CBD Conversation with Dr Saoirse O'Sullivan & Dr Andy Yates

CBD Conversation with Dr Saoirse O'Sullivan & Dr Andy Yates

Introduction:

Joining Anuj Desai (the host) are Dr Saoirse O'Sullivan (pharmacologist) and Dr Andy Yates (pharmacist) who are at the forefront of cannabis science. This discussion focuses on the difference between natural and synthetic cannabinoids. It is a fascinating conversation delving into the different types of cannabinoids and the functions of each of them. You might want to keep a pen and paper handy as you'll definitely want to take notes and get stuck into your own research after listening to this one. 

Summary:

  • A cannabinoids is ‘anything which binds to cannabinoid receptors or is structurally similar to the chemicals which bind to the CB1 or CB2 receptors’.
  • All cannabinoids are different and interact uniquely with the body.
  • There are three main groups of cannabinoids: endocannabinoids, phytocannabinoids, and synthetic cannabinoids.
  • Endocannabinoids are the structures our bodies create that bind to cannabinoid receptors.
  • Phytocannabinoids are mostly derived from cannabis sativa.
  • Synthetic cannabinoids are made in a lab in an attempt to replicate the characteristics of a naturally occuring cannabinoid.

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    With all the questions and research surrounding CBD it’s no wonder it can be a bit of a minefield to learn about! We take our role of creating pure CBD of the highest quality seriously which is why our focus at BeYou is on science, innovation, and products. As a leading CBD brand in the UK we're beholden to the regulation set out by the MHRA preventing us from making claims about CBD. While this often makes it harder for us to answer some of the questions we get, there are some experts in the field that you can go and listen to.  The question is, where do you start, and who do you trust?

    People have often asked us to do a podcast to help spread our knowledge and those CBD experts we are in contact with. However, we also have an obligation to use our time pushing boundaries and taboos. So we prefer to leave podcasts to seasoned industry experts who have these conversations in an attempt to empower all of us!

    The Cannabis Conversation is a podcast which gets deep into CBD as an industry. We provide it as an external resource to give you a starting point for your own research and to help you get started on your CBD journey. We know a lot of you prefer to read about CBD so, hit play and read along, or just listen, or just read(!) and see what all the hype is about.

    It is hosted and led by Anuj Desai, a commercial advisor, lawyer and founder of Canverse – a leading consultancy in the cannabis industry.

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    The Transcript:

    Welcome to the cannabis conversation with Anuj Desai, where we explore the new legal cannabis industry. We're speaking to the professionals that are helping to shape it. So I hope you had a very good week. More great news on the cannabis front, coming from New York this time. This week the New York legislature passed a bill to legalize recreation cannabis. New York is obviously one of the biggest states in the U.S. and it's estimated that annual revenues could be as much as two and a half billion dollars in just a couple of years time, which is obviously quite sizable. What's really nice about this story is there's a very strong social equity theme to it with some rules to prevent basically the big players from some really dominating, so there's open competition in the state. 50% of the licenses, I think, are reserved for social and economic equity applicants, but also some of the tax revenue that is collected will be redistributed and reinvested in communities that have been disproportionately affected by the war on drugs.

    This is really great news on a number of levels, and hopefully we'll serve as a very good model for other states and indeed other countries that are looking to pass reforms in this area. On a personal front, things have been getting busier and busier for me, which is great. Really, very lucky to speak to a huge variety of people across the whole sector. And that really is just one of the best things, because just I'm constantly learning. Every day I'm learning new things. And they have said that a key factor in quality of life is lifelong learning, so I'm very grateful for it. I am speaking to lots of entrepreneurs and it's funny, I do still seem to speak to a lot of people who are really, really keen on starting cultivation businesses and I wouldn't discourage anyone, but I think it really is a very hard business.

    I've seen to people across the whole value chain and really understanding that growing cannabis, particularly medical cannabis in Europe is really very challenging from a regulatory perspective as well as getting all of the testing regimes and the quality and consistency of the product and fitting that all into the very strict rules around production, manufacturing and processing a medical cannabis product. I think people might not have an idea of just how hard that all is. And many, many big businesses who have been doing it for a while still struggle to maintain that. What I'm actually finding a bit more interesting are the companies that are focused on generating IP and researching formulating and producing medicines. I think that's a hugely exciting area. And I think because there's just so much work to do in this area, there's lots and lots of scope to build some really solid long term businesses if it's done the right way.

    As ever, if you are in need of a UK lawyer, please do get in touch at Anuj, A-N-U-J @canvas.global or via LinkedIn. Got some great clients at the moment, helping them with a variety of areas, such as investment fundraising, corporate M&A and some big commercial deals. We're also helping people with brand and data protection and day-to-day legal needs like that too. So if you have a need, please do get in touch. Now on with this week's show. Really, really interesting episode. It's a 101 on cannabinoids. Enjoy. On today's show. We have professor Saoirse O'Sullivan and Dr. Andy Yates. Saoirse and Andy have a number of roles within the medical cannabis space, but primarily here to talk in the capacity of being advisors to Artelo Biosciences. But they can tell us a bit more about all the wonderful things they're up to in a minute. Guys welcome. How are you?

    Great. Thank you.

    Yeah. Awesome. Thanks for having us.

    Yes.

    Real pleasure. I think this is a great topic, actually. We're going to talk about cannabinoids and synthetic cannabinoids, which is not something I covered specifically. So I think there's quite a bit to talk about. To begin with, let's do the traditional thing and let's start with a bit about yourselves. Perhaps Saoirse, you want to start and tell us a bit about your background and how you got into cannabis and why, and the various things you're up to now?

    Yeah, okay. So I got into cannabinoid research in 2002, actually. So I moved over as a post-doctoral research. This was after my PhD. I moved to Nottingham and started looking at how cannabinoids affect the cardiovascular system. And this was a three year contract and I basically got hooked on cannabinoid science during this time. I just found it so interesting. It was still really early days. And when people were discovering the cannabinoid receptors and the endogenous compounds that activate them. So it was really an exciting time to be in a novel research area. So it was only supposed to be for three years and I ended up staying there for 18 years and worked my way through the ranks of academia, eventually leaving last year as full professor of pharmacology. So I spent that whole time doing research on cannabinoids. It started off very much, preclinical, doing laboratory experiments and cells and animal models.

    And then I worked towards human work. I did studies in healthy volunteers and clinical trials. So I really started moving towards the therapeutic uses of cannabinoids and how we can best tap into that. And that led me naturally to working with the pharmaceutical industry, which is why I ended up leaving academia, was because I wanted to try and make a real difference and really try and help clinical trials get initiated. Try and help companies to understand the science that was out there and what we already knew and trying to help them match the science with a potential market. So that's what I do now, is I act as a consultant to various companies, and we're talking today about Artelo Bioscience, who I've working with for a number of years, but that's what I'm doing at the moment now.

    Brilliant. And you mentioned you got hooked on cannabinoid science. What was it that drew you to it? And particularly in 2002, very early days, were there any issues with stigma and overcoming that that you encountered when you decided to look into this area?

    Yeah, so firstly I'll say that I really got into it because it was just very exciting because of the novelty of it. And it was also a super friendly community to work in. So when I started going to cannabinoid science research conferences, I just really found that people were really friendly. They were very open to collaboration. Everybody just wanted to see cannabinoid science excel. And I had come from working in hypertension, so high blood pressure research, which was quite a hierarchical, patriarchal research area. And so it was just a real change to move into the cannabinoid community. And so it was a combination of the science and the people who worked there that was really what kept me in it. And because I could see there was just huge potential. So that was quite exciting too. As a scientist, you don't often get to tap into research area that is still in its infancy and therefore you can really be part of the journey.

    So that was exciting, but yes, definitely came up against a lot of stigma over the years. So the first five, 10 years trying to get research funding was incredibly difficult. Trying to overcome that barrier, that there was a science behind these campaigns, that there were receptors. There was an indigenous cannabinoid system, that what we were doing was real science, was difficult even within the scientific community. So it was very difficult to get funding. People just didn't take it seriously. I mean, there's still an element of that that people think it's all about just sitting around and getting high. I get that kind of comment a lot when I tell people I'm a cannabinoid scientist. I don't think they quite take it as seriously as if I said I was a geneticist or something, but it's changed a lot in the last three to five years.

    I think there's just been a massive sea change in terms of public acceptance and acknowledgement of the potential of campaigns. And so that's made it an awful lot easier and has actually really facilitated this industry, moving on leaps and bounds in the last three to five years. And it's really on an upward trajectory now, if you look at the amount of research that's being done, it's crazy. I used to know all the names in cannabinoid science and now papers are coming out and I'm like, "I don't know these people. I don't know these people." And so it has really expanded. So that's amazing to see. You started with a little baby and now it's become this huge entity of itself. So that's what's kept me in it.

    Yeah. Fantastic. And yeah, it's great to have that longevity of experience to talk about. As I said before the show, a lot of people I speak to in the last five years have got into it, but you nearly pushing 20 years, which is amazing. And to see it change so much is crazy.

    Yeah. And you just have this long term memory of stuff that you've seen and read and heard and conversations that you have and cannabinoid science and cannabinoid pharmacology is very complex. We're talking about a whole plant, which is hundreds, if not thousands of molecules. When I started this in 2002, I thought it was complex. So I can't imagine what it's like for somebody coming into this area now, because it is so complex and cannabinoids work on so many different targets in our body, receptors and proteins and ion channels and it's massively complex. So yeah, if I thought it was bad 18 years ago, I can't imagine what it's like to be a new press in this field of research.

    Yeah, absolutely. We'll go on to talk about cannabinoids in a second. Andy, would you mind just give us a intro on you and your background and the various things you're up to?

    Sure. I can't agree more with Saoirso. Thankfully, I'm not new to it either. I was also doing research on cannabinoids science back in around the year 2000 at the university of Nottingham in a lab, very close to Saoirse, although I don't think we ever formally met. I'm sure we passed on a corridor.

    We must have passed in the tea room at some point.

    We must have and so I got into cannabis research because when I was doing my pharmacy degree, I strangely enough studied a module, an option on module called drugs of abuse. And within drugs of abuse was the cannabis plant and how people used it. And I was always fascinated actually. And it was put together very well on that module, just about how cannabis, if you wish to classified as a drug of abuse and harmful and alcohol and tobacco, which obviously used as the standard medical drugs that were legal, were not passed as harmful and therefore not illegal. And that got me thinking about, well maybe there's some interest work to be there. I didn't really go into it from a medicinal side of things. I just came in from a general interest that this drug had got this label.

    And yet the evidence didn't stack up to support where I saw it at the time. So I actually my PhD thesis on synthetic cannabinoids, which I know we're going to talk about in this podcast. And my role at the time was to say, "Well okay, all the things that go on in the head are harmful and all the things that go on in the body may be less harmful, get you less high. So my research was really to see whether we could design molecules that just targeted the receptors we thought that existed in the body at the time, leaving the ones in the brain and therefore being able to create a medicine. I think things have moved on massively since then. And I spent nearly 12 years in large pharma industry, mainly for AstraZeneca working in a whole host of different roles in the drug development and commercialization cycle.

    And I guess to my surprise, having done a PhD on it, and learned some of the wonders that I believe cannabis medicine and cannabinoid can offer, not really ever seen large pharma take them off on a big scale. I mean, you'll hear later that one of the drugs we're working with today at Artelo Biosciences, came from the laboratories of AstraZeneca. But as a general rule that they didn't seem hugely interested in them. So when I left AstraZeneca in 2016, I decided that actually there was a great opportunity to bring all my pharmaceutical company experience, plus my knowledge and passion, if you wish, for cannabinoids into the industries and businesses that were setting up in the here and now in the last five years. And I really believe we've fallen on our feet, working for Artelo Biosciences and obviously, Saoirse and I were there right from the beginning.

    So I think we've helped build the company in a way that it's rolling because we're now working on three different drugs that each modulate the body's cannabinoid system in different ways. And of course that for Saoirse and I with the science background is incredibly exciting, because it's more shots and obviously you can start to see right from the get go that if they're all slightly different, then they will all have potentially different uses, different side effect profiles. And that way we can pick the winners for different diseases that we'll get into from the portfolio opportunities that we've got.

    That's brilliant. And thank you. That's a really great summary of your background and how you came to be studying this area and a very nice segue into the main topic. So we'll talk about synthetic cannabinoids in a moment and we obviously use the word cannabinoid a lot on this show. Maybe we just start at the very beginning and what is it that actually defines a cannabinoid? And what are the defining characteristics of it? Is it simply that it's something that binds to the right receptors or is it wider than that?

    So I think the official definition, which is actually under debate within the science community and even whether this needs to be altered or not, is that a cannabinoid is anything which binds two cannabinoid receptors or is structurally similar to those chemicals which bind two cannabinoid receptors. Because we know that an awful lot of the plant compounds and the compounds that we make in our body, don't actually bind to CB1 and CB2, and we still call them cannabinoids or endocannabinoids. So it's a fairly broad term, but any chemical that comes from the plant or is structurally similar or binds to either the CB1 or the CB2 receptor is called a cannabinoid.

    Well, the only thing I was going to add to that was that I do a bit of a presentation developing cannabinoids. And of course it's a nice title to have, the Renaissance of Cannabinoid Research. But I get to a point where I actually just talk to the people that are in the discussion, that really we should actually treat for drug development perspective purposes. We need to think of cannabinoids as snowflakes. They all look the same on maps maybe, but actually when you get down to the microscopic level, they're all individual and that plays out the pharmacology, the legal status of them, country by country and the manufacturing regulatory body. So it is a really fascinating discussion. We use this throwaway term cannabinoid without really actually thinking sometimes what's behind that word.

    Yeah.

    Yeah. And from a drug point of view, you have a class name like that usually implies they behave similarly. And with cannabinoids, we know that's not true, as Andy said. They all have a very unique physiological and biological effect. So lumping them under this umbrella term makes it really difficult for people to be able to dissect the evidence of what they do because they all do different things.

    Yeah. I would expect over time, the nomenclature will expand to cater for these different types of cases.

    Yeah. At the moment it's broadly just put into endocannabinoid, phytocannabinoid, and synthetic. At the moment that's currently how they're categorized, is just by those three terms just to define where they've come from, but that really needs much more refining.

    Yeah. As you brought those up, why don't we just talk a bit about those three classes and broadly what the differences are?

    Yeah. So a phytocannabinoid as the term phyto derives from the word plant means that it has come from the plant that is generally cannabis sativa, although some plants do make chemicals that have some cannabinoid receptor activity. So we can't say it is unique to the cannabis plant, but it is mostly the cannabis plant that makes these compounds. And then the endocannabinoids are the compounds that we make in our body that bind to cannabinoid receptor. There's probably eight or 10 of these different molecules. And they're just all named together under the term endocannabinoid. And then a synthetic cannabinoid is something which has been made in the laboratory. So it's not come from our body, not come from a plant, but has been produced synthetically in a laboratory to either be the same as one of these compounds.

    So you can make synthetic versions of a cannabinoid, a phytocannabinoid, or an endocannabinoid, or it can be a derivative. So changed slightly to alter the characteristic of that molecule. So that can make it more potent or just change the profile of the molecule. So sometimes a synthetic is exactly the same as a phyto or an endocannabinoid and sometimes it's structurally different.

    Right. So you've tweaked bits of either an endocannabinoid or a phytocannabinoid to, I assume, enhance certain characteristics.

    Yeah.

    So as a good example within the Artelo portfolio, we have two synthetic cannabinoids where we actually have a third which modulates the endocannabinoid system. Let's talk about the two synthetic cannabinoids. We have a cocrystal of CBD, cannabidiol and in order to make that cocrystal cannabidiol, we need cannabidiol. Can either get that from a plant or you can get the chemist to make it. So they're bioidentical. Either the chemistry is identical. We have chosen in our molecule to use synthetic because it's a cleaner profile. You don't have some of the other phytocannabinoids in there. And we just get chemists to make it, we bring it in, but we can also use phyto CBD for that. Our other molecule, R2713 is completely different from all these chemical structures you might find in a plant. It truly has been designed in a chemist mind, probably actually in a chemist computer to mimic how the atoms and the bonds look in a phyto derived cannabinoid, but looks completely different chemically.

    And because of that, we can do things and design that molecule to be better, if you wish, in inverted commas, than what you can get from the plant. With nature, you're stuck with what the plant chooses to produce for you. With true synthetic chemistry you can go away and design that molecule to do certain things that cannabinoids from the plant can't do.

    Just to add to that, that can be in terms of biology. So making it a more potent compound, or it could just be changing the physical properties of the chemical, making it more soluble, which we know is a problem with cannabinoids. So it can be because you're trying to alter the chemistry or the biology of what the plant makes.

    Right. Very useful distinction. It's worth mentioning at this stage, I think, is there a terpene that is also considered to be a cannabinoid?

    Not that I'm aware of. In a terpene that binds to the CB1 or the CB2... Oh, are you thinking about. Beta-Caryophyllene?

    That's the one. Yeah.

    Yeah. So it binds to the CB2 receptor. And so could be termed as a phytocannabinoid as opposed to a terpene because it has cannabinoid receptor activity so therefore could come under that vague class of being a cannabinoid.

    Right.

    And people are looking at whether it could be used because CB2 is very good for anti-inflammatory properties. People are looking at whether that compound could be used for inflammatory conditions.

    I mean, yes. So much to get your heads around.

    It's mind boggling. 

    Completely.

    And wherever you look at cannabinoids, it always strikes me that even those people that write upon it at the highest levels have their own interpretation of what we've just talked about or sometimes they tend to get it actually wrong. And I've seen that a few times in my passing that you can see a description of something that talks in depth about how THC cannot be synthetic. It's like, "Well, it can be if you make it in a lab."

    Yeah.

    It's complex.

    Yeah. And what number are we on at the moment? Is it 144 phytocannabinoids? Or is it more now?

    Yeah, I'm not sure that we have an exact number, but it is getting towards the 150 mark, I think. And then hundreds of other types of chemicals, which aren't specifically class a cannabinoid. So the terpenes, the flavonoids, all the other chemical constituents of the plant.

    Yeah. Fantastic.

    There's a point that you made there which I think is worth bringing up. It's not something that Artelo is specifically researching, but as you can imagine, in a plant there's a packing order of which cannabinoids the plant pumps out the most. And when we're getting down to these very, very minor cannabinoids, there's no way that economically you'd be able to get and extract them from the plants, but they may be very interesting from a pharmacological or biological perspective. And this is where the interplay between phyto and synthetic is so nice. So we identify one that's made by the plant at a yield of 0.01%, but we can get the chemists to work on that, scale that up and end up with a very pure form of this synthetic version of the phytocannabinoid, that thought of interest.

    Andy, that was a beautiful segue into my next question. So as we drill down onto synthetic cannabinoids, you've mentioned a couple of reasons, but why create them in the first place? There's obviously a big section of the cannabis community who are very passionate about the plant and its part in medicine, but clearly there are some advantages to synthetic cannabinoids as opposed phytocannabinoids. Would you mind giving us a picture on that at all?

    Well, there's one really important thing that synthetics did for us that never really gets acknowledged often when people talk about it, is that the first synthetic compounds that were made were designed to bind to the CB1 receptor. And they are what led us to the discovery of the CB1 receptor. So without them, we wouldn't know because they made radiolabeled synthetic molecules that could be used as research tools. That's why they were first made back in the eighties and those radiolabeled molecules are what showed us that we have cannabinoid receptors in our brain. And once we found that we have these cannabinoid receptors in our brain, which were lit up with these synthetic molecules that were made designed to bind to them, then we realized we must have an endogenous cannabinoid system because why do we have these receptors if we don't make molecules in our body that bind to them. So without those first synthetic research tools that were developed in the eighties, we wouldn't know that the endocannabinoid system existed. So I'd just wanted to get that in there as a little flag, a little one love to synthetics.

    Little hurrah, to the chemists out there.

    And that's why they were first developed. What happened next is different, but the first ones that were developed were developed as research tools.

    Right. Okay.

    And that's how I came into the medicinal chemistry side of cannabinoids, is research tools. They were just starting to find a usage in pharmaceutical companies who obviously like synthetic cannabinoids because there's intellectual property around them. If you try to patent something that comes from the plant and has been around since the 1970s in public, then you can't get a solid patents positions on those things. So pharmaceutical companies like new chemistry, means that they can get intellectual property. And that means they can protect their investment in the R&D that's required to turn those molecules into licensed medicines. And I know people don't like to talk about intellectual property and profit for pharmaceutical companies, but it really is the driving force for all the innovation we've had in medicine in the last 50 years. The fact that somebody can protect what invest in.

    So that's one reason why synthetic cannabinoids that are structurally diverse from what the plant produces are important. But of more importance from a medicinal perspective, a medical perspective is that you can do things with these molecules that you can't do with a plant derived cannabinoid, such as, as Saoirse said, R2-7-13 has been designed so that it's more soluble and therefore more bioavailable. We can get a very small capsule reliably and consistently to patients and they absorb that cannabinoid, whether they're fed or fasted. Whatever their situation is, they get the same dose of the cannabinoid. And that's because we've changed the properties of the molecule. When it goes into the body, we've done some other things to the drug. THC for instance... Most of your listeners will be familiar with THC, is known as a partial agonist to the cannabinoid receptors. I'm not a professor like Saoirse, so for me it's dimmer switch time.

    That's my analogy. I started it.

    Well, I've borrowed it. It's a good analogy for me to use. So, no matter how much THC you take, you'll only ever switch the lights three quarters on with that dimmer switch analogy. With the drugs we've created, you can take those lights up to a 100%, or actually up to a 110, 120% in some cases. Now, why might you want to do that? Well, you might want to do that if you get to see that some of the effects of your cannabinoid are different from THC. Because you'd expect there might be a difference, because we are a full agonist and THC is a partial agonist. Obviously you've got to watch the side effects as well. It might be that there's more side effects, but ran in a controlled randomized clinical trial, all of that can be worked out.

    We've obviously seen some data with R2713 with its ability to put weight onto patients that we're perhaps a little surprised with. You wouldn't perhaps get to see that with what we've seen from the literature around partial agonists. So our thinking is it may be something to do with the way it works pharmacologically. The second thing we've done with R2-7-13, is we've made the drug less able to pass through the blood brain barrier. So the blood barrier is as the name suggests the barrier that separates the brain from the peripheral body and what we can do by putting in some chemistry that stops the molecule freely floating past that blood brain barrier, is we selectively keep the drug in the body and acting on the peripheral receptors. Why might we want to do that? Because we know that a lot of the CNS effects of cannabinoids are generated in the brain.

    And therefore, if you can stop it from getting into the brain, your highs, your euphoria, any psychosis that you might expect, all that will be lessened because we're getting the drug to do the job at the site where we want it to, which is in the body. So all of that can be achieved through synthetic cannabinoids. That just can't be done in the same way with plant derived.

    Thank you. That's really good explanation. And again, great to get that context of the benefits, I suppose, of synthetics over phytocannabinoids. Follow on question two this is, how do you actually go about creating these then? I've read about biosynthetics created from yeast and things like that. Are these some of the methods that you use, or what are the main methods that people use to create these in the lab?

    Yeah. So you can do it in different ways, obviously, if you're trying to recreate the phytocannabinoid. So let's say we want to make THC, first of all, chemists will elucidate the structure of THC and this was done. 

    In the 1940s forties for THC. Yeah. And then infamously the sixties is when it was further done. But the forties is when the first chemical structure was elucidated.

    There we go. So you got structure, you literally got the building blocks. I think of it as Lego. So you know how Lego's mapped out. So in that case, you'd give the job for the chemist to say, "Build me an identical one." And then they'd get their little bits of Lego and they would use their chemistry and stick it all together. And the two would be absolutely identical. Couldn't tell the difference. So that's how you mirror making a synthetic bioidentical version of a plant derived. But then the next obvious thing is that if on THC, you've got methyl group, which is a carbon and three hydrogens. Well, the way a chemist's brain says is, "Well, what happens if I turn that into an ethyl group?" It's two carbons, a propyl group, three carbons, and you start to build off what is the original phytocannabinoid.

    And then you hand it to someone like Saoirse, you say, "What's happened to pharmacology?" And you'll get reports back that, less finding of CB1. More selective to CB2. So we try things and at a certain point we probably have enough information to use, what's known as, SAT. That's called Structural Activity Relationship. We can start work out that if we stick big groups over here, at the north of the molecule, that lessens CB1 binding. And if we change that and stick it on the south of molecule, we increase CB1 binding. And so we can rationally choose what our next chemical steps are to optimize the molecule to whatever we want it to do. Then the molecule of interest most to me, which is R2713, which is the one we go into the clinic with Artelo Biosciences, this doesn't look anything like THC. You wouldn't be able to identify it in a police line-up that it looks anything like THC. And what they've done there is, that chemists have then done, using a computer, they've sucked the elements of THC into a computer.

    And they then used it in silicone modeling. So they've matched on different chemistry, but biologically it looks the same. So to the receptor it looks the same. To our eyes, it looks completely different. And again, they've done that for the reasons we just mentioned before, around developing a better molecule, and that's what we've done. So we've got what's called a benzimidazole structure in ours. Different ring system all together. We can literally decorate the molecule all around the outside of it with different chemical groups or loyalties. And again, we went through that same process, well, AstraZeneca on our behalf because they did some of that hard work in the labs. And then we licensed the molecule from them. They went through this rational drug design and ended up with a structure that looks nothing like THC, nothing like CBD and yet hits the CB1 and the CB2 receptor really hard as agonists, very potent. And we now make that at a chemical factory, very high purity, 99.9% purity.

    And we make it in about eight chemical steps. Adding A to B to make C and then we add some D to that and we build it up.

    Wow. Well, the thing that really struck me when you were describing that was just how many options you have when you were tinkering around at that beginning stage, which helps to explain why these things take so long. Particularly relevant with COVID, but why it takes so long to develop drugs when you take 10 years or whatever, and all of the preclinical trials that you have to do. You find the right bit, the right methyl or ethyl group to stick on it. And then you've got a thousand places you could stick on it.

    And then you've got to match all of that to the biology as well. So at the same time, you're doing experiments to try and figure what is tweaking that molecular structure doing to my biology? Is it making it better or worse? And so you are always matching that up so that eventually you end up with a molecule that seems to be perfect for the job that you want and gets all of the benefit with as little side effects as possible. So that's why drug discovery is very long and very expensive.

    Yes. Yeah, no, no. Makes complete sense. Are there any particular challenges to synthetic cannabinoids or this in general? It's a difficult question to ask, I guess, in relation to phytocannabinoids.

    I wouldn't say challenges. Here in the UK, when I was doing my PhD back in 2000, a lot of the symptomatic cannabinoids were really good for us to use in the research world because they weren't controlled drugs. They weren't THC, which was a schedule on control drug. So we were happily making them in the laboratory as pharmacological tools, future drugs, et cetera. And the one thing I think that's probably worth bringing to bear on this webcast and for your listeners is that then... I don't know when it was, but maybe around 2010 that substance spice came onto the scene, which was synthetic cannabinoids designed to get around the Misuse of Drugs Act and chemists were making all those changes we just talked about, but they were doing it in an uncontrolled way. And the first person to test them wasn't a cell system and it wasn't an animal model. It was humans on the street. And as you can imagine, there were some pretty nasty effects of these.

    No one had any idea what the dosing was and they've got then this bad reputation since that time and the government cracked down on them a lot more. One of the issues with synthetic cannabinoids, I think is a practical issue, is that nowadays they're seen perhaps through a different set of glasses, which is, "Well, these aren't very good, are they?" And they started to look at them with much more scrutiny. So they're not as easy to work with as they once were from a controlled drugs perspective, even though I've just told you that our drug doesn't really past the blood brain barrier, it doesn't really get you high. So, but yeah, it now falls into that bucket. So that's one of the things that's challenging about them.

    Yeah. I would just totally agree with that. I think that people hear the word synthetic and cannabinoid together and they automatically go to spice type molecules and that you're messing with plant molecules in a bad way, as opposed to the fact that synthetic just means you have produced it in a lab. And I think that word synthetic, the meaning of it, and especially for patients and the public perception has altered it a lot because of spice compounds. So now there's a stigma... When you work in synthetic cannabinoid science, there's a stigma. We used to have a stigma before 20 years ago, we have a new stigma, which is getting over this concept that synthetic equals bad and it doesn't. It just means made in a lab. Yes, there are bad synthetic campaigns, but there's an awful lot of really good to compounds as well that are being developed in drug discovery. And I think we need to work quite hard to really dispel that idea that synthetic equals bad.

    Yeah. I guess it's a problem that cannabis has in a number of specs where everything's reduced to good or bad and there isn't the nuance, everything is skunk and it's terrible for you or-

    Exactly.

    ... all of these things without fully appreciating just a huge wealth of different things inside the plant.

    Yeah.

    And the other thing as well is, I would like to get this over to any of your listeners, that do come from the cannabis plant is natural. Natural's good for me. And without doubt for some people that's the case, that's their mindset, that's their belief system. But what I can reassure everyone of is that in order to make a medicine, as Artelo are doing, and in order to get that medicine licensed by the MHRA and the EMEA and FDA, depending on where you live, you have to go through so many hoops to show that it works. That the side effect profile is beneficial against the effect you looking to have. So the benefit risk ratios, right? Do you make it to a high purity every time? And every time patient takes it, the same dose goes into them.

    So all this quality is just built into a medicine, right from the beginning. And of course in the case of a lot of plant derived cannabis, that's just not true because the money isn't being spent on them do all of this evaluation. It's a bit like, as I said before, even with the plant derived, often the first people to get the new formulation or the new strain of the plant is the patient. It's not gone into any cellular models and it's not gone into any animal models first to establish itself. It's just assumed it must be okay for humans. So I think for me, you mentioned issues with synthetic. I think there'll always be a group of individuals in the cannabis community that will see synthetics as bad. That they want the natural stuff in the plant that can't harm me. I mean, I come from the School of Pharmacy literally where you know that there's plants called, deadly nightshade for a reason. Not all things that are contained in plants are good for you.

    I was just going to add to that. But then there's some conditions where it's really important that we're not tinkering, that we have a very firm idea of what chemical is needed, what molecule is needed, at what dose and that can only be done through these programs. So there are conditions for which you really want to have all of that information up front before you go into a patient rather than maybe somewhere there's a bit of tolerability for being able to tinker around with different strains or doses. But there are some conditions in some really vulnerable patient groups where I don't think that's appropriate.

    Yeah. Yeah. And it's really useful to add that context to it. I went to a talk by professor Dedi Meiri where he was saying, he often comes up against this natural versus synthetic argument. And then people say, "They are good to plant." And I'm going to make this number up, but I'm pretty sure he said something like 70% of plants are poisonous, so it's not always... And dead nightshade is a good example of that. So I think it's good to offer that balance.

    Another thing that perhaps just to give you your listeners another perspective, and it's not to knock at all cannabis medicines. I mean, because-

    We're all massive enthusiasts.

    Yeah. What I work on is helping patients get hold of good quality, high quality, ethical, legal cannabis medicine, as in extracted from the plant. I'm not a knocker at all. I just feel blessed that I can wear both hats, but just to give you an example, when we're working with our synthetic cannabinoid, R2713, which is going into cancer patients who have anorexia with a hope of producing weight gain on them, given them their quality of life back. When we control for that medicine, when it comes out the lab and we put our specification on it, it needs to be greater than 99%. Now that other 1% of stuff, we also need to know what it is and how much of it's there. And we need to, what we call qualify it. Now, when thinking about the cannabis extract, sometimes you might be lucky to get 85% of THC or CBD.

    And the other 15% is seen as the entourage effect, that's the other stuff. We would call that in the pharmaceutical business, contamination.

    That's the unknown.

    Yeah. Unless you can control for that, that contamination or that entourage effect is the same every time and you guarantee it's the same every time. Then, really, actually every time you take a cannabis extract, then you potentially will get a different effect, because you're not controlling for what the other stuff is. I just wanted to bring that in because it's another thing that we massively control for the MHRA inspects, the plants where we make our drug so that they know it's made consistently safely, ethically every time. And this doesn't always happen with other plant derives cannabinoids.

    Absolutely. And actually I'm just conscious of time. So I think we need to wrap up now, but that whole idea around entourage and polypharmacy I wanted to go into. So perhaps we can maybe have a follow up because I think it's a fascinating area.

    It is a whole massive thing in itself. I could literally talk all day about entourage. It is-

    Brilliant.

    Yeah. It's a massive topic and it's a very interesting hypothesis.

    Well, that's perfect then. That gives me another show idea, which I always love. So yeah let's get you guys back on and do that, but for the time being, I'd like, say thank you for joining me today. It's really, really interesting. And obviously we only just scratched the surface, but I think it'd be really, really valuable for the listeners to hear this. So thank you.

    You're very welcome. It's been a really good chat.

    Likewise. Take care.

    I feel like we could talk all day.

    Yeah. Hopefully it'll be informative to your viewers so that they can go away and form their own perspectives and views on these important matter.

    Absolutely. And I'm looking forward to part two already, so yes. Brilliant. Thanks guys. Have a lovely day.

    No problem. Lovely to meet you. Bye.

    Cheers, thank you.

    Cheers.