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Ep #41 Transcript | Saoirse O'Sullivan: THC, CBD, Inflammation, Traumatic Brain Injury, Diabetes

Full episode transcript below. Beware of typos!

Nick Jikomes

Saoirse O'Sullivan, thank you for joining me.

Saoirse O'Sullivan 3:44

You're very welcome. It's lovely to be here.

Nick Jikomes 3:47

Can you tell everyone a little bit about who you are and what your background is what you're doing today?

Saoirse O'Sullivan 3:51

Yeah, sure. So, um, my name is Sasha. I started cannabinoid research nearly 20 years ago in 2002. I took a job at the University of Nottingham which had a really thriving cannabinoid research group at the time. And I started investigating how cannabinoids affect the vasculature. And that's the background that I came from was a cardiovascular background. It was only supposed to be a three year job. But I got hooked on cannabinoid pharmacology and basically never left the university until 2019. So I stayed there for 17 years, my research basically grew expanded in into lots of different research areas in terms of indications for for for cannabinoid use and also moving more towards human human trials. So I started doing healthy volunteer studies and small proof of concept clinical trials. So I've got a lot more translational as my career went along. And then in 2019, I made the leap after just becoming made professor, I decided But actually what I wanted to do was leave academia and work in industry. So for two years, I worked as an independent consultant as a scientific adviser to lots of pharmaceutical companies. And one of those was a company called our tele Biosciences who are based in LA. And, and I have just very recently taken up a permanent position with them as their vice president of translational sciences. So it's my job to basically turn cannabinoids fillings into new medicines, which is really always been my objective is to try and try and get the science that we have and the good evidence basis that we have into clinical trials and just trying to get more research being done. So that's, that's, that's who I am and where I am now.

Nick Jikomes 5:44

Yeah, so I think we'll circle back to some of that towards the end. In the beginning, let's briefly spend some time for people that don't have as much of a background in in cannabinoids, what are cannabinoids? Particularly Can you describe some of the major plants in endogenous cannabinoids and what the similarities and differences are?

Saoirse O'Sullivan 6:01

Yeah, so there were three kind of broad categories of cannabinoids, there are the ones that come from the plant from the from the cannabis sativa plant. And they're known as phyto cannabinoids. And then there are cannabinoids that we make in our body. And they are known as endocannabinoids because they're made endogenously. And then there's another group of compounds which are synthetically produced. And they're called synthetic cannabinoids. But they all basically the definition of a cannabinoid, which is fairly loose and up for debate is that it either comes from the cannabis plant or that they bind to cannabinoid receptors, or that they are structurally similar to one of those two things. So really, it's quite a broad umbrella term that encompasses quite a lot of very structurally diverse compaines. And who also have very diverse pharmacology. So you can't say that all cannabinoids work in the same way. They're very, very unique. And so the phyto cannabinoids, the major ones that we know about are tetrahydrocannabinol, which is the probably what you would call in the pharmaceutical world as the active pharmaceutical ingredient of cannabis. It's the most abundant chemical in most cannabis varieties. And it is the part of the plant that will get you high. It's the part it's the it's the only chemical really in the plant that binds to receptors called CB one receptors. And so most of the biological effects of cannabis come through that. And and then there's the less abundant cannabinoid, which is cannabidiol. And the novel A lot of interesting cannabidiol recently, it's quite different pharmacologically. It doesn't bind to cannabinoid receptors, really with any way to finish it. But it has some really unique and interesting pharmacological properties that make it quite an interesting drug that's being investigated. And then there's lots of minor phytocannabinoids We call them because they, they occur in really quite low levels in the cannabis plant. So there are dozens of these and they all again have quite a unique pharmacological profile, and are being investigated. So some of the ones that people are interested in are cannot the Geral cannabichromene and some of the Veyron so tetrahydrocannabivarin can other Devaron. And so there's multiple campaigns in the cannabis plant, it's really quite a complex group of chemicals. And then for the endocannabinoids we've got two main endocannabinoids we have anandamide, which is like our body's version of THC. So it has a fairly similar profile to THC and that binds to the CB one and CB two receptors. And it brings about a lot of similar actions in the body as THC does. And then we also have another compound called to AG to arachidonic glycerol, which is also a CB one CB two agonist. And then we have a whole load of other compounds which are sometimes called endocannabinoid like compaines, like palmitoylethanolamide and OLIO methanol in the mind, which don't bind to cannabinoid receptors, but they do kind of act on the family of molecular targets that cannabinoids bind to, or they can competitively occupy the enzymes that break down endocannabinoids normally so they can increase endocannabinoid cannabinoid activity and indirectly cause cannabinoid receptor activation. So there's probably about maybe six or seven endocannabinoids that we make in our body that we're aware of that list the growth, and then synthetic cannabinoids, there were hundreds and hundreds of them, you know, they've been developed since the 80s. As originally as research tools really so that we could understand cannabinoid receptors better and that has gone off in various directions, some of which are positive and some of which are very negative. So Yes, but you can structurally make you can synthetically synthesize any campaigns to either selectively inhibited or antagonize the cannabinoid receptors either within the brain or peripherally restrict them. So there's a whole host of other campaigns out there that are being developed in a pharmaceutical sense as well, which could be very therapeutically beneficial. So as I said, it's a it's a big family of campaigns, and they're all quite different. So it's hard to the the concept of cannabinoids is quite a broad thing

Nick Jikomes 10:31

I see. So we'll spend most of our time talking about some of the plant cannabinoids. Before we get there, I want to talk about endocannabinoids a little bit without going into excruciating detail. For someone who's unfamiliar, what would you what would you say are sort of the broad physiological functions of endogenous cannabinoids in our body?

Saoirse O'Sullivan 10:53

So that's quite a hard question. Because it depends on what body system you're talking about, there isn't, you couldn't kind of just generalize a single biological response, because it depends on the tissue in which you're talking. So in blood vessels, because those are dilatation, you know, in your role or tissue, they, they have an impact on neurotransmitter release. In peripheral nerve terminals, they affect neurotransmitter release in adipose tissue, they affect the amount of adipose tissue that's there and energy storage, same as in the liver, and then skeletal muscle. So the the impact of endocannabinoids is, is very tissue specific, but what you can see is that they're finding every self, they are the cannabinoid receptors so that the proteins on the cell surface to two which they bind are found in every cell. So the CB one receptors everywhere. So they have they have functions in in almost every cell, but it just is it is dependent on what tissue you're talking about. You couldn't generalize them a little

Nick Jikomes 12:03

I see, is it fair to say that in most of the cells and tissues that they operate in, they're playing some kind of homeostatic function preventing things from going too far in one direction? Or the other? Or is that only true in some cases?

Saoirse O'Sullivan 12:15

And it's a word I've heard used a lot, I mean, so yes, in that one, when there is cell damage, so for example, if a cell is starved of oxygen, or if it you know, is being has oxidative stress, or there's some kind of there's actual physical injury to a cell, then there will be a release of endocannabinoids and there will be an upregulation of cannabinoid receptors, particularly the CB two receptor. So the CB two receptor is known for being enhanced when when things are going wrong. And primarily the, the concept, the idea is that that is supposedly in a protective fashion. So that's what we definitely think is that these things are upregulated in order to try and resolve the situation, which is true of many other compounds. I mean, that's what our body does, if something goes wrong, we upregulate different chemicals in order to try and make things right again. So I don't think they're unique in that in that ability. And, and yes, that's definitely the concept of what they do.

Nick Jikomes 13:26

So there are

Saoirse O'Sullivan 13:27

times when up regulating the endocannabinoid system is not necessarily a good thing. And so, you know, like any system, there's always a balance, where too much of anything is usually not a good thing. And again, that's true of almost any chemical signaling system in our body.

Nick Jikomes 13:46

I see. So you mentioned that when there's physical damage to cells, you tend to get release of endocannabinoids. Although you'll get release of other things as well. Yeah, I know that there's been quite a bit of research for the different plant cannabinoids and other cannabinoids with respect to their potential to have neuro inflammatory or neuro protective effects, or I should say, anti inflammatory effects. And you also mentioned the CB two receptor, can you talk a little bit about what we know there in terms of CB two receptor and inflammation and which cannabinoids tend to have anti inflammatory or neuroprotective effects?

Saoirse O'Sullivan 14:17

Yeah, well, the short answer is, pretty much every cannabinoid that's been tested, does tend to have some kind of anti inflammatory effect when tested in a cell system. I mean, most of the experiments that we were talking about and experiments that I've done myself are in cellular systems, but in general

Nick Jikomes 14:35

altri dish with so yes,

Saoirse O'Sullivan 14:37

so cell culture dishes where we, you know, we we grow up cells, you know, whatever our cell of interest is, and then you treat them you do something to damage them, and then you treat them like cannabinoids, or sometimes it's an Oregon, you know, a piece of tissue and but in general, any cannabinoid I've ever tested and that's including vitamin C noids or endocannabinoids or synthetic cannabinoids have an have an anti inflammatory effect, I mean some to more extent than others. But it seems to be a fairly general characteristic of cannabinoids is that they are anti inflammatory. It's not and the CB two receptor as well as well known for being anti inflammatory and CB two agonists have a very anti inflammatory effect and there are some pharmaceutical companies looking at whether or not they can use CB two chemicals which have been designed just to activate the CB two receptor for different kinds of situations of organ damage like chronic kidney disease or chronic liver disease. And but the anti inflammatory effect and antioxidant effect aren't always through the CBT receptor. So I think there are other mechanisms by which cannabinoids are anti inflammatory and antioxidant. And we don't always understand what they are. And sometimes it can involve GPR 55, which is a receptor that it's been identified that cannabinoids can act through. And so it's not always just through CBD, through CB two is what I want to point out is that there are multiple ways in which and some of our we're still don't actually really know how they're working. And, but but they are anti inflammatory.

Nick Jikomes 16:20

So So almost every cannabinoid it's been tested has some kind of measurable anti inflammatory effect, at least in the lab. And inflammation is, well, it's something that that we all experience to some extent in different ways. But it's very broad term, CB two receptors, a major player inflammation, but there are many other ways to have inflammatory or anti inflammatory effects. And it sounds like each cannabinoid probably has, to some extent, unique or partially unique mechanisms by which it has this kind of effect, meaning they're not all gonna act on different forms of inflammation the same way Is that accurate?

Saoirse O'Sullivan 16:54

That is very accurate, that is very accurate. And also, it depends on the cell type, because the machinery within a specific cell will dictate how that cannabinoid act. So if it is a CB two receptor agonist, but it is a cell in which CB two isn't very well expressed, then obviously, you're not going to see a very good anti inflammatory effect in that cell. But if it's a cell where there's loads of CB two, then yes, it's going to work really well. So it depends on or if it's because it's inhibiting cyclooxygenase. You know, if it depends on the machinery within a cell, also sometimes what the mechanism of action can be so

Nick Jikomes 17:32

we, you know, we all have, I think every everyone pretty much has an intuitive notion of what inflammation is, you know, we all get bruises and bumps and things. But can you just define, in a more clinical sense? What is inflammation? And why? Why would it even happen in the first place, we always talk about it being a negative thing, but why does our body actually do that in the first place.

Saoirse O'Sullivan 17:56

So a lot of the things that the body is doing, like releasing, cytokines are passive prostaglandins in the inflammatory process, or to resolve the situation, it's because those campaigns will have some kind of beneficial effect. But then the problem becomes when that goes out of control. And it doesn't just resolve the situation and then go away. But for some reason, the inflammatory process continues, or the stimulus for the anti inflammatory process continues. And so you start getting chronic inflammation and chronic upregulation of these pro inflammatory compounds like cytokines and prostaglandins. And that's when the problem comes, I think most of us will experience, you know, short bouts of inflammation that resolve themselves naturally, but it's when it's when it doesn't resolve or the stimulus that's causing, it isn't going away, that you get problems. And that's when we're trying to kind of come in with anti inflammatory processes.

Nick Jikomes 19:01

Can you have too much anti inflammation?

Saoirse O'Sullivan 19:07

Well, that's a good question. Um, well, I suppose if it's not necessary, then you can and if you Yeah, I don't I don't know. I don't think I've never really thought about that before. And,

Nick Jikomes 19:20

like, if you were taking if you were taking anti inflammatories of any kind, such that you were preventing the normal inflammatory process from being triggered. Would that be would that be a problem?

Saoirse O'Sullivan 19:33

Potentially? Potentially, it could be because, as I said, some of these campaigns are being released for an important reason, because they have a job to do a specific job to do in that local area of cell damage. And so if you're blocking all of those pathways, then actually the damage may not resolve the way it would not work naturally. So there I suppose there could be I mean, it's not something I actually know an awful lot about. So I shouldn't I shouldn't comment too far, but I'm I'm guessing that there could be negative impacts of having too much anti inflammatories, but they're only going to be anti inflammatory if you have an inflammatory status at the time. Yeah.

Nick Jikomes 20:15

So getting into some of the specific cannabinoids, let's just start with THC and CBD because they're the most talked about plant cannabinoids. As you mentioned, THC is the principal psychoactive or intoxicating ingredient ingredient in cannabis. CBD is not intoxicating. And it's famous for some of its medical applications such as with epilepsy, do both of these tend to have anti inflammatory effects? And if so, can you kind of compare and contrast how exactly they're working and whether or not there's distinctions there?

Saoirse O'Sullivan 20:44

Yeah, so so they do both have anti inflammatory and neuroprotective effects. That's been quite well documented, but the pharma college pharmacology behind it is different. So the mechanisms of how they operate are different. So for THC, it would be primarily through CB two receptor activation, because THC is an agonist of the CB two receptor. But for CBD, it there are multiple mechanisms, but it's not, it's generally not through the CB one or CB two receptor, maybe sometimes some responses have a CB two element, which is probably indirect. And we could come back to that. But other mechanisms of action have been through, and some nuclear receptors called P pars. And through modulating Kox activity or like so and CBT can modulate enzyme activity as well. So if it's inhibiting some of the enzymes that are producing inflammatory mediators, then it can block inflammation that way, the GPR 55 receptor has been implicated as well as some of the anti inflammatory effects of CBD. So the mechanisms of action are different, but they both have an anti inflammatory effect.

Nick Jikomes 21:56

So just to try and tie this to like a simple real world example, I have met people at different instances, instances of my life, who might say, I have two people that say like, you know, I have neck pain, or you know, some muscle, my body is sore. And then they try a cannabis oil or a cannabis topical or something like that. And for one person, it works. And they say, Oh, my God, that was great. And for another person, they say, you know, it didn't really do anything. Could that be that maybe the topical had, say, a particular combination of cannabinoids, or maybe it just had THC or just CBD. And the mechanisms underlying each person's inflammatory state are different, and therefore the same product might not work for two people. Is that Is that a reasonable supposition?

Saoirse O'Sullivan 22:42

Yeah, I think there's there's other confounding factors that could be in there as well, it could be that they haven't taken the right dose, you know, that can often be the issue with with self medication is that you don't necessarily know how much you're taking. It could be that the route of administration isn't appropriate. So for a topical product, I would query do we know whether or not that topical product is actually permeating through the transdermal layer. So you know, if that hasn't been shown with that product, then actually you can be putting it on your skin all you want, and you're never going to have an analgesic effect. So, there are there are many, there are many kinds of confining factors when it comes to why a product will or won't work. And some of it will come down to the fact that we are very different as humans and the origin of our pain can be different. So yes, if it depends on the type of pain that you have about which compound is going to be better so that the general pier is that CBD is probably better for inflammatory pain. And while THC is better for nerve related, so neuropathic pain, particularly chronic pain, but that's a that's a real generalization. So there are different types of paints and because they have different pharmacology, you know, we know the CB one receptors really critical for pain transmission. So if it's a nerve problem, probably THC is going to be a more appropriate product than CBD. But if you've got arthritis or joint pain, or something where there's a strong inflammatory component to the, what's generating the pain, then probably CBD will work. And then also, everybody's just different. So you know, some people are just not responders to sorry, my emails popping up here. Some people are just not respond to as to collaborate, you know, so the, not everybody will find a beneficial effect from a cannabis based product and that's pretty well documented in in the Sativex trials. So as they did more and more clinical trial work and side effects. So that's the product that's licensed probably for the longest in this space. So it's a one to one ratio of THC and CBD it's licensed in most countries for reducing muscle tremors in Multiple Sclerosis but in some areas It's also used for pain. As they did more and more clinical research with that product, they did a a, an initial phase where they looked for responders and non responders. So they would give everybody the drug, see who worked for and who didn't. And then take the responders and then randomize those people into be their sort of extra placebo, because they basically had to enrich their studies that if you always did all your trials with just all comers, including this large proportion of people for whom this product will just never work, then you're always diluting the power of your data. So, you know, for some people, cannabis just won't work.

Nick Jikomes 25:41

Interesting. So you mentioned you mentioned in their route of administration, and I'm wondering if you can talk a little bit about sort of paint, paint for people what the contours are, of our knowledge around bioavailability of cannabinoids generally, and how that varies according to how you're actually consuming a cannabinoid.

Saoirse O'Sullivan 26:03

So I'll start with oral, because that's an area that I probably work in a lot because most people who take medicines want to take something orally it is probably the more typical route of administration for people, it's what they're familiar with. So already cannabinoids have very poor bioavailability. So probably only about 10% of your cannabinoid will get into your bloodstream.

Nick Jikomes 26:29

So that means that when you say orally, you mean swallowing something, as opposed to putting it under your tongue? Say?

Saoirse O'Sullivan 26:35

Yeah, yeah, so I'm talking about orally swallowing, we can come back to sublingual, but swallowing something, probably only about 10% of that cannabinoid will make it into your bloodstream. And that's for a variety of reasons. But cannabinoids are very fatty molecules, they are not very soluble, they're not very absorbable. The ones that do get absorbed into your bloodstream, you know, if they go through the normal process of going to your liver first, then there will be what's called first pass metabolism and they'll be broken down. And, but some of them will also just be chucked back out again, back into the large intestine. And you actually excrete a lot of the cannabinoid intact because it never gets absorbed or, or broken down. So poor bioavailability orally, and probably the best mechanism we have is inhalation. That's why people have always smoked cannabis is because the bioavailability of inhaled product is about maybe 40%. So it has a very different pharmacokinetic profile, though. So the compound will appear in your blood quite quickly. Because it's very easy to get it a lot easier to get absorbed in your loans than it is in your guts, you know, going all the way through your gastrointestinal system. And all the hurdles that a compound has to get to to in order to get absorbed is a lot more difficult than in your in your lungs. And so you've got a very fast onset, and you get much higher peaks, so you get much greater exposure, but it declines quite quickly. Whereas orally, it takes a long time to get that peak exposure to your cannabinoid. And at but it also lasts for longer. So you have the area under the curve will probably be the same, but the profile is very different. Where you mentioned sublingually. So a lot of people take cannabinoids sublingually with the concept that some of them will be absorbed into into orally, so within your mate through the blood vessels that are in your in your mouth. The problem is that's not really actually been very well demonstrated to actually happen. So there isn't an awful lot of evidence that you actually have absorption of cannabinoids through your mouth. And so really, the oral bioavailability is probably similar. So the bioavailability of sublinguals is probably similar to orals.

Nick Jikomes 29:18

Is that because you're actually in fact swallowing what you because you're just swallowing them. Yeah. So are you saying it has been demonstrated that there's not good sublingual absorption or hasn't been shown one way or the other, the other.

Saoirse O'Sullivan 29:30

So it hasn't been shown that there is any sublingual absorption. So if they just they're too big and they're too fatty, to get into your, into your bloodstream that way so they're just the physical property of cannabinoids don't really lend themselves to mucosal absorption. And so and it hasn't been demonstrated, demonstrated that that actually happens. So when people have seen them get across into your mucosal say across and cause a barrier It's taken like eight hours or so. So but things that have been shown that definitely would indicate that they're not sublingually absorbed would be the fact that the bioavailability of cannabinoids when they're given orally, or sublingually, is better if you eat. And that only makes sense if the absorption is Gi. And so it's so it's true for any oral product, if you have a high fat meal, when when you take your cannabinoids, you will increase the area under the curve. So you'll increase your plasma exposure to the cannabinoid by about three or four fold. So

Nick Jikomes 30:36

I see so many things orally with fatty food, the bioavailability goes up three or 4x.

Saoirse O'Sullivan 30:43

Yeah, yeah. So and that is also true for compounds that are delivered sublingually. And that wouldn't make sense if the absorption wasn't gi because why would food be affecting how you absorb a drug in your mouth? So I think it's just yet to be demonstrated. I'm not saying that it doesn't happen or that there aren't clever things that people, you know, that, that pharmaceutical people could develop a method of getting through the oral, you know, into orally. But it just hasn't been really showing yet.

Nick Jikomes 31:20

One thing I want to move to you mentioned that you you had studied earlier in your career, at least, cardiovascular effects. And I'm really interested to hear you talk about the blood brain barrier and blood brain barrier permeability. So can you start off by just explaining for people in basic terms, what is the blood brain barrier? And what does it what does it normally doing in our bodies? And then what do we know about some of the, the the effects of cannabinoids on this barrier?

Saoirse O'Sullivan 31:48

Yeah, so the blood brain barrier is basically the defense between your blood and your brain. And the reason you need a defense system there is that there's stuff in your blood that your brain doesn't necessarily want to be exposed to. So you don't want your brain seeing everything that's in your blood. Because they would it would be damaging to the brain basically. So it's, it's a way of keeping out anything that shouldn't get passed. So it normally at a capillary level, where where you have that kind of greatest transference of gases and substances between your blood and your your tissue, the invasion tissue, normally, that's quite porous to allow for a lot of exchange, you know, we want glucose and you know, everything to be passing very easily between tissue in the blood. But in the brain, we don't want that. So we have adapted that barrier, instead of being quite porous, we've adapted it to being a much tighter barrier. So the cells are really tight together. And there's actually a number of cell layers at the blood brain barrier to make that even tighter. So it's like having triple glazing, as opposed to single glazing. And there's, you've got endothelial cells when the vascular side of things and then you've got a couple of layers of different types of brain cells as well, that make this really tight barrier. And it's very much in control of making sure that all of the bad stuff that's circulating in your blood doesn't get into your brain. And when things go wrong, that can become leaky. So that barrier can begin to break down and you can start seeing holes, either between cells, or actually through a cell and things like, well, there's a couple of things that will happen, you can have too much fluid leaking into the brain. So you can have a demon that can cause swelling of the brain. Or you can have things like cytokines or too many immune cells getting in or, you know, being exposed to lactate, or a lot of different things that are in your blood that you don't really want in your brain. So if they get leaky, that really can damage the brain and the blood brain barrier does get leaky and a lot of neurological conditions. And our research looked at having other noise affect the blood brain barrier, and whether or not any of the positive effects of cannabinoids, which had been seen in some neurological conditions like stroke, and could be because they were having a direct effect on this blood brain barrier function. So we we set up. And we set up experiments where we mimic the blood brain barrier in so in cell culture conditions, we grow all of the different layers of cells that are appropriate for a blood brain barrier. We grow them together. And we make this basically like in vitro version of a blood brain barrier. And we make it leaky by expec, causing a stroke within the cells. So we deprived the barrier of oxygen and glucose to mimic what would happen in a stroke. And the barrier gets leaky. And what we find is that we looked at different options. ammonoids But primarily most of our work was focused on cannabidiol at that time, because there is quite a lot of data showing in an animal model that if you give cannabidiol, that it, it prevents that it doesn't completely prevent the stroke, but it reduces the size of the damage caused by a stroke. So that that area of the brain which you know, would normally have necrosis or tissue tissue, cell death is a lot smaller, if you give cannabidiol in advance that we don't, that's not very translationally relevant, because we don't always know when people are going to have a stroke. So it's very hard to pre medicate them with things. But anyway. And so we were looking at whether or not cannabidiol would work in the in the blood brain barrier. And basically, what we found in a nutshell was that it was very beneficial. So it cannabidiol helps to make the blood brain barrier tighter. So it can if we induced that leaky barrier, by inducing a stroke like environment, then it makes cannabidiol makes the cells tighter much faster, and it reduces the inflammatory response, the cell damage caused by that stroke.

Yeah, and that persisted even when we so it was it worked when we gave CBD before the stroke at the same time as the stroke or even up to I think it was six hours after the stroke was induced. So and we looked at the mechanisms by which that happened, and one of the major receptors that was involved was the serotonin receptor. And the serotonin receptor is known to be involved in a lot of the neurological the brain responses to CBD. It's like the major brain target for CBD. So it was primarily by the the serotonin receptor and this other nuclear receptor I mentioned before called P PA. So we did a lot of work on that. We also looked at some of the endocannabinoids. And we found that there were there were two in particular that also had this kind of protective function on the blood brain barrier, and they were OEA and PA, so the Endocannabinoid like molecules that I mentioned before. And then we also looked at some of the more novel minor cannabinoids. So we looked at CBD A which is the acidic version of CBD, which is what the plant actually makes. And we looked at CBG. And we looked at CBD V. Collaborative Baron, because that is a compound that people are interested in, maybe in epilepsy or other neurological conditions. And they all they all had a good response. I'd say the best probably came from CBD a and CBG and CBD B. Were also anti inflammatory, but I don't think they were as good as CBD. I mean, their responses weren't as overwhelming as a CBD was to be honest. But yeah, that was quite a lot of work that we did. Showing that cannabinoids in general are protective at the at the blood brain barrier, which probably underpins quite a few of the neuroprotective effects of cannabinoids if you can really maintain that barrier integrity and and keep the brain from being exposed to things that it shouldn't be.

Nick Jikomes 38:10

So based on what you said, is it fair to say that for CBD and some of these other cannabinoids, the neuroprotective effects are often what you might call preventative meaning that the molecule needs to sort of be there when the insult happens to the brain. And it doesn't, it doesn't do anything afterwards.

Saoirse O'Sullivan 38:28

So so it does, both cannabinoids do but the problem is, experimental studies tend to either pre administer the cannabinoid or give it at the same time as the insult. There's not enough researchers actually looking at happens, what happens when you give these compounds after the problem has already been established. And I'm probably talking more about the historical literature. I think people now are doing more translationally relevant research, and they are including, you know, doing that post insole treatment, but it is true to say that their best effects are seen when you give them an advance. But yeah, I think there are situations where, you know, a problem is coming so far, like sports. Yeah, exactly. So there are conditions where that's relevant. But they were, you know, for something like stroke that was never relevant, because you never know when something is going to hit you like that. Yeah,

Nick Jikomes 39:25

I see. So I think I think you know, there is, I don't remember the specifics. But you know, in mixed martial arts, and I think American football, they're looking into the different CBD based products are sponsoring research, but that's an area where you think it's plausible, where you know, if you know that there's going to be physical, you know, damage to the brain that's likely to be happening, that having something like CBD in your system could actually help mitigate some of the damage and some of the risk there.

Saoirse O'Sullivan 39:52

Yeah, yeah, I'd really welcome seeing that kind of research being done because the hypothesis is very plausible. And there's there is an animal data to show that CBD is protective in models of traumatic brain injury. And endocannabinoids have also been shown to be very protective in in traumatic brain injury. And there's good evidence to show that CB two agonists are. So we've got a lot of animal data to support that kind of research. And and it's I think it's really important that their studies are being done. I hope they're using effective doses of CBD. I think that that's, you know, sometimes where some clinical studies fall down in this area is that the doses of CBD use are quite small. And so yeah, I really welcome seeing that kind of research, because the theory is really strong. And the science that supports that, that that clinical research is very strong.

Nick Jikomes 40:46

Ballpark, when you say relevant doses of CBD, what are you talking about? And how does that compare to what's in a CBD products that you're likely to buy in a store.

Saoirse O'Sullivan 40:58

So it's quite different, it's quite different. And so this is where this kind of, there's a, for me, there's a big difficulty in people using the evidence that we know about the clinical use of CBD into and translating that into over the counter use of CBD, because you're not talking about the same kind of, of doses. And most clinical trials that use CBD use hundreds of milligrams per day. So anywhere between one and 800 milligrams per day, if you are somebody who's epileptic, the average kind of doses, something like 12 and a half milligrams per kilogram per day. And that is, is very different to over the counter products where you're, you know, you're probably, you know, some of the tablets I've seen of CBD are maybe only 10 milligrams per capsule. And if you remember, I said that that's only 10% orally bioavailable, then only one milligram of that 10 milligrams is probably going to get into your five liters of blood. So if you do the math on that, what is the circulating level of CBD, knowing that the potency of CBD at any of its molecular targets is quite low, you need micromolar concentrations of CBD to have most of its biological effects, just doesn't marry from a, you know, from a pharmacological point of view.

Nick Jikomes 42:27

So in theory, if you were to consume CBD orally, you would get more of it into your bloodstream if you ate it with a fatty meal, or if you inhaled it, say

Saoirse O'Sullivan 42:38

yes. But with a different profile. Profile. Yeah. So there is there's other things to take into account, like the fact that there will be accumulation with time, you know, and so, you know, what I would like to see is more research being done on this kind of chronic low dose CBD and what biological effects it's having. Because the problem is none of the science that's out there really supports low dose CBD, everything that's been ever done in animal models, or in clinical trials is with much higher doses. So what we need to start seeing is, is there is there a really an effect that we just don't know about that happens with low. I mean, I've only used the word micro dosing, but you know, that, you know, using maybe up to 50 milligrams a day, what is because there will be accumulation with time, and you know, there will be there will be changes that will happen over time. And there's, you know, definitely people for whom they're seeing drastic effects. So, a double, we just need to see some more science behind that. And it's not being done at the moment because this over the counter use of CBD is quite novel, whereas the scientific research into CBD is is older, you know, that that's been going on for, for maybe only by 10 years, actually, I started doing research on CBD in 2005, when hardly anybody was doing research back then were everybody was still looking at THC. You know, there was hardly anything being done on CBD. So we, there's still a lot to be done. We're coming back to the effective dose of CBD. I did analysis on this where I looked at all of the clinical trials that have been conducted with CBD, and analyzed whether they were effective. So what did they meet their primary endpoint? Did they have a significant change in their primary endpoint, and the one differentiating factor between the trials that were successful, and the trials that were not successful was the dose used? So if you were a successful trial, you tended to use over I can't remember the exact cutoff. But it was over I think, maybe 300 milligrams per day. And anything less than that on the trials were not successful that meeting their primary endpoint.

Nick Jikomes 44:59

Yeah, that's what I've heard around about 300 is where you tend to see some effect. And we really don't have much evidence for things below that. Out of curiosity, when they do these clinical trials, do the patients tend to have an empty stomach and take just the medicine? Or how does that play? No,

Saoirse O'Sullivan 45:14

they will be, they will be advised to take with feet. Yeah, yeah. But there's so many things that, you know, I think what we need to do is, is make CBD more drinkable. So, you know, it's really not very effective giving somebody or CBD knowing that only 10% of that gets into them. So we need to find better ways of getting CBD. And then we don't need to give so much such high doses. Because if you could give, you know, 300 milligrams of something that was 40% bioavailability. By available, you know, then then you'd be getting, you know, you'd be able to reduce your dosage, you probably see less side effects. So I think getting making better versions of CBD ones that get into your system better using pharma, pharmaceutical strategies to make better formulations of CBD are all things that can be done to mean that the doses that need can start coming down. But mostly at the moment, we're excreting most of it.

Nick Jikomes 46:12

I see. I want to move on to a couple other topics that I want to make sure we get to. So one of them is just the general area of metabolism and diabetes. So I think a lot of times when we talk about cannabinoids, you know, people are often talking about the psychoactive effects or the neurological or psychiatric effects. You often talk about things like inflammation as as we've done, I think a lesser, an area that gets less attention is metabolism. So I'm particularly interested in the general effect of some of these plant cannabinoids on metabolism, as it relates to things like blood sugar levels and diabetes application, you talk a little bit about what's going on in that area.

Saoirse O'Sullivan 46:50

Very little. And so, I mean, historically, cannabinoid research is very CNS biased, because we knew, we know that a lot of what the adverse effects of cannabinoids are through the CNS. And so most of the focus has been around the CNS effects, its impact on, you know, cognition, memory, neurological disorders, you know, it's been very CNS bias and pain. There has been an awful lot less research done on everything below the neck, but I think that's beginning to catch up. But probably still really not enough research is being done. And diabetes is an area that I was very interested in for a long time. There is good literature out there animal literature to show that CBD was effective in animal models of either type one, or type two diabetes, and these, these are fairly old studies, I'm not talking about things that, you know, have just been recently done. These are things that were done, you know, easily 1520 years ago. And so there was good data to show that CBD was effective in these models. So there was even one good study with THC, showing that it was beneficial in a in a model of diabetes,

Nick Jikomes 48:14

when you say effective for diabetes, what exactly does that mean?

Saoirse O'Sullivan 48:18

So some of the things that CBD was shown to do was to reduce the inflammation in the pancreas to improve the islets of Langerhans to improve insulin secretion, and to what a lot of the research was also about resolving a lot of the comorbidities associated with with diabetes. So the other problems like neuropathy or glucose handling or impacts on the heart, so a lot of the you know, are impacts on the vasculature that was researched the idea was, we looked at how how your blood vessels function, which is worsened by diabetes, but if we gave the animal CBD that was improved, so vascular function, so there was lots of kind of secondary impacts of diabetes that have been shown to be improved by CBD. So we are in collaboration with GW Pharmaceuticals about must be 13 or 14 years ago, and did a trial in type two diabetes off the back of all of this literature that was suggesting that there was a positive effect of CBD. And also another compound we were interested in was a compound called thc v tetrahydrocannabivarin. Which is you know of the THC family, but instead of activating the CBD receptor, the CB one receptor thc v actually blocks the CB one receptor. And it was already known that blocking the CB one receptor was has quite good cardiometabolic impact So there was a drug on the market for a while called rimonabant that was a CB one receptor antagonist. And it was a very effective anti obesity anti diabetic drug. But it was able to penetrate the blood brain barrier get into the brain. And it also blocked the CB one receptors that within the brain, and that didn't have a good consequence. So, because our CB one receptors are so critical in your own function and well being and there was a there was a major side effect of low mood depression and even suicides with this compound. And thc v, or suggest suggested to be an alternative to rimonabant because it is a different type of CB one blocker. So I won't try and go into that because it's quite complicated. But it blocks the CB one receptor, let's say in a more gentle way than rimonabant. And so the theory was, well, maybe we could use this plant derived compound as as an anti obesity drug as well. So we trialed them both and we trialed them individually, and we trialed them in combination. And what we found, disappointingly, I'll start with CBD was that we didn't see any impact. So we did 12 weeks of treatment. And but we only did 100 milligrams twice per day. And that we know in hindsight was just not enough. So this was early days for CBD trials. I mean, I mean, we published it only about three or four years ago, but the actual trial was initiated a good 12 years ago. And, and I think we just got the dose. Well, to be honest, I still believe that there is a potential for CBD and diabetes and, and weight loss. I mean, weight loss is one of the major side effects of CBD drugs.

Nick Jikomes 51:47

But it is not yet epidemic Epidiolex a side effect of Epidiolex is weight loss.

Saoirse O'Sullivan 51:52

Yeah, one of the main Yeah. So um, loss of appetite and loss of weight is a significant side effect. And there are there's a company trialing CBD for product release syndrome. And because of CBDs effect on appetite and eating, and so part of Willi syndrome, I don't know if you know us, but it's that that genetic disorder in children where they have hyperphagia that can't stop eating, and so people are looking at whether or not CBD could actually be used in a condition like that to try and reduce appetite and, and help that condition. So So yeah, I still believe in CBD. But I think we got the dose wrong in that study. But we did on the positive note and see positive effect of THC v. And in that we saw a significant reduction in resting blood glucose in the in the type two diabetic patients. Unfortunately, though, that research isn't really going anywhere anymore. I mean, I GW didn't pursue investigating these campaigns in diabetes, they moved, that would have been around the time they started doing a lot of their Epidiolex studies in epilepsy focused in that area?

Nick Jikomes 53:13

They didn't it sounds like they didn't pursue it because they had this Epidiolex thing they were working on. And maybe they wanted to focus on that not because it wasn't looking promising. Exactly. 100 milligrams, what was the dose for THCV?

Saoirse O'Sullivan 53:27

No, that was five milligrams five. Yeah,

Nick Jikomes 53:31

wow. Well, that's really interesting, because that's a workable dose that someone you know, could encounter out in the real world quote, unquote, whereas you know, 300 milligrams of CBD,

Saoirse O'Sullivan 53:42

I may I may have to check myself on wash. I'm sure it was only five milligrams. Anyway, I'm gonna have it's gonna give on myself. I'm pretty sure it was like five or 10 milligrams because it's more potent, you know. And then then CBD is interested in a five milligrams of THC.

Nick Jikomes 54:02

But in any case, it was a lower dose than you did for CBD. And you saw a positive effect. It actually lowered blood sugar levels in people with type two diabetes.

Saoirse O'Sullivan 54:10

Yeah, so three months of treatment. Yep. epidemiological data on people who smoke cannabis. Yeah, there's more often than not, there is a positive effect on cardio metabolic status. So cannabis users tend not to be obese, and tend to have better blood lipid profiles, and just general kind of cardio metabolic profiles. So there's definitely, you know, they're not they're not overweight and diabetic, that's for sure.

Nick Jikomes 54:45

Yeah. I mean, that's sort of interesting. I don't want to spend too much time on it in the time we have left and I know that there's no like complete answer here. But I'm sure you're referring to Canvas users, meaning people that are consuming predominantly high THC products and teach He's famous for having, you know, eating junk food as a side effect, basically. So how would you even start to think about that? Are those two those two themes, things would seem naively to be in conflict?

Saoirse O'Sullivan 55:10

Yeah, well, the this the story about THC and feeding is more complicated than just It stimulates appetite. So it does. So if you know, you will have an acute response where you want to eat, and often that is high fat, high sugar foods. But if you look over a 24 hour period, people don't consume more calories than they would. So they eat but then they don't eat for a while, and then they eat again. So it's not, it's not inducing over eating

Nick Jikomes 55:38

all of it into one, one bout of feeding. Yeah.

Saoirse O'Sullivan 55:42

And over with chronic use, and there can actually be a weight loss effect of THC. So I've seen data where THC was given to obese animals, and chronically will cause a weight reduction, because THC also access other receptors that actually have a weight reduction effect. So it's not that THC doesn't necessarily and people who are, let's say have normal weight, cause an increase in weight, but where it can cause an increase in weight is in conditions where there is wasting. So in AIDS related wasting or in cancer related wasting THC, and usually in the in the in its synthetic forms and Navona Dronabinol has been shown to stimulate appetite and increased body weight, or at least stop the reduction in body weight that would be seen in those patients. So it is licensed in America for HIV related weight wasting.

Nick Jikomes 56:48

Interesting. I didn't know I don't think a lot of people know know about that research.

Saoirse O'Sullivan 56:54

But that's, that's one of the oldest things that a cannabinoid has been licensed for. So that licensing was in the in the 80s. Because, you know, when people started looking at them biological effects of cannabinoids, you know, that stimulation of appetite was one of the things that was very obvious. And it was one of the things people did research on your ability to suppress nausea and vomiting as well. So the, you know, the licensing for chemotherapy induced nausea and vomiting has been around for a very long time.

Nick Jikomes 57:28

Yeah, I mean, that part makes perfect sense. So So what you're saying is that there's at least some evidence out there some in humans, some in animals, that THC can actually stimulate weight gain in wasting conditions where you're underweight but actually potentially do the opposite. In other in other circumstances. Yeah.

Saoirse O'Sullivan 57:45

Yes, that's exactly right. Yeah.

Nick Jikomes 57:49

I want to talk a little bit about permeability in the gut. We talked about the blood brain barrier.

Saoirse O'Sullivan 57:56

We're definitely jumping all over the body here.

Nick Jikomes 57:58

Oh, yeah. Well, I want to get I want to get to all the major spots. What talk to us about in terms of like gut health and gut effects of some of these cannabinoids?

Saoirse O'Sullivan 58:07

Yeah. So I think my, my research on good permeability actually preceded my research on the brain barrier permeability. So I started working in the good first. And then, because it was very good data, which I'll come to, that's why I ended up moving into the blood brain barrier as well, because we knew we had a lot of data under our belt about what these compounds do in the gut. So we've got the same kind of barrier system in the ghosts were things that are inside your intestines, you know, we do want to protect your body from some of those things. Because there will be things in there like bacteria, for example, that would be quite dangerous if they were able to cross the intestinal barrier into your bloodstream that could cause inflammation. And so but the the gut barrier is a little bit different to the blood brain barrier. It is just a single layer of cells, but their toll cells are columnar cells like this. And so there's a bit more bump to them. So instead of being like triple glazing, it's just like having really thick blocks. And, but and they can become leaky. So again, either between the cells that kind of junction between the cells where normally they're, they're really tight together that can become leaky, or you can have substances passing through the cell itself. So we did a lot of work on on inducing permeability in an in vitro model of gut permeability. When we were basically me, we retreated them with cytokines, we made them inflamed and that increases causes a leaky gut. And then we looked at different cannabinoids and what they did and we found that both THC and CBD were very effective at stopping gut permeability that we induced by inflammation. So they help To the that barrier to get back into shape much, much faster than it would do by itself. And there's lots of other data we also did data on, on bits of samples. So I was very fortunate that I, my office was next door to a good surgeon. And so we got lots of bits of tissue from people who are having parts of their intestine removed. So they were IBD patients, or they were patients with appendicitis. And so we had samples of normal gut, from patients. And we had samples of inflamed guts, from patients, different types of patients and for in those patients, and we found that CBD was very anti inflammatories, and we could reduce the amount of cytokines that was being produced by this inflamed tissue. And we mostly just looked at CBD in those studies, and PA, which is that palmitoylethanolamide, we didn't, we didn't look at THC in any of those human tissue studies. But we looked at the mechanisms of how they act and how they stopped the basal production of cytokines. And also if we, if we made them even more inflamed by putting on more cytokines, hey, they reduced the inflammatory response to that. So that is supported also by lots of other people's data where they've given, you know, these compounds like CBD and PA, to animals to whole animals that are models of colitis, or IBD, gut inflammation, and they have all shown that cannabinoids are very effective at reducing gut inflammation. And, you know, reducing gut permeability, and basically improving the indices of, of inflammatory bowel disease.

Nick Jikomes 1:01:46

Interesting. So, in the time we have left, I want to give you space to talk about a different kind of topic. So at the very beginning, you mentioned something that was interesting to me. So you mentioned that you used to work in academia, and now you work in industry, that's actually not the part that I found interesting. It wasn't that you did your PhD and then said, Oh, this is not for me, I'm going to go to industry, or then did your postdoc and said, This is not for me, I went to industry, you actually ran like the full gauntlet, you became a professor, and you sort of got to the place that every aspiring academic is is aiming for. And then you made the transition. So can you talk to us about how that happened? And why you made that choice?

Saoirse O'Sullivan 1:02:26

Yeah, it was really interesting. And it was literally one month after I was notified that I was promoted to professor that I handed in my notice, and it shocked a lot of people. And, and I don't want to get too, like personal about it. But I definitely feel like I had run my course with academia. And I love research. I absolutely love research. And I love working with students. But there is a certain slowness, to academic research that I found quite frustrating. And so things don't really move much of a piece. In summary, not for everybody. And, and I just, I felt like I could make a difference, a bigger difference somewhere else. And there were other aspects of academia that were bothering me. And I thought that when I was made professor, that I would make me feel differently about the university, but a different didn't. And for me, that was the point at which I knew I really have to go and do something different because I thought, you know, this hasn't made me feel more in love with academia. And I thought it would, you know, I've gotten to the point where I thought I, you know, wanted to be, but actually, I really do want to go out there. I want to do something different from from a personal challenge point of view. But I also want to feel like I'm making more of a difference. And I think I didn't feel like I was making enough of a difference in academia, because, you know, your time is always torn between so many other endeavors. When you're an academic, you know, you're, you're a teacher, you're a mentor, your HR expert, you manage budgets, you're, you know, trying to do your research, you know, you're trying to be collegiate winning timetables, margins, you're just being torn all the time. And I felt like I would rather be more research focused and actually not have some of those challenges on my time. So, so yeah, they were the they were the things that motivated me to want to leave. And I also thought, you know, I have enough time in me that I could make a start on a new career. You know, I'm not, I think, I think I felt that if I stayed any longer, I probably would never leave. So, so that felt like a good time to go. And then the other big thing that was happening at the same time, which was very serendipitous, was that there was just this I feel a huge sea change in all things to do with cannabis. So in the last five Five years, at least in the UK, we have seen things change. It's such a race, you know, we we've we've changed the law about medicinal cannabis, there's been a real change and public perception and acceptance about the therapeutic utility of cannabis, there's been a real flurry of companies that are interested in doing cannabinoid research 20 years ago, there was none of this, you know, 15 years ago, people were not interested in talking to me about cannabinoid science, whereas now, you know, you've suddenly become really popular, because you know, about a topic that is having a heyday. And so I felt like, there was a wave, and I wanted to be on that wave. And from a different angle, that I wanted to be part of the movement. And, and that may be a different place to do that was in a, in a commercial setting. So all of those things kind of all kind of happened at the same time. And, you know, probably in a different, you know, in a different set of circumstances, I would have stayed, but it just seemed right at the time. So I decided to, to go out by myself and do consulting, because I had already been doing some consulting on the side, because some companies had been approaching me for advice, because I did get work and stroke work and, you know, cancer work. And so I was giving advice to people. And I already had my foot in the door. And I thought, well, I can do more of this. And let's see how it goes.

Nick Jikomes 1:06:22

So let's, let's talk about consulting for a second. Because it can be this sort of this amorphous thing you say, I'm consulting for people, like, are they literally calling you on the phone and saying, tell us about how THCV works, please. Maybe for the people that, you know, might be academics now that could that might be curious about consulting. Can you give us an example of like a representative consulting project? What are you actually doing and delivering?

Saoirse O'Sullivan 1:06:50

Yeah, yeah. And it was really interesting, because I wasn't sure what I'd end up doing. But the typical thing that people wanted from me was to know what the evidence base was. So they might have a particular compound that they were, you know, they owned, or they were interested in licensing. And so they would want me to say, color compound X, they would say, tell me about compound X. One is the science behind it. What does the evidence show? You know, what would be a good home for this compound? Like, what indication what disease? Should we be thinking about? What would a clinical trial look like? You know, so sometimes I'm saying, Okay, well, this is what your trial should look like, these are the patients who might want to do so it's that kind of whole, you know, looking at the evidence base, and giving advice on on how you could potentially move that compound into a clinic. Or it could be just about a disease area, and what the general evidences for cannabinoids in a particular disease area and then helping people, you know, understand what the right compounds might be, by knowing the science and the mechanism of action of lots of different compounds. And you can figure out, okay, in acute kidney disease, it's really CB two that you want to be targeting. However, whatever you do, however, your campaign works, this is the molecular target. So this is what you want to do. So a lot of the research was, what a lot of the work that I did was kind of commissioned reports like that, where I would, you know, really get nitty gritty, into the science of what was already published, and put it all together for them and present options to them about, you know, how they might go forward. And sometimes it was just about education. So going into companies and teaching them the basics of cannabinoids about how they work, the history of them, you know, the, all the different ways that they're different, you know, like how we started this conversation today. But just like really giving them that cannabinoid 101. And it's quite important to people who who've never done, who've never worked in this area before, this is a complex area. And so having somebody who is an expert who can kind of break it down for them, was something that was, you know, really worthwhile doing. And I also did a lot like talks for people. So going into, you know, on their behalf, you know, speaking to societies or at conferences, that organized events where I would go and do education pieces on, you know, any of those above things, so that there were lots of different, you know, maybe talking to the media and trying to think of what some of the things that have done

Nick Jikomes 1:09:28

by me, but if I could summarize so far, what you are telling us in effect is that as a biologist with your kind of background, you are getting paid professionally, to read, comprehend and summarize the literature for people and to give talks, educational talks to people. Yeah, so a subset of the things that an academic would already be doing. Yeah,

Saoirse O'Sullivan 1:09:50

exactly. So I wasn't doing anything different than my skill sets. But what was different is that you're putting a commercial spin on it. So sometimes I'd be looking at what the competition is, who else is out there doing this? What clinical trials are being run already, you know, what companies are out there doing what? So sometimes it's, you know, it's more commercial than that. But yeah, I've got to read more in the last couple of years. And I think I did in the last 10 years in academia, when, when, you know, I was doing and when I was doing research, as an academic, I've, I've actually probably learned a lot more in the last two years about areas that I never worked in before. So I feel like I have a much broader understanding now than I ever did. So it's been, it's been really great. I've definitely found it really educational. And I've really enjoyed it. And what I found is that there are people out there who want expertise like this, I've never had to advertise. I've never, you know, really, it just kind of worried it might, I'll get a phone call from somebody saying, Oh, I, I hear that you can give advice on this kind of thing. And, and that's how it happened. So it was an interesting journey. But I have now taken a permanent role with so one of the companies for whom I was doing science advising for the longest time, probably for four years is a small biotech company called or tele Biosciences. And they recently offered me a permanent role. And so I have, I'm now working for them, not on a full time basis, but almost full time. But doing the same thing. So really being that translational, you know, expert about helping turning science into, into medicines, you know, knowing all that nitty gritty, cannabinoid background that's in my brain from the last 20 years, and using all that knowledge to help them move their products forward and their development plan. So that is great for me, because it's real, it's tangible. There are medicines being made, there are trials being done, and there are hopefully people who are going to benefit from it. And that, and that was always what my goal was, and I feel like now, I'm possibly getting to that point quicker than I would have done in academia.

Nick Jikomes 1:12:05

Yeah, so you mentioned earlier this, the slowness of academia. And you touched on, you touched on right after that, you know, getting pulled in so many different directions with so many different responsibilities scientific, administrative, and otherwise, is that where the slowness comes from? What do you think causes the sort of the pace of academic science? Or what's your diagnosis

Saoirse O'Sullivan 1:12:25

there? I think it is all of those things, I think that getting the kind of funding that you need to do fast moving research is difficult. And I was never a massively successful grant, you know, awardee, I did get money through my time definitely like, but I wasn't one of these people who was getting million pound grants. And so I was, you know, I was always looking for money, you know, I could have done bigger, better research had, I had infinite, you know, funds available, available to me, and I'm sure every academic would say the same thing. So that was always a massive rate limiting factor, that you're you were doing things and not as fast, or using the latest technology, I went into a clinical research organization a couple of weeks ago. So there's somebody who we pay to do our research now, the machines and the technology that they have, and the high throughput pneus, if that's a word of some of the stuff that they're doing is unbelievable. Academia just can't compete with us, you know, you can, you can screen your campaigns so fast with some of the technology they have. And there we are, in my lab with these old, you know, plate readers that are 20 years old, and the one PCR machine and, you know, two cell culture hoods that everybody's fighting over, you know, it just, yeah, it's a different, it's just can be a different world. And I think that there's a lot of, you know, brilliant people in academia, who, who would have made bigger and better discoveries, if they if they've just been easier, you know, and they had more funds available to them.

Nick Jikomes 1:14:09

Do you think, you know, this? This is a Do you think they're I don't mean this in the sense of, there shouldn't be people getting this type of training as much as possible. But do you think there are too many science PhDs in the sense of there are too many people fighting for the same finite pool of resources? And that paradoxically, you might actually be able to move faster? If if you were able to get more funding per lab?

Saoirse O'Sullivan 1:14:35

That's yeah, I don't know. That's really interesting. And yeah, I mean, I'd hate to say that there's too many people being trained because, you know, everybody who has a good scientific mind should be using it. I think there's limited resources. I think, you know, I think I'd blame that one before. I blame there being too many people, but I understand where you're coming from there are currently way more brilliant people out there, then there is funding. I mean, you know, if you if you are somebody who's who's writing grants, most of the time you're getting a grant redirection. The feedback is, this is a great study, but it's just not a priority. So the problem is you're putting your science in there with other great scientists. And it's just feels, it began to feel like you had no control over whether you got funding anymore. Being an excellent scientist just wasn't good enough anymore. You know, because everybody is excellent. So you're in a pool full of people who are scoring really highly. Everybody's scoring really highly. So what differentiates you and 10 years ago, as a cannabinoid scientists, we weren't getting a lot of funding now i so that might be different for me. Now, if I was in academia, where I'm suddenly working in an area that's more sexy than it was 10 years ago. So it could be different for people in this space now. But I know a lot of brilliant cannabinoid scientists who pretty much left doing cannabinoid research about 10 years ago, because it was just too hard to get funding in that area, because people didn't really see it going anywhere. And so I think, I think the, there's just not enough resources out there. For people. I did see another interesting conundrum, similar to the one that you put to me recently on Twitter, where somebody said, if there was less science out there, we'd be able to concentrate on the science, the little science that was being produced better, but because there's so much science being produced, and published all the time, well, we we can't keep track of missing some of the gems because of the sheer volume of research.

Nick Jikomes 1:16:34

Did you on that note, did you see the recent PNAS paper on this topic?

Saoirse O'Sullivan 1:16:39

So I haven't, I haven't done this what was being talked about on

Nick Jikomes 1:16:43

Twitter, it could be so it was making the rounds recently, I have not dissected it thoroughly. But basically, the gist of it is, what they found by analyzing a large corpus of literature across many fields is that as any given field of science gets bigger, as measured by like, the total number of papers being published, the field basically moves slower. And I believe a measure for that was like there. As the field gets bigger, there's more and more inequality, the Gini Coefficient of the citations goes up, meaning that that people just keep citing the same pool of like Mega papers. And effectively, you know, the ideas really do become entrenched by that measure, at least. Yeah, it's okay. I

Saoirse O'Sullivan 1:17:24

mean, it is it is a really interesting concept. Yeah. And you lose, you see this book with the volume of research anymore, I used to know, all of the cannabinoid researchers paper would come out, and I knew the names. And now there's so much stuff, I get these alerts from PubMed, there's so much research coming out, I can keep track of it all, because it's coming at, you know, faster than I can read and digest. And I don't know any of the people anymore. So I definitely feel like I'm losing a handle of some some parts of the research, you know, but that's, that's not necessarily a bad thing.

Nick Jikomes 1:17:58

Yeah, when when I fantasize about this stuff, sometimes, you know, imagine an alternate universe where, you know, an academic is not applying for a grant like every goddamn year over and over again. But an individual is simply awarded, like a perpetual grant, say, and you know, for the next 25 years, you're going to just go do your thing. And sort of like you're getting 25 years worth of grants all at once as an individual, rather than having to have a different group of your peers justify this one set of experiments twice a year, every year ad infinitum. Yeah.

Saoirse O'Sullivan 1:18:32

And we waste a lot of our time writing, but I felt like that was one of the most unproductive uses of my time, writing grants that didn't get funded, rewriting them, you know, just that whole process. It takes more time than it's worth.

Nick Jikomes 1:18:48

Yeah. I mean, it really does, in many ways, remind me of the private sector in the sense that, you know, when you talk about disruptive innovation, right, the the story is always, you know, the small, unknown startup disrupting the incumbent, because as organizations get bigger, whether it's government, whether it's a corporation, whether it's, you know, our academic institutions, there's just more administrative structure there, and it just sucks away time from the actual thing you're trying to do. And you just move slower. Yeah, yeah. Anyways, we have a few minutes left. Any exciting upcoming areas of cannabinoid research that you're working on or that you're, you're watching that you think are going to have some interesting insights that that come up. Uh huh.

Saoirse O'Sullivan 1:19:34

Yeah, that's an interesting one, what's going to be then the next big thing in, in cannabis medicine. And so there's an awful lot of stuff that's kind of at phase two, you know, so still small clinical trials, you know, not quite moving forward to potential licensing and So I'm not sure what's going to be new and that in terms of what medicine is going to be next to be licensed, I don't think I can put my money there. But I think what there is, is definitely a huge, much bigger number of clinical trials being done being carried out than there ever was. So I think that we will see a change in the next kind of three to five years in terms of what are they available for licensed cannabinoid based medicines. And I think that there will also be, there's not as much research, I think, really just being used on medical cannabis as a whole plant product, because, you know, people aren't, you know, from a, from a commercial point of view, it's not patentable, people aren't investing the kind of money to do big trials in that in that type of research. So I don't see an awful lot of big headlines coming out from from whole plant products, I think that the kind of the short term future is going to be more about specific and patented products in terms of their, their, their, their therapeutic use of cannabis based medicines. But, you know, there's an awful lot of, you know, it's hard to choose one, but there's an awful lot of and I don't want to, I don't want to choose one and appear biased by choosing something from the tallow portfolio, but there was a, there's a lot of things out there, that, you know, as I mentioned, with the, with the sports story, there's a lot of things out there that have a really strong scientific background, they're being pursued in, you know, good clinical trials, randomized controlled trials of decent patient numbers, that if they're successful, you know, could really change the face of things in the in the short term future. So I find that very positive. And I think that the, the future of cannabis based medicines is really bright. There's lots more companies coming into the area looking at, you know, really putting their thinking hat on and saying, What can we do differently? How can we do our trials better? And what how can we, you know, be smarter about the products that we're using and the indications that we're using? And the delivery mechanisms and the formulations? So I think as more and more kind of pharmaceutical type companies get involved in this, we'll see more innovation in this area. And I think, I think we'll start to see the, you know, the utility of cannabis being actually utilized. So, you know, people have said that cannabis is like a Pandora's box of medicines. I totally believe that. I think it's tapping into it, that's always going to be the difficult thing. But I'm a lot more hopeful now than I was five years ago, because there has been this, you know, great flurry of, of companies trying to now actually use that knowledge and produce something. So not a specific thing, but just in general terms I'm very optimistic for for cannabinoid based medicines.

Nick Jikomes 1:23:02

All right, well, seriously, O'Sullivan, thank you for your time. You're very welcome. Thank you very much.


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