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 webinar. We have a double header for you tonight.

The first part is going to be live. The second part has been pre-recorded due to technical difficulties in the presentation, but it does not lose anything on the impact, I promise you. Little bit of housekeeping for those of you who are new to our webinars.

If you want to ask a question of our speaker, if you just move your mouse over the screen, a little control bar will pop up. It's normally black and at the bottom. You'll see there's a Q&A box.

Just click on that and type in your questions there. We will hold all those questions over to the end. And we have not only got our presenters on tonight, but we are very, very pleased to have Shelly and Christian from our sponsors, Elle Vance and Elivette.

A very, very big thank you to them for the Sponsorship of tonight without them, we would not be able to bring you these webinars. So, Shelly and Christian, welcome to the webinar in the background and thank you very much for your kind sponsorship of tonight's webinar. So to kick us off tonight, we are going to be hearing from Doctor Joseph Waxlach.

He started his academic career receiving a BS and an MS from Montclair State University. He then attended Cornell College of Veterinary Medicine, graduated 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. And was an associate professor at the University of Florida in integrative medicine and nutritional service. His background in sports medicine has produced many publications on working dogs, obesity, canine cancer cell biology, and arthritis management.

He is currently professor at Cornell University College of Veterinary Medicine and recently joined the LIET team as their chief medical officer to oversee their research and clinical trial programmes. Joe, welcome back to the webinar vet and over to you. Thank you very much.

I really appreciate the introduction. So today we're gonna, we're gonna start off by by hopefully talking a little bit about the endocannabinoid system in general. And This is the endocannabinoid system in one small snapshot here.

What you can see is that what we're really talking about is a pre-synaptic to post-synaptic signalling system, and this is where majority of the endocannabinoid system is located, which is the central nervous system. And what you can see is that there's a whole bunch of fancy molecule names here. Basically, all these are fatty acid precursors that end up getting metabolised during the signalling and the neurotransmission process and cause a pre-synaptic release of these strange fatty acid moieties, which are basically depicted here as little tiny circles, and then they Actually go and act back at that pre-synaptic terminal at the CB receptors, and those are basically cannabinoid receptors.

And there's really CB1 and CB2 are thought to be the two primary endocannabinoid receptors that sort of influence homeostasis of the central nervous system. To that effect, what you can see is that those little tiny circles eventually actually go to that post-synaptic neuron, and this is where they actually are primarily metabolised. And so there's this consistent release during neurotransmission of these small fatty acid molecules that actually go and temper or sort of create the homeostasis of the actual central nervous system.

So we can start to understand that when we start talking about some of the plant-derived endocannabinoids that can affect the system, how we get these strange psychotropic effects. So to that end, We see that there are two major molecules that actually do affect that CB receptor which are called anandamide, which is to arachadonal ethanolamine, which basically is an arachedonic acid precursor, which we all probably remember or get cajoled back into the prostaglandin system. So it's not a far cry from that system.

You can see the other major one on the right hand side is aracaonnoglycerol, which is basically another acheddonic acid derivative that is involved in this endocannabinoid receptor signalling pathway. So to that end, how do these strange synthetic, or we'll call biosynthetic pathways in the hemp plant affecting these different pathways, primarily the CB receptor? Well, the CB receptor is primarily influenced by THC, which you can see here as part of the pathway of hemp plants.

And what you can see is that there are two major molecules that basically get conjoined together, OA and GPP. Through a a syn synthesis or transferase activity into what's called CBG. CBG is actually the mother of all of the actual cannabinoids, and that is actually what ends up deriving.

All the other cannabinoids like CBC or THC or CBD. Based on synthase activities that are actually in the cell, of each and every plant cell. So based on the synthase activity, We end up with different types of cannabinoids.

And what you can end up seeing here. Is that THC is a major derived cannabinoid as well as CBD. CBD of course, is the one that we're gonna be talking about because that is the one that's derived from hemp plants in general.

And it all really depends on the hemp cultivar and the hemp that you're using, as to how much CBD you're going to be, supplying from that hemp plant, as well as how much of some of these other cannabinoids may actually be in the hemp plant as well. And so you can start to understand why each and every hemp extract is Going to be a little bit different, OK? And so when we start talking about hemp extracts and quality control in a little bit, you're gonna start to understand why we need to have a better understanding of what's in each and every one of these hemp extracts that people are taking now, animals are taking, and this is why we've done a lot of studies with our plants in terms of the elevate product in an effort to better understand the ratios of these and how dogs, cats, and other species are assimilating to these cannabinoids.

So I just showed you things like THC, CBD, CBG, but in all reality, those are not the actual mother molecules. It's actually THCA and CBDA CBGA, CBCA, etc. Those are actually the ones that are formed in the actual plant.

During the actual heating and extraction process is when majority of the products you see on the market are turned into CBD, CBG, or have little trace amounts of THC. And we know that THC is not something we want because we don't want the actual effects, the psychotropic effects of THC. We want to see things that are more rich in some of these other cannabinoids.

What you have to understand is that CBDA, CBD, CBG, CGA. All of these things tend to have physiologic effects at the right concentration. And so you can see from this graph here is that We have a whole lot of different activities, so you can see CBG is or CBD is involved in anti-inflammation, anti-convulsive, antipsychotic, neuroprotection, antioxidant, anti-cancer related activities.

CBG has similar activities, but a few less, and has more potent activities and things like alpha adrenergic receptors and potentially the 5 hydroxy 1A tryptophan receptor. THC is something we're not looking for because of the dysfunction and cognitive abilities, the psychological reactions, and then some of the muscle relaxation, things that we basically can't be providing things like THC to our animals. Therefore, CBD has become the focus, as well as some of the other derivatives of CBD, which are, of course, the acids which are the mother molecules.

So if we take a closer look at how CBD may be acting at the level of receptors, it's really not about what we talked about initially, which is this CB1 CB2 interplay. This is why CBD does not have psychotropic activities, because it does not actually act at the CB1 or CB2 receptors directly as a direct agonist or a direct antagonist. What we tend to see is that CBD actually acts at other receptors that may be involved in that neuropathic or nociceptive pain response, such as the TRIV family of of receptors, as well as the NMDA receptor activity.

It actually has some inhibitory activities towards the opioid receptor, as well as other receptors such as calcium channels and alpha-1 adrenergic receptors. You also can see the CBD molecule going into the COX enzyme. So COX 2, actually, which we know is what's making prostaglandins and things of that nature, we know that the prostaglandin production can be inhibited by CBD because of it has potential, ability to down regulate COX activity and directly inhibit Cox itself.

Interestingly, if you look on the right-hand side of this this cartoon, you can see that a lot of areas where we tend to activate receptors, and those tend to be the serotonin receptors, 5 hydroxytriptophan 1A and 2A in particular. We also have activities of improving glycine receptor activity as well as GABA activity. And so we can start to understand how we have these potential neurologic effects, not only through TRV inhibition, but we may also be influencing neurotransmission through glycine and GABA receptors.

We also see that there's a strange thing called the PAR gamma molecule that's basically showing how CBD can be an agonist of that, and that is part of the anti-inflammatory response by activating the PA alpha and gamma receptors to actually diminish potentially cytokine production. Now we've been talking a lot about this from a neurologic perspective, but we also know that the immune system has some of these receptors. Therefore, there may be some immune regulatory capabilities of CBD as well as some of the other cannabis.

Now cannabidiolic acid, which is CBDA, has very similar properties, and we're gonna talk about this today because that is something that we find in our product and this is something that we actually look for in the L of that product, because we're starting to find that these acids, and it doesn't matter if it's CBDA or THCA or CBGA, they tend to be absorbed better than actual CBD THC or CBG. So this acid form, just having a carboxylic acid actually creates a better absorption in general, and it appears to be across many species and we won't get into the dynamics of that at this point, but that's why we feel that cannabidolic acid is as important because it has all the similar effects of CBD, but we may be able to, in essence, use it in a synergistic way and or as a replacement for CBD to some some degree. So it has not only anti-inflammatory and anti-convulsive type of activities, it has anti-emetic activities, through the 5 hydroxytryptophan receptor, and there are some anti-carcinogenic behaviours that that this molecule may may impart on cancer cells.

But what we can see is it's definitely acting in an anti-inflammatory way, as well as acting at the trip receptors very similarly to CBD. Now in the hemp extract, what we tend to find is that it's not just cannabinoids, they actually tend to be a large number of fairly high concentration of things called terpines. And those terpines are the smell that you actually smell when you look at a hemp or smell hemp extract, similarly to beer and hops.

So we have terpines such as mersine, pinines, carophyle, and lemonine. All of these actually have potential synergistic anti-inflammatory, and or neuro stimulatory or neuro neuro inhibitory activities, that you can see on this, this flow diagram. And in all reality, we think that the urine profile may be helping some of these hemp extracts, in terms of their overall efficacy through what might be called an entourage effect, which we won't get into a lot, but we think that there may be some improvements in function of CBD, CBDA and some of the other cannabinoids if they are, put together with some of these urines.

So I think one of the major issues that we have here in the United States in which Doctor Dave Tittle will go over is some of the regulatory hurdles that we have, in terms of providing hemp extracts to our dogs and cats. And in all reality right now, our regulatory body, the FDA does not have any real comment other than saying other than saying that it should, it can be sold, but we should not be selling it as veterinarians because we We don't have FDA approved drugs that are involved that are derived from hemp at this point, and that it's really comes down to the fact that, the, the, there are no animal supplement laws and therefore, what we can do here in the US is actually quite a bit in terms of distributing these products. And what the FDA is now, is now doing is basically having sort of a, a period of, discussion around what needs to be done to, in essence, regulate these types of products on the market, and we've actually put in a letter saying that we know that we probably should have good pharmacokinetic data on the species of intended use.

There should be some safety studies, 3 to 6 months minimally. There should be some efficacy studies to show that these are have efficacy in certain ailments, which then gets us into the FDA route of the drug. And we must also have clean certificate of analysis, traceability from the farm to the actual product, and then of course, if we can develop some compliancy for this FDA rules, we actually would then be able to, in essence, certify it probably through a a a body called the National Animal Supplement Council here in the US.

If we can actually follow these types of guidelines, we can have safe and effective hemp products across the board, which currently in the US the variety of different hemp products and what they have in them is is so large that it becomes a bit of an issue and sort of taints the idea of hemp use. And this has really come to light because we threw out a paper last year where we looked at 29 products off of the shelf, and we actually had a certified laboratory that's certified for measuring cannabinoids, look at a variety of products, and this is a nice depiction of the actual cannabinoid cannabinoid profiles of a whole bunch of products that were in this assessment. And you can see all of that is a CBD and CBDA product based on this chart because it's got not only the CBD which is blue, but it's also got this orange bar, but it's also got a lot of minor components just like a lot of the other products do too.

All of these products were below the 0.3% THC level that is a standard here in the US. Doctor Tittle will go over some of the standards in the UK.

And the CBD oil concentrations or the the CBD concentrations in these products were between 0 and 88 mg per mL, which was a huge difference because there were two products that had no CBD. A little bit more concerning is that 4 of the 29 had heavy metal contamination because hemp is known as a bioremediator of soils, therefore we have to make sure that we're testing for things like heavy metals. We also showed that about 27 of the 29 did have we'll say appreciable or close to their the level of cannabinoids that they said they did.

And that unfortunately, if we looked at it about 10 of the 27 or within 10% of their actual labelled amounts, but they still at least have had appreciable amounts of CBD. And unfortunately, almost half of these were not labelled appropriately by saying things on their packaging about mitigating pain or having a specific amount of CBD in the product. If you say that you have so much cannabidiol that is basically making a drug claim on the.

And that's why things are vague and hazy in terms of how we label these things. You can say there's 2500 milligrammes of cannabinoid in this bottle. That is absolutely 100% legal to say, but once you start calling out specific molecules, you actually start to get into this hazy area of a potential drug claim.

And only 22 of the 29 could actually give us a complete certificate of analysis on the product to tell us the actual cannabinoid concentration that was in the oil. And so that's a little bit discerning is that some companies can't even provide you a certificate of analysis. That said, I think that's what we have to ask for as veterinarians.

We have to ask for complete certificate of analysis, and this is a certificate of analysis from the product that we send to Proverta, which is a certified laboratory. They give us the overall cannabinoid profile of each and every batch that we make. They also provide on the right hand side, you can see that's a full profile of different metals that could be contaminating the product.

We then have microbiologic on the left hand side, we have microtoxin testing. In the middle we have different pesticides, and then of course you can see there's a urine profile on the right hand side on the top, and then of course other solvents that could be left over from the actual processing of the hemp extract. So this is the kind of thing that I think we should all be looking for when we start talking about hemp extracts.

So, let's move on to other things that we need to ensure ourselves that we have a safe product. What we did is we actually did our typical dose, which is about a 2 meg per kg dose of cannabinoids, which is a 50/50 mix of CBD and CBDA. And we gave that twice a day for 12 weeks to dogs, and then same thing for cats.

And what we ended up showing is through this paper is that there were no deleterious effects in the dogs or cats as far as serum, serum, CBCs and chemistries were concerned, and we also did physical examinations showing no adverse events. Associated with the actual consumption of these oils in dogs or cats, and the biggest aversion we had were cats and head shaking because cats really did not like to be dosed with CBD oil, even if it was in a nice fish base. So that said, this appears to be a safe dose to provide for a longer period of time.

In an effort to better understand the CBD and CBDA concentrations that were being absorbed, we actually did another study where we looked at a pharmacokinetics over 24 hours as well as a 1 in 2 week provision of this twice a day, 50/50 makes 2 mg per gig of the product. And this is actually on the right hand side you can see week one and week two, those are CBD and CBDA concentrations in the bloodstream. Using three different forms.

The first form was in a medium chain triglyceride base that also had sesame oil, and then the second one was a lecithin and sesame oil base, while the third was actually the elevate chew that is already being marketed. And what you can see is that the CBD concentrations seem to be fairly reliable across week one and week 2 at at . Midway between a dose, which was 6 hours after our morning dose.

We were at the 50 to 100 nanogram per mL mark, which is what's been proposed as a sort of a therapeutic amount, which you can also see is that CBDA was similar and, however, it appears as if we could get really good CBDA absorption using a Lecithin base, which is what we've now started formulating our chew with to promote a higher CBDA concentration in the bloodstream. So these are kind of things and then we'll say that the research that that every company should be partaking in to provide evidence for veterinarians that we can get it into the dog, which is a good thing, or the cat. And what I will say at this point is we are really focused on dogs and we're looking to do more in cats, but what we can tell you is that in cats, the absorption is about 1/3 of what we can see in dogs in general.

Therefore dosing may be a little different in cats, and we're still working on trying to figure out exactly what that dose might be. So if we think that this could be acting, we do think that it could be worthwhile and, and we'll call a neuropathic pain where we end up having this sort of, we'll say wind-up phenomenon of the central nervous system, as well as the perception of pain through things like the TRIV and the glycine receptors, which if we can actually, you know, in its agonise and eventually desensitise trip receptors, we may be able to dampen the response if we can actually promote better glycine. Which is hyperpolarization, we can potentially dampen the neuropathic pain response.

And of course, we also think that CBD and CBDA may be able to diminish the inflammatory response which we know that inflammation may may be part of this transmission of the neuro neuropathic pain response as well through a whole bunch of different mechanisms. Not only is it through glycine receptors, TRV, it may also be through GABA, adrenergic, and then you know, the opioid receptors where we may be influencing the input from that. So that said, is there any evidence?

Well, this is our first clinical trial, which we feel the FDA should be looking at in terms of the folks are marketing these things for things like what we call it mobility. Is there any evidence that we may be able to improve that? So this was 22 dogs that were enrolled, 16 of which completed.

The study, and these were dogs who were in, had osteoarthritis at two or more joints typically, and they basically were on other modalities and particularly the non-steroidals. So about half of the dogs were on non-steroidals. They had radiographically confirmed, OA pain, and they had no concurrent or organ failure of any kind, other than some had a mild elevation in liver enzymes due to hepatomas.

And what we did is we actually looked at them over a 4 week period of time. We crossed them over, they were either on placebo or the CBD oil. At the dose we've been talking about 2 makes per kg of that blend of CBD and CBDA from a hemp extract.

And we looked at the canine brief paint inventory and the Hudson activity scores, both of which are fairly well validated, scoring systems for owners to assess pain and or activity. And what we can see on the upper left panel there in terms of that graph, you can see that the Hudson activity scores definitely improve all the dogs were on CBD oil, and they actually kind of slowly went down when they are on the other, there may be a little bit of a bleed over or bias effect that was occurring due to the, the crossover. .

Similarly, C bippy, which is canine brief paint inventory, did go down, and then you can see in the placebo started to go up. If you look at the middle panel, with the actual change from baseline scores, you can see that there's a fairly nice significant effect, between the actual olive oil and the placebo group in terms of change from baseline scores where the placebo doesn't really change their median score and the actual elevator oil actually goes down about 20 to 30 points on average. So there was definitely an effect and it was one of the first things that has been shown to, to basically the first study to show efficacy in an osteoarthritis clinical trial.

So if you don't believe us, well, there are actually a couple of other studies. The second study was done by another group looking at it. A 20 mg CBD once a day dose versus 50 mg once a day in a coconut oil base.

They also did a less than liposomal type of product that was at 20 mgs also and so they basically gave that to dogs once a day, and those dogs were fairly big, average weight of about 41, and these dogs all had arthritis. They were randomised into. 4 different groups, 5 dogs in each group, and you can see that they did the Helsinki index pan, which is another validated pain score, and of course they also had a veterinarian assessed dogs well the veterinarian was blinded to the actual treatment groups.

If you just look across the graphs here, you can see that the placebo group showed no real effect over time, and you can see that based in the panel B here, Helsinki pain index, is that over time when you compare the intergroup, not between the groups, only within the group, you can see that there are decreases in the 50 mg per day dose as well as in the the 20 meg liposom encapsulated. There was a statistically significant decrease in in owner perceived pain by day 30, and then even you can see here by day 45, they were saying that there seems to be a recrudescence of the pain, but it's not quite as bad even two weeks after. So there may be some, we'll say cumulative effect of of providing some of these CBD products.

They also had their veterinarian assess things like getting up from a sitting position, ease of walking, laying position, and running, and probably the most interesting thing was that ease of movement from getting up and sitting down seemed to be improved while running and walking was was not so much. To that effect, we also wanna kind of follow out something that was shown to be a little bit elevated in our initial study, which was, alkaline phosphatase enzyme did go up in some dogs, not all dogs, which is, of course, kind of a conundrum here is why don't all dogs have these increases in alkhos. And in their study you can see that there is a modest increase in in the alkhos activity, but the ALT activity was within normal limits and and normal.

Same thing that's that we in essence have proved in our study. So third study actually recently came out from an Italian group. And they actually were basically studying a to make per kg per per off route, and actually they say that there was a trans mucosal delivery cause they just basically wiped it along the gums inside the cheek pouch of the dogs and they didn't ensure that they swallowed it, whether it was oral or whether it was transmucosal is really hard to determine.

However, what they basically did is they allowed dogs to be on spread ferrococcy or gaba or amitriptyline, depending on what they're on already, and then they put the CBD on top versus just a straight MCT oil, and they followed these dogs out for 12 weeks, having the owners fill out the canine brief paint inventory, and these are straight off of the paper, you can see the CB. Dogs, they basically at time 0. There's a PSS and a PIS, which are two parts of the C bippy, which is a pain sensitivity scale and a pain interference scale.

So the PSS and the PIS were both around 5 to 6, and then they both went down to about 2.5 to 3.5, and they pretty much stayed there throughout the study in general.

Quality of life scores started at 2.5 and ended up at about close to 3.5 by 12 weeks out, which is a 1 point increase in quality of life.

And then you can see the control group really didn't have much of a change at all. They did start off at about 5.8 and 7.25, and then they sort of ended, which you can see there is a 4.9, which is about a 1 point drop and then a 1 point drop.

So there is definitely a placebo effect, however, the statistics did bear out that when compared at each time point between the groups, there was definitely a statistical statistically significant difference over time in the CBD group but not in the placebo group. To that end, it appears as if we are starting to grow a body of evidence to suggest this may be worthwhile. Lastly, I just wanted to touch base very briefly on the atopic dermatitis study that we're doing.

This is a data that is just hot off the presses, 17 treatment dogs, 12 placebo dogs at the same dose that we were giving. The veterinary dermatologist did a cadai scoring on lesions and then the owners did a VAS puritis score over time at 2 and 4 weeks. And we did 2 different groups and we also did some cytokine analysis of the serum.

As well as owner satisfaction. And just to briefly go over this, what you can see is that the ulnar pits definitely did go down at 2 and 4 weeks versus the placebo group, which appears to be significant across that treatment group. The cadai scores, which was actual lesions observed by the dermatologist, did not change over time.

Which is interesting cause it suggests maybe the inflammation doesn't go away, but the actual perception of pruritis does. This is the change from baseline where you can see that there's definitely a statistically significant difference at 2 weeks, almost at 4 weeks, in terms of the change in the VAS baseline, about a 2 to 3 point drop. For the average dog, and then if we actually looked at owner satisfaction, whether they would continue due to the response, 10 of the 17 said that they would in the treatment group, but only 2 of the 13 in the Placebo groups said they would continue, which is definitely significant.

We looked at ALT and ALP. ALP did not change. We did see a few dogs.

You can see about a half dozen of the dogs did have increases in Alfos, which is interesting, which is seeming to prove out with all the other studies. ALTs did not change across the board, 0 to 4 weeks. MCP and and IL-6 global inflammation appears to not be changing much.

And then things like the Kadey score, which has been correlated to aisle 34, there were no changes in the treatment nor the placebo group, and aisle 31, which is a pruritus, correlate, also did not change in the treatment or the placebo group. Really suggesting that CBD and CDA products have potential for neuropathic issues, very likely through TRV and glycine receptors, possibly even 5 hydroxytryptophan, and interestingly, it improves pruritus too, but it appears to be through potentially neurologic input from the from the peripheral nervous system of itch rather than probably inflammation at this point. We don't know that for sure.

We're still looking at some of the data, but it sure seems like we have an interesting molecule here that might be able to cross a whole different, array of, disorders that involve, you know, neuronal input. That said, we're gonna hand this off to Doctor Dave Tittles, we'll hand it back to Pete and Bruce who will basically take you through Doctor Tittle's, presentation. Thank you.

Thank you, Joe. That was certainly food for thought and we've had some nice questions coming in. Some of them we have answered directly, but we will hold the others over to the end.

So while Peter's busy changing over the screens to play us that recording for the second part of our double header that I promised you. I'd just like to introduce the speaker of the recording. Dave Tittle qualified from the RVC in London in 2000.

He has spent most of his veterinary career in private practise in coastal North Devon. In 2010, he passed the RCVS certificate examinations in veterinary anaesthesia and was subsequently awarded the RCVS Advanced Practitioner status in 2015. He attained his GP cert from the ESBPS in 2018.

As well as his anaesthesia and analgesia commitments in the first opinion and referral services at Charter Veterinary Hospital, he also runs referral chronic pain clinics, utilising a variety of techniques. He is thrilled to have been asked to join the LIET Advisory Board in 2019. So, Pete, if you can run the recording for us and we will pick up those questions at the end.

Hi there, and thanks for joining this evening. Thanks also to Joe, as always, for his detail and insight into this exciting subject area. So I wanted to start my section on the presentation with a recap from our last webinar regarding the regulations surrounding the use of CBD containing products in the UK.

You can see on the screen, extracts from a statement released by the VMD in September 2018. The VMD consider that veterinary products containing cannabidiol are veterinary medicines and should be regulated. And as such, administration of an unauthorised product containing CBD without a veterinary prescription is an offence under regulation 8 of the Veterinary Medicines regulations.

As Joe discussed, it's imperative to select a product that has proven pharmacokinetic data with robust safety and efficacy studies, and we should always request and scrutinise certificates of analysis to ensure that a company can assure us of a full product traceability and that the product is manufactured in a good manufacturing practise compliant facility. And by ensuring that all of these factors are considered, we can offer patients and owners additional options for treatment, yet still adhere to the UK prescribing cascade. And my interpretation of the prescribing cascade and how I utilise this in justifying prescribing the Alavan product in my clinics, is that I'll always use a veterinary licence product initially.

This is usually some form of non-steroid or similar, followed by another veterinary licenced medicine such as tramadol or paracetamol with codeine. And as you'll all be aware, some animals will often require additional drugs or combinations, or utilisation of an off-license method of delivery, such as an infusion therapy to aid their condition as it progresses. By this stage, we'll likely be reaching for a licenced human drugs such as gabapentin or amantadine.

Some of these drugs or combinations of drugs may have deleterious effects on animals, or again, may not meet their analgesic requirements. It's also worth acknowledging here that there continues to be some exciting developments in the field of analgesia, especially in dogs. So my interpretation of the prescribing cascade and how I utilise this in justifying prescribing the Elavand products in my clinics, is that I'll always use the veterinary licence products initially.

And this is usually some form of non-steroidal or or similar, followed by another veterinary licenced medicine such as tramadol or paracetamol with codeine. As you'll all be aware, some animals will often require additional drugs or combinations or utilising an off-license method of delivery, such as infusion therapy to aid their condition as it progresses. By this stage, we'll be likely reaching for a licenced human drug such as gabapentin or amantadine.

And some of these drugs or combinations of drugs may have deleterious effects on animals, or again, may not meet their analgesic requirements. It's also worth acknowledging here that there continues to be some exciting developments in the field of analgesia, especially in dogs. Again, as we discussed in our last webinar, there are 2 human licenced CBD products available in the UK.

These medicines are specifically licenced for the control of signs associated with multiple sclerosis or the treatment of seizures, and 1 also contains significant amounts of THC. In addition, prescribing of both these drugs is limited to specific Home Office authorised human medics in the UK so are unsuitable for veterinary applications. Where it's clinically indicated and justified on the cascade, it will offer clients elevants for their pet.

These animals are often in need of something more to maintain their quality of life. And I'll prescribe Elevans in addition to the current treatment regimes, unless there is a clinical reason to withdraw these other medicines. And in my opinion, and following advice from the VMD this use is wholly appropriate and justified, and I will always obtain informed client consent before prescribing.

Neuropathic pain is defined by the International Association for the Study of Pain. As pain caused by a lesion or disease of the somatosensory nervous system. It's a clinical description, not a clinical diagnosis, that requires evidence of a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria.

So as it's difficult to determine the exact cause of neuro neuropathic pain diagnosis, especially in animals, we assume that in many cases it is present and attempt to treat it. The term neuropathic pain may be subdivided into the categories peripheral neuropathic pain, central neuropathic pain, or mixed neuropathic pain, which is both peripheral and centrally based. A neuropathic pain results from an injury or a malfunction within the peripheral central nervous system, which can often be triggered by an injury, and the injury may not actually cause damage to the nervous system, but nervous system can exert an effect here.

People will often describe neuropathic pain as per the statements on this slide. And we need to try and interpret these potential signs in our veterinary patients in order to try and recognise and treat their clinical signs. So, is the dog that presents as an emergency for your last consult on a Friday night, spontaneously yelping but then seems settled when it arrives, suffering from an underlying neuropathic pain state.

It's really important to try not to overlook these patients and to attempt to treat them appropriately. It's nice to be able to differentiate between hyperalgesia and allodynia. Again, the International Association for the Study of Pain have quite clear definitions of the different pain terms and categorization.

Allodynia, which is pain due to a stimulus that does not usually provoke pain, and hyperalgesia, an increased sensation of pain from a stimulus that normally does provoke pain. And the prominent clinical signs associated with neuropathic pain, and both are seen in both central and peripheral pain disorders. I wanted just to pop up a slide that highlights a few disease conditions where there's potential to see evidence of the development of neuropathic pain.

This list is far from exhaustive, but goes some way to show the breadth of clinical conditions that may be involved. In humans, diabetic neuropathy is well recognised as an inciting condition for the development of a neuropathic pain state. But I also must acknowledge and thank Joe who blatantly adapted this slide from one of his.

When treating chronic pain states, it helps to understand at what level of the pain pathway your selected drug is aiming to exert an effect. For example, non-steroidal drugs are the mainstay in the management of chronic pain, as they exert both central and peripheral effects, and the majority of clinical conditions that evoke a pain state will often have an inflammatory component. Whereby the use of local anaesthetics can have an effect on both transduction at the nociceptor level or transmission within the dorsal root.

Local anaesthetics are the only drug class that will provide complete analgesia, inhibiting transduction and transmission of nociception. As you can see from the slide, opioids act at multiple levels of the pain pathway and are exceptionally useful, especially in an acute pain setting. Although there's a lack of definitive evidence for an analgesic effect from Tramadol, it's got a UK licence and it's commonly utilised in an attempt to modulate the ascending and descending pathways.

Amitriptyline is also believed to affect modulation of pain pathways and is commonly prescribed to treat neuropathic musculoskeletal pain. Licenced to humans as an anti-convulsant, the mechanism of action of gabapentin from neuropathic pain perspective, isn't clearly defined. It's believed to antagonise either the NMDA receptor or calcium channels within the CNS but does appear to have asphyxia at managing pain states.

Amantadine and memantine, which Amantine was originally considered as a metabolite of Amantadine, are both NMDA receptor antagonists and so have a role alongside ketamine in affecting the transmission and perception of a pain stimulus. The drug classes listed here are not an exhaustive list. For example, selective serotonin reuptake inhibitors such as fluoxetine are not really commonly used in veterinary medicine in the UK.

They are understood to be poorly bioavailable in dogs with little evidence of clinical efficacy. And the use of a full spectrum products such as elevans and antagonises CBD receptors, which results in hyperpolarization of the neuron, and this diffuses the stimulus effecting transduction. And transmission of that stimulus at the level of the spinal cord via the dorsal root ganglion is again influenced by the endocannabinoid system.

Cannabinoids have a role here, binding to CB1 receptors on the pre-synaptic neuron and suppressing excitation, mod the modulating the ensuing signal. Neuropathic pain and seizures are the only two conditions for which phytocannabinoids have been granted a marketing authorization in human medicine. There are several ongoing studies exploring the potential use of phytocannabinoids in the treatment of a number of clinical conditions in animals.

Many of these studies are funded by Elevans and or Elevet. But a few are also funded by other animal health and pharmaceutical companies which are developing hemp or cannabinoid-based products. Aside from this, there is plenty of anecdotal evidence, which includes benchtop studies and veter vet and owner feedback, as well as numerous case studies showing different degrees of efficacy in supporting conditions such as separation anxiety.

Joe has already alluded to the exciting recent study evaluating the use of the Evet product in the potential management of atopic dermatitis. Phytocannabinoids and complete or full spectrum hemp extracts impact on quality of life is well known by now. There's evidence of its effects in geriatric and oncology patients, both human and animal, and there are a number of studies being conducted in these areas too.

The human product Sativex does contain THC so it's not directly comparable with complete spectrum CBD. Sativex has been shown to ameliorate limb stiffness and improve motor function in multiple sclerosis patients and is licenced for the treatment of this. Prescription and supply of this product for human use is closely regulated by the Home Office, as I talked about earlier.

Epidiolex has very specific licencing for human seizure management and the precise mechanisms by which it exerts its anti-convulsant effect in humans aren't really known. Can, cannabidiol does not appear to exert any anti-convulsant effect through interaction with cannabinoid receptors. And whereas there's not been any specific studies exploring drug safety or interaction of cannabinoid products in dogs, there is Gamble's paper in 2018 which showed no adverse effects with conventional non-steroidal use.

As the number of licenced veterinary analgesic products is essentially limited, we often reach for human licenced adjuncts or alternatives when required. And again, these combinations often have no specific safety data against their use in animals, but we'll use them based on anecdotal evidence. In my opinion, so long as owners are carefully counselled regarding this information, justified use in this way is of benefit to animal welfare.

And I comfortably prescribe Elevans concomitantly with non-steroidals, gabapentin, tramadol, memantine and amantadine, paracetamol and other drugs. And owners are advised to expect their pet to display increased so initially, especially if they are on SSSRIs or tricyclics. And there is a theoretical risk of serotonin syndrome, although it's not been documented to date with these cannabinoids.

I would avoid administration of any cannabinoid product during the perianesthetic period, . If it means that benzodiazepines are an essential part of the anaesthetic protocol. And I always do warn owners whose pets are also receiving gabapentin and tramadol, for example, that the pet may be sedate for a few days.

Although in clinical practise, I rarely see this happen. So, I wanted to spend the last 10 minutes or so, just going through a few of my cases over the last few years who have benefited from the administration of Eevvans in addition to other therapeutic agents and modalities. So, firstly, Mason, Mason couldn't take many conventional medications due to an intolerance to non-steroidals and long-term underlying renal insufficiency.

If administered non-steroidals, he would generally develop marked hemorrhagic gastroenteritis quite rapidly. And he also has underlying renal insufficiency, so again we had further argument to avoid the use of non-steroidals. He could tolerate paracetamol, but became markedly sedate and other analgesics that we tried, such as tramadol and gabapentin, which was unacceptable for his lifestyle.

His owner is very informed, she's actually one of our anaesthesia nurses, and was keen for us to try and advance to see if he could benefit in his latter years and maintain a quality of life. And he did respond really well to his treatment regime with occasional acupuncture sessions as well. Gina recorded a testimonial with Mason for Elevance.

I always like to add that I wasn't present for any of the two recordings you'll see tonight, and I had no influence on what the owners decided to say to the camera. Although on a more sombre note, Gina lost Mason at the end of last year, so it does seem fitting to acknowledge him now. So rest, rest in peace, Mason.

This is Mason. He's nearly 13. He's a stashable terrier.

He was struggling a little bit, out for walks, just a little bit slow, not quite as fun, jumpy self. Didn't really want to play ball as much as he used to. So he's just got a little bit of arthritis in his front legs, so I just decided I wanted something just to help him along his way, and just get his life back really.

Just went a bit quiet. He's been on the elevvan oil for a year. He's doing really well on it.

I can tell, I've had a couple of days where he wasn't eating, so I couldn't give it to him. He went downhill in those few days, and then he came back to how he was as soon as I started giving it to him, which is really good news for him. He's playing with my puppy and my other dogs at home.

It's brought back his quality of life and his er enjoyment of being a dog again, running on the beach and playing with my others. Billy was seen at my pain clinic for some years due to a generalised osteoarthritis as he aged, and his dedicated owner presented him for regular acupuncture and knew his idiosyncrasies and character intricately. Working through many routine drugs and combinations over time, we discovered unacceptable side effects including diarrhoea, vocalisation, pacing and unacceptable sedation.

He responded well to acupuncture and periodic infusion therapy. Gastrointestinal non-steroidal side effects were acceptable when we used mavicoibrococcy, in his cocktail of drugs. Benefits of elevans were noticed soon after he started, and included increased mobility and heightened demeanour and awareness, decreased pacing, wandering and vocalisation at home with fewer GI signs.

We documented an overall improved quality of life for both him and his owner during the last 18 months of his life. Sadly, senility advanced rapidly during his last few months to a level that was no longer acceptable for him or his owner's quality of life. Josh is an 1115 year old German Shepherd with a history of bilateral cruciate disease and subsequent surgery.

And as a result of his surgery, he developed progressive generalised osteoarthritis, which over time affected his forelimbs as well. And he also likes playing football. He receives a number of different medications to maintain his analgesic requirements, which includes Elavanse, from which he's benefited for some time now.

We've titrated his dose up over time to ensure that he obtains maximum benefit. And again, I wasn't present or had an influence on the recording of his owner's testimonial. It's really worth highlighting the huge difference in Josh's quality of life since starting Evans, and he just remains so bright and happy.

Josh is about 1115 and he's either a German Shepherd or a German Shepherd collie cross because his nose is a bit narrower, so we think he could be a collie cross. And we got him when he was about 10 months old as a rescue dog. When he was about 2 1/2, he snapped a tendon, and when he had X-rays, they said he'd already got arthritis coming on, which was a bit of a shock.

And so probably about 3 years ago, it started to be quite debilitating and he was limping. So he had an infusion of liracaine, which was a painkiller to kickstart his pain threshold and he's having acupuncture and all sorts. And that was kind of stopping it getting any worse.

And then when the vet mentioned the new product, the CBD oil, we, we kind of jumped to it because he said that it had made a difference in other dogs. We were told it might make a difference in about 10 days, and actually for him it, it, it didn't have a dramatic difference, but it was cumulative so as he's, as he's gone on, he's just got better and better. So he's better now than he was two years ago.

And he's definitely happier. He kind of realised that he must have been in pain because now he's smiling and before we kind of got used to the slow decline and hadn't really realised that he must have been uncomfortable, and now that he's not uncomfortable, you can see, yeah, just how happy and relaxed he is. He's walking further and further every day, and it's just amazing.

So my final case is Shankley. He's a morbidly obese Labrador who requires assistance to mobilise. He's got a history of left elbow osteoarthritis diagnosed some years earlier by his referring vet, and he's referred to me with an acute deterioration in his mobility that was associated with his right limb.

His referring vet had been unable to control his pain requirements by the addition of tramadol to his ferocoxib. Our presentation, initially he was unable to walk with a marked right distal limb swelling. We provided rescue analgesia, as you can see on this slide, and he required both ketamine and then lidocaine infusions, ultimately to control his pain requirements in the acute setting.

As you can see from these extracts from his CT reports, he has multiple issues which were con contributing to his presentation. A right-sided septic osteoarthritis was diagnosed following his bloods and CT and treatment was instigated, and this was in addition to his bilateral shoulder disease, left-sided elbow degenerative arthropathy, intervertebral disc disease, and bilateral otitis to boot. He was hospitalised with us for 7 days and and then we examined him a further 7 days after discharge.

And at his revisit, the sedative effects of tramadol and gabapentin had been unacceptable to his owner at home, and she'd chosen to decrease his tramadol and gabapentin dose, and there'd been some deterioration in his ability to mobilise. So we had a an intelligent discussion and opted to add Elevanse to his regime, and I also asked her to give some thought to continuing gabapentin at 3 times daily dosing. He stopped, stopped his tramadol, but ensured that he had some available for an emergency situation, should that arise.

And subsequently had his six week check, although he gained further weight. Individual names, gait and pain scores had all improved, so yeah most definitely improved mobility and quality of life. Moving forward, we've managed to control his clinical signs and lowered pain scores on this drug regime, utilising the Elavans with no negative effects.

Sadly, the, the COVID, pandemic has influenced ongoing treatment options for him, but we do hope to be able to start acupuncture and hydrotherapy sessions soon. At the moment we're trying owner led physiotherapy at home, and he remains mobile with an improved quality of life. So, really just to summarise, .

We most certainly should be mindful and observe for any signs that are suggestive of the occurrence of neuropathic pain. Accepting that it is difficult to diagnose, especially in veterinary patients. We should proactively treat for neuropathic pain, if we have any suspicion of its presence.

And we believe that cannabinoid products do have a role in the management and control of neuropathic pain. And finally, thanks for listening this evening, and I do hope this webinar has served to reassure you of the role of cannabinoids in veterinary medicine. Thanks very much.

A big thank you to Dave in his absence. It's always fantastic to hear the hands-on and on the ground, work that is being done and the results that we're getting. Because it kind of just backs up what the research is showing is going on there.

While I'm thanking people. I'd like once again to say a big thank you to Ellie Vance and Ell Yvette for their generous sponsorship of tonight. And a lot of the questions that have been coming in have been answered.

But I would like to bring Joe back on again. Joe, if you're there, we've got a question that's coming in from Brendan. And Brendan's question goes, CBD, CBDA, how selective or preferential is the COX 2 inhibition?

If the dog is no longer responding to other COX-2 inhibitors, does it mean it will not work? Yeah, I think that's an interesting thought for sure because we do know that the CBDA appears to be more cox to selective and actually CBD and THC have no real good inhibitory capabilities. It's actually only THCA and CBDA that have have fairly good inhibitory capabilities.

And interestingly in dogs you actually get a fairly High THCA concentration from the very small amounts that are actually in the actual Lev product, which is a very interesting thing, and that's actually been shown to be a very big neuroprotectant in Parkinson models and Alzheimer's, etc. So there are some things about the THDA which are are just we don't know a lot yet, but the CBDA has been also shown to be COX2 preferential, though it does have some COX 1 inhibiting capability, and it has to be a fairly high concentration. So actually if you look at the the pharmacokinetics of it, it probably has more of a role in decreasing CO2, expression.

In the actual cell than it does the actual inhibiting the the enzyme itself because you need to be at a micromole concentration and we probably don't get there in, in many instances when we dose dogs, but we what we do get is probably enough PA, alpha, or gamma activity at the nucleus to decrease cyclooxygenous expression is what we would think would happen. So as far as as, as far as not being responsive to NSAIDs, I think due to the other potential benefits of TripV as well as NMDA that I think were probably better because it's almost like a multimodal. It's not just about COX and it may not even be about COX, it's about the neuropathic pain response of the spinal cord and perception.

I think, Joe, that, that's one of the exciting things about a relatively new field and, and there's so much potential and, you know, as we heard Dave saying and you earlier, you know, the results are there. We've now just got to understand why. And, I do like your multimodal scenario because I think that really is a true thing here.

Yeah, I know, I, I agree that it it it is it's, it's much more than just anti-inflammatory, which is the interesting part. Quick one for you, Joe, cause we're just about to run out of time though. We've had quite a few questions coming in about other species, specifically the exotics and the little furries and our friends, the guinea pigs and that.

Anything you can fill us in on, man? Yeah, we, we don't have a lot of data in any other species, and I will tell you that we're starting to look at things that have strangely enough macaques, they, they have a completely different metabolism of cannabinoids than dogs and and cats, so I would say if we're talking about guinea pigs. It's an open book.

Nobody really knows at this point, and all you can do is, is, is probably do a graded, you know, an increasing increasing dose response to see if you can get a clinical effect and if you can't at 2 to 4 megs per kg, then, then maybe guinea pigs metabolise a lot different and so I would be a little hesitant to go and start treating others and, and I think there's been a another quick question that came up before that I didn't get a chance to answer and the question was about giving this orally and that it gets all broken down by the liver. Well, everything gets broken down by the liver, but can we get enough in to where it actually gets to a pharmacologic level? And I think a lot of the work now is showing that it can and it is actually far better than absorb.

Far better with food. So always give with food if you want to maximise your, your absorption and your clinical response. And the idea of delivering a trans mucosally would be a great idea.

I'm just unsure that we get enough absorption trans mucosally, but that would be, that would be sort of a panacea to to to do it transternally or trans mucos. That's fantastic. Unfortunately, we have run out of time.

It is just up to me, Joseph, to thank you personally for your live presentation and the very interesting information you brought us. And then also in his absence to thank Dave for the time spent, to bring this to us. So thank you for that.

Thank you. I appreciate the, the time with y'all. And last but not least, thank you to our sponsors, Ellie Vance and Ellyvette, and most importantly to all of you that have attended tonight.

Thank you for your time. Thank you for being with us at the webinar vet. And I hope you have enjoyed tonight's presentation.

To my controller, Phil and Peter showing the video in the background, thank you very much for all your help. And from myself, Bruce Stevenson, it is good night.