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Ep #11 Transcript | Matthew Hill: Endocannabinoid System, Stress & PTSD

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Matthew Hill. Thank you for joining me. Thanks for having me. Where are you located? And can you tell people a little bit about your scientific background?

Matthew Hill 1:58

Right now I am a professor in neuroscience at the University of Calgary at the Hotchkiss brain Institute. I've been in science for about 20 ish years since I started grad school. through that whole time I've kind of always been focused on studying different aspects of the cannabinoid system in the brain, which is the biochemical target of THC from cannabis, studying the receptors studying Endocannabinoid molecules themselves and kind of understanding how they modulate the way that the brain regulates things like feeding and anxiety and stress and kind of different homeostatic processes. More recently, moving into cannabis itself now because looking at some of the effects of cannabis on the brain to understand that in a bit more depth,

Nick Jikomes 2:42

interesting you, you've done a lot of work on Endocannabinoid biology, things related to stress, anxiety, pain, and there was a really interesting story a year or so ago. And you're involved in this I believe, about a woman from Great Britain who had a really interesting and peculiar genome, and her endocannabinoid system was different from the average person's. So can you describe the story of that woman and what you guys discovered?

Matthew Hill 3:09

Yeah, so Joe Cameron, kind of is this interesting, you know, these the kind of fun things in science that happens, just this kind of random biological thing. And one person informs us so much and creates this very interesting phenotype. And Joe, I think, I mean, she was in her 70s, I believe, she kind of went through life, not really noticing anything specific with a phenotype, but she had for so long, it's actually kind of interesting. Apparently, the way that the doctors came across her is she had gone in for hip surgery, which is an incredibly invasive and typically painful process. And afterwards, when they had been offering her bed, she was like, Oh, I, you know, they gave her like one single Tylenol or something. And that was the extent she did not want anymore. And everyone was a little surprised by this. So they sort of asking her about, you know, Is this normal, and she kinda started describing how she's never really had pain. So then they started bringing in more people to have conversations and do tests with her and then realize she really had this fascinating kind of inability to feel pain phenotype, and mean these people have been found before, but the way that their genetic mutations have been that have kind of made them not experienced pain has been fundamentally different than what Joe had more often is that there's some change in like a neurochemical receptor, these other people who are pain sensitive that impedes the body's ability to sense pain at all with Joe. It's unclear, I would say if she can completely not sense pain entirely, in some ways, as much as it just doesn't infants or affect her in any way. I mean, she describes kind of learning certain things like oh, you know, she put her hand on the stove and smell burning skin big Oh, don't do that, which is a little surprising. But she did seem to have some sensitivity to cold still. So there was some specificity in some of the things that Joe had said. I was first contacted by the doctors in Britain about this because they were really focused on the pain phenotype. And there was this is a group that did a lot of molecular nociception work. And so they were curious about they had sort of going through her genome. And what they had discovered was that she seemed to have this kind of mutation where she had a chunk of DNA kind of right around where the gene for fall, which is an enzyme that regulates the metabolism of endocannabinoids. right in that region, there was this this kind of genetic effect, basically a lesion that seemed to take out a chunk, and it didn't directly affect the phosgene. But as a consequence, it seemed to influence expression of fond some capacity. It's still not exactly clear how this is the case. But basically, what it resulted in was that she seemed to have very little of this enzyme far and what fod does is it chews up and breaks down endocannabinoids. So if you have less of that enzyme, as a consequence, you've predicted that means you have kind of elevated Endocannabinoid tone. And so you kind of like high endocannabinoids all the time. And this is an interesting thing to look at because of the fact that we make a lot of assumptions of what elevated Endocannabinoid activity would kind of look like in a human you know, does is it gonna look like what would happen from THC or not. And so, there have not been I mean, we have some genetic variants in the endocannabinoid system that creates small changes in Endocannabinoid levels where they might be a little bit and there are phenotypes you can pull out, but nothing has ever looked like like Joe Cameron. I mean, so they were asking me to measure her Endocannabinoid levels, they sent me the blood. And that was when we found out that her Endocannabinoid levels were quite high higher than any human I'd ever measured up to about 1000 samples from things we'd looked at before. And so it did seem like this genetic mutation that she possessed was somehow causing her fault to not function properly or or be expressed. So that is a consequence, she was kind of living in the state of persistently elevated endocannabinoids.

Nick Jikomes 7:03

And so how much higher were levels was 20%, higher was twice as high.

Matthew Hill 7:09

So as a frame of reference, I would say if I measure an animate in the circulation of most average humans, it falls between 0.5 and one peak a mole per mil. So that's kind of the range, you typically see it. People who have the more common genetic mutation and fog, that doesn't completely cause it to have a loss of function, but it impairs it a bit. And that's been studied extensively, their levels go up to maybe like 1.2 Pico moles per mil, so again, not much of a change, Joe's were

Nick Jikomes 7:37

about 2.2. So it was double or more more than doubled than what the average person would have most of the time. And so she had this interesting pain phenotype she couldn't. It's not necessarily that she could not sense pain, but she certainly wasn't bothered by it in the way that the average person would be. was anything else interesting about her her personality or anything like that?

Matthew Hill 7:59

Yeah. So that was when they reached out to me again, they were interested this purely in a pain context. And so after we looked at the levels, and we're like, yeah, this, this person clearly has only been on cannabinoids, I kind of went back to when I said, You know, I think it would be really interesting to look at what her emotional processing is like, simply because you would assume, based on all the stuff that we've seen with the animal work, and what we started to see in humans, that if you have elevated endocannabinoids, they should have a consequence on how you react to stress how you process stress. So they started kind of doing interviews with her about emotional events, they tried to do some basic scales, she basically scored the lowest you can score in any kind of inventory of anxiety or depression. But interestingly, through the interview processes, they would talk to her, she would start talking about events that most people would have found, like incredibly traumatic, like her first husband had committed suicide, he had bipolar. And she had lived with him through various periods that were very tumultuous. There had been a lot of other events that have been car accidents and stuff that she had been in. And the way she described these events was just very kind of like, you know, this is shit that happens like this is life like it was it just kind of rolled off her back. She didn't view it as being particularly salient emotionally in any way, necessarily. And she basically said she had never really experienced, like the sensation of fear, really, or being scared at stuff, which we found really fascinating. And I mean, prior to COVID, part of the hope was there would be a lot more investigation into this. And in fact, the colleagues in Sweden that I've been doing a lot of work with looking at fun humans, they became interested in they actually wanted to try and bring her over to Sweden to do some scanning and some more in depth emotional batteries to try and get an understanding of her affective processing. But COVID happened and so things kind of fell apart there unfortunately, but it really is this like incredibly fascinating phenotype that that she possesses. With like a very highly sunny disposition and this kind of insensitivity to pain. It's Largely what we would predict from someone who has a really high end and have my tone around the clock.

Nick Jikomes 10:05

So Ananda mind is often referred to as the bliss molecule. And I used to wonder how true that was just given, you know, it sounds kind of like this pop science term that, you know, a magazine would use to describe a molecule. So is that actually a pretty accurate description of this molecule in terms of what it does and what it regulates?

Matthew Hill 10:24

I mean, certainly, some of the way that that bliss molecule came out was because of how Rafi Mishima named it, I mean, because the even in the word an and amide is the Sanskrit word for bliss. And Rafi is kind of in our joke was that this is like, you know, the molecule of bliss in the body, based on how we conceptualize cannabinoids? Yeah, I mean, I guess you could say to some degree, I mean, I always feel like it's difficult popularizing these things. I mean, we saw, we went through decades of dealing with people using the term endorphin rush in an incredibly erroneous manner for virtually every description of stuff because people learn that, you know, they got endorphins with something. And they assumed that this meant everything was pleasurable. But you know, I certainly have what we understand about what happens when you elevate an amide. It does, you know, take the edge off of aversive events. And it seems to, I would assume favor more positive salient events in the head, just simply by kind of reducing the salience of negative events that would shift positive bias towards things and we know the endocannabinoid system tends to enhance rewarding aspects of stimuli. So I would assume like, you know, based on the way Joe presents, you know, she looks like she's just kind of happy go lucky with everything that happens to her no matter how crazy things get. So in that sense, Sure, I'd say it's got some validity to it. But there's always a downside, we just haven't explored it enough to see what it is yet.

Nick Jikomes 11:48

So this woman has altered pain processing, she's in this persistent, great mood, basically, what, what are like the downsides? What Why is it an animal and just at higher levels? And all of us? Why didn't? Why did it not evolve that way?


Matthew Hill 12:04

I mean, I think I'll take this from an anxiety perspective, because that's, you know, what I study and what I think about, I would say, you know, someone who has Joe's phenotype, in an evolutionary context is, that's not it's not actually a beneficial trait for a population to have because, and Joe commented on this herself, I mean, she's lived, despite the kind of stressful and dramatic things that have happened to her locally, with with her marriage and other things. I mean, she has lived a relatively sheltered life in a small rural town in Scotland, she hadn't been exposed, you know, this wasn't someone who lived in Bosnia during the wars, or was around during, you know, Vietnam wars, or any kind of tumultuous period in recent modern history where having a hyper vigilant phenotype and being fully aware of the threats in your surroundings would be an advantageous phenotype to have to ensure survival. I mean, it's, it's the kind of balance you would assume when things are good. Having a phenotype like Joe's is great, because then you're not burdened by unnecessary anxiety or worries about things. But if you live in a state or a period in history, when things are highly tumultuous, and there's a lot of threats in your environment, having that kind of casual happy go lucky perspective is not going to ensure your survival very well, because you are much greater likelihood to not recognize threats in your environment and put yourself at risk.

Nick Jikomes 13:22

So for most of our evolutionary history, things haven't been as good as they are today for a lot of people, and we haven't lived in safe environments. And that's presumably why most humans aren't walking around with this type of phenotype.

Matthew Hill 13:34

Yeah, I mean, I say anyone who I always kind of look at because of a stress person, I always look at things through the evolutionary lens. And you're like, there's a reason why evolution likes diversity in a population because things change so rapidly, and things change so violently at times that if you didn't have people sitting on all sides of a spectrum, of any given trait at any given time, with whatever the environmental demands are, you know, you know, right now, Joe's phenotype is great. But yeah, 200 years ago, maybe not so much. And so I think it's just evolution will always favor there being diversity, because at different periods in time, there's going to be different traits that are advantageous and will ensure survival. I mean, we look at someone with an anxiety disorder right now, who like if you're agoraphobic or you don't like going outside, you can stay in confines, or if you have social anxiety disorder, and you don't like being around people as much, you know, are currently you know, not the COVID environment. But our current modern environment, those kind of traits can be more detrimental to someone because of the necessity of social functioning and the way that things are played out. But historically, if you lived in a time of like a lot of, you know, threats and attacks, if you were someone who stayed at home and kept the kids there, and didn't really want to leave because you were worried about what was outside the chances of you surviving and your offspring surviving are a lot greater. So mean anxiety is is crummy when it's out of context, but it's actually an incredibly advantageous trait. So I can see why, you know, if we were all Joe Cameron's, we wouldn't Probably not have survived and thrived as long as we have.

Nick Jikomes 15:04

So this was an interesting use case where someone has really high levels of an and amide. But can we back up a little bit and can you describe at a high level what is the endocannabinoid system and was an and am I doing with respect to things like FDA, this enzyme you mentioned, and things like the CB one receptor under normal circumstances and most people,

Matthew Hill 15:22

so the endocannabinoid system is bad. I mean, it's just a very widely distributed biochemical system in the body. It's composed of enzymes or molecules and the enzymes that make those molecules and break down those molecules. And then it has the receptors that those molecules act on. That kind of thing that I think makes the endocannabinoid system interesting is just because of the biological kind of similarities and redundancy between the endocannabinoid molecules and some of the molecules that come from cannabis. The system was really discovered because it ended up being the biological target of THC from cannabis. And so THC binds to cannabinoid receptors. There are two that we know of and are well established the CB one receptor, which is really the one that's predominantly in the brain, and it's very widely expressed in the brain, it's very important for regulating or transmission and forms of plasticity. And then there's the CB two, which is primarily an immune receptor. It's mostly found on immune cells. It's certainly on microglia in the brain, maybe on some neurons, but if it is, it's incredibly low levels. THC acts on both of these as do endocannabinoids.

The Endocannabinoid molecules themselves, there's two there's an animal which is one that we've been talking about already. And there's another one called to arachidonic glycerol, they're, again, both very similar in structure. They are regulated by an entirely different enzymatic paths that make them and break them down. So the molecules do exist in kind of different worlds, let's say because different processes will drive synthesis of one versus the other. The one thing I'd say the field hasn't entirely figured out yet is why there are two Endocannabinoid molecules. I mean, most neurochemical systems in the brain tend to diversify at the level of the receptor, where you have a molecule like serotonin or dopamine is a singular molecule, and it signals through, you know, five to 25 different receptors depending on what transmitter system you're looking at. And that's where you see the diversification endocannabinoids, kind of the opposite, because in the brain, we're really just talking about one receptor CB one that's just really widely expressed, but yet it's acted on by two different molecules. And if you look at the effect of those molecules, they generally do the same thing. They both activate CB one in a similar manner to how THC does. The CB one receptors kind of got this interesting localization because it's found almost exclusively on axon terminals. So what that would mean is when it becomes activated, what it basically does is it turns off neurotransmission because it's an inhibitory receptors, so whether it's activated by THC or endocannabinoids, when CB one becomes active, you just see less synaptic neurotransmitter release. That doesn't necessarily mean it's a depressant, like some drugs or kind of central nervous system depressants. Because if cannabinoids are turning off inhibitory transmission in the brain, they're actually enhancing excitation. So it's very synapse specific and can get incredibly complicated with how they actually regulate brain activity when you kind of look at the net effects together. But, I mean, what a nanometer to ag would kind of normally be doing is, I mean, they certainly are involved in regulating basic processes and making sure that the brain exists in, you know, I would say a homeostatic range. Like if you really had to boil down what the point of endocannabinoids are in the brain, the main argument I would make, and I think a lot of people in the field of omegas, they're really there to make sure everything kind of keeps in check there. I view them in many ways as a molecule of homeostasis, like main job is to keep things where they should be, because of their ability to regulate neurotransmitter release. If we look at something like you know, epilepsy, we have a state of hyperactivity, and there's too much excitatory transmitter being dumped out endocannabinoids will be trying to curb that and put the brakes on the system by activating CB one and limiting the amount of glutamate release. So they're trying to prevent that hyper excitation and over excitability of a circuit. So that I mean, they're, they're really a buffer in many ways to make sure that the brain activity doesn't go too far to control when we are too far, like down in the other direction. So they can really gauge the the kind of basal activity of a circuit and respond appropriately to make sure that parts of the brain behave the way they should, if they get kind of bigger step up at a process level, like something like feeding, which you're very familiar with. But like you know, endocannabinoids are a really important regulator of feeding processes. So we know that like, if you go a period of fasting and you don't eat or an organism doesn't eat for a period of time and obviously, start burning through your energy reserves in the body and so your body wants you to eat. Endocannabinoid levels seem to start elevating within feeding circuits like in parts of the hypothalamus. You see Endocannabinoid levels go up during periods of fasting and they kind of show If the excitability of the circuits to try to enhance the activity of clusters of cells that are going to drive feeding activity and enhance them, so they almost act as this on switch to try and drive feeding behavior. And then once food consumption occurs and macronutrients hit the body even as quickly as when the guts start sensing them. Endocannabinoid levels in hypothalamus start plummeting and going back down. And so they're very responsive to nutritional status and hunger state. And so in that sense, again, it's like a homeostatic mechanism you have any long enough your body needs the endocannabinoids, mobilized in a process to drive you for food seeking behavior. And then once you've eaten and satiated yourself, they go back down the sense of stress, we see the same thing. endocannabinoids seem to at rest be kind of keeping some circuits in the brain, especially within the amygdala, kind of quiet under ambient conditions when there's no threat. And then what we see is that in response to a threat, there's this really rapid loss of an Endocannabinoid signal. And that seems to facilitate activation of these circuits that drive like the generation of an anxiety state. But then as we go into the stress response, we mobilize hormones like glucocorticoids, like cortisol in humans, and these hormones then seem to actually jack up into connection endocannabinoids in the brain, as a means to turn everything back off and help turn off the stress response and help us come back down to a resting state. So we're not kind of hyper vigilant and anxious still. So again, they can almost every process you look at, you can make the same argument for pain, I could say the same thing for inflammation, you see the same thing over and over with how endocannabinoids behave, they really respond to disturbance in a physiological process, they act to modulate a neural circuit to influence a behavioral drive that will help bring things back to where they should be. And then once everything goes back to normal, the levels start to normalize. And the signaling goes back to this kind of low level tonic state where it keeps things you know, at rest.

Nick Jikomes 21:53

And as this why endocannabinoids are so localized in space and time, they tend to get used when and where they're needed. They're not just sort of flooding the entire brain or anything like that.

Matthew Hill 22:03

Yeah, yeah, I think it's something that a lot of people don't appreciate is how precise that kind of spatial temporal action of endocannabinoids is. I mean, like when a neuron releases it, it only hits a couple of synapses, and it's very specific and how it influences those synapses. So, I mean, and this is always one of the reasons when people ask like, you know, if you have a drug that will boost Endocannabinoid levels like a fine editor, where you inhibit an animal metabolism and and and my levels go up. They're like, why doesn't that like look the same as when someone smokes cannabis or consumes cannabis and THC? It's the brain. And the only thing you can try and say is well, you you got to think like an animal. It's not being made everywhere in the brain where there's CB one receptors, presumably because some of those are going to be more hit by to Ag and, and the amount of anatomy that's being made by a cell is going to be you know, if it's nothing driving it, it won't be that high. So if you inhibit for an and amide will start accumulating, but it's only going to be accumulating in the parts of the brain where it's normally active. you consume cannabis and THC gets in your bloodstream and it's the brain it indiscriminately. It will just saturate every CB one receptor it can find. And so that seems to be one of the main reasons I would say you get this very big difference between boosting Endocannabinoid levels and actually consuming cannabis in terms of the psychological and intoxicating effects, you see, because THC just has no discrimination that hits everything again, because it's not dictated by synthesis the way that endocannabinoids are.

Nick Jikomes 23:24

And is this so when we think about the normal function of the endocannabinoid system, you've essentially told us it's this homeostatic mechanism that regulates more or less everything from you know pain and anxiety, to feeding behavior to to all sorts of stuff. Is that why? Something like cannabis? Something with THC has so many different effects and side effects that seem to go in every direction? Some people say that they consume cannabis, it makes them less anxious. Some people consume cannabis makes them more anxious. Is that does it have to do with this flooding of the brain with THC and the fact that these receptors are controlling so many processes?

Matthew Hill 23:58

Yeah, I think it's I mean, the joke we always have is like cannabinoids influence everything but regulate nothing. Because they, you know, they're not essential for anything to occur. They're just they modulate everything. But I think for sure, I mean, that's why there's so many diverse effects of cannabis on someone when they consume it. I mean, you have hemodynamic effects on blood pressure and vasodilation you have you know, some effects on feeding which again, like you said, it can go in either direction. I mean, we classically think of the munchies as a consequence of cannabis, but you consume too much THC and it goes in the complete opposite direction. People can start vomiting uncontrollably. People lose their appetite if they kind of, you know, I don't want to say overdose but over consumed THC or cannabis and they have too much of it. Like you said, you know, most people, most recreational cannabis users use cannabis because they say it reduces their stress and anxiety. And if you ask people who tried cannabis who do not use it recreationally, almost always they say because it made them anxious. So it's interesting that you get this. And I would say it's weird. It's not like a graded response where some people have reduced it. Anxiety and other people doesn't really do as much. It's like a polar opposite response where for some people, they find it helps them calm down and other people throw them into a panic attack. So it's very interesting that a drug can do that when it's one drug targeting one receptor. But some of this is going to be individual variation with receptor expression. And one of the things that we've learned from the animal side of things is these kind of opposite effects like what you were mentioning with anxiety. This seems to be dictated by CB one receptors on different neuron populations. So what we what we've learned from mouse genetics is that we remove cannabinoid receptors off of excitatory neurons, so cannabinoids can no longer suppress excitatory neurotransmission. We lose all the effects of THC, in terms of the standard intoxication effects. So the datian the changes in body temperature, pain processing, all these things, they're all lost. If you take CB one off of excitatory neurons, you take it off inhibitory neurons, it does very little. Yeah, all the effects of THC look pretty similar. However, if you start going to really high doses of THC, where you get these opposite effects, then that seems to be where CB one on the inhibitory neurons plays a role. And so in the context of anxiety, because that's the easiest one to explain, you can take this to the amygdala. So if we look at the amygdala and the basic sense of, we know the amygdala becomes too excitable and anxiety states and in individuals who have anxiety disorders, it's hyperactive, there's more activity than we should normally be having. And we know things like benzodiazepines and most drugs that treat anxiety, reduce neural activity in the amygdala, usually by promoting inhibitory transmission. So if we look at how cannabinoids regulate anxiety, what we've learned is that in the amygdala, if THC activates CB one on excited Tory neuron, it decreases the amount of excitatory transmitter like glutamate that's going to be released. And as a consequence in the amygdala, that will calm the amygdala down. And so that seems to be why THC is, you know, moderate and lower doses is reliably anxiolytic. Because it seems to be primarily suppressing glutamate release in the amygdala and keeping it quiet. As you start jacking doses up and you go to a higher level, then it starts to saturate CB one and gabbeh. And it seems to do the opposite, because now what it's doing is turning off inhibition, and then you get the opposite effect. They're getting more excitation. And so you get this, it's almost like you kind of cross the threshold and it flips Yeah, suddenly before it was quieting it down, and now it's making it more active.

Nick Jikomes 27:25

So that's interesting because in so in the scientific world, you often talk about something like an inverted U shaped effect where something switches at a low versus high dose. And that's what the sounds like in the cannabis world, where people aren't really so familiar with some of the mechanisms that can be at play here. People talk about a multi phasic or bi phasic effect. Yeah, and it sounds like that's exactly what we're talking about. The basis for that is at a relatively low dose, you're affecting one type of neuron in the brain, say excitatory neuron. In this case, an Endocannabinoid at that dose would actually make things quieter, but then you go up higher, and you start hitting those inhibitory neurons, and you get the opposite thing happening. Yeah,

Matthew Hill 28:05

yeah. And that's, I mean, so if we, if you delete CB one on glutamate, and you give them low dose THC, it doesn't reduce anxiety anymore. So you need it there and exactly like you're saying, if you delete it off of the inhibitory GABA neurons, and you go that high dose where they normally get anxious, they no longer get anxious. So we know that those different receptor populations mediate, but you're exactly right, it is entirely an inverted u curve. And normally, where we would sit is probably somewhere on the A sending arm of the first part of the U, because depending on what your basal level of Endocannabinoid function is, because we know if you completely disrupt them to connote a function, that also enhances anxiety. But we know if you kind of go all the way around the inverted u and you end on the other side, too much also increases anxiety. But the disrupting if you reduce Endocannabinoid function that is probably increasing anxiety, because now you're affecting the CB one and glutamate. So again, you're causing more excitation, because you're kind of removing that brake system that would normally exist on the excitatory neurons. So it is entirely an inverted u curve. But yeah, by phasic tends to be how people in general public will refer to it that, you know, you're usually safer with low doses and you go higher doses. And, you know, everyone has a different threshold, but you cross that threshold, and kind of everyone will have an adverse event.

Nick Jikomes 29:18

Yeah, yeah, I definitely know people who I mean, this all makes a lot of sense. Because it you know, I know people who can consume a lot of THC and have no side effects, or anything approaching a normal dose. And then there's other people who, you know, even two and a half milligrams of THC can be problematic.

Matthew Hill 29:34

Yeah, it's and the thing is that I mean, there hasn't been enough work in this but it's interesting because it makes you wonder how much of this is just dictated by individual variability and CBD and expression. So one of the things I've always been fascinated by is there's a lot of reports in the literature that women will have a kind of a narrow window to have an adverse event, they've women will more likely have an anxiety or a panic like response if they consume cannabis. Even at lower doses than is typically seen in men, and some of the stuff we've seen in the animal work and some of the suggestions we've seen come out of the pet imaging in humans is women may indeed actually have more CB one receptors than men. Which just means that that that window of when you go from too little to too much might be a much narrower threshold. Now if this was the 70s, the 80s when cannabis was like 5% THC, you would have a lot more room to play with that window. Nowadays when you're talking like 25% THC this can like you could probably cross that threshold with like a single toke like one toke is not going to do too much too much, too. Jokes is too much like that's how narrow it seems to be for some people from what I've seen and heard about, like how quickly they can go from it being okay to not being okay.

Nick Jikomes 30:47

Yeah, I want to talk more about this concept of the endocannabinoid system acting as a stress buffer. You've you've so far described it as almost like a universal buffer, it's regulating almost any process you can think of in a homeostatic fashion. So can you maybe back into this by describing a typical, like healthy stress response, what's happening in the brain and body under a state of stress?

Matthew Hill 31:10

I mean, normally what will happen is, you know, you kind of think you're just going about your day, things are fine. There's nothing there. And then, like the example I tend to use just because I get to meet people and get to is like, say you're walking through a forest and you're just kind of whenever you're on a hike, you're doing your own thing. And then all of a sudden, you hear like a stick break.

And it's and that you know, there's nothing in your vision that you can see, but immediately everything about you changes. So you've suddenly what has happened is your brain has perceived that there's a potential threat in your environment. And this is basically what will be the most classic trigger for a stress response is your brain perceiving an immediate threat around you. And what happens very rapidly is you'll get a dumper norepinephrine into your forebrain, which causes a lot of shifting and reorientation of your attention so that you start to focus on details in your environment that you probably were taking for granted prior to that. So this is the shift into a state of hyper vigilance, where like if you're in the dark, what you'll notice is your pupils will rapidly dilate and you can suddenly see a lot more than you could before because now more light gets in because your body is trying to prepare you to look around and figure out where that threat is coming from. Your the adrenaline when it hits your bloodstream aside from your pupils will make your heart rate go up, makes your blood pressure grow, go up so that you are ready to deal with this threat as it presents itself whether it be you know, running away or engaging in a fight. And you kind of your brain also in terms of anxiety, especially if you can't see where the threat is, your brain is now constantly trying to search and figure out where that threat is coming from. So you can assess how potentially damaging it's going to be for you. And whether this is going to be something you're going to have to contend with or not. Because you know, maybe it was just a stick falling, we don't know. So that kind of way that your body flips into that mode prepares you to deal with the threat at hand. The other thing that happens is you get the kind of hormonal response, which is this release of cortisol, the main function of what cortisol does is when a hit your blood is it causes a mobilization of blood glucose essentially. So the way I was trying to explain this to people is like the classic form of the stress response is, the adrenaline component is basically the mechanism to get, you know, the trafficking of oxygen and glucose accelerated. So you can deliver this to your muscles in your brain. So you can run away and you can focus on your environment. And the cortisol arm of that response is basically giving you more fuel. So it's basically like, okay, let's get more sugar into the blood, let's make sure that we have glucose to feed the brain and to feed the muscles so that we don't fatigue. And you kind of go into that state. Now normally, you should be able to assess whether there is a threat within a couple of minutes. So the stress response in a typical sense is very short lived. It's really an assessment, you've got to figure out what's around you. And once you've assessed that or removed yourself from the situation. So the threat is no longer present. Everything has the kind of turn back off. I mean, the adrenaline response is obviously very quick, it's very quick to turn on, it's very quick to turn off the cortisol response. Again, it's a little bit more slow. But one of the things I think that we hadn't always appreciated in the brain, let's say is, like when I started doing work, the impression I always got from the way the field described stress recovery is that it was essentially a passive process, that once the brain had said, Okay, this threat isn't present anymore. You know, no need to keep driving the stress response. It just basically turned the light switch off. And then what you saw was like a passive recovery phase. And actually, I don't think that's the case anymore. And I think what what we've really learned about the endocannabinoid system in this context is that it is an active mode of stress recovery. So it is becoming mobilized by the release of the stress hormones. And part of what it's doing in that state then is to turn the amygdala back off because the amygdala becomes very active in response to threat. It's in our and it's what kind of helps shift our perception to try and do threat detection in our environment. So as we call in No calm the amygdala back down is Endocannabinoid levels go up. This is part of the normative recovery response. And one of the things that, you know, you think about this, in the context of how this can be pathological is it's like not everyone turns their stress response off properly, there are people we can see, who stay in that, you know, you know, they get pushed over the edge to have a stress response and to kind of stay locked in it for some time. I mean, there are also people on the other end of the spectrum, like who would load high and psychopathy who never mount a stress response, because they don't really perceive anything as a threat. So, you know, you can kind of see pathologies on both sides of the spectrum there of how not mounting a normal stress response. If it's too much, or too little, why it doesn't, you know, effectively work in the long run.

Nick Jikomes 35:41

So, I start to think about things like PTSD here, where you have some kind of stress or anxiety response that fails to shut off properly. And based on what you've told us, the endocannabinoid system is at least an important part of the equation for the switching the turning on and turning off part. So can you maybe talk about, you know, what is PTSD? from a scientific perspective? And what do we know about why some people have this dysregulated stress response that outlasts the actual threat?

Matthew Hill 36:11

Yeah, I mean, PTSD is a very, I mean, it's not as complicated with this and like depression, which is super, super heterogeneous, but PTSD is, it's very, I don't know, it's hard to describe, in many ways, in terms of why some people have this response after exposure to a traumatic stressor. And others don't, I wouldn't say the field has a strong grasp on that. I would say that's kind of like a big thing that people have been trying to understand for some time, is there some way we can predict who you know, if 10 people get exposed to a trauma, which one of them will subsequently develop PTSD and Who wouldn't? That obviously, would be incredibly valuable information for us to understand, it seems more likely that it's probably some latent biological signal that doesn't present itself until the trauma itself has actually unmasked this, this latent difference that we're seeing. And that has made it very difficult. What we do know we see is, in the aftermath of the trauma, there are kind of various trajectories that people will have, there's kind of the super resilient phenotype where, you know, there's no short term effects, like there's no kind of acute stress syndrome right afterwards. But also, there's no development of PTSD, then there's the kind of group of people that do have this very robust acute stress stress into them and the immediate aftermath of the trauma, but it kind of wanes, as if a normal stress response over time, and it goes back to normal, and there's kind of no long term changes. And then there's the I think what a lot of people think is more classic PTSD, which is in the immediate aftermath of trauma, there's not really any visible traumatic stress symptoms. And then in the weeks and months after the traumatic event, things begin to emerge and present themselves. And then you have the last, which is just the people who go right into the traumatic state and stay there and it goes into full blown PTSD. What differentiates individuals that we've looked at post hoc, there does seem to be, you know, alterations in the way that the brain is processing information, there seems to be some issues with how say, the prefrontal cortex is communicating with the amygdala. So the prefrontal cortex should, in many ways, kind of keep top down control over the amygdala and prevent it from slipping into states of hyperactivity when there isn't threat like because the prefrontal cortex is so important for reference memory, a lot of the thought is that there's this conversation, you know, I hate anthropomorphizing how brain structures talk to each other. But it's kind of the easiest way. But there's kind of this conversation where events present themselves and the prefrontal cortex is kind of telling the amygdala No, this is safe, don't worry about it. We've seen this before, or this isn't a threat anymore, it was before. So now it's time to calm down. So if the prefrontal cortex isn't having that conversation with the amygdala the way it should be, the consequence of that, in some ways is that the amygdala is going to kind of go out on its own. And the default mode would often be threat detection to say, okay, you know, from a survival perspective, if you don't have that input, telling you what's safe and not safe. From a survival perspective, the default would be everything is potentially dangerous, so act accordingly. And so the lack of functional connectivity that we seem to see in PTSD would suggest that you're not having that top down control over the amygdala as much and that may be influencing certain aspects of this. There's certainly states of hyper arousal and hyper autonomic function. So individuals with PTSD definitely will have elevated adrenalin they will go into episodes will they'll have kind of re experiencing events and panic where adrenaline levels will shoot up and they'll have massive autonomic changes. And the sleep their their sleep patterns are often really really messed up, especially REM sleep can be kind of this period where they start having very violent traumatic re experiencing nightmares. And there is a lot of belief now that actually that sleep phase is very important for kind of reconnect validation of the traumatic memory and the way that it evolves and generalizes over time. And that this is due to some kind of disruption in REM sleep, it's favoring this, this re experiencing. And so and then because of that, there's also this horrible quality of sleep, which obviously contributes to a lot of the other issues.

Nick Jikomes 40:20

I think an interesting thing to talk about here are the different potential treatments that different people are exploring and advocating for PTSD. So staying on the notion of like sleep and nightmares first. There's a there's no hard evidence for this. But I believe there's indirect evidence that THC in cannabis that contains THC might suppress REM sleep. And some people have attempted to at least make the connection that perhaps medical cannabis could be useful in treating PTSD, the idea being if it is suppressing REM sleep, you take it to help you fall asleep, you're suppressing these nightmares. And maybe there's something there. How much is there that that we know about in terms of medical cannabis?

Matthew Hill 41:01

So it hasn't it? Sadly, it hasn't been done as much depth as it should. So most of I mean, you're right in, in everything you said. So, I mean, there is some literature looking at law, this was done in the 70s. When you know, you can do this way better now with with sleep architecture studies. But it's certainly there is evidence to suggest that when you give someone THC, you do get a suppression of REM sleep. I mean, even in the initial fall inhibitor trials, they saw this, they saw that it reduced REM and a favorite non REM sleep. Which is interesting, because it does tend to also increase total time sleeping. So not only you getting sleep, but it seems to be favoring more like, I guess, light sleep and deep sleep phases over REM, which could have some benefit for people, but definitely in the context of PTSD. So I agree, I've always thought that would make sense. And the reason I think that it makes a lot more sense is if you look at the evidence has actually been done in populations of people who are afflicted with PTSD. There's kind of clusters of anecdotal studies, which, you know, you would usually normally not put a lot of weight in, you know, 1000 anecdotes are still just 1000 anecdotes, it's not data. But if you're a good scientist, in my mind, if you have 1000 anecdotes, that all say the same thing, then that is where you form a hypothesis from and design a study to test it because you wouldn't be stupid to not pursue that. So then people started looking at this is kind of retrospective things in clinical populations, where they looked at what were people saying when they got put on THC or cannabis, where they were people with PTSD claiming that they were having less nightmares and improve sleep. And this kind of kind of popped up again, and again, in these chart review studies that were really not well controlled. So in terms of actual science, there's been two studies that were done. And both of them were done by the Canadian military. And they were done using an isolated THC pill. It's an abalones, like a synthetic THC, that's pharmaceutical grade. And then the first study, they just did an open label trial. So this was again, not properly done, necessarily, because it wasn't blinded. But they have we're dealing with a population of war vets that all had treatment resistant PTSD, that were very bad with nightmares. So people had incredibly bad nightmares, and very poor quality sleep. And they hadn't responded to panel or any of the benzos or any previous drug treatments that have been attempted on them. So they gave them NAB alone and just tracked them. So it wasn't blinded. But what they found was very profound effect, I think was like 85% of people on the first night stopped having nightmares. And they tracked it for a while and it looked like as soon as they took them off at the nightmares reemerged and came back. So it seemed like Okay, that was some decent evidence. So from there, they actually did do a double blind placebo controlled crossover design study, which is what you should do, the only downside is it was kind of small, it was only like 12 or 15 subjects. So it wasn't huge, but at least it was done properly. And this study basically built off of what they had found and replicated even more substantially, because in the crossover arm, it was very clear that regardless of whether they knew they were on it, like because they're blinded, as soon as they were taken off of the THC and put onto the placebo, almost immediately the nightmares came back. And you would call it back on.

Nick Jikomes 44:00

Yeah, I think you would expect that right? You know, anything from, you know, this study to SSRIs. There's this phenomenon of REM rebound, which I know is quite robust if you suppress REM sleep, and then you stop suppressing it, it actually comes back with with quite a force.

Matthew Hill 44:14

Yeah, I mean, this is certainly something you see in in cannabis withdrawal studies. When people go off of cannabis, when they're trying to go into sensation to cessation, they often will report like very intense nightmares over the first few nights. It's obviously different than what's going on in PTSD. But yeah, I mean, and the thing I take from that as well as it's not only like are you dealing with a ram rebound, but like this isn't, it's not a cure. This is a it's a treatment, like if it proves to actually be effective in the sense this is like a real time management tool. This is not I mean, I think that's where some people get confused by things. They think that Oh, it means that cure some it's no, this doesn't because you as soon as you go off, but it comes back. So this is really just a tool to help me manage a symptom like this, but it seems to be an incredibly effective tool in the sense that If this works, the question is Can this sustain over time? Or will this develop tolerance? Will there be other consequences? I mean, obviously, some of that would be influenced by if someone starts escalating use over time. Versus, you know, a lot of the ones in Canada, at least in the military, when they interview them, they say that they only use a small amount of cannabis, they only use it at night, right before they go to bed. And they've been doing this for years, and they've not developed tolerance, and they will report consistent benefit on their part. But again, it hasn't been studied properly. So it's really hard to say definitively.

Nick Jikomes 45:30

Interesting. So assuming the results from Canada held up and are robust, it is something it is a tool, it's a management tool, but it's immediately effective. That would be the upside. Yeah, the downside is, you know, we haven't done the studies, we don't know if it's going to be effective forever. And it's not a cure to management tool. There's two other treatments based on your work and other people's work that come to mind in terms of treating these things. One would be thought inhibitors. And I don't know much about the clinical work there. So I'd love if you could describe that. And the other one, that's probably the most famous right now, are the MDMA assisted psychotherapy trials, which do seem to be a potential cure. So can you kind of compare and contrast each of these tools that we've been researching?

Matthew Hill 46:12

Well, I'll start with MDMA, just because I can't really say much about it. I mean, I, I've seen the clinical data, the psychedelic stuff is interesting, I mean, to some early stuff with psilocybin as well. I don't I mean, to me, this is more than just simply a biological mechanism. This is like, there's something about the experience, the hallucinogens are creating an altered state of consciousness that are allowing people to either have some kind of differential impact from therapy, or consolidate that information in a different manner. So it's more sustained, or it allows them to access the core trauma in a different manner that they can psychologically process it, I'm not sure what's going on there. It does seem to work with the right therapist. So I'm very curious to see where the psychedelic space is going to go as now there's more recognition of this. And so there's kind of increasing resources being put into it to kind of study it. So as for the fire inhibitor side, so I definitely think the finance side has a lot of potential, this is something I'm very excited about to see that it's finally moving forward.

Nick Jikomes 47:12

So just just for background, so you talked about find the beginning, but you're when you say font hybrid, you're talking about a drug, so a pill that you would take a pharmaceutical, it would inhibit this enzyme called FDA and thereby increase in antibody levels.

Matthew Hill 47:25

Yeah, yeah. So you get a nice sustained increase in an antibody levels, they go up quite a bit, like even higher than you'd see with Joe Cameron. But they're going to those levels. And so, so we've done like I was involved in one trial that was done. In Sweden, we help process some of their blood samples to look at some of the outcome measures for the anatomy, the fact that it was just a study done in healthy controls. And so this was Marcus Heilig and Leah mayo. And what they did was they just dosed people either with placebo or inhibitor for 10 days. So you had nice stable drug levels and a nice stable, sustained elevation and anonymized. And then they did a couple of things they look, they put them through kind of a stress challenge, where you know, you have to do this public speaking and mental or verbal arithmetic stuff in front of a crowd, and to kind of really stresses people out, and you get a nice solid stress response in people. And they also did an acute kind of fear conditioning and fear extinction task where, you know, they try and couple a stimulus with an aversive outcome, you get a nice, stable, conditioned response, and then you try to extinguish it. And I'll just quickly kind of sidestep, to say that the fear extinction thing is really important in the context of something like PTSD, because this is seems to be one of these processes that is not working. Normally in PTSD, they can't extinguish aversive memories the same way that normally can. So this is one of the reasons why there's been this interest in endocannabinoids. there too.

Nick Jikomes 48:45

Yeah. And for people who don't know, fear extinction, that would be the process by which the brain learns to stop responding to something that is no longer a threat.

Matthew Hill 48:54

Yeah, so the way I would say this is it's, you know, if you had been in a situation where you've been, let's say, you're in Vietnam War, and you've been in the forest, and if you heard a bang, when you're in the forest, you're like, you know, that that's predictive of an adverse outcome that, you know, they saw this, and a lot of the Vietnam vets, they came back, they would, you know, go for a hike, and you'd hear something, and you would respond as if you were still in Vietnam, because you're in a forest and you hear a bang. Now, the extinction process is understanding that this is a different context now. So even if I'm in a forest and I hear a bang, here, it's not going to relate to the same dangerous outcome as it did when I was in Vietnam. That's kind of the way that you'd uncouple those processes or even something like a stove. If you put your hand on a stove and you burn it, you're like, Oh, you immediately instinctively Remove your hand away from it. But you'll learn over time that if that element isn't turned on, it's still safe to put your hand down there. So that you're kind of learning that the stove isn't always dangerous, like it's a it's a specificity thing. So if you can't fire extinguish you just kind of become permanently scared by the stove or you'd always be terrified in any forest, if you hear a bag, so that's kind of if it doesn't work, right what that process looks like. And what the animal literature would say is that cannabinoids can augment or accelerate fear extinction and make it occur more readily. So people will learn faster that something is safer, they'll learn faster than it's not dangerous anymore. So that was kind of what Leah and Marcus were wanting to test in their study was in humans, does this look the same? And so what they what we saw from the trial after giving 10 days of this fire inhibitor, so if we look at stress, yes, defined habitare blunted the kind of adrenaline response to stress. So if we look at the sympathetic response, looking at skin conductance, or another readout of adrenaline, that was blunted, if you had high levels of an end of mind, so that's consistent with what we would expect from like what we know about the stress response, they also did some unbiased measurements of facial muscle changes. So you know, our facial muscles can become very expressive. And like one of the things that we tend to do is if something's negative, we'll like wrinkle or for our brow versus if something's positive, you smile, so you can measure different muscle tone on the face. And what they found was that normally, when you get stressed, there's more reactivity of the muscles that are, like indicative of a negative facial expression. And the FDA inhibitors selectively blunted the ability of stress to promote those muscle changes as well, which is just another kind of unbiased readout. And even when they ask them, how stressed are you, those that have had the fall inhibitor self reported less stress, less stress responses, they felt less stress. So it kind of re capitulated what we would have expected. And on the fear side of things, it's interesting, because one of the things that we've learned from the animal stuff that appears to be true in humans is it doesn't do elevating an animal doesn't do anything to the fear conditioning process itself. And that's actually really important to be able to couple aversive events for survival. So, you know, the animal work has shown it doesn't really do much there. Now in humans, we know their fear conditioning looks entirely normal. But then when you look, the next day, when you go through fear extinction, they seem to fear extinguish, better, and they remember it. So if you look at how well the consolidation of that fear extinction, memory was the inhibitor augmented that quite a bit. So that was kind of really promising, because it was the suggestion that, you know, we are replicating a lot of these anti stress and kind of pro fear extinction effects that we've seen in animal work. And what we would assume and what we'd be wanting to look for is hallmarks of potential treatments for simulate PTSD. So that was very encouraging. And then more recently, there was a study that just came out from Johnson and Johnson with their fall inhibitor. And it was in the context of social anxiety disorder. And what they were able to show was, again, some what we predicted they had a bit of dosing issues that looked like the dose that they used was kind of right on the cusp of being able to effectively elevate an animal, their anatomy levels weren't super high. And so I think they're redoing this now. But when they looked at the individuals that actually had the elevated inanimate from the fall inhibitor, they did find that it had benefit in improving symptoms of social anxiety disorder. So it did kind of seem like it was doing what we would expect in that sense. And then almost immediately after that paper came out another paper from Johnson and Johnson in humans using that font editor came out looking at amygdala reactivity, and also showed in humans just by simply dosing people healthy controls with the fire inhibitor and then using threat cues to activate the amygdala. We could blend that or they could blend that at least by elevating an and amide. And the only other real clinical thing that's been interesting that's come out is the cannabis withdrawal studies that have been done where they've been showing that individuals who try to quit using cannabis, if you give them a fall inhibitor, then they are able to reduce their cannabis use. And it also in that context, improved sleep and anxiety. Sorry, this piece of hair. I'm just gonna try and get this down. I don't know why it's poking up, but it's driving me insane. Okay, so,

Nick Jikomes 53:55

okay, so in summary, the default inhibitors look pretty promising. They're not, they're not messing with your learning, but they are eating for your extinction, which is exactly what you would want for something like PTSD. And I don't know the answer to this, but I would speculate that the VA inhibitors might not have that many side effects. So what do we know about any negative side

Matthew Hill 54:14

effects? Yeah, so it's funny, the way that I always had this described me from the pharma side of things was they said, foreigners have the side effect profile of a glass of water, which, surprisingly, I learned is actually a concern from the pharmaceutical perspective, because the concern is that means it's not having enough of a biological impact, because everything like there's always some side effects, even things like aspirin, like every over the counter drugs. And so they were actually initially concerned that the fall inhibitor was even getting in the brain because they couldn't see anything. There was no psychoactive effects. There was no observable changes. No one could report it, like people who had been dosed couldn't tell if they're on drug or placebo. So they actually did a pet imaging study in the brain to make sure it was getting in and it was and then they did the REM sleep study, and that's how they learned that Okay, there As a central signal, because they could get a suppression of REM sleep by giving full inhibitor. So it really doesn't seem to I mean, there is some confusion out there because there was that disastrous trial that happened in France with a fall inhibitor where someone ended up dying. But that, as we learned in the aftermath actually had nothing to do with the target of Bob. But it had to do with really bad chemistry on the on the compound itself. And it seemed to be forming covalent bonds with like liver enzymes and preventing drug metabolism and doing a multi ascending dose trial did not prove to be a safe way to go with that without having done the proper talks in advance. But as an actual target with all the data that's come out of, you know, Pfizer, Tad one Sanofi side, one mercs ad one, Johnson Johnson side, one, these are multiple companies have gone through phase one, some interface to none of them have ever reported anything significant as a side effect profile, which is actually very encouraging.

Nick Jikomes 55:54

And so is that where we're at in the clinical process? Not we're not at phase three yet, but maybe about to start that.

Matthew Hill 56:00

Yeah, I would say this, though a lot of there was such a, I mean, the font hibbott er, when I first got made by Pfizer, it unfortunately was first used in a very shitty kind of pain trial that didn't work. And that just immediately deterred everyone from going your phone inhibitors, and I'd say killed the whole fire inhibitor program for at least five years. It was very frustrating because they had put all this work into developing a really, really clean drug. And then, so so to get some interested in again, but the problem was once interest in the fine images started again was right around the time, pharmaceutical companies kind of decided to abandon psychiatric neurological diseases, which is become a trend because it's just too hard. Yeah, and is you and many people know, there hasn't really been new classes of psychotherapeutic for psychiatric or neurological drugs in decades. I mean, we're basically repurposing old mechanisms and trying to create new flavors of the same drug. File inhibitors actually represent an entirely novel target that has never existed before from a drug perspective. So that's why I think it's actually kind of exciting. But I think the problem was like when the pharmaceutical companies lost all those interest, mostly indications you would use for inhibitors for would fall under psychiatric or neurological and so the drug there was just like no interest for years. And ultimately, it was really the cannabis withdrawal study that was spearheaded by Cyril D'Souza that got the kind of was the really the first data that was done, which showed some kind of positive effect where they showed that you you had these effects on cannabis use, you had effects on sleep and anxiety. And so it gave some, okay, maybe there's something here and was around the same time that Marcus and Leah had started their trial and fear and stress stuff and humans. And now it seems to be ramping up. I mean, I know, Johnson and Johnson's I assume that they're pursuing the social anxiety angle more since their first trial was moderately successful. I know there's a lot of other companies now growing interest in fire inhibitors, given that there's now four published reports in humans in the last two years that have all shown significant effects. All relatively in the domain, at least, all every single study has had a measure relevant for anxiety or stress, and all of them have showed benefit in there. So I think there is going to be clustering in that space. I would say in the next five years, we will have completed clinical trials for social anxiety disorder, PTSD, probably other flavors of anxiety, generalized anxiety disorder, maybe phobias, maybe panic disorder. Yeah,

Nick Jikomes 58:21

I was gonna say like, based on everything I'm hearing, it sounds like this is a promising Avenue, not just for something like severe PTSD, but almost any anxiety or stress disorder, even if it was mild.

Matthew Hill 58:34

Yeah, I mean, some of the stuff like that my labs doing now we're actually becoming very interested in this idea, kind of going back to what I'd said about how, you know, I view an and amide and endocannabinoids as being homeostatic regulators. And in that context, we've always focused on how stress disturbs the system. And therefore, stress messes up an endocrine signaling, and that may result in changes in anxiety. But it made us start thinking about, you know, there's a lot of other chronic disease states that have co morbid anxiety with them. And many of them are stressors on the body. So you know, we started looking at things like gut inflammation. So kaleidos, we just published a paper not long ago now looking at comorbid, anxiety and colitis. And what we found was that the kind of persistent inflammation that exists when when the gut is inflamed, is enough to drive the HPA axis to get this persistent elevation in court, which recruits CRF signaling in the brain, which seems to be able to cause you know, fought tivity to jack way up in an atomized levels to plummet. And so, and we also similarly did a thing using an epilepsy model showing the same thing that, you know, sustained repeated seizures resulted in this kind of comorbid anxiety, which we know is very present in epilepsy in humans. And again, the fire inhibitors were very effective in reducing that because it seems like business crashing and randomize from these chronic disease states and that that loss of an and amide might incidentally be resulting in the development of this anxiety that develops with the disease. I mean, it's interesting because you look at kind of some of these diseases and you can get people with epilepsy, anti epileptics, and they target the hyper excitability. But I mean, in many of these diseases, same with cleitus, the primary treatments that they use don't address the comorbid psychiatric issues. And that kind of anxiety and depression that hovers around a lot of these chronic disease states is a massive quality of life impediment that largely goes on addressed. And we became really intrigued because Dave Finn over in Ireland has, you know, kind of longing looking at these relationships between pain, inflammation, it can happen, and he had a review a few years ago, where they were looking at a lot of these studies that had looked at chronic pain, especially inflammatory pain, with cannabinoids have been used. And what they found was that even if it wasn't that effective as an analgesic, in almost every single study, it improved the comorbid psychiatric side effects. And in every study, very much people reported improvements in quality of life, even if the pain is still present. And so I've started to believe that these are a sociable phenomenon that I mean, they are driven by a common Genesis in some capacity. But I think once they fully manifest, they are targetable separately. And so I think there's a lot of value in looking at the cannabinoid system as a, as a mediator of kind of comorbid, psychiatric issues and a lot of chronic disease states. And in my personal belief, is that's why so many of these chronic disease states, people self medicate with cannabis, because it helps them regulate the anxiety and the sleep disturbances that are present. And even if it's not curing the disease, it makes day to day life more functional and better. And that's relevant. And I think that that is actually a domain that has been largely sadly ignored from a pharmaceutical perspective, because they focus exclusively on primary outcome measures. When you talk to people who suffer from a lot of chronic diseases, and it's how they can survive day to day, you know, people are, I think most people aren't expecting a cure at this point for a lot of these things that we don't even really understand the biology of but if you find a tool that helps you manage yourself despite having affliction from a disease, that's a huge benefit.

Nick Jikomes 1:02:00

Yeah. And what about So you mentioned kaleidos, and comorbid, anxiety in the fall inhibitors might help with the comorbid anxiety. But if you're inhibiting fun and increasing an antibody levels, is that happening at all in the periphery? And are there any outright anti inflammatory effects from elevated demand? amide outside the brain?

Matthew Hill 1:02:18

Yeah, I mean, so we had done intentionally central administration, because we wanted to see if we could manipulate the anxiety independent of the kaleidos, even though it actually did seem to improve the cleitus a little bit too, which is interesting. But yes, we know it for systemically administered fall inhibitors. Like we know that that there's been multiple studies that have shown that they can improve colonic inflammation as well. So the argument we made in the paper is, yeah, based on those studies and our data, this could in theory, be a two pronged approach. I mean, you could certainly make the same argument for epilepsy because we know cannabinoids have the potential to curtail some of the hyper excitability that exists in seizure disorders. So again, you might have some benefit in that capacity, as well as improving some of the comorbidity issues with anxiety and depression. Well,

Nick Jikomes 1:03:02

you mentioned very briefly there that so you did studies where you're putting a fire inhibitor directly into the brain on purpose, because you wanted to separate out the anxiety effects in the brain from the actual kaleidos part of it. But you said you noticed some effects on the coitus nonetheless, and this is not an area I know a lot about, but it's triggering some memories I have of reading about gut brain interactions. Yeah, I

Matthew Hill 1:03:25

mean, there's definitely something there. I mean, others have previously shown that you can play with central cannabinoid receptors and actually have influence on peripheral inflammatory processes in the gut too. So it wasn't entirely surprising. But it did surprise us a little bit, because ours was an acute administration. And the other ones had been more sustained. I mean, ours was a few hours. So there was the opportunity for something the effect wasn't massive, but it did definitely bring down the inflammation slightly. So that was interesting. But yeah, the endocannabinoids definitely have a lot of this, you know, brain body. They influence all these brain body perspectives. I mean, even the feeding stuff, there's a huge wealth of information outside of what we know how it influences hypothalamic circuits. There's a lot of evidence to suggest that cannabinoids peripherally can influence feeding states by regulating vagal nerve activity, or regulating sympathetic outflow. And they can regulate metabolic processes so you can give drugs that don't enter the brain. And they still have an impact on feeding. I mean, there's this very fascinating story that has really not ever hit the light of day from a drug company that had developed a peripheral CBN agonist years ago. So they thought, you know, if we make it so it can enter the brain, they would be able to be devoid of psycho activity. And since there was growing evidence that a lot of the analgesic effects of cannabinoids could be driven by peripheral mechanisms, that kind of peripheral nociceptors that they thought okay, we can make a peripheral CBN agonist and use this as a means to treat pain without psycho activity. And they presented the data at a Cabinet meeting and I don't think it's ever been anywhere else, the drag had to be canceled. I think in a week, every subject developed fatty liver and gained a significant amount of weight. Their hlt levels shot up, they had clear signs of liver inflammation, and they had observable fatty liver and they had gained I think something like four kilos or something in 10 days. Oh, wow. Like they literally refer to it as the flog, Rafik, they said they've never seen anything like this. And they had no way of explaining it. But they said the only thing they could come up with was that there must be some competing central process that can arise, activate that limit this from happening. And when you exclusively target only peripheral CB one receptors, you seem to really have this profound influence on peripheral metabolism and hepatic function. That was like, fast. Was

Nick Jikomes 1:05:47

there any change in feeding? Or was this all metabolism?

Matthew Hill 1:05:50

There was definitely changing feeding. Okay, how they said the people ate a lot. So it was kind of an interesting thing. I mean, there was this, they even said, like there was this thought afterwards when someone was asking them, and they said they'd have to see they didn't know the species specificity, because I don't think this happens in rats or mice like and none of the studies, has anyone ever seen this effect come out in rodents. But they were saying, you know, this would be a very ethical approach to flog Rob, that was like where the joke came from, because as opposed to force feeding animals, if you can actually induce fatty liver, and and promote food intake, and very rapidly cause this metabolic shift, that would be a better approach to making flog rather than the horrific ways that it's kind of done right now in France.

Nick Jikomes 1:06:32

So circling back to anxiety, so the story in the beginning this woman, she had pain processing issues, and she had basically a really good mood her entire life, she was almost unable to experience anxiety. We've talked about stress, we've talked about pain, can you actually describe or define those terms and how they're different? And and maybe let's turn it stress, anxiety and pain? Yeah.

Matthew Hill 1:06:58

Okay. I mean, I'm not a pain person, or what I mean, I just I kind of think of pain is like a noxious stimulus response to a noxious stimulus, like a burden or an injury in some capacity. I mean, there's no denying there's an emotional component to pain, like, we know that like, the degree of an injury and the personal, you know, for like, the way that an individual experiences pain don't correlate very well. And certainly in chronic pain states, you see this. So, pain can certainly be influenced by stress and emotional state, for sure. So, if we're talking about stress and anxiety, I think that like these two are definitely dissociable phenomenon. Stress is kind of harder to define, because I feel like it's very nebulous. And, like a joke, it was the kind of like something that can be a noun and a verb or, or fucking shit. Or an adjective, adjective. Yeah. Just the way people describe, you can be stressed out, it's something that can happen to you stress can be a thing. So I think the easiest way to describe stress in the most basic terms that's all encompassing is that it's, it's a real, it's a, a real or perceived threat to an organism's well being. So anything that would challenge the well being of an organism, its survival, its ability to, you know, reproduce its ability to acquire food, its ability to do anything, a challenge that would be presented with would be considered a stressor. So, and this can be very different from person to person. Some people will perceive things as very stressful that others find quite innocuous. And it's often based by shape my personal experience and history things we've gone through. So I think stress is a is kind of a constellation of biological responses that happens in response to this challenge. So like I said, you get an adrenaline response out of the sympathetic system, you get a glucocorticoid response to the HPA axis, you have kind of behavioral changes that occur. And I think anxiety is one of the behavioral changes that tends to occur in tandem with stress. But I think stress and anxiety are dissociable from that, and what I mean is, anxiety is kind of a behavioral state where there's not an immediate present threat, but there's the sense that something could go wrong. So the way that people often confuse anxiety and fear and the way that we always try and you know, I live in the Rocky Mountains. So the joke that we have a period how you separate anxiety from fear is, anxiety is going on a hike and seeing a sign at the bottom that says someone has seen a bobcat today, fear is when you see that Bob cat. So there's a difference between the idea that there could be a threat in your environment. And that's what anxiety is, whereas fear is typically the response to a real and present threat. And so anxiety is kind of a state where a lot of our systems move into a state of vigilance. Like I was saying before, we're trying to perceive our environment more we're trying to find where a potential threat could be, so we can identify it, assess it and then respond accordingly whether it's actually a threat or not. So when we become stressed out anxiety is one of the Hallmark behavioral changes that happens with stress. Because obviously, when a challenge presents itself, usually part of what we're trying to do is assess the nature of that threat that's presenting itself. So I would say the anxiety component is is very typical to stress. But there are people who, you know, have chronic anxiety in the absence of any observable stressors in their life. I mean, this is kind of the nature of anxiety disorders. And that's why I always think that anxiety is separated from stress in that sense, because it's really a behavioral state that can occur and if the brain's filtration systems, for how we intake in environment information, how we process it, if that's just skewed slightly, so that, you know, something like we've said before, like the prefrontal cortex isn't talking to the amygdala and helping to reference previous experience to understand safe versus threat, you might just get this development of an anxiety state in the absence of anything because it's kind of become this default mode that will favor survival.

Nick Jikomes 1:11:01

I see. So stress, anxiety, fear, we've talked about font inhibitors and how the endocannabinoid system ties in to things like stress and anxiety. We talked about pharmaceutical fun had bitters and the promise they show, but another fun inhibitor that is interesting that people know about but might not know is a fun inhibitor is CBD. So can you talk a little bit about CBD how good of a fight hibbott er, is it? And what kind of doses do you think are needed to to have that activity happen, or people that are consuming 10 or 20, or 30 milligrams of CBD that they bought at the store? likely going to see that kind of effect?

Matthew Hill 1:11:40

Well, the first thing I'll say is I'm not convinced CBD is a fun, a better ABF inhibitor. So CBD The one thing I think that has been more consistent is that CBD has been found to elevate a Nanda mite levels. So there has been some evidence to suggest that it inhibits FDA. But there's also been evidence that has suggested that it actually triggers the biosynthetic enzyme responsible for an animal, so it causes that enzyme to become more active. So that makes more anatomy. There's also evidence that it might block in into my transport to metabolism, and therefore keeping endermite around longer. And lastly, there is actually because for us it's tethered to the endoplasmic reticulum, which is inside a neuron like not near the membrane, it's deep inside, there is a binding protein that an animal has to couple to move through the cytosol to go from the membrane into fire to get chewed up. And that's called fatty acid binding protein five, and we know CBD binds to that and can displace inanda might as well. So four separate mechanisms. Yeah. So yeah, it does seem like CBD can elevate an animal, maybe through fog, maybe not. But well, the first thing I'm going to say is, I don't believe that anyone taking oral oils of CBD at 1020 or 30 milligrams is doing anything outside of creating your lab lack of sounding crude, very expensive shit. Because the bioavailability of it is so incredibly low. From what we've seen from the studies that come out of Johns Hopkins, you basically don't even get detectable CBD in the blood until you are consuming a dose of about 100 milligrams.

Nick Jikomes 1:13:19

And is that from swallowed pill form CBD.

Matthew Hill 1:13:24

It's from Yeah, I mean, sometimes it's oil mixed into something that swallowed and ingested. Sometimes it's in a pill form. It's not a sublingual, so I mean, the the pharmacokinetics and sublingual are definitely a little bit more unclear, I would say. But from most of the PK work has been an even the stuff with epidiolex. From GW, the bioavailability is pretty poor. I'm one of the things that I've learned about CBD dosing in the general public is, most people are not aware of what the clinical dosing actually is for CBD. I mean, if you look at those pediatric epilepsy trials, those kids are getting they refer to it and mix per kid per day. And those kids are getting like 20 makes per kid per day. That's per kilogram.

Nick Jikomes 1:14:08

So how many how many raw milligrams would that be?

Matthew Hill 1:14:10

For some kids? I mean, this is like, because the dosing the use is 10 or 20. But the raw numbers I've seen go up to 2500 milligrams, they definitely are almost always over 1000. I've never seen a pediatric epilepsy study really that shown benefit where there's dosing per child that's coming under 1000.

Nick Jikomes 1:14:28

So it's a rule of thumb swallowing CBD at low doses, probably isn't doing much.

Matthew Hill 1:14:36

Yeah, I would say so I would say it's something that I've actually tried to understand this because if you go through the literature, I've never seen a clinical study that has used oral CBD at a dose lower than 300 milligrams, it's ever seen a positive effect, and every failed trial of CBD I've ever seen is those that hover around 30 or 40 milligrams.

Nick Jikomes 1:14:56

Do you think it's possible that other routes of administration could allow for some efficacy to be observed, just because the oral route is so inefficient.

Matthew Hill 1:15:07

So there are pluses and minuses to different routes of administration that you'd see if something CBD so if it goes pulmonary, so if you inhale through vaporization, or smoking, the bioavailability is way higher, you're gonna get massively higher levels of CBD in the blood. The only downside to the inhalation route outside of potential damage to the lungs from inhaling, is it's also cleared a lot faster. So what you end up getting is a spike. So you get a lot of CBD in the blood, and then it goes away. The reason for the use of oral in the in the pediatric epilepsy studies is twofold. One, obviously, they're not going to get kids to inhale or smoke anything. So that had taken it down. But two, they are trying to achieve stable blood levels of CBD around the clock and dosing. And basically, the approach they've taken is oral has terrible bioavailability. But it's half life is so much longer once it gets in the system, because of the way that it slowly diffuses out of the gut. So they just overboard dose in that route so that they achieve the blood levels that they need. But they're stable, and they're not spiking like this where they're going up and down, they kind of go up and they'll stay up at a more appropriate level. So certainly an inhalation route would get much better bioavailability, but it's also much shorter lasting. So I guess it's just a question of what someone is trying to go for. I've been baffled by because I know physicians who tell their patients to take 10 or 20 milligrams oral CBD oil. And when I've asked them and said like you're actually a doctor, like you should be familiar with the clinical studies that have been done. So how do you reconcile like in good conscience, basically telling people to continue taking a placebo? Because that I can't honestly wrap my head around how I mean it the way I refer to it is that CBD homeopathy that those like, there's an essence that may grace your body of CBD, if you take 10 or 20 milligrams, you're You're shitting it out, most of it's not leaving your GI tract. So I really struggle with understanding how you could do this and their response as well. The patients tell us that they find benefit from the dose, so we don't want to tell them otherwise, because they're benefiting from it. And I'm not necessarily against the you know, the benefit of placebos. Although I have a little bit of an ethical issue when people are spending their own personal money on it, as opposed to it being something that's prescribed. I mean, Canadian something is differently, obviously, in terms of the medical system, but it's a little different. If it's me, it's it's prescribed and covered for you versus it's something that you're shelling out money out of your own pocket, especially if you don't have the financial ability. Because even 20 Meg's of CBD oil today is not cheap, you're still spending a decent amount of money on that. accumulatively.

Nick Jikomes 1:17:41

So what about something like a sublingual absorption? Is there anything known there? Or what do you expect in principle that to be more bioavailable?

Matthew Hill 1:17:50

I would guess it'll be a bit more bioavailable. I mean, there are certain things with oral we know like if you take oral CBD if you if you eat a fatty meal, right before you take it, your bioavailability goes up like fourfold. So I think if you don't, if you take it on an empty stomach Avenue in four hours, the prediction is that it's something like four to 6% bioavailability of what you take of CBD actually gets in your blood. And if you eat a fatty meal and take it, it goes up to like maybe 20%. So it doesn't prove it a fair amount. But you can do that. Like, obviously, if you consumed a fatty meal and then took it, it would be better than not, I would imagine just sublingually you'd probably get a bit more. I don't know. I mean, even in the oil studies, they always acknowledge that some of it probably is absorbing sublingually because it's going in the mouth unless it's an encapsulated pill. The oil goes in the mouth, and some of its going to get into the membranes there. So you probably are absorbing a bit of it. It's just not entirely clear. So I would guess Yes, but I there's just I mean, the whole idea of even doing kind of good, clean pharmacokinetics on anything is there's so few people doing this. I mean, there's the group at Hopkins, which is really doing a good job of this, I would say because they're giving us the most information comparing like oral inhaled, vaporized versus smoke, CBD versus THC. So they're really kind of nailing down the bones of this, that everything aside from this is largely come from like GW for the rapid dialect studies, some random clinical studies that have just measured blood levels.

Nick Jikomes 1:19:18

What do you make of so just knowing what you know about the endocannabinoid system and clinical clinical trials and how they normally function, you know, typically when we develop drugs, it's a single molecule that has some level of specificity to it. And, and, you know, the talk about the idea of a dirty drug. And, you know, people like Ethan Russo, who I talked to recently are big on this idea of an entourage effect of combinations of drugs, even if some of them are present at very low levels that might not do anything detectable on their own can actually change or enhance the therapeutic value of other compounds. Do you? Do you have any thoughts on that and how, how likely that is to be true for some of these conditions? compounds?

Matthew Hill 1:20:01

Well, I mean, one thing we know about CBD is it does, especially at high doses, it can saturate a lot of the enzymes responsible for breaking down other drugs. In theory THC could too, but THC never really reaches the levels because of the intoxicating effects at relatively low doses. So people never often achieve those levels, which is why we don't see a huge amount of drug drug interactions with THC. But in the, for example, the pediatric epilepsy studies they have clearly found that the kids on the high dose CBD they start seeing some of the other drug levels accumulating go up because you're inhibiting metabolism. So I think if you're taking reasonable levels of CBD, there's always that concern. There was even a study that just came out recently, and it said dosing at like 1000, Meg's of CBD, which is not unheard of, because that's the clinical levels and healthy controls, they were able to see elevations and liver enzymes like lt and stuff suggesting that there might be some some possible effects on liver. So I would assume that you have probably a pharmacokinetic interaction that could occur with other drugs, independent of anything else. In terms of kind of the dirty drug like this on I mean, do you mean like entourage effect kind of stuff? Like Yeah, exactly. So I think that there's probably something to an entourage effect. I don't know if we're going to be able to chase it down, to be honest. And I say that because I think it's going to be much more complicated. Like the idea of trying to understand singular substances, and then multiple interacting substances, and how they're going to interact with each other is very tricky. I mean, I know the group in Australia has been screening a lot of the kind of lesser cannabinoids, and other things that are in cannabis, like, you know, instead of CBD and CBG, some of the terpenes and stuff. And at least what they're looking at is they're trying to see interactions at CB one, and they're not. Yeah, being that it's interacting there. But that doesn't mean that. Yeah,

Nick Jikomes 1:21:46

yeah. I mean, that's, that's a weird experiment. Because I mean, as far as I'm aware, none of those other compounds are known, you know, other than THC to really do much at CBO. And anyway, so you can, it's sort of really hard to definitively prove a negative in an essay like that. But But your point, it's also really hard to prove the positive statements here. And I only the only way I can even think about it is you would have to give humans or animals in some way that was rigorous. an entourage of compounds and give some other group a different entourage. And you'd have to, you'd have to measure the effects at the behavioral level and the neurological level.

Matthew Hill 1:22:21

I mean, there are groups starting this I know Ryan vandrie, and Ziva Cooper, Ryan's at Hopkins and Zeb is at UCLA. I mean, I know they're starting to look at I mean, their approaches, they'll take the THC and then add a single terpene or a single cannabinoid, and then measure, you know, like when what you're saying, whatever their end point is, be pain responses, or your own psycho or your own, like, how high Am I that kind of thing? Is this rewarding? Is it a versiv? So they're kind of doing some baseline looking at that to see, I think that's probably the best approach because that will at least help narrow down. Yeah, which molecules might be more interesting for entourage type interactions, and then you can start trying to understand the molecular aspect of that a little bit more in a different capacity. So I think there is potential for this to go down. I agree the reductionist approach like it, cb one is, I mean, I think it's necessary to rule that out. But I don't think that that argues against an entourage effect, because all that tells you is Yeah, molecules we didn't think we're acting at CB one, indeed, are not acting at CV one. And so we're not seeing an interaction at that point. But you know, because cannabinoids THC is going to affect, you know, neurotransmission snapchick transmitter release, if you have some of that indiscriminately affects the GABA system, right, independent of CB one that obviously you could interact with how can I have nodes or influencing GAVI transmission? So, I do believe that there's potential for this. I mean, even if you take something like CBD, who's pharmacology like, what is CBD doing? No one really knows. Sure. Maybe it's boosting an and amide in some kind of ill defined way. I mean, the other mechanisms are maybe it's kind of like an allosteric modulator of serotonin when a receptors that's possible, though, there is some arguments against that as well because people have had some problems replicating it. cc Heather has put together a really nice mechanism, I think by showing that CBD actually inhibits adenosine uptake because it competes for the adenosine transporter essentially and so you'll enhance the synaptic actions of adenosine, we'll see what is

Nick Jikomes 1:24:17

can you describe what adenosine is.

Matthew Hill 1:24:19

So the way I tend to describe this when I'm talking to people in the general public is adenosine is a system is actually quite similar to endocannabinoids. But it is what is inhibited by caffeine. So like if you if you want to boil down to it, I mean adenosine functions similar to the endocannabinoids out regulates transmitter release, but so caffeine inhibits adenosine and that's part of the mechanism of how caffeine probado causes alertness and affects arousal states. So if you think of CBD, I always think if you're going to find a drug you want to relate it to based on that mechanism, I would say it's almost like an anti caffeine and that would explain some of the kind of, you know, supposedly, you know, pro sleeping some of the genic effects and some of the anti inflammatory effects and some of the other mechanism CBD certainly makes sense in the context of enhanced adenosine signaling. But who knows if that's going to be kind of the be all and end all I think it's this is the problem you have a drug that like, you know, tickles so many neurochemical systems but doesn't really get into bed with any of them. So

Nick Jikomes 1:25:18

yeah, so it's doing a lot which gives it a lot of potential but it's it's difficult to actually work out what's doing what.

Matthew Hill 1:25:25

And I would say that one of the biggest disconnects a lot of people, the general public don't understand about why the medical and scientific community is so reluctant about CBD is I would say General, scientists become skeptical of massive claims when there's no clear mechanism of action, like when you cannot, I mean, I know like Brian Roth screen CBD through his G protein essays and said he couldn't see it binding to or influencing a single receptor. And that included serotonin one day, but he looked through every gpcr in his library and couldn't see CBD interacting with any of them. And he said, maybe it was the dosing wasn't high enough. But I mean, the reality is people are claiming effects from CBD at doses that are like, incredibly low. So if it was actually doing something on a biological system, I feel like we would be picking it up at some point. I just, it's hard because the problem is, can avenues are so sensitive, unless

Nick Jikomes 1:26:15

I guess the potential counter argument there would be, you know, earlier, you cited this, you know, this other type of protein interaction CBD has, so maybe it's not having strong effects at a receptor level. But maybe it's some other intermediary that it's influencing?

Matthew Hill 1:26:30

Oh, it's certainly possible. It's, I think the thing is, at this point is the amount of people who've been studying it, no one's been able to come up with a consistent readout or story that makes sense. And I think that's been one of the things that's hampering it. And I think the problem is, unlike the kind of history of cannabis, because the history of cannabis influenced research and the cannabinoid system so much, we know people have been using it for centuries to regulate pain, we knew that the munchies was a really big side effect associated with cannabis use. We knew that people use it to reduce stress and anxiety. So it really dictated the physiological processes that became investigated. And it made sense. So we had insight we knew to look at pain circuits, we need to look at feeding circuits and emotion circuits, because there were these very protocol typical effects of THC that had been well established. CBD on the other hand, you know, 15 years ago, I could have walked into a room of 1000 people and said, How many of you know what CBD is, and maybe three would have raised their hands now, like 998 of them. And the problem is, in that period of time, the amount of anecdotal reports that have come out, I would say it would be easier to assemble a list of diseases that people claim CBD doesn't cure than things that people claim it does. Because virtually every single disease out there, someone has made some argument for how CBD cured it for them. And so from a scientific perspective, like even I was referencing that anecdote stuff before, we can't believe any of it, because it's just gotten to a level of such nonsense where everyone believes that every single disease is cured by a molecule that doesn't have clear pharmacological activity and is being taken at doses that doesn't even have clear bioavailability. So it's very hard to take insight from the clinical perspective and the human anecdotal responsiveness and try and design experiments to test things out. And so I think a lot of it has just become this like me to redundancy thing where people like Well, let's look at things that were really affected by THC like pain and inflammation and sleep and anxiety and see what CBD does. And I'm just kind of like, sure, but like if we're trying to reference cannabis as the reason we look at these then why would CBD be relevant because CBD and THC compete for biosynthesis. So given that for the last 30 years THC has been so enriched in cannabis breeding, because that's what people want out of it. By default, CBD has been bred out of cannabis almost entirely. So over the last 2030 years, if you took a strain of St. Cannabis, you would be lucky to have found 1% THC or CBD in any of it. Yeah,

Nick Jikomes 1:29:02

I can tell you so we're putting together a paper right now that looks at just under 100,000 laboratory testing samples of cannabis flour and conservatively I would say more than 95% of cannabis flour use commercially has less than 1% CBD Yeah,

Matthew Hill 1:29:20

that's about what I would predict. So that's consistent with it. So this idea that's permeated the public that CBD is medical and THC is recreational make zero sense to me because I'm like I don't understand how in the same breath we can be referencing the fact that people have been using cannabis in a medical context for decades to centuries depending on the culture. And then yet at the same time try claiming that this is not due to THC is actions where we know it has a pharmacological effect on CB one receptors and we know that CB one receptors regulate the processes that people claim are being benefited by it. We have no concept of this with CBD so Yeah,

Nick Jikomes 1:29:54

I do. I agree that you know one of the one of the biggest misconceptions that's out there is this tea THC is the fun one and CBD is the medical one. Is there still, you know, historically, I think there's been, you know, quite an allergy to THC in at least certain parts of the clinical community where most of the studies have looked at, you know, the abuse potential and things like this. Do you see that changing? Is there a lot more clinical work happening these days around THC in its potential medical benefits.

Matthew Hill 1:30:25

I mean, the funny thing is like everything that had been done clinically had almost all been done with THC, private because it all been done with NAB alone or Marinol or isolated THC and all these medical studies that have been done, like everything that had been done with side effects, that was mostly THC, everything had been done in Canada was with NAB alone. So it's weird to me, like I'll talk to clinicians. And they'll be like, well, there's no evidence at all, but cannabis has any benefit of PTSD. And I don't see it doing anything but damage. And I'm like, it's really weird that you say that, because like there is clear data that isolated THC has been done in experimental settings. And granted, there are some issues with the study, but you can't deny that there's data that exists. And to say that something that was found with isolated THC will not generalize to cannabis. Sure, that's possibly true. But that's incredibly naive. It's

Nick Jikomes 1:31:13

weird. Yeah, because it is mostly THC.

Matthew Hill 1:31:16

Yeah. So it's very strange. And I think, to be honest, I mean, I'm not a physician. So I'm not, I always tell people, I'm not bound in the same problematic space that a physician could be, because I'm not prescribing something. I'm not telling people what to use. I'm just looking at what the data is and repeating it. And so it's different from a physician's perspective, because I feel like especially on the heels of the opiate crisis that's been going on for years now, physicians are incredibly reluctant to say anything that could be interpreted as endorsing a drug that could have some abuse potential, because of the history of what's happened in the in the context of prescribing drugs that have abuse potential. And, well, that change. I don't know, I mean, we're over two years into legalization in Canada. And now I mean, to in some, and the data that's been put out from Health Canada has generally shown that there's been zero impacts on almost anything that we can measure in the country like it's it's it's like y2k all over again. It's the most anticlimactic. I mean, and the thing that blows my mind is I'm I'm fundamentally confused by more countries aren't talking about how boring legalization in Canada ended up being like it didn't do anything. And so I I'm surprised that in the space of that time that more physicians haven't. I don't know. I've tried. I've tried to have conversations with physicians about it. I mean, there's clearly risks associated with cannabis. And it's not something that works for everyone. And there's clearly subsets of people that respond badly to it. And it's, it's easy to say that though it's it's it's just I feel like there's this insane push to always believe data suggesting adversity. And there's this very strange reluctance to ever embrace any data that suggests benefit.

Nick Jikomes 1:33:07

You mentioned, you mentioned opioids briefly, I'm going to talk to Yasmin Hurd in the near future. But you know, setting aside the the question marks around mechanisms of action, what do you think about the work that suggests CBD might be used as an addiction treatment?

Matthew Hill 1:33:25

I mean, Yasmin's works, probably some of the most interesting has been done out there because it does. I mean, I also like how Yasmin went pipeline from animal studies into humans based on a phenomenon she observed there. I think I mean, to me, it makes sense in terms of the measures she's looking at, because she's largely looking at craving and anxiety measures, in individuals with with opiate use issues. And so I'll be curious to see what Yasmin's data looks like in the larger context of a relapse study where they're actually looking at more direct measures of opiate use, and outcome measures. But I, I mean, I think it's an interesting approach that she's taking.

Nick Jikomes 1:34:03

Can you just briefly summarize for people? You know, what, what's the main? What's the basic summary of that work?

Matthew Hill 1:34:10

I mean, it's been a while since I've read it, if I can remember correctly, Yasmin was looking at individuals who had opiate use disorder, and had were abstinent, and they gave them CBD and looked at measures of I think it was 306 100 milligrams in her studies, and I think both of them had some efficacy. And I think I can't remember the duration of dosing, but I know that the measures they saw signaling where it reduced some scores on craving, and it reduce signs of anxiety. And the reason those are relevant, is because those obviously tend to be big predictors of relapse. Because if someone is, we know stressors and anxiety can be big triggers for people to relapse, drug use, and we know that craving obviously has a huge component and relapse. So if you have a pharmacological intervention that can reduce some anxiety and also reduce craving by logic, you would assume that that would have benefit in in actually curbing use long term. Which was why it'll be interesting to see when that gets put into test and an actual clinical study if it actually shows that it has efficacy in that space.

Nick Jikomes 1:35:13

So in our last few minutes here, what you know what's on the horizon that's interesting, either in your lab or generally in this field of Endocannabinoid biology.

Matthew Hill 1:35:22

I mean, I think despite the fact that my career is almost entirely been endocannabinoids, and not much in cannabis, we've recently moved into some cannabis stuff. And I think that things become interesting why this is cool is been with this kind of repurposing of these vapor chamber technologies that was developed for nicotine delivery through vaporization. So there's a Maury Cole has this company down in San Diego that makes these vapor chambers and he'd worked with a lot of the nicotine researchers and some of them started moving into cannabis like Mike Taff, then at UCSD, and he started working with maurey to convert these chambers. So you actually basically try to replicate like vape pens, where you take cannabis oils or THC distillates, and you vape them to animals. And this may not sound like a huge technological advancement. But the entire field of understanding the effects of THC on the brain has almost entirely been performed using injection approaches for the last, you know, 3040 odd years meaning

Nick Jikomes 1:36:15

meaning injecting THC directly into the brain of an animal

Matthew Hill 1:36:18

or into the periphery in a big bolus where you dump it in. Now, what had not been appreciated that much is how different the pharmacokinetics of it are. So what we've learned we have a paper right now where we've just compared inhalation to injection, and we've looked at the pharmacokinetics of it and others have sort of do is to and what we've seen is very clear. If you inject THC, it's a liquid, a lot of it immediately sequestered into the fat. This was where Steve Mahler and Daniel pmle did down at Irvine to show that you actually get a huge amount of THC that goes right into the fat pads. And what seems to happen then is that THC then slowly leaks out into the bloodstream for hours. And because it's leaking into the bloodstream before it hits the brain, it often hits the liver, which means it makes a whole boatload of this metabolite called 11 hydroxy THC, which is actually a little bit more potent than THC itself and has more retel access to the brain. And so what you see from an injection is if you measured a single blood time point of blood THC level, someone would say, Oh, it looks like roughly the blood level someone achieves from smoking a joint. But what they don't realize that when you smoke a joint, that's the peak level that lasts for like 510 minutes, and then it clears and when you inject it, it sits there for like five, six hours. And so the from a pharmacological perspective, what this means is that injections of THC are causing hours of sustained activation of CB one receptors that is not at all reflective of what's happening in reality when someone inhales cannabis. The other problem is a lot of the animal work had been using synthetic cannabinoids that weren't THC, just because of FDA or DEA issues with it being a schedule one drug. And they're like, Oh, it's easier. And it's pretty much the same thing. And now we know that's not true, because we know the synthetics are biased agonists and recruit all these different pathways. So basically, we had kind of look back on this whole literature of animal studies looking at the object, what people were assuming cannabis was doing to the brain is being based on injections that is a THC or synthetic agonist, which don't behave the same. And so this idea of using a vaporization approach, so animals inhale it, well, again, doesn't sound like that technology, when you think of things like optogenetics, or dreads are stuff. It's not a technological advancement, but it is a huge step forward in the field, because now all of a sudden, we have an approach that really models how people consume it. And it models the PK of how THC is going to be metabolized in the body, how it's going to impact the brain. And we are definitely seeing different effects from doing this. And I think that now this is becoming the new wave. There are multiple labs in Canada using this technology and tons in the States.

Nick Jikomes 1:38:42

Can you just describe very concretely like what the setup is that a mouse or a rat would be in and what they might be doing after inhaling.

Matthew Hill 1:38:51

So the way the Shavers work is you can either like we have to set up some of them, you just put the animals in kind of a clear Plexiglas chamber. And sometimes we have a big setup, but we can just put their whole home cage in and leave them so we don't have to disturb them, the cages or the boxes there and then become sealed. It's kind of a negative pressure environment. And it has like a, basically a vape chamber that's pretty similar to what you'd find in a pen, but a bigger one that you put the oil into. And using the system, you can kind of tweak it using the computer setup to do controlled delivery. So we do a 10 second puff, where, you know, it basically blows THC vapor into the chamber for 10 solid seconds. You get like, you know, about 30 seconds of a Cheech and Chong room that's just like cloud and you can't really see anything and then through the negative pressure, it slowly dissipates over the next couple of minutes. So the animal inhales at during that period, and we do that for 1015 minutes. And that gets us at the blood level we would expect from someone smoking a joint or two and the animals clearly intoxicated, like you can see it like they kind of sit there they won't do a lot. Their eyes are kind of closed. You know, we've measured body temperature they get dropped by the temperature. We've started doing a lot of munchies studies and they clearly definitely eat more. They Go into for 30 minutes after their high they binge. But what's interesting is they binge and then they don't eat for like four more hours. So while they're high, they just the week appreciate them and then they'll just keep eating beyond satiation. So it's just like humans. And then as soon as it But the interesting thing is like so pot smokers in humans is not associated with obesity, in fact, more often than not are less obese than the general population. So it's interesting because what you end up seeing what we keep seeing in the animal stuff is this bingeing that happens in a very restricted time window, and then like almost no food consumption for the period afterwards. We haven't like got them successively high to see if we can re get feeding boats to occur over and over again, but we definitely get a clear munchies phenotype out of them.

Nick Jikomes 1:40:44

Is there um, I assume someone is measuring motivational drive, like if you train the animals to do a task? Or they just lazier? Well,

Matthew Hill 1:40:53

so we had previously done some stuff on THC injections. With that we're trying to do this more now looking at reward learning tasks, and how it influenced that as well as a variety of learning tasks. My buddy Ryan McLaughlin has done in Washington, he was one of the other people that really kind of pioneered this. And he actually did the first thing, he was the first person that actually showed you can train animals to self administer cannabis vapor hits. So he put them in kind of basically an instrumental conditioning situation where the animals would learn to like lever press, and it's fascinating to watch, because you could see the videos of the animals like labor present and run over to the port, and kind of like bask in the neighborhood as it comes. So they clearly enjoy it, it clearly is rewarding, they'll work for it, you know, you start doing extinction, you get extinction burst for the animals, like starts going crazy to try and get cannabis vapor clouds. So and it's interesting, because one of the things Ryan showed since then, which is relevant for me, we found interesting as well, is that if you let animals self administer cannabis, then you stress them out. They actually do have blunted stress responses, same as what you see in human. Yeah. So again, it's nice because we're able to recapitulate these kind of real life phenomenon that we see in cannabis users. And the reason I like this is I feel like now we can actually properly study cannabis. And I honestly feel like the way that the field has approached studying cannabis, again, largely due to this DEA regulations. And the fact that this technology just wasn't easily accessible, has been subpar for some time. And I think it's really significantly influenced a lot of the way that we think especially about the adverse effects of THC or cannabis, because a lot of these studies have been done with incredibly massive doses that are having far more biological impacts on the brain and body than what we would normally see from cannabis consumption. And so I you know, I don't doubt that there will be like adverse outcomes that are coming from this mean, we're starting to do some prenatal and adolescent exposure. And there's certainly things that you start to see, I mean, the prenatal stuff is consistent, you always see, you know, reduced birth weight, there's consistently some behavioral phenotypes that kick in later in life. So there are effects that are clear that are coming out of this. So we're like, Kay, we are confident that this is probably more reflective in a translational manner of what's really going on in humans than what we would have seen before that so. So I have to say, I think this is actually a really exciting kind of new avenue of things. And it's a little bit out of my normal wheelhouse, but it's still kind of in the cannabis cannabinoid space. So

Nick Jikomes 1:43:15

that's awesome. Yeah. So in the next year or two, we'll we'll actually start to see probably quite a few animal studies come out that are using these paradigms. Yeah,

Matthew Hill 1:43:24

I mean, there's at least 20 labs that I know of now in Canada in the states that have got this technology or variants of this technology working in their own groups, and are doing studies like this, and I believe even Yasmin's moved over to the chamber approach as well. Now, I think it's just kind of like if you really want to be asking questions that are gonna be relevant to humans, like the argument I always make is I'm like, we don't inject alcohol anymore. We don't inject nicotine, there are other ways that these drugs are administered because we as a field have recognized that route of administration impacts PK, much more than people appreciate it. For cannabinoids, it's far more relevant than I feel like a lot of people had given credit for in the past.

Nick Jikomes 1:43:58

Well, that's great. It's a positive note to end on. I look forward to seeing some of that research come out. Thank you, Matt, for your time. Is there anything any final words you want to leave people with? Do you have a website or any place where people can find you and your latest thoughts?

Matthew Hill 1:44:13

No, I mean, I'll use this as a shameless pitch for an organization that I'm the director of which is called the ccic. It's an organization of physicians and scientists that kind of tries to promote accurate education about research in science regarding cannabis and cannabinoids all the way from plant science, basic biology through the human use clinical outcomes and public health and we have an annual conference that's this year will be run virtually which details can be found at ccic dotnet. But it's a great review of the most up to date science being done by Canadian and American cannabis scientists. So this year, it's people like Ziva Cooper and Ryan vandrie and CC Hillard, a bunch of Canadian people looking at some of the data that's coming to Health Canada will be you know, updating legalization data and use patterns and things like that. So I encourage people Look at the website and attend the conference if you can't if you're really interested in understanding more about kind of the current state of cannabis science in Canada in states.

Nick Jikomes 1:45:10

All right,

Unknown Speaker 1:45:10

well, thank you, Matt.

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