Good evening everyone, and a very merry welcome to the last live webinar of 2021. Our topic tonight is cannabis use in veterinary medicine, and I had the pleasure of introducing you to our speaker, Steven Satow. Stephen originally started college to become a registered human nurse, but did not enjoy working with humans as patients.

Instead, Stephen became a registered veterinary technician and then obtained certification as a surgical research anaesthetist through the Academy of Surgical Research, and then a registered laboratory animal technician through the American Association of Laboratory Animal Science. In addition, he's also a certified veterinary pain practitioner through the International Academy of Pain Management, where he also serves on the board of directors. Stephen is the executive director for the Academy of Laboratory Animal Veterinary Technicians and Nurses, holding a BTS credential in research anaesthesia.

His primary employment is as a laboratory manager with Howard Hughes Medical Institute at Stanford University in the Department of Neurobiology. Steven serves on a multiple scientific advisory boards, professional veterinary organisation boards, and as an avid lecturer on the topics of anaesthesia, pain management, cannabinoid medicine, and research best practises. If you have any questions or comments for Steven as we go along, please hover your mouse on the screen, click on the Q&A box, and we will cover as many of those as we can at the end of the session.

But without further delay, let me extend a very warm welcome to the webinar vet Stephen, and over to you. Hello, everybody. Good evening.

Thank you for joining me. I know the 22nd is, is kind of a tricky time for us all, but I am so happy we get to spend some time together and talk about one of the topics I am very passionate about, and that is cannabis use in veterinary medicine. It is interesting.

I started talking about this, particular, area of interest about 7 years ago, and, boy have things changed from when I first started talking about this when we had almost no, veterinary papers, published. So we have a whole plethora of papers published now. Which, I'm gonna be showing you several of today, which is very exciting.

It is interesting. I am in the USA, and it, it, it's fun to hear from my colleagues in the UK about the challenges and woes of, of cannabinoid medicine in the UK compared to the US. It sounds like, the UK.

Is about a few years behind where we are at in the United States as far as regulations, legality of these types of products, but as we have seen quickly in the last three years, we've seen a lot of laws in favour and, allowing the use of cannabinoids being passed for animals. So I, I do think whether or not it is a, a legally recognised product in the UK at this point or not, it is really important to be aware of these products that our pet owners are using, and certainly as things start to hopefully lighten up for you guys as, as far as regulations go, to be using these types of products safely. Because we are on a bit of a time constraint today and I could talk about this for about 8 hours, I would encourage you to check out the website Vetan Academy, that's V E T C A N N Academy.com.

That's essentially my proceedings for tonight and when we start talking about looking for products to choose, there's a great section since I will not be able to cover that in this lecture today. So before we continue, we, we do need to understand some really important terminology, and the biggest piece of terminology that a lot of people get confused about whether they're talking about utilising these products in practise, or reading it in law, is the difference between hemp and marijuana. So when we say cannabis in general, which is the common term that we see in a lot of laws that are being passed or just in in common vernacular of people.

Cannabis is kind of an overarching term for both the hemp and the marijuana plant. In the United States, a hemp plant, is a cannabis plant, but it has less than 0.3% THC, which is the, the compound or the molecule that gets animals and people high or intoxicated, whereas marijuana has greater than 0.3%.

I don't recall off the top of. My head where the UK falls, but I think it's somewhere close around there. Other countries have increased the amount of allowable THC and what is defined as a hemp plant, but by and large, for Western countries it is 0.3%, THC or greater.

Cannabis can be meaning hemp or marijuana. I use it in the sense of talking about the specific compounds that come from these plants. Marijuana, at least in the United States.

And I believe in the UK is illegal for us to prescribe, recommend, for our animal patients and until you are very, very, educated and well experienced with marijuana or THC use, I am definitely of the mindset that we as veterinary practitioners should be sticking with hemp products and using very, very low, if at all, any THC just because of the, the risk to our patients, . Becoming intoxicated and having less than desirable side effects. Some other terminology I think we need to be very familiar with, especially for this presentation, are the following.

So phytocannabinoids, these are compounds that are coming from the hemp or the marijuana plant itself. So this is generally things like CBD and THC. For the sake of this lecture, we are focusing on CBD with some talks about THC, but we need to understand that there are several 100 other phytocannabinoids things that are like CBD within these plants and these products are available to pet parents.

Then we have these compounds called endocannabinoids. Now, endocannabinoids are compounds that sit at the same receptors that phytocannabinoids sit at, except endocannabinoids are produced by your body. They're endogenous compounds that your body is producing for signalling between cells.

Terpines are the aromatic portion of the cannabis plants, so If you have ever smelt cannabis, whether that's in a legal or an illegal dispensary, you can tell that these different types of plants have different aromas. It's similar to wine tasting. Some might smell more grapey, some might smell more oy, some might smell more citrusy.

We get the same experience and the same kind of . aroma from various varieties of cannabis plants, and that is really dependent on the terpine makeup, and those terpines have their own therapeutic effects. Now we're gonna touch on briefly in the pain section, but they, they add to what's this, what's called this thing known as the entourage effect that we're gonna talk about.

And then we have flavonoids. So flavonoids are the taste component of different varieties of cannabis plants. So similar to terpines, different varieties are gonna taste a little bit different based on these flavonoids.

And then we have the acronym, the endocannabinoid System, which is what we're gonna start this lecture off with, understanding just kind of the basic principles, so you can understand how these compounds are working in the body. Now, it's kind of interesting when we're talking about cannabinoid medicine and especially trying to manipulate or utilise or modulate the endocannabinoid system, is we need to understand that this system, even though it's been with us forever, it has only Be professionally and and scientifically described in the last 40 to 50 years. And it's interesting because this is one of the largest receptor systems in the mammalian body and even non-mammalian species, but we just only recently became aware of it.

I love this paper. This came out in 2013 by some National Institute of Health scientists here in the USA, and they say in the introduction, they further suggest that modulating the endocannabinoid system activity may have therapeutic potential in almost all diseases affecting humans. I would insert animals, including obesity, metabolic syndrome, diabetes, diabetic complications, neuro neurodegenerative diseases, etc.

Etc. Etc. So this is a really interesting target for medical scientists to be looking at.

Certainly a lot of pharmaceutical companies are looking at using phytocannabinoids from the plant or creating synthetic versions of these cannabinoids to modulate this endocannabinoid system just because it is so far reaching and has so much potential for medical benefit. Now, the endocannabinoid system, what is considered the classic endocannabinoid system, the classic endocannabinoid system is comprised of two main receptors known as the CB1 and the CB2 receptor. The CB1 receptor is predominantly found within the central nervous system, and different species of animals have different densities of the CB1 receptor, in the brain and in the spinal cord.

And this is the tricky part as far as utilising things like. CC because depending on the density or how many of those CB1 receptors they have up in the brain can really predict for us how sensitive these animals are going to be to things like THC, the more intoxicating compounds. Dogs in particular have a high density of CB1 receptors in the brain compared to humans.

That's why these dogs seem to need less THC to get that intoxicating effect compared to our human, their human counterparts. Whereas cats, we see less of a density, and cats, interestingly enough, seem to tolerate THC a lot better than dogs. They also, are less inclined to accidentally get into some of the owner's THC products, which is, very nice for us, but when they do, definitely have less dramatic effects.

The CB2, receptor is found more in the periphery, and we see a lot of CB2 receptors. Expression on immune cells, in particular glial cells. So this is kind of an interesting target for a lot of pharmaceutical pharmaceutical companies looking at creating compounds that can work through the CB2 receptor in modulating our immune system, especially for autoimmune type diseases.

So very cool target. It is a little bit more difficult to reach with phytocannabinoids. But is very interesting and fun nonetheless.

What's also interesting about the endocannabinoid system is I mentioned that we have always had an endocannabinoid system, and it's only recently that we have started researching it, within the medical science community, but we do have lesser species out there that have what are called orthologs or ancient receptor types of the classic endok assistive receptors. So even the most primitive species that we have alive today on the planet known as the hydra, which is a deep sea species of kind of tube worm thing, have ortho. Logs that are receptive to phytocannabinoids and even endocannabinoids.

And we have to remember that phytocannabinoids are not just from the cannabis plants. Several plants. In fact, many, most plants have certain types of phytocannabinoids, in particular things like echinacea.

So if you drink echinacea tea, echinacea has a pretty powerful endo phytocannabinoid, that helps with memory and, and waking our brain, our brains up. So, our, our. Evolution and these these receptor types have been evolving together and have been receptive to exogenous and endogenous compounds to modify the system.

Now, the body, as I mentioned, produces these things called endocannabinoids, and these are essentially neurotransmitters or precursors to neurotransmitters and precursors to several other, transmitters that we're, we're familiar with. But so far in the literature, we have 5 main endocannabinoids that have been well described, with 2 being the most dominant, that would be anandamide and 2 AG. 2 AG is our most common endocannabinoid that is found within our physiology.

And as I mentioned, these are precursors to several other compounds that we might be familiar with. In particular, things like anandamide, when that is broken down, that can also be turned into oxytocin. So a lot of times we hear oxytocin being released, after breastfeeding, postcoital, post, you know, some sort of interaction with.

People, anandamide is actually Sanskrit for the word bliss. So not only do we have a surge in oxytocin, but we have a pre-surge of anandamide which then turns into oxytocin. So really interesting physiological impacts by these endocannabinoids, and I believe in my neuro section, I have a a fun paper that just came out about how important these endogenous cannabinoids are for our brain health.

Now, when we're talking about the affinity of either endocannabinoids or phytocannabinoids to those receptors that I talked about, this is a little schematic that I, I drew up. I hope it, I hope it makes sense to you, but on the left hand side of the screen here, we have, this is supposed to be a CB1 receptor, and I, I want to note that the CB1 receptor is the only receptor when it is agonised, has that effect that is causing that high effect. So the CB1 receptor is responsible for that high effect.

So, in our normal physiology, we have an endocannabinoid that sits or has some affinity for that CB1 receptor, and it sits in what what's called the orthosteric binding site, which is a primary kind of lock and key mechanism for that receptor. So those little diamonds are supposed to be representative of endocannabinoids, and then we have things like phytocannabinoids. So the THC class of phytocannabinoids are the only phytocannabinoids that are going to sit in that same spot where typically our endocannabinoids are sitting, the things that our body is producing.

In fact, THC, delta 9 THC has such a strong affinity for that CB1 receptor, it can kick off that endocannabinoid from It's normal seat. So it's kind of like when you are, are giving buorphenol or morphine, we don't necessarily want to mix those together all the time, and we want to be very cognizant of timing and dose because we know that butorphenol can kick off morphine from that opioid receptor, and we know that butorphnil is maybe gonna be less effective for pain management compared to our, our morphine, compounds. So the same thing is kind of happening with THC except THC is really powerful and will create some intoxicating effects.

What's kind of interesting about THC and because it does sit as an orthosteric binding site, we can have technically down regulation of endocannabinoid production. So, you know, I'm sure we were all educated when we were younger, but then until recently the cannabis industry is really promoted that you cannot become addicted to cannabis. That is a myth.

You can certainly become addicted to cannabis, specifically THC. You cannot become addicted to CBD, but you can certainly become addicted to THC and until your body kicks. In, if it was down regulated and producing those endocannabinoids, you are going to have some withdrawal symptoms.

Thankfully, in people, we don't have this described in animals yet. We know that, that, that down, regulation is only occurring for about 72 hours, . Until it starts to kick back on again in producing those endocannabinoids after you have stopped consumption of THC.

Now, when it comes to other compounds, other phytocannabinoids within the cannabis plant, they sit at a little bit different spot than THC. They sit in what's called an allosteric binding site. So they sit kind of on the side and this other little part of the res of the receptor, and when they bind to that part of the receptor, they kind of change the shape of that orthosteric binding site where THC or those endocannabinoids would typically sit.

When it does this, It loosens or can dampen the effects that we would see from THC specifically. So there's a lot of interest in producing a CBD, a pure CBD product to actually reverse the effects of THC. I, I think we still need a lot more, work to really have a product for that.

But I will say anecdotally, I have had good success with this for those intoxicated, patients where we weren't necessarily wanting the amount of THC that they consumed. What's also kind of interesting is when I first started talking about this, I've had some other colleagues start talking about cannabis as well in veterinary medicine, and they're very hopeful, very excited, but we're shy about using these compounds because the endocannabinoid system is fairly new to us, and they just were concerned about the overall. Physiological effects.

But I would argue against that because we have several medications that we use almost on a daily basis, especially in a surgical practise that work through or, by the endocannabinoid system. And two drugs, that I'm, I'm sure we're all familiar with that work through the endocannabinoid system are ketamine and propofol. We also have a, a more common drug that's used in the UK compared to the US, but paracetamol also works in part through the endocannabinoid system.

So we've been modulating and playing with the system for a long time, let alone the thousands of years of, of use that people, have been. Self-dosing with and giving their animals as further evidence as far as the safety because we have yet to have a medical report, defining THC intoxication as a cause of death for an animal or a human. We also have a new expansion of the endocannabinoid system, and this is called the endocannabinoid OM, given the promiscuity of some of these phytocannabinoids and even our endocannabinoids.

So, these are just a few of the other receptors that we see some binding affinity of either endogenous or phytocannabinoids, . To, in particular, these particular receptors, I, I find particularly amusing such as the serotonin receptor, TRIPV receptor, which is, a very important receptor for inflammation and pain signalling, and some of our nuclear receptors such as PAR alpha and PAR gamma which are really important for cancer mitigation. And certainly gene expression of other different types of diseases.

As I mentioned, the CB1 CB2 receptors are G protein coupled receptors which, makes up the largest amount of receptors in our system, and, we also see some affinity to the GPR 55 receptor which was argued at one point to be possibly considered one of the, the 4th opioid receptor. All right, as far as toxicology goes for these particular compounds, we have this great paper published in 2012, out of Colorado after Colorado made recreational, marijuana, legal in their state. And what this study did is they looked at 125 cases of dogs that consumed, .

Unintentionally, their owner's stash of marijuana. And out of the 125 dogs, two of them were euthanized. And what's, what's kind of interesting about the dogs that were euthanized is in talking with some, board of toxicologists, friends of mine, Dr.

Justine Lee and Dr. Ana Brutlag, we all agree that if finances weren't a limitation, the two Animals that were euthanized based on their intoxication, probably could have been saved. And what was kind of stand out about those two particular cases that were euthanized is one of the dogs did eat a tray of brownies.

So not only did you have the THC intoxication, but you also have the theobromine intoxication as well. And then the other dog, I believe, ate some raisin cookies with some THC in there. So not only did we have the THC, but we also had the raisin toxicity.

In 1972, this paper was published. This was done in rats, dogs, and monkeys, and they were actually trying to find an LD 50, so lethal dose of THC in dogs and monkeys and rats, and in the dogs and the monkeys, they gave between 3000 and 9000 milligrammes per kilogramme of THC to these animals, and none of these animals died, which means we have a very high, therapeutic index. Very good safety margin.

Of course they are totally intoxicated. That is not pleasant. We still have to offer excellent nursing care, but as far as injecting or orally administering THC, we are likely not going to give a dose that is going to kill the animal in the sense of like giving the same amount of pentobarbital, or some other more kind of toxic drug.

It is very difficult to kill an animal with THC. As far as CBD goes, we have, we don't have. Good enough studies in canines and felines so far, but in rodents, they have been giving around 3000 milligrammes per kilogramme and have been unable to kill an animal with even those super high dosages of CBD.

There has been a great write up by Doctor Brutlag. She's one of the, the toxicologists I mentioned earlier. This is available free for download.

I believe it's on our website as well. She also did the toxicology chapter in the cannabis, medicine textbook that we published, earlier this year. So you will see that at the end of the presentation.

As far as PK studies go, and our small animal friends, we have, 6 PK studies, giving orally, sorry, 5 of the products were given orally to dogs. One of them was given transmucosally, and we do see good absorption orally or trans mucosally. We have found that in dogs that are getting it with a small amount of food, we get better absorption.

So this whole idea of giving it 2 hours transmucosally, before a meal or 2 hours after a meal is not really panning out. We have enough evidence really showing that giving it with a small meal, giving it, into the stomach is gonna have good absorption. As far as our feline friends go, we only have one PK study in our cats that is published.

There are multiple that are being published or being written right now. And then we have a great safety study that was done by our friends in Canada, giving pretty high dosages of CBD and THC to cats and showing good relative safely to our cat friends as well. Both of these studies show that cats probably will need higher dosing compared to dogs or more frequent dosing.

There was some concern because these phytocannabinoids, when they are harvested, depending on the acidic environment there in, oxidation, heat, especially, you can convert some of these phytocannabinoids into other phytocannabinoids, in particular CBD into THC with heat or acidity. And there was some concern that when we give. CBD into the stomach that the CBD would turn into THC and then create intoxication in that animal.

Thankfully, I believe last year, when did we publish this paper? In 2020, sorry, I had to look at the date there. We published a paper showing that this does not actually happen and, that has since been proven in people as well that even though theoretically.

We can turn CBD with hydrochloric acid on a bench into THC that is not happening in the stomach for whatever reason. We don't necessarily understand why that is not occurring. We think there's some sort of protein or lipid binding that is, offering a protective mechanism for CBD to not transform into or decarboxyate into THC.

Long-term effects. This is always a point of interest for a lot of practitioners because we do want to give these things long term, and we do have some research on that. There is this great study that was published in 2019.

This is a 56 week long study. This is very, very long for a veterinary paper. This is not necessarily.

Veterinary paper, but for most of the veterinary papers out there, 28 weeks is considered a long-term study in our literature. This is 56 weeks, almost double that. And these, dogs and these rats were getting really, really, really high dosages of THC and CBD.

They were getting about 25 milligrammes per kilogramme of THC and CBD, for 52 weeks after acclimation, and These animals did great. There was no need for medical intervention intervention. Yes, they were intoxicated.

They were high for several weeks, but as I mentioned earlier, because THC sits in that orthosteric binding site, you can become addicted to it, you can become addicted to something, you can also build up a tolerance to it. So, tolerance was built up over several weeks and the animals were fine by the end of the study. We also have this paperwork that was submitted to the FDA.

This was never written up in a formal study, but this was part of the documentation for an FDA approved CBD product here in the United States called Epidiolex. I believe that's also available in the UK, which is a purified CBD product. This study was for 39 weeks and they were giving anywhere between 10 and 100 milligrammes per kilogramme QD to these animals.

There was no need for medical intervention, however, they did note that there were, increases, slight increases in ALT liver enzymes, and moderate increases in ALP, which we will talk about cause I, I am doing a study now to see where that ALP elevation is actually coming from. Point of this slide is that these animals are receiving the CBD for 39 weeks at relatively high dosages, typically not dosages I would use in practise, and were overall fine by the end of the study, and this product didn't get approved, so it certainly did not concern the FDA either. When it comes to cancer, this is a big area of interest, and this is a point where I really want to stress, we need a lot more research.

I am not scared about using CBD products in these animals, but to think that we are going to treat or cure cancer with these phytocannabinoids, I think is a little naive at this point, and we need to be very cautious. The reason I say that is, there's been multiple papers. This is one of my favourites from David Mary, who's a researcher out of Israel.

He has found that each specific type of cancer is going to need a very specific ratio or formula of phytocannabinoids and terpines for that particular cancer. So it's certainly not gonna be one CBD product fits all for all these different types of cancers. It's looking like we're gonna need special mixtures of CBD THC, maybe some CBC, CBN, all these other phyto.

And urines to actually target that specific type of cancer. In fact, there's been a lot of push for THC being used in cancer patients. And, and when I talk about THC use or phytocannabinoid use in cancer in general, I try to stress to people that there's two different dosing schedules that we need to consider.

There's dosing of phytocannabinoid products for symptomatic relief. Nausea, pain, appetite, and then there's dosing for anti neoplastic or anti-proliferative effects of cancer. Two very different things.

And THC has been by and large, really kind of pushed, as far as the compound that needs to be used to kill cancer, whereas we actually have more research, in humans, cancer cell lines showing that THC can be. Increasing the amount of cancer for certain types of cancer, in particular squamous cell carcinoma. So if your animal, if your patient has, cancer, the owners are interested in using a phytocannabinoid product, I steer away from high levels of THC in those products because I am concerned that it could actually have a negative instead of beneficial effect.

As far as canine specific cancer cells, we do have a few studies that have been published, which is very exciting. On the left hand side of the screen here, a colleague of mine and, and a friend of mine, Doctor Joe Washlag did a really cool IC 50. So these are plated and a petri dish, canine cancer cell lines.

We have Canine osteosarcoma, mammary carcinoma, and lymphoma. And what he did was he bathed these particular cancer cell lines in CBDA, which is the acidic form of CBD before it becomes known as CBD and found, CBDA didn't do a very good job at killing these cancer cells with CBD in particular. Wow.

So, CBD did kill those cancer cell lines pretty well. And then when he mixed them together and added those urines in there to get that entourage effect, we get just as good efficacy at killing those cancer cells as Bencristine and doxorubicin without the negative side effects or concerns that we have to be, worried about with typical chemotherapy agents. Doctor, McGrath at Colorado State University was also part of this study that's represented here in the bottom corner, bottom right corner with canine glioma cells and found that CBD was really good at killing this aggressive type of cancer cell in dogs.

However, for both studies, If we were gonna translate this IC 50 bath into a dose for a living animal, the dose would be relatively high. It's gonna be between 5 and 7 milligrammes per kilogramme or higher, which can be cost prohibitive. A lot of clients come in.

Wanting to use these compounds because it's more natural and they think it might be cheaper than chemotherapy, but with the doses necessary to actually kill cancer, it's probably going to be as expensive, if not more expensive, than chemotherapy. As I said, this is where entourage effect is very, very important, utilising multi, compound products instead of just relying on one compound at a time. The good news is about using phytochebinoids with traditional chemotherapy.

We have a number of human studies showing that the addition of phytocambinoids, things like CBD actually helps chemotherapy drugs work better, where you can actually decrease the dose of the chemotherapy drug, which is always advantageous for most of our patients. As I mentioned, THC, I would be very, very hesitant. I have this great paper here that you guys can access on the Veterinary Cannabinoid Academy Facebook group.

I don't have this on the website, but it's, utilising low THC products for cancer mitigation. We do have one study published. I think there's a lot of limitations to this study.

This was from a veterinarian in Thailand. I do appreciate that this veterinarian wrote this up, but I, I am a little bit sceptical, but I, I am happy that it has been published. This nasty tumour after several weeks of oral dosing of a cannabis product, this tumour shrivelled up and fell off the cat, so very exciting stuff there.

When it comes to pain, this is another common area of interest pet owners want to use these types of compounds for, and in fact, the National Institute of Health here in the United States does have a cannabinoid interpine pain conference every year, which is very exciting. If you want this, proceeding, textbook, I'm happy to send it to you if you email me. And I just want to touch on terpines really quick because I'm not gonna spend a lot of time on them.

They are, as I mentioned in the beginning of this presentation, the aromatic compounds found within the cannabis plant in addition to phytocannabinoids. My favourite terpine is mersine, which is often found in hops that make beer, also found in mangoes and several other plants. And what's really cool.

About Mursine in particular is it can be reversed with naloxone and yohemine. And if it's being reversed with naloxone and yohebine, we know that these compounds are likely working on our, or are working on our opioid receptors and our alpha receptors, which are two very receptors important for pain, management. OK.

So, how is CBD working for pain? CBD itself is working for pain by doing a couple of things. And the most prominent thing that it is doing within our physiology to decrease pain scores is it is decreasing inflammation, not by the same means as nonsteroidal anti-inflammatories, and not necessarily by The same means as steroids, but even higher in the physiological process in the inflammatory cascade by preserving endocannabinoids from breaking down into arachonomic acid.

So, I also mentioned that ananamide is a precursor to oxytocin. Ananamide and 2HG, the two most common endocannabinoids, when They are broken down by the body by some hydrolyzing enzymes, fatty acid amide, hydrolase, ha, and MAGL. It is broken down into acheddonic acid, which, as you know, is a catalyst for this inflammatory cascade.

So CBD will help preserve and keep around those endoketaminoids longer, so it's not turning into this catalyst for the inflammatory cascade. Whereas other phytocannabinoids, in particular the acidic forms and CBG, which is a precursor to CBD and THC, have actual COX inhibiting effects. So these are working like traditional non-steroidal anti-inflammatories.

Hence I mentioned using multi-compound products to create this entourage effect so we get essentially a Multimodal pain management plan with one particular product, which I just think is brilliant. I, I'm so excited about that. So the acidic forms are working like traditional non-steroidal anti-inflammatories.

The question we get all the time is, can I mix traditional non-steroidal anti-inflammatories with these acidic forms since they are working similarly? And what I, we know so far is, yes, this. Appears to look safe.

We do not have any adverse effects so far. We don't necessarily understand why we are getting this, this, benefit without seeing some of the detrimental effects, such as when we mix two non-steroidal anti-inflammatories together or a non-steroidal anti-inflammatory and a steroid together, but we know so far this does appear to be safe in animals and people. As far as clinical studies that we have available, we have 5 that have been published, all in dogs for osteoarthritis.

So this is a chronic pain state. We don't have acute pain state data at this point, but some of the stuff that is in the works is also looking promising and certainly for all. Of the OA studies, that I'm showing here, there was a decrease in pain scores.

There was only one study, done by, Doctor Mejia, again out of Doctor McGrath's lab showing maybe less than stellar results, but in general it was all positive and showing relative safety in canine species. What's interesting and part of the research that I was talking about earlier in multiple of the studies that I showed you, on the pain scoring and, and treatment for osteoarthritis, a few of the dogs in those studies did have an increase in ALP, a liver enzyme in the, the canines, and there was some concern as to why the ALP was increasing. And in general, we need to remember that an increase in ALP alone is not necessarily as Concerning as multiple liver enzymes being increased, ALP alone, occurs with several different drugs that we give chronically and by and large the data is showing that it's not a major concern, but something that we should look out for.

So what are some of the postulations as to why the ALP is going up? This is something that I'm very interested in in doing a study on right now. So when we submit blood work to a reference laboratory or do it in a hospital, we are getting a total ALP.

Concentration measured in that serum or that plasma. What is not being done is looking at the specific isoform of ALP, whether it's coming from the liver or if it's coming from the bone. There have been other studies in rodents and certainly in people now because there are companies looking at CBD for osteoporosis in women showing that osteoporosis actually increases bone density.

So if we are increasing bone density with the administration of CBD. Is that ALP going up because of bone growth like we see in younger animals? So that's what we're trying to figure out now.

I'm hoping to have results by next year, but I have a, a high suspicion that we are actually getting a benefit from this increase in ALP instead of a concern for hepatic insult. For neuro disease and anxiety, again, another common reason and people want to use this stuff in particular with epilepsy that became quite popular with Charlotte and her CBD product. So Doctor McGrath has published one study so far showing that CBD at 2.5 milligrammes per kilogramme twice a day, did have a reduction in severity and frequency of seizures in dogs that are on multiple anti-epileptic drugs at the same time.

Their goal was 50% reduction. They did not meet that goal, but with their longer term study that they have going on now at 4.5 milligrammes per kilogramme, I suspect they are gonna reach and probably exceed that 50% threshold that they were trying to to reach earlier.

The reason that I, I think this 2.5 mg per kg dose failed is generally animals often need higher dosages compared to humans, and for the human CBD product, they normally start children at 5 milligrammes per kilogramme. So I do believe the higher dose is going to be successful, but 33% reduction is noticeable to pet parents, so I certainly think this is a great option for them to consider.

What's also nice is we now have a study that was published, I believe this month or last month showing that we can safely give CBD with phenobarbital. We know that they are not necessarily going to increase serum concentrations of either particular compounds like we thought they were going to because of the interruption that CBD can have with cytokine B450 enzymes. We know it can safely be given with Keppra because we have different, metabolic roots, so not concerned there, and it can certainly be given with KBR as well.

Now, here's that that study I was talking about and kind of excited to share with you. Remember how I mentioned that endocannabinoids are broken down into achedonic acid. So here at Stanford, this is a lab just down the hall from us, they discovered that during a seizure event, an epileptic event, there is a surge in the production of endocannabinoids up in the brain.

And they know that these endocannabinoids are being produced at this high concentration as a neuroprotective, advantage, for the brain. Unfortunately, after the seizure event has occurred, the body wants to get rid of that high concentration of endocanabinoids relatively quickly, and it turns it into a achonomic acid, which is not necessarily good cause that's a less than fun inflammatory process that's happening, that can lead to all sorts of different things such as memory loss, fatigue in general, sore joints, just general malaise, and what, what I am suggesting. Is not only is CBD going to be possibly beneficial for decreasing or minimising severity of epileptic seizures, but it should also technically be helping with the postictal stage as well.

So, very exciting stuff, that, I, I hope we get some more data on soon. As far as tolerance to CBD. When we're talking about tolerance for epilepsy, it has been described in human literature that, people that are on CBD for a long period of time can build up a tolerance, and this is really no different than the tolerance that we see built up with phenobarbital and even Keppra, and The way you solve this problem of tolerance is in the abstract, the human study, they gave more CBD without concern.

So if we do see tolerance built up over time in our epileptic patients, we can just increase the dose. This is not something we typically see with use of CBD and other conditions. When it comes to anxiety, and stress in general, we have, one really poor small animal study and then one decent small animal study, and then we have a a fun study in fish where they, they did get fish drunk.

You can see in the bottom left corner here where they gave the fish ethanol, the fish swimming around like a drunken fish. And then they gave the same fish, CBD and you can see the fish is not swimming and it's little, adaptive. Swimming patterns to avoid predators.

And in fact, we have met multiple other studies of rodents, being given phytocannabinoids and then exposed to a snake or some other prey species, and they are not having that adaptive evolutionary response to get away from that animal, but does show that these compounds are being useful for, decreasing, sensitive sensitivity to stressful events. This A study that I don't necessarily appreciate, I believe, was, was poorly designed. This was in dogs.

They took dogs out of a shelter setting and acclimated them for two weeks. I think as veterinary professionals were all very aware that acclimation of 2 weeks out of a shelter setting is not adequate. And then they put these dogs in a sound room and they blasted loud sounds after dosing with CBD and found there was no major change.

. So I think there's a lot of limitations to this study. I'm glad it didn't show anything particularly negative, but that study failed. Another study that was a little bit more positive, but not necessarily screening success was with, again, shelter dogs being given CBD.

And exposed to humans, where there might have been some aggression before, and it did decrease aggression towards animal caretakers within a shelter setting. So that was semi-positive. And we have to remember how CBD is working within the brain for stress and anxiety in general.

It is not necessarily gonna be sedative like some of the other drugs that we might be using like trazodone or gabapentin before they are acclimated. Really what CBD is supposed to be doing is helping with memory formation and processing. CBD and sorry, not CBD endocannabinoids during, foetal development are also very important for neurogenesis.

And neuro pruning. So these compounds are working very similarly to our endogenous compounds. They are not necessarily decreasing anxiety in the traditional sense of like GABA production, but they are helping with memory formation and processing in stressful events.

We also know that these phytocannabinoids in particular and even endogenous cannabinoids do have some affinity for other important receptors when it comes to stress and anxiety in particular dopamine and serotonin receptors. So theoretically we could, we should be watching out for our patients that are on traditional SSRI SNRI type drugs, and CBD together. There is a Very, very small potential.

It has never been described. I am personally not very concerned about it, but I, I do think it's worth sharing. There is a possible increase for serotonin syndrome if you are on high chronic dosages of SSRI drugs, SNRI drugs, and CBD products at the same time.

Again, it hasn't been described in humans who we know, are mixing these compounds together and certainly has not been described in animals either. OK. And what's kind of interesting when it comes to these products, the urine profile is gonna be very, very important.

We know that these tines can certainly change, how the physio the physiological effects are expressed with phytocannabinoids, given at the same time. You can see in this study here, this was in humans, on their left hand side of the screen, you see a very similar phytocannabinoid profile that's THC and CBD, and then on the right hand side of the screen you see different urping representations and how those are changing the affect in the people that were consuming these products. The product on the top of the right hand side of the screen, A has a lot of Neildool, which is a tarping that is often found in citrus fruits.

So citrus fruits, by and large, we, are normally, when we smell those fruits are uplifting, they're, more awake. Awakening to our physiology compared to compounds like mersine, which is found in the bottom product which was successful in decreasing anxiety scores in these people. Mersine, as I mentioned, is that same compound that can be reversed with naloxone and yhemine.

We know that this is more of a, a a dulling or a calming type turpine. Same with Liol, which is also found in lavender. Feline cognitive, dysfunction and certainly, canine dementia or canine, sundowner syndrome is are a few of the areas where I see a lot of great success, at least anecdotally.

I haven't seen a paper on this yet, except for this one suggesting that, feline cognitive dysfunction might be a really good model for CBD research for Alzheimer's disease. These animals, as you know, can be pretty dull, they get lost and confused at the end of the night, maybe. They're vocal, maybe there's even a little bit of aggression.

In my personal clinical experience with giving CBD to these types of patient, populations, there is almost an immediate turnaround in those patients. It, it even causes some concern with pet owners cause they're like, they're acting like a puppy again and, and they weren't anticipating that, that good a result. So, this is one of the areas where I really love to use CBD in those canine, cognitive, and feeling cognitive disorders.

As far as eyes go, when I first started talking about CBD products in particular, I was very cautious about using CBD because there are human studies suggesting that CBD can increase intraocular pressures. As I mentioned, things have changed and studies have come out, and I think I was maybe mentioning that so much. The company that did this study, got tired of me saying that, so they, they incorporated it in one of their studies, and they showed, at least in healthy dogs that, giving CBD at relatively high dosages did.

Not increase intraocular pressure. So, it does look like it's probably gonna be a safe option for those animals. However, you know, that's one study with a small amount of dogs, so I would just stress caution, but so far it doesn't look like it's gonna be a big concern for us.

When it comes to dermatology. There was this study that was published in 2020. I, I, there's a lot of limitations to this study.

I, I think it's creating a lot of unnecessary concern, because they were trying to tie, a CBD product to this adverse reaction in this dog. And if you look at this, this is typically not something we see with something that is consumed as far as an adverse reaction. To me this looks like a chemical burn, .

And one of the other limitations in this particular study is they did not test what was actually in the product, nor did they have what's called a certificate of analysis to really assess what was in this product. So I do not think that this is actually caused from CBD, especially because we have multiple studies showing that CBD can actually be beneficial as far as its use in inflamed or traumatised tissues where we have an overexpression of ECS receptors. This, product I believe should be available hopefully in the United States and UK next year.

I know they are certainly working on getting licencing for this, but, this, this particular company KPal has created a CBD product, and did some studies showing that CBD is decreasing puritus, at least by about 50% in dogs with atopic dermatitis, . There's a few, Italian studies as well, showing very similar results using a CBD product and decreasing puritus in those itchy animals. This is a kind of interesting study looking at the expression of endocannainate system receptors in, gingival tissues and cats with stomatitis.

Anecdotally, I am also very excited about the use of. In stomatitis cats for multiple reasons. One, we know that at high enough dosages, CBD can be immune modulating, so hopefully some benefit there.

We know it's gonna be pain decreasing, and then certainly gonna stimulate, appetite in our feline friends. So I do like to use this stuff transmucosally, in our stomatitis cats. I believe there's some studies currently going on and, hopefully we'll see those results next year.

As far as GI disorders, there's a lot of interest in utilising CBD for infla inflammatory bowel disease, and syndromes in people. There's a lot of good data suggesting that CBD products are really good at calming these inflammatory processes, in humans. We do have some great studies showing endokeamin system receptors in canine and feline GI tissue, and what's kind of cool about this is If we are using CBD products specifically for GI diseases, I believe the dosing can be a lot lower because we have those receptors along the GI and we don't necessarily need a full systemic dose to get into serum or or plasma levels, or yeah, so we don't need to get a high enough dose in the of CBD in the serum or plasma to reach those receptors elsewhere.

They are found well, in good concentration in the GI. What's also kind of cool is we do have some studies showing that we have some positive metabollo effects after 3 weeks of supplementation with CBD and Doctor Jewitt at UCLA has been giving phytocannabinoids and synthetic cannabinoids to rodent models. And showing that there's an increase in natural killer cells and a a a healthier microbiome for animals that are given these synthetic or phytoanbinoids, which is also very great because we know that the microbiome is super important for not only our immune system, but certainly behaviour and just general health.

All right, so kidney disease is another area that people want to utilise these products more so for those animals in particular cats that are uncomfortable and maybe could benefit from a non-steroidal anti-inflammatory, but maybe there's some concern about utilising non-steroidal anti-inflammatory. It does appear, at least from human literature and certainly the Limited veterinary literature so far that utilising phytocannabinoid products is going to be useful, in these patients. And it's also nice because if that animal was on a non-steroidal anti-inflammatory and we're a little bit concerned about that because they're not eating or drinking well, we don't have that same concern when it comes to phytocannabinoids.

In fact, there was a. A consensus statement from a group of human nephrologists, showing that while there is little data in humans showing true safety, in their human populations, there are enough, reports of anecdotal use by chronic and acute kidney failure patients showing, good results and relative safety. When it comes to anaesthesia, even though we do have receptor affinity at multiple other receptors, it doesn't look like it's gonna be profound enough to where we need to really change anything when it comes to anaesthesia.

Anaesthesia is the great art of giving things to effect. And certainly when we are utilising CBD products, we may need to decrease dosages, we may need to increase dosages of things, but we are giving the same anaesthetic drugs to effect. I would not change anything, major at this time.

There has been one abstract that was presented about hopefully decreasing the amount of anaesthesia needed for patients that were on a CBD product. It was not necessarily showing that we were able to decrease the Mac with CBD products, but overall, it, it did appear to decrease overall pain scores in the weeks, following the procedure when in combination with traditional pharmaceutical, analgesic drugs. Common drug interactions when you are giving a CBD product, benzodiazepines, gabapentin, a chromazine, tramadol, trazodone, phenobarbital, we can also see some fairly transient, lethargy when we start a CBD product with these drugs, in particular with benzodiazepines, it does look like, these animals, even if it is a purified CBD product and you mix it with.

Benzo, these animals do look intoxicated. Again, that is fairly transient. In, in that case, I would say decrease the dose by 50 to 75% of the CBD product or the benzodiazepine, and that usually goes away.

Again, that doesn't happen in all patients, but I, I do think it's worth mentioning that benzos seem to have the most interesting, drug to drug interaction. Other common adverse events are that we might see, we, as I mentioned, lethargy, vomiting, or poor stool. I don't think this is from the phytocannabinoids.

I think this is from the carrier oils. Less common, we have inappotent in particular, if the, the product you're using has a lot of a urine called humulin in it, that is an appetite suppressant. So be careful there, .

Pris as well, very uncommon, but again, I think this is more related to the ingredients used in kind of the chew formulas that you might see or the the carrier oil, rare but noteworthy, hyperesthesia in particular and brachiocephalic breeds like pugs or Labradors, similar to like what we see with Benadryl in Labradors, some labs. Respond well. Some dogs don't repel respond well at all.

Notable, but cessation usually cures or rectifies any of these concerns. In-house testing, I do like if the animal is going to be on a product for greater than 3 months to do a non-steroidal anti-inflammatory panel, so looking at the liver enzymes, if they are on phenobarbital at the same time, and if you have that clip or have that reference lab fairly cheap, value, I would run a phenobarbital to see if those those are changing given the cytochrome B450 impacts. We have a lot of concern about the quality of products.

We published this paper in 2020 as well, and we found that some products had very concerning levels of, contaminants in there, in particular lead. So I would be cautious, and I would ask for something that's called a certificate of analysis. We don't have time to really go over that today, but if you go to the Vetan Academy website, we have a whole section on understanding and reading a certificate of analysis for assessing these products that pet parents might bring in.

I'm very proud of a textbook that we had released this year with a number of colleagues of mine, called Cannabis Therapy and Veterinary Medicine. This is available by Springer Nature. And with that, I will take any questions with the small amount of time we have left.

I, I wanna thank you so much for joining me and I hope you enjoyed. Wow, thank you so much for that, Stephen. I, I feel like I have learned so much.

I can't even tell you there's so much that you've covered in that. And I have to admit it's not a topic that I, I know, or should I say knew a great deal about, but I definitely feel like you've expanded my brain considerably, this evening. So I'm just gonna say, give people a few minutes just to pop any questions if there are any coming through, but I imagine everyone else's brains are probably expanding and they're wanting to digest it.

But we'll give them a second. And I think, did you say your ALP study is coming to the conclusion next year? So can we expect some some results from that next year?

I think we might have to have you back, Steven, to be honest, to kind of tell us everything that you found out at that point. Yeah, we can certainly do that. I'm, I'm super excited about it cause that's a very common concern we hear from a lot of practitioners, and I'm, I'm very excited to hopefully prove that we should be not as concerned as as maybe we are, so very excited about that.

Yeah, it's and it's interesting what you're saying about the the ocular swelling as well and, and how, you know, we have these concerns, don't we, about, about using some of these products and all you know should, should we or shouldn't we? And I think you have, you've laid a lot, a lot of queries and concerns to rest this evening, which is great and thank you so much for. Providing the wonderful studies and things that you that you have.

I know you guys said that they're all available, aren't they, so that we can share them across, and you said there's there's access to the, to these journals, so which is great so everybody can, can access those if they want to see if there's any other. Questions I think everybody's just absorbing all the information that you've just provided us with. There's just so, so much there to take on board.

So I don't think there's anything coming through at the moment, but I think you've just done such a fantastic job, Steve and I think that's a, a credit to you. So thank you so, so much for that. To everyone that has joined this evening, thank you so much for your time.

I really do hope you've enjoyed the session as much. As I have, and you, you have this time now to go and digest it, have, have a mulled wine maybe whilst you're doing it, have a little sit down, a little think about it all, and come back to us obviously with any feedback that that you may have. Thank you obviously to, to Dawn, our controller behind the scenes, here for making sure that everything ran smoothly this evening.

And most importantly, of course, a huge thank you to you, Stephen, for sharing your extensive knowledge with us. And the night before your birth. No less.

So have a lovely day tomorrow. I do hope you, you do celebrate in style. As I said earlier, this was our last live webinar for 2021.

We will be back, don't worry, on the 6th of January with our first live member webinar of 2022. But for now, it's a good night and happy holidays from everyone here at the webinar best. Thank you.

Cheers.