anti-inflammatory by doing blood work on a regular basis. It was also nice to see in the study that we had quite good bioavailability of our CBD. In our dogs and cats had about half the bioavailability, so I think there's still some work to be done on cats.

You could go to the next slide, Steven? Sure. That kind of, was, a, a, a study that we had done, after we had done this actual study on osteoarthritis, and this was done about, over 2.5 years ago now, where, we actually did some basic pharmacokinetics on dogs and then we looked at the actual, effect on osteoarthritis.

So we recruited a number of dogs for this study. To, really look at the pain relief effects that we, could, could really detect from owner respective surveys. So if you go to the next slide, we'll kinda go through this, one by one, Stephen, and we can kinda give the folks a, a good overview.

Absolutely. There you go. So this is our, our clinical trial.

We actually enrolled 22 dogs and 16 actually completed. There was no adverse effects that we could really see from, from giving this on, on a daily basis twice a day. You can see on the chart there, these were the dogs and their average weight, sex and their quote unquote worst limb, that we could detect on a, on a force plate.

We definitely did our radiographs to identify the fact that most of these dogs have multi-joint osteoarthritis. They could be kept on their non-steroidal and be enrolled in the study, and we had 9 dogs that were on NSAIDs while being given, the LA vet or equivalent of Elevanse product. We basically saw, no, no real differences in, in their overall blood work which we'll, we'll go over in a minute.

But this was in a crossover design, just because we didn't want any dog to not have the potential benefits. So we did a 4 weeks on either placebo or on the actual hemp-rich nutraceutical or supplement. And then we did a two-week washout and then switched them over to the other arm of the actual study.

We did our vet paying gate reps analysis, so that was myself and my colleague here at Cornell, CBC's chemistry, and of course, we did the validated canine brief paint inventory as well as Hudson activity scales. So next slide, Steven. And these are our canine brief pain inventory scores on the CBD oil or placebo versus the total Hudson activity scores, and you can see in both of these instances, the overall pain and activity index decreased from the CBI while on the actual CBD oil, and we saw no real changes in the placebo group.

Which was quite encouraging that it was also recapitulated in Hudson activity scores, which is actually a radiographic correlate for activity that's been been shown in the literature by Hudson colleagues. And so you can see that the activity in the dogs went up and that was one of the more remarkable things is, is that we had a really nice response rate, particularly in the older more geriatric dogs who had multi-joint osteoarthritis. And so, it was really quite encouraging to see such such nice changes in scores.

That said, move on to the next slide. And I think this is actually somewhat remarkable for us is that we actually saw some changes in, in overall disposition while in the clinic. The dogs seemed to be easier to, to actually manipulate.

They showed a little bit less pain on manipulation, so we saw some changes in their pain scores while on the CBD oil versus well on the placebo. However, we saw no changes in in their overall crepitus and their, their gates were the same, but I think this is a, a testament to the fact that if, if we're not alleviating pain minimally, we're actually changing their disposition in, in the clinic, which is actually something that we probably should have addressed through a behavioural study as well. So that said, next slide.

Yeah, this is one of my favourite quotes from Doctor Ethan Russo, who is known as one of the foremost cannabinoid researchers out there. Interestingly enough, he's a human neurologist. His, parents were both veterinarians and his brother is actually an internal medicine specialist in, in the United States, a veterinarian also.

And what he says is cannabis and insert the word hemp there is a heterogeneous botanical mixture, and the results from one study cannot be applied generally to other plants or products. And the reason we bring this up is because Elevance's product and Elevan Ellevvet's product is, is so unique in the sense that it's about 1 to 1 of CBD and CBDA. And that's not a typical formula that we see with a lot of product on the market today.

So when we read studies that are coming, from Lev. In the United States, we have to understand that we can have some extrapolation, but we can't necessarily assume that we're gonna see the same efficacy that we, might try to get from using a different product. And just going back, Joe, when we're, we're talking about some of these pain scores, can you tell us about some of the people involved, such as the faculty that were assessing these animals, being included in the study and what that means for caregiver placebo?

Yeah, and I, I think that was sort of one of the more unique things about our study, and I think a lot of the academic studies that that are done is that we tend to enrol veterinary students, veterinary technicians, as well as veterinarians into these studies, and of course, there's no shortage of dogs with osteoarthritis, who are geriatric, so, those folks. Tend to be a little bit, I think, more true to themselves in terms of, of the actual scoring. So I think the placebo effect is just definitely lessened in in in this environment, and so I think that's why we didn't really see any true placebo effect, and the dogs were on the placebos cause folks were trying to be as honest as they could be.

We, we had one young lady who came in after treating her dog for a long weekend as a vet tech thing, you know, that her, her dog had jumped on the bed for the first time and followed her upstairs, you know, she was crying. So there's, there's definitely a nice subset of dogs that that really do respond quite well to this. That's awesome.

Thanks, Joe. All right. Some of the other areas of interest right now, are dermatological conditions.

These are two studies that we're looking at the expression of endocannabinoid system receptors, in dogs with atopic dermatitis, and then we have cats with hypersensitivity dermatitis. So there's a lot of debate right now kind of going on with the best form, to maybe help with these types of conditions and certainly there's people interested in, in transdermal formulations and certainly some debate with whether we should be using systemic formulations, orally and we're, we're really excited here in the United States. We're actually doing an atopic dermatitis study using products.

With the CBD CBDA to see if this is gonna help with the pruritus, with dogs with atopic dermatitis. And what I think is really interesting about these particular studies are some of the graphics that were in the study. So, these graphics on the, the left-hand side, we see what's normal expression of our endocannabinoid system receptors, our CB1, CB2.

And then our one of our nuclear receptors, P for alpha, in normal cat tissue. You can see that highlighted with the, the green staining there. And then on the right-hand side, you can see overexpression in inflamed or irritated cat dermal tissue, where we see this proliferation of these endocannabinoid system receptors.

So we see Innocannabinoid system being active in almost everything we do, and hopefully by, by supporting the innocannabinoid system and all these new receptors that are popping up, with these phytocannabinoids, we can hopefully get this under control and that's what we aim to prove in some of our studies coming up. Joe has done some really awesome in vitro work with different cancer cell lines. Joe, do you want to talk about this?

Yeah, sure, Steven. This is actually some cancer cell work that we got some funding from the AKC Health Foundation to examine. Basically, if you look at the upper right hand graph there, those are the five different cell lines, varying from round cells to osteosarcoma to breast cancer cell lines.

And it was kind of interesting because we actually got pure CBDA and pure CBD in and of themselves and looked at its cytotoxicity. And, and what you can see is that if you remain around 100, that means you're not particularly cytotoxic even if you go to a higher concentration. You can see with cannabidiol that that at around 2.5 mcg per mL, roughly to about 5 is where we have we'll call the IC 50 inhibitory concentration 50% and That was pretty interesting from our perspective, and then we wanted to actually look at the, the actual Elevan product in the cell culture.

So we got the extract and then put that in. And what you can see is that our our entire curve for all the cell lines kind of moves to the right a little bit. Where IC 50 basically goes down 50% across all the cell lines, and so whether that's the effect of, of both CBD and CBDA alone, or whether it's the effect of the entire plant extract, including the urines, is, is really hard to decipher, but there's a definite shift towards a more cytotoxic potential when you have the whole extract alone.

Yeah, really interesting. I think that's a good argument, Joe, for the entourage effect, and I, I'm really hopeful that keeping these molecules together, is the best thing and it so far it seems to, to show so. Would you not agree?

Oh yeah, surely, Steven, I think this is what sort of convinced me of this, this entourage effect and this sort of synergy between molecules. We, we talk about synergy all the time and oncology and something you look for, so, yeah, awesome. All right.

So, cytochrome B450 is an area of interest for a lot of practitioners out there and, and what the potential for drug interactions might be. And the reality is, is we have a lot of theoretical inducers or inhibitors of this CYP 450, that are creating different enzymes that are important for metabolism of different drugs, different nutrients, all kinds of different things. And even though we have these theoretical drug interactions.

The work so far in companion animals and even humans is not showing, this manifestation in the clinical setting. So, we do have certain, medications that we tell owners, hey, when you give this Elavanse product with things like tramadol or gabapentin, We may see that animal be a little bit more sleepy or lethargic for the first couple of days, and that's a small percentage of animals. And what we tell people is that could potentially be potentiation, maybe this cytochrome B450 interaction.

But what it also might be is that animal might be, might have been uncomfortable still, even on those traditional analgesics. And when we add this extra support with CBD CBDA. I think we might be able to take some of that edge off so these animals are not sleeping the first couple of days because of a drug interaction.

They might be sleeping because they're actually more comfortable and they're catching up on quality sleep that they weren't getting on just the single pharmaceutical that they were on before, or maybe they just needed that extra little, push to get. Them more comfortable. So we have to be concerned about drugs and potential drug interactions.

The reality is, is we just don't see this manifesting, like the literature might suggest to us, and we expect to see some studies out of Auburn University within the next couple of years, specifically speaking to this. It's also important to note that we've had a couple of studies. So far, in companion dogs, where they were on anti-epileptic drugs, and anti-epileptic drugs, particularly phenobarbital, we expect to have some sort of cytochrome P450 interaction.

And again, we just did not see this manifest. In fact, Auburn University, as I mentioned, And they are taking blood samples of animals that are on traditional anti-epileptic drugs and CBD products and looking for this, this, change in either the, the pharmaceutical drug or CBD in these blood concentrations. And again, it's just not happening like we thought it might occur in real life.

Joe, this one's you. Oh my gosh, that's, that's our president. Sorry, yeah, this is a very strange, strange world of hemp extracts.

It's very exciting, but there's a lot of, we'll say misinformation out there, particularly with the idea that that CBD isn't absorbed, and I think A lot of this comes from some of the older literature where they were giving it in a, in a dry capsule form rather than with a food or an oil matrix. It's been very well proven now that that CBD is absorbed better when you give it in a high fat meal. It's been shown in rats and people and I think we've actually just now shown it in dogs as well as some other groups have shown this too.

And I think what we have to also start thinking about is, is that maybe it's not just about CBD, maybe it's about CBDA, maybe it's about CBG, maybe it's about some of the other cannabinoids like CBC. So there's a, there's a whole raft of cannabinoids and different profiles. I think we're just at the cusp of really learning about a lot of this stuff.

And then of course, the CBD is this the best for pain relief. I think Steven's kind of gone over the idea that CBDA may also have its utility as well. And so I wanted to go over a little bit of work that we just did in pharmacokinetics.

So Steven, next slide, please. So we actually had 6 beagles, and we actually looked at serum at 1 in 2 weeks out of twice a day dosing to look at the whole variety of different cannabinoids, primarily CBD and CBDA because of those are the two that we were most interested in. We had our typical oil that, that we, have already marketed and then we'd have a new lipid emulsion that we were developing as well as the soft chew that we already have.

And then we did a transdermal form which is done at a slightly higher concentration of 4 Migs per gig in dogs along the pinna. So we basically, when we gave the oral forms of this, we had a half a quarter can of food when we administered the oil, twice a day. And then they were given their daily meal an hour after administration, and we looked at a whole variety of different cannabinoids here.

You can see we looked at CBD and CBDA which are the ones we're gonna focus on, as well as two metabolites of CBD that are very often found in, in people. However, we really didn't see high concentrations of that, suggesting that dogs actually metabolise it slightly differently. That said, next slide, we'll show you the graphs here of our CBD and CBDA.

That were in the bloodstream at week 1 and week 2 on the two different oils which are oil A, B, as well as the chew, and then our transdermal. You can see that I have a red line for both of these graphs for the CBD and CBDA which is 100 nanograms per mL, and the blood was taken 6 hours after their morning dose. At the week one and week 2 time points, and you can see we're above 100 nanograms or at least surely above 50 nanograms.

And that's what we think right now, and I can't say this for sure. We think that's probably very close to a therapeutic dose. And you can see between CBD and CBDA if we were to add them together, we are surely above 100 nanograms.

And we can also see that this oil B, this new emulsion that we're creating is actually slightly better, particularly for CBDA absorption. So we may get that slightly better anti-inflammatory effect from the CBDA. And what I will tell you is this is actually the first data to actually show that CBDA does get into the bloodstream as CBDA because a lot of the previous literature out there suggests that CBDA probably would turn into CBD.

But the technology to actually measure some of the stuff in the serum just wasn't there just 10 years ago. And we're really finding that all these cannabinoids tend to be absorbed independently of one another and don't have a whole lot of biotransformation in vivo. Next slide.

So, I just wanted to give you some credit really quick. I think this is really amazing that we have this, these, these serum concentrations of CBDA cause I believe you're the first researcher and, and certainly the first product to really show that we do get absorption of these acidic forms, which is I think really critical and kind of groundbreaking. So I think this is awesome work that you're doing and very, very excited about it.

Yeah, no, I mean, I think all of that's really making a good stab at trying to do all the right things here and trying to understand exactly what's happening in dogs, and, and in cats. And so, I mean, I think we still have a lot to learn, right? We, we still have a lot to learn about, CBD and CBDA and how they may interact together and how 1 may help the absorption other potentially.

We know that we need food to help get these things absorbed and that we know that it has the ability to mitigate some pain, which, of course, our mechanisms still need to be figured out for sure. Safety, of course, needs to be done, Steven. We still need to do a longer term study or somebody needs to do a longer term study on old dogs.

I think we can both agree on that and . Plenty of areas of investigation that are ongoing right now. We're looking at acute pain, in the TPLO model, post-knee surgery.

We're looking at idiopathic seizures, we're looking at quality of life during chemo as well as ectopic dermatitis, which, I think it was due to yours and and the leadership at Evette slash Evan that's really leading the way in this area. So yeah, very exciting. I am so excited that we have has have disproven this long held myth about gastric conversion of, of these of these acidic forms.

We still see this in the literature today where people haven't necessarily caught up on their literature reading and particularly your study, showing that this doesn't happen in the stomach. It's very, very exciting and then certainly you know, it was hard for me to swallow, no pun intended. Understanding that these molecules get absorbed better with food.

You know, I used to be one of those practitioners that would say, we need to hold it under the tongue or hold it in the cheek to get absorbed, hopefully trans mucosally when, in fact, it's, it's actually the opposite. Get into the stomach quicker with a fatty meal and we'll get better uptake. So really interesting stuff.

Thanks. Absolutely. OK.

So, we talked about the bioavailability of some of these products and, and certainly getting CBD CBDA into the bloodstream to hopefully interact with our innercannabinoid system and all these other receptors that have affinity, . For these phytocannabinoids, but what I think is also really interesting, especially for animals that have things like irritable bowel disease, chronic colitis, that type of thing, is we actually have these endocannabinoid system receptors in our GI. So, I, I think it's really, really important to get good PK data to look at these cannabinoid levels in the blood, but also understand, we can stimulate in a positive way the endocannabinoid system just through oral consumption, of these particular molecules because we We do see these receptors in the GI.

So I just think this is really interesting. Again, we need a lot more research on this, but really shows kind of the potential and, and kind of the, the interesting targets we have ahead of us as we delve deeper into the research of these phytocannabinoids. Michael, I believe this is your turn now.

Great. Thanks, Stephen. Thank you, Joe, for an excellent overview of the science.

I'm Michael Williams. I I work with Elivet in the US and Ellie Vance here in the UK. I co-chair the EIET Veterinary Advisory board in the US and I received my scientific grounding with a PhD in biochem from Oxford University.

. Firstly, I want to address the the the pathway for UK veterinarians to prescribe CBD products such as Elivans. As we all know and have seen, CBD and hemp-based products are now fairly ubiquitous, and are freely available on the high street and a range of online stores. You can type in CBD at Amazon, and come up with a whole range of different products there.

So freely available, . And while the MHRA does allow the sale of CBD products for people, the BMD has stated that CBD products in the UK are medicines, and, and, given that no CBD products are currently authorised for use in veterinary medicine, there should be no product on the market in the UK that's specifically labelled for veterinary use, in the UK. Instead, the VMD, website directs veterinarians to the prescribing cascade, and, Stephen, if you can move to the next slide.

So under the prescribing cascade, a CBD based product, a suitable CB CBD-based products such as Elivans can be prescribed, as a extemporaneous, that's hard to say, extemporaneous preparation. On the VMD website, there is a specific clause, related to the use of CBD products, that states and I'm gonna quote this word for word. As there are currently no CBD products authorised in the UK for veterinary use, a veterinary surgeon may prescribe a legally obtained human CBD product under the provisions of the prescribing cascade.

So therefore, you know, pet owners can freely purchase legitimate CBD containing products such as Elivans, and veterinarians in the UK can prescribe these as long as they're not labelled for veterinary use. Stephen, if you move to the next slide. So some background on Evans, .

While, Elivet has been on the market in the US, Elivet, is the US based company, for several years and is now really the leader in hemp-based, veterinary supplements in the US. Elivan was set up more recently to sell a range of products. For people, in the UK and Europe.

We are based in the UK, we're a head office facility down in Devon, where we process and stock our products and provide telephone customer support. We also have a direct sales team, that can conduct telephone and on-site education and training. Products can be ordered from our website or by calling our customer support team.

And we have free next day delivery across the UK. Stephen, if you go to the next slide. All our, Elivans products are made from the same, unique hemp CBD CBDA extract that, Stephen and Joe have been talking about, for Elivet.

It's the identical, extract. It's grown, from the same proprietary hemp cultivar, as you can see a picture of our farm on the, on the left-hand side, on the same pesticide-free. Farm here in, there in Colorado.

The product is extracted in the identical way and there's further purified, as Stephen mentioned, to meet the more stringent UK requirements for THC absence. All our products undergo extensive third-party laboratory testing. That's something that you should always confirm before using a CBD product, to confirm the target, cannabinoid and tine content and to ensure that.

Contaminants are absent such as bacteria, microtoxins, heavy metals, pesticides, and, I think really importantly, as you've heard today, the Elivans products as well as the Elivet products are supported by, really an expanding set of PK, safety and and efficacy studies. So with that, Bruce, I'll pass back to you for Q&A. Guys, this was absolutely fascinating.

And I'm, I'm sure that everybody is sitting listening as riveted as I have been. I came into this webinar with safe to say, practically no knowledge of this and have been fascinated and hung on every word that you've said. So Steven, Joseph, and Michael, thank you so much for your time and your explanations.

My pleasure. What was really cool for me was watching all the questions and everything else. And our audience are, are keen and their mind is running in the right direction.

And every time they came up with a question, within a minute or two, you guys had answered it. So, the questions, have been coming in thick and fast, but I'm not gonna go through all of them because as I say, you have, covered a lot of them. I'm also folks, attendees, I'm going to take some poetic licence here and I'm not going to go through each individual question.

I'm gonna lump a whole lot of them together. Stephen and, and Joe, I think from, for you guys here, the question is coming through about using these products together with all sorts of other drugs. And I'd be here all night if I was saying them.

NSAIDs and, and skin preparations and steroids and everything else. I think the summary question really is, are there any contraindications to using this product, specifically in relation to an animal that is on another product? Sure, I'd be happy to answer that, and I believe Elevance does have some, some literature that will be available soon to kinda answer this question with a whole host of different drugs on it, which will be a great resource for all of your attendees by visiting the Elevan Sciences.com website.

I think right now my only concern with using . These particular products, at least at a full dose, I would start much lower than I, I typically would at at maybe what the box or the, the bag may suggest is with benzodiazepine. So things like alprazolam, some of these other anzolytic drugs that, pets are on.

And what we can see sometimes when they are on benzodiazepines and then you add something like a cannabinoid product as we can see certainly some more lethargy. We can see, the, the animals, seeming a little bit more concerned, like, what's going on? I feel kind of extra funny right now.

So I think we do have to be careful with benzodiazepines and I would say it's such a small percentage of, of concern for other drugs to where it's not even a big concern for me to, to mention, out loud at this point. I think if, if practitioners are concerned about drug to drug interaction, it is always safe to start a little bit lower and dose escalate, to see how the animal is going to react. And more often than not, especially, you know, when I was still in practise and, and not involved with Eevt full time.

Working with these clients one on one, we typically see them decrease the traditional pharmaceutical drug over time to where the animal is generally just relying on the CBD CBDA products. Excellent. And I, I think I'd like to just sort of add cause I think we're getting a lot of questions on, on, you know, the use of non-steroidals and, and I think we are maybe we hit on this, you know, that it has some potential anti-inflammatory effects through potentially the COX pathway.

But there are so many other pathways that seem to be more interesting, such as a glycine receptor, such as 5HT receptor, you know, that I think, you know, between those two as well as trip 1 receptors where CBD may have it, have activity. We're really not seeing the idea that, that we're having any major effect, on, on dogs with who are already on NSAIDs. Like we're not seeing huge, you know, increases in kidney or liver enzymes, and we occasionally do see the spurious alk phosphorrise, and we just really can't explain that, and that seems to be a, a very dog-specific thing and that's why I think we say that just, you know, follow the blood work and the rises weren't egregious, so.

It was a very interesting that you, you mentioned that, because one of the questions we got was, about the effect on the liver and that sort of thing. And you talk about doing blood work. What would be, the recommendation when the animals are on this, these products to be running those bloods?

Oh, I, I think we should sort of treat it like any, any new drug we're gonna put them on. I mean, you're gonna do some blood work after you put a dog on phenobarbital, maybe 3 to 4 weeks out, maybe even a little earlier or something like that. NSAIDs, we typically tell people 2 to 3 weeks out, have some blood work done, make sure there's no negative repercussions.

And then, and then if you, you see that everything looks fine and even if you see a mild dog phosphorize, our internal medicine people here don't get too concerned when it goes to, you know, 250 or 300. They're more concerned when it's, you know, 3000. So, and I think, you know, we see these things with prednisone and we just kind of, I've always lived with it, right?

That, well, we see a small rise in a hos and we know that it induces some of the cytochrome P450 system and And I think this is the same kind of thing. So I think, you know, due diligence, we're veterinarians for a reason and, and that's why we, we wanna follow these patients out. Excellent.

On that line as well with, you know, being veterinarians and, and following them out and everything else, there's loads of questions that are coming through about other uses. So we're talking about pain control and osteoarthritis and the studies that Joseph and his team have done. But what about the uses and, and the, the science behind dermatology, IBD, all these other, epilepsy, all of these things.

Steven, we got, information that's gonna be coming out with between you and Joseph? Sure. So, Elave here in the United States is running an epilepsy study.

We, Joe and I actually have a call I believe tomorrow with another university about hopefully starting some GI studies specifically. When it comes to epilepsy, we do have, one study that was published, I believe last summer out of Colorado State University, and they were using, more CBD dominant, product, and what they found was, the animals that were receiving the CBD product did have A decrease in severity frequency and, and, length of these particular seizures. But when you compare it to the, the, the control group, it wasn't statistically significant.

And the dose they were using in that particular study was 2.5 milligrammes per kilogramme twice a day. And they are continuing on with a higher dose of 4.5 milligrammes per kilogramme twice a day over the next few years.

And I, I think they will see better results. I think we're gonna see some really interesting, hopefully positive results just because I think we do have some really interesting cannabinoid and terpines, that maybe the other product didn't necessarily have in it. I was just reading a paper that came out at the end of the year last year out of Japan.

It was actually a case study, with, 3 epileptic patients, and it's interesting because I, I believe the percentage of change for the animals in the Colorado State University study that were receiving the CB product was around 33% and only one of the 3 dogs in this, this, case report out of Japan. Didn't necessarily see effects. So the trending is about 30% of these animals may not necessarily respond favourably.

So we do have stuff coming out, we, Joe, when do we think that the preliminary results from the epilepsy study might come out? Yeah, I, I would, I would like to say that we'll have at least 10 through by the summer, and it's a double blinded crossover, so it's, it's, you know, a long study. It's about 6.5 months altogether.

And I would say that, you know, just even talking to the investigator, he's not seeing any major differences in, in, in the, in the blood levels of some of the actual drugs that they're already on like phenobarb, KBR so I think that's somewhat encouraging, but that's not a full data set yet. And you know, he, he says that some of the owners are really pleased with what's happening. I can't tell you whether that's true data at this point, but I think we'll know, we'll know a little more this summer for sure.

Yeah, and I believe some of our, our, our dermatological results will be out this summer as well. Excellent. It's really nice to know that this is all going on in the background and we'll be out and available.

Steven, you've opened a can of worms, talking about doses. So I'm gonna back it bat it back to you. Lots of questions coming through with what products are available for dogs, for cats.

Are they available in this country now, and what doses should be used? Yeah, so I think Michael described the, the prescribing cascade pretty well, and I think you'll all have access to that or you can go to the, the BMD's website and, and look that up. And I'm sure I'm the American, so I don't want to speak to your, your rules and regulations.

But when it comes to dosing, what you'll notice is, The Cornell study in particular concluded with a 2 milligramme per kilogramme twice a day for osteoarthritis. And this seems to be a dose that we're kind of adopting, and trying for a lot of our other studies. What's notable about that is, is we see a lot of patients that do really, really well at 1 milligramme per kilogramme or even a.

Milligramme per kilogramme. And again, that goes back to that term that I mentioned earlier in the presentation, known as the endocannabinoid system tone. How many of these endocannabinoid system receptors and even some of these other receptors that have affinity for these phytocannabinoids are open?

How many endogenous ligands are open? In personal experience, again, this is Just anecdote. I find that the animals that come into the clinic that are really, really painful, really, really lame, really, really amped up or nervous or, or excitable, they seem to take a little bit longer and may require higher dosages compared to the more docile animals, that maybe aren't as amped up and have this, this.

Maybe better control of the endocannabinoid system. So, in general, I think the 2 milligramme per kilogramme, area plus minus 1 mg per ig is, is a good place to start. And then you may have to dose escalate or de-escalate, depending on how the animal is doing, and that's just being really involved with that pet owner or, or town.

That pet owner, you know, keep a diary of how your, your pet is doing while on these particular products. And Steven, if I could just add, because there, there's a few questions here where, where I would suggest that, folks on the, on the on the webinar follow up directly with Elivan's Sciences on the website, you'll find our our customer support telephone number. And you can reach one of our veterinarians on staff in the UK that can talk through some of the the how to use type questions that are coming up.

Excellent. I think that's great, Michael. That's really, really good advice because yeah, there are loads of questions coming up with how do we know how many milligrammes and what the concentration and everything else.

So, folks, I think Michael has, has hit the nail on the head there. Go to the Elivan's website, get hold of the customer service. These are people that are trained in these products.

They can answer all your questions. We, unfortunately, are starting to run out of time. A couple more questions maybe, bit more lighthearted here.

And I'm not gonna ask Greg whether this is, he asked this from personal experience, but he, he wants to know, do dogs also get the munchies? That is a, that is a good question, and, typically, the munchies is, is more associated with THC consumption, which again is not necessarily being relevant to the Elovans product. What we can see is we can see increased appetite with the addition of CBD CBDA, not only because it is playing on this endocannabinoid system which does help regulate appetite.

To an And with our IHG receptor and whatnot. But we also have to consider when we make our animals more comfortable, that in itself can be appetite stimulating. So if our animals uncomfortable all the time, they may not want to eat, you know, if, if we're chronically painful, food's not on our mind a lot.

So, certainly getting them more comfortable can cer certainly be helpful. Excellent, excellent. Another, we've got loads of comments coming through about how fabulous and how interesting the webinar was.

And as Anthony, would normally say, if we were in an auditorium, you would be hearing thunderous applause. So there is a lot of support and thanks to everybody involved, Stephen Joseph and Michael for all your inputs. Another trend of question, and this is the last one we're gonna have now is about palatability of the products and convincing animals, dogs and cats to actually take these products.

Sure. When it comes to palatability, some, I would say a majority of animals are fine with, these products. Certainly some animals have an aversion to some of the terpines in there, but we really believe that the terpines are really critical for some of the, the therapeutic effects that we're seeing with these sets of molecules.

For the animals that don't necessarily appreciate the smell of it, my dog personally, he loves the oil in hummus, and it, it mixes really well in hummus, and he's happy. We also, I believe have capsules available where you can put them in a little gelatin capsule, and certainly, We can get more creative by mixing it in peanut butter or all kinds of fun things. So there's not a lot of medicines that, that animals do like to take, and I think we just have to use all the tricks in the bag that we're familiar with with getting these products into, our, our companion animal friends.

And I think the fact that it absorbs best when given with a fatty meal, most animals will quite happily have a fatty meal. So, in fact, probably most humans do, so. That's all we have time for tonight.

I'm afraid we have run out of time. We could, take these questions and keep going all night, but that's just not possible. I would like to thank Elle Vance and Elivette in the US for their sponsorship of tonight's webinar and especially to thank Steven and Joseph and Michael for being on with us and sharing their insights and expertise.

Gentlemen, thank you so much for your time tonight. Thank you. Last comment, guys.

Go to Elevans's website, get, look up that number, talk to their staff. They are there to help us and support us and answer all those questions that we just have not been able to get to tonight. So thank you to our sponsors, thank you to our presenters.

Thank you to Phil, my controller in the background, and most importantly, thank you to everybody for attending tonight. From myself, Bruce Stevenson, it's good night.