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Matthew Hill 4:06
My name is Dr. Matthew Hill. I am a professor of neuroscientist at the University of Calgary at the Hotchkiss Brain Institute. My lab historically is focused on endocannabinoids and stress regulation. We really have looked at how stress exposure affects the end of Feb nine system and conversely how endocannabinoid signaling effects stress responses and emotional behavior. More recently, we've moved a lot more into cannabis exposure itself using role models of cannabis vape exposure and looked at neurodevelopmental consequences from pregnancy or adolescence.
Nick Jikomes 4:39
And so for those who don't know, so you've been on the podcast before I've had a number of podcasts. We've talked about endocannabinoid biology so people can go look those up. But can you give people a brief overview of the endocannabinoid system and what its major sort of pieces are?
Matthew Hill 4:54
Yeah, so I mean, the endocannabinoid system was first discovered as basically the biological system that exists in the brain in the body through which THC which is the psychoactive constituent of cannabis exerts its effects on physiology and, and the human body. And pretty much actually every species along the whole mammalian tree and even down below. It's a very well conserved system it mostly exists is to reset receptors. So there's the cannabinoid CB one receptor and the cannabinoid CB two receptor. CB one really is the meat of the action. That's what drives almost all the effects of THC. It's really widely expressed throughout the brain. It sits on axon terminals, so really what it does when it becomes activated is that kind of influences how neurons will talk to one another. The CB two receptor is really more of an immune based receptor. It's primarily in the periphery, it's on some immune cells in the brain. And there is some controversy over whether it's actually in neurons as well. But really, what we think of CB two mostly doing is regulating inflammatory responses from immune cells. So when it gets activated, it kind of calms those cells down, reduces the release of inflammatory molecules. And these receptors obviously don't just exist, because you know, nature thought humans would find cannabis one day and teach you and activate them. So there are kind of endocannabinoids that the body makes that are molecules that act on these receptors, that even though they structurally don't really look very much like THC, they bind to the receptor and kind of mediate a lot of the same functions. And two of these were discovered, the first one that was discovered is called anandamide, and that name is kind of a plan words because it was wrapping Shulam, who was in Israel, when they discovered this and it's essentially the Sanskrit word for bliss, Amanda coupled to a mic because it's an amide bond that connects the ethanolamine with the arachidonic acid and the molecule itself. So anandamide was the first endocannabinoid that was discovered. And then the second one was just to arachidonic glycerol, which, again, is structurally very similar to anandamide. It's basically just arachidonic acid, this one has a glycerol tail on instead of an ethanolamine. And, yeah, they both activate the cannabinoid receptor. And then there are clusters of enzymes that are involved in both the biosynthesis and degradation of both those molecules as well.
Nick Jikomes 7:06
So so we've got a few pieces to the endocannabinoid system, we've got a couple main receptors, CB one, mostly in the brain doing stuff related to neural function, CB two, much more highly expressed in the periphery and places like the immune system. So it regulates inflammation and things like this. There are a couple major endogenous cannabinoids, and they end of mind in to AG that are just naturally in our body. And the other thing that that we often talk about here is how these, these molecules act on demand. What exactly does that mean?
Matthew Hill 7:41
Yeah, so I mean, basically, most neurotransmitters and other signaling molecules that are released tend to be at stored and these little packages we call vesicles. And usually in the brain, at least, the neurons, these neurotransmitters are all pre made, and they're loaded into these particular packages, and they're just essentially sitting to wait. And when a neuron becomes activated, and it wants to talk to the next neuron, on the other side of the synapse, it will release these these vesicles doc, and then they get released, and then they cross over and activate receptors on the other neuron. And that's, then there has to be some recycling where these neurotransmitters get like fed back, and they get metabolized and resynthesize than repackaged. So that's kind of the classic, typical way that neurotransmitters function endocannabinoids are kind of on demand in the sense that there's no there's no packaging of them. They basically are synthesized from phospholipid precursors, they just exist in the cell membrane. And they are what we call retrograde signals in the sense that they work backwards. So they're almost entirely formed in the postsynaptic neuron. And then they act backwards to the presynaptic neuron where they then regulate how much neurotransmitter gets released of other types of neurotransmitters like glutamate or GABA things that regulate excitation and inhibition.
But so basically, when that postsynaptic neuron becomes active, the activity patterns of it initiate activity of these biosynthetic enzymes that rapidly cleave these lipids out of the phospholipid membrane and that neuron and then just make the Endocannabinoid and as it's made, it gets released. And it kind of acts on demand in that fashion, in the sense that it basically is synthesized when it's needed, and it's released when it's needed and x and then it gets degraded right away. So it's a relatively short lived signal. It doesn't kind of exist in these specific color packages the way most neurotransmitters do. I see. So most neurotransmitters are made, and they're stored for some period of time. So they're ready to go ahead of time they're stored in vesicles. Basically, endocannabinoids are released on demand in the sense that they're sort of made right then and there after some signal tells the cell that they're needed, they get released, they get quickly degraded. And so in that sense, they're on demand. They're not sticking around for a long time, and they're very spatial, temporally precise. Yeah, exactly. I mean, and that's really, when people always ask what the difference between endocannabinoids and like THC from cannabis is because they both act on the same receptor. A lot of it boils down
Under the spatial temporal precision, and so no cannabinoids are very precisely released from a cell to act exactly in a very discreet area, in the immediate proximal area around where they're getting released act of receptors there and influence the kind of very local environment of that those neurons that it's affecting, whereas THC when someone consumes it and it gets into the blood and then just hits the whole brain, it very indiscriminately activates, cannabinoid receptors, and it pretty much does so with whatever ones I can find all at once. And so you get much more of a, you lose that that spatial temporal precision, and you just get kind of like blanket activation across the brain.
Nick Jikomes 10:36
Yeah, and I suppose that you know, I get asked time to time why if we have an endocannabinoid system, we have these endogenous cannabinoid molecules that activate the CB one receptor, just like THC does, you know, why don't we walk around feeling like we're under the influence all the time? That's the answer. THC, you know, is hitting all the receptors at once. Whereas the endocannabinoids are really working in a sort of synapse by synapse way.
Matthew Hill 10:57
Yeah, and I mean, even if we look at like, there's drugs that they've made now that are in the public, but they're going through clinical trials which inhibit the metabolism of these endocannabinoids, like there's one for anandamide, explicitly that's gone through a fair amount of work. And so people take this and they're anandamide levels go up quite significantly. But they don't get high off. They don't report any intoxicating effects. It's nothing like cannabis. And again, this is because that, that that drug is basically only enhancing anandamide signaling at the synapses, where it's already acting, it's not making it everywhere, all at once the way THC does. So even when we boost endocannabinoids, it still doesn't seem to produce the same kind of intoxicating, quote unquote euphoric and other aspects that we see from THC and cannabis.
Nick Jikomes 11:39
And so when an antibody gets released, so it gets released from the postsynaptic neuron, the neuron that's listening to some input from another neuron, when it gets released, it goes back to the first neuron sending a signal to the second neuron, what's the basic effect it has on that first neuron. And mostly,
Matthew Hill 11:55
what it does is it'll turn off neurotransmitter release, because cannabinoid receptors are generally inhibitory receptors. So when they get activated, their main goal is to really dampen transmitter release. And so it really is almost like a thermostat model in a lot of ways. I mean, in the most basic sense, obviously, there's far more complex versions of endocannabinoid signaling. But like if you think of it in the sense of one neuron dumps out excitatory transmitter and it activates the neuron that's listening to it. When that neuron that's, that's receiving all this input becomes too stimulated, it will start making endocannabinoids to then act backwards and turn off that incoming neuron so that it doesn't get burned out, essentially. So it's like a feedback signal for the most part. And so this is why we always tend to say, really, the main role of endocannabinoids is to maintain homeostasis, to kind of keep everything where it should be. And usually they get brought online when something gets disturbed and we move out of a range we want to be in its role is to kind of bring us back to the range we want to be in.
Nick Jikomes 12:53
I see so so if a neuron just gets too active, starts sending too many signals, that basically triggers the release of endocannabinoids. And they quiet down the activity basically,
Matthew Hill 13:02
in the most basic sense. Yeah, I mean, obviously, I said, there's way more complex versions of this where it can like regulate inhibitory transmission and like result in synaptic potentiation. Or it can really influence things like acetylcholine and serotonin and other neurotransmitters where it has more of a like a modulatory effect. But in the cleanest example of explaining how it works. It's kind of the circuit breaker model where too much input tells the cell to turn that input back off and endocannabinoids are the mediator of that whole
Nick Jikomes 13:28
circuit. And so given how widespread CB one receptors and anandamide are in the brain, they're there all over and many, many, many different parts of the brain. Do they sort of influence everything? Or are there like particular types of behaviors and things with it, they're more involved in regulating.
Matthew Hill 13:49
I mean, they probably do regulate mostly everything, but it seems to be to varying degrees. So the receptors really are virtually everywhere. The only place we really don't see a lot of cannabinoid receptors is in aspects of the brainstem where there's kind of like, cardiopulmonary regulation, which is the main reason why we don't have fatal overdoses with THC the way we do with things like opiates because opiates well, they're very similar receptor. opiate receptors are very similar to cannabinoid receptors. And since they're inhibitory, and so when someone takes like an opiate, and it activates those receptors in the brainstem, it will quiet down or activity in those parts of the brainstem that regulate breathing and heart rate kind of unconsciously. And so someone will pass out from the sedating aspects of the opiates. But as they pass out, also their breathing and heart rate slows down to the point where they will, it can be fatal. And that's because the opiate receptors exist in that part of the brainstem can Emory receptors don't exist there. It's really one of the only areas they don't exist. And that's why they don't seem to have that same risk associated with them. They also weirdly don't exist in dopamine neurons. They exist around dopamine neurons. dopamine neurons tend to be the one neuronal population where people will have really not consistently or really ever found evidence for CB one receptors being in them. So, which is again kind of bizarre and interesting. And there's got to be a strong reason for that. But But yeah, I mean we have them in our feeding circuits we have them in our, you know, parts of our brain that regulate arousal and sleep processes we have cannabinoid receptors in the part that regulate memory and cognition, anxiety and emotional states, which is kind of why we see this wide range of behavioral responses to cannabis and cannabinoid consumption because it just hits these receptors in so many different areas. And for some people, some effects seem to predominate over others. And again, that's not entirely clear why, like, you know, some people will get very chilled out and relaxed from smoking cannabis or consuming and some people will get panicky. Some people get like insatiable munchies, some people kind of get in thought loops where they can't break out very easily, or they can't remember things very well. So the receptors are all there. It's just for some people, some effects seem to predominate over others. And
Nick Jikomes 16:02
so your your lab has done a lot of work to do with endocannabinoid regulation of stress and emotional behaviors, generally speaking, can you give people like a brief overview of you know, what is what is the normal acute stress response? And what is the HPA axis? And what are some of the key pieces there?
Matthew Hill 16:20
Okay, so before I even talk about cannabinoids, the stress response is basically, it's like a coordinated biological response through multiple systems in the body, that essentially, the goal is essentially to just prime an organism to be able to deal with the threat at hand. And so for humans, a lot of this, I mean, for almost all mammals, I would say, actually, this is really almost entirely geared in the context of predatory threat. Or what we often kind of nowadays just call fight or flight responses. And the idea behind that is essentially, if your brain perceives a threat in its environment, so that can come in many different flavors, but like some sometimes this is something that's real and right in front of you. And sometimes it's something that you have to kind of think about, and you see a situation and you think of the outcomes, and you're like, Okay, this could go to a bad place, and that can stress people out. But basically, once the brain has determined that a stimulus or an environment is stressful or threatening, it activates a cluster of cells that possess a peptide called corticotropin, releasing hormone. And this is all clustered in the paraventricular nucleus of the hypothalamus. And when these cells become activated, this is the beginning of what we call the HPA axis, and HPAs hypothalamic, pituitary adrenal, and it's essentially a cascade. And so starting in the hypothalamus, those corticotropin releasing hormone or what we call CRH, they get released, actually, it's one of the only neurons in the brain that released directly into the bloodstream, they actually leave the brain itself and goes into the bloodstream in the pituitary, bloodstream, and it dumps CRH there, and then that acts on CRH receptors in the pituitary, that triggers the release of another peptide called ACTH. That goes into your general circulation through the whole body. And that then goes down to the adrenal glands that will trigger the release of a hormone called cortisol, which most people are familiar with in the context of it's, it's kind of like the general stress hormone that we are familiar with. And so when we get stressed cortisol levels go up. And really the main function of what cortisol does, despite everyone talks about it in kind of a lot of different ways, but really, a lot of what cortisol does is mobilize blood sugar, that's kind of its primary goal. And so cortisol will elevate blood sugar levels. And the point of this is to essentially give your your muscles in your brain fuel to be able to deal with the threat at hand, I mean, at the same time, you'll get adrenaline release coming from your sympathetic system. And that will cause your heart rate to go up and your blood pressure to go up because your blood vessels constrict. And that will be, it's essentially creating a mechanism to deliver that, that elevated blood glucose or blood sugar to the target tissues, be it muscle or brain to keep things active, so it can flush out lactic acid from muscles and replace it with glucose. So muscles don't fatigue quickly. So if you gotta run, you got to run. And if you got to fight, you got to fight. So it kind of is a mechanism, essentially, to make sure that we have the ability and the energy resources to deal with a threat at hand and survive. So I mean, in a brief sense, that's what the stress response is, I mean, obviously, things go along with that, like you get anxious and you become hyper vigilant when we become stressed. And that's just because we're obviously trying to scan for threats in our environment, figure out if we're safe. If there's something that's going to be challenging to us do, we need to pay attention to more threats coming around the corner. But that's kind of what we would classically defined as the stress response. And so where the cannabinoid system comes into play with that is, there's this one part of the brain that we know is really important for stress processing called the amygdala. And so the amygdala is like, I don't know, if everyone does, does a lot of things. So amygdala aficionados would kill me for kind of reducing it to being involved in a lot of surveying of thread, but that is one of its main roles. It does do a lot of other things like process, reward and deal with memory. But really, one of its main roles is to survey the environment for threat and essentially Information is funneled there from sensory cortices and it gets evaluated in the amygdala. A lot of this is due to CrossTalk that goes back and forth between frontal cortical regions in the amygdala evaluating previous experiences have things predicted threat or not, has this been safe or not. And if the if it's kind of deemed as something that could be threatening, let's say if the main evaluates this as a as a negative stimulus, something that possesses a threat to the organism, it will then activate through a series of projections, the HPA axis as well as the sympathetic response. So we know the amygdala is really important for gating and initiating the stress response and one of the things that, that we've been working on for probably about 15 years at this point now is so anandamide, at rest in the amygdala seems to be at a relatively high level. And what happens in response to stress very abruptly is that anandamide signal actually crashes pretty quickly. And the loss of that anandamide signal seems to pull the brakes off of these excitatory neurons coming into the amygdala. And as a consequence of that, what we see is that this causes more release of excitatory transmitter and as a consequence of that, amygdala neurons themselves become more active. And when those Amiga neurons become more active, they then activate their downstream pathways that will drive the manifestation of the stress response. And so we know that this loss of anandamide signaling is relevant because if we inhibit its metabolism and clamp it at a high level, we can prevent or at least damping the magnitude or the initiation of a stress response. We can do this just by playing with anandamide in the amygdala explicitly. There's been some really nice human imaging work that's come out very recently as well. That's actually visualized using a pet tracer how much fall which is the enzyme that metabolizes anandamide. So how much fall exists in the amygdala so people who have more fall have less anandamide because that enzyme chews up anandamide. So if there's more than enzyme around there's, by default, usually less anandamide. And what they found is that people who have more fun their amygdala and therefore less than ENDA might have a more reactive amygdala the threat. So their amygdala becomes more hyper reactive when they get exposed to potential threatening cue. And as a consequence of that, they will then manifest greater indices of kind of anxiety or stress responses. And so that's half of the story, because that seems to be how endocannabinoids will regulate the initiation of a stress response, but then the stress response kicks in. And then you get the whole HPA Axis activation, and your cortisol levels will go up. And then the second half of what we've been studying, and this is something that several labs, Jeff Tasker and sacha Patel and many others that we collaborate with or friends with. Look at this too, is that when those glucocorticoid, hormones start elevating, in response to stress that actually then triggers the synthesis of the other endocannabinoid to AG. And then that acts as a feedback loop to turn everything back off. So it's essentially a closed circuit model that we see going on in the amygdala where stress comes in and a threat comes in and as a consequence of that threat, anandamide drops, that helps drive activation of the amygdala that results in the generation of a stress response. The ensuing elevation of stress hormones then triggers the release of more endocannabinoid this time being to EEG, which then acts to turn everything back off and help bring us back down to steady state levels. And this is part of the reason why we don't just kind of get stressed out and stay in periods of stress for long periods of time. But we're able to recover when we're removed from that threat and go back down to our steady state levels and be like, Okay, we're safe. Now, there's no reason for us to still be stressed out. Similarily, we kind of think this is actually one of the mechanisms that may make people more vulnerable. Developing stress related psychiatric conditions, like PTSD, for example, is that maybe their endocannabinoid system doesn't quite function properly. So they're not quite able to turn all those circuits back off. So they stay in that elevated state of stress for longer periods of time, and therefore become a bit more vulnerable to some of the adverse effects of stress. So,
Nick Jikomes 24:03
you know, when we encounter a threatening environment, you know, a tiger jumps out of the bushes to eat a mouse or us something scary happens, the brain has to detect that through its sensory systems. One part of the brain through which a lot of that information goes is part of the amygdala. And the amygdala is able to then turn on the HPA axis and release cortisol and cause all of those physiological changes that are the fight or flight response that make your pupils dilate, that increase your blood pressure and heart rate, all of the things the body needs to do in order to be alert and to move itself away from a threat and all of these things. And what you're saying is, there's a system in the amygdala that involves endocannabinoids, that sort of gates that response. So you know, there's these potential threatening signals coming in to the amygdala. And if they come in strong enough, the HPA axis in the fight or flight response will get turned on But you only want to do that if there's a legitimate threat. So you sort of want a braking system to keep that off unless you really need it. And the endocannabinoids are basically doing that. Yeah.
Matthew Hill 25:09
Yeah. I mean, if you think about this, like, just in a health perspective, like so, I mean, one of the things you get when you're stressing, we're saying, you get this elevation and blood pressure and heart rate, like you don't want to stay in a situation where you're just kind of jacked up, and my heart is pounding for long periods of time, because you're obviously going to start putting damage on your heart, you're gonna start putting damage on your blood vessels. I mean, this is what hypertension is. And this is why we monitor our blood pressure, we try and make sure if it's too high, we go on drugs to bring it back down, because we don't want the damage associated with chronic stress, the wear and tear that goes on our body from that.
Nick Jikomes 25:42
Yeah, and so you mentioned also, you know, obviously, you want to have this acute stress response, you know, when and where you need it, meaning you want to detect actual threats in a valid way, you want to be able to accurately assess the environment environment, you want to be able to turn on this HPA Axis when it's needed, then quickly turn it off. Cannabinoids would seem to be a very good thing for doing that just because of their on demand nature that you described earlier. And you also mentioned that, you know, then it's it's natural to think that if someone has chronic stress, or they have a disorder like PTSD, where they are sort of hyper vigilant all of the time, you know, it's natural to think, you know, does the endocannabinoid system have a role to play there? Is it not being regulated in the way that it's supposed to be? Is there any evidence to support that at least directionally?
Matthew Hill 26:34
Yeah, I mean, so we have done a lot of animal work with chronic stress where we've seen that the I mean, we kind of refer to as like a collapse of the endocannabinoid system, because it just seems to get weathered over time from being engaged so regularly by the stress response. We've done some work in populations of people with post traumatic stress disorder, and the data is very variable. And some of this depends on the nature of post traumatic stress disorder, whether it's like kind of a chronic lifetime thing, like some people have had a lot of trauma. So there's been some work done, like, for example, refugee populations. That looks very different because I feel like that's kind of like a permanent chronic stressor. But when we talk about acute trauma, it's it's more like what we're saying here that it seems like the endocannabinoids the individuals that go on to develop PTSD, we have at least found in two populations. Both of them are related to 911 exposure, and New York. Both of them we do see lower levels of contaminants are associated with PTSD or greater symptoms within PTSD. There is some work that's come out of Toronto again, using PET imaging to look at this enzyme fog which metabolizes anandamide, and they found individuals with social anxiety disorder have higher levels of this enzyme throughout the brain. And again, we've been predicted those people that in turn, have lower levels of anandamide because they have more of the enzyme that's chewing it up. And so there is these kind of remnants of evidence that are in that sense. We've we were involved with one clinical trial that was done in healthy controls giving the drug that boosts anandamide and we found just a normal people that had no psychiatric conditions, even just boosting anandamide them, even if you ask them, none of them would be able to report that they felt any different. If we then stress them out. We did see they had pretty robustly blunted stress responses. So like, they didn't have an autonomic change, like their adrenaline didn't go up nearly as much subjectively they didn't report feeling as stressed out. There's some other physiological measures of facial muscle movement that were blunted as well if they have high levels of anandamide. So even if they couldn't consciously perceive that they're actually less stressed their body was physically experiencing less stress in the context of high anandamide. So, those results were quite exciting. And they've now spurred there's been a couple of actual clinical trials, one in social anxiety disorder that had some mixed but sort of positive results. There was some issues with the drug in that one, but there's a to like large scale PTSD trials right now, with this drug that boosts anandamide signaling to see if indeed, it will have potential to actually help treat it because again, is if this idea that the endocannabinoid system isn't functioning properly, we want to enhance it. And that should hopefully restore stress resilience to some degree.
Nick Jikomes 29:08
Yeah, so So with respect to the stress response in the amygdala stuff. On the one hand, you want to be able to acutely quickly crank up your endocannabinoids to turn off that response when when you need to when the threat has been avoided. On the other hand, you mentioned that, you know, this is a gating mechanism. So you want to sort of tonically steadily release some amount of anandamide, to keep that HPA access from turning on the via the amygdala until it's needed. And you know, that sounds a lot like the concept of endocannabinoid tone. And so can you explain for people exactly what that is? And maybe how much natural variation do we see between individuals and just sort of the baseline levels of endocannabinoid tone?
Matthew Hill 29:52
Yeah, so I mean, endocannabinoid tone would basically be this idea that you know, even though it's made on demand, so this is a mistake I think a lot of people make about The idea of on demand, people seem to think on demand means that only goes up under periods of sustained activity. But that's not exactly true. We just mean with on demand that it's not stored in vesicles. It's just released as it's needed. And we also know neurons in the brain are always active to some degree. And even when we're sleeping, the brain is always active. So it's not like the brain is in a state of quiescence or anything. So these neurons are kind of generally active, and there is some baseline production of endocannabinoids. That's always ongoing. And this I always kind of visualize this as basically being a mechanism to set the tone of a circuit. So if there's a lot of basal endocannabinoid being kind of produced by these neurons, because there's a high level of constitutive activity, as a consequence of them, maybe that's kind of gating the amount of basal input that's coming into the cells. So it kind of keeps things in check. So everything exists in this like happy zone where activity levels are where they want to be. It's hard to predict exactly how much variation there is from person to person. I mean, we've done peripheral measurements on at this point, probably 1000s of humans measuring their endocannabinoid levels. One thing we know, we've done a couple of studies where there's been measurements over repeated days, and it does look like people are stable in the sense that if someone has high endocannabinoids, upon repeated assessment, they continue to have high endocannabinoids. And if they have low, they continue to have low. So we do think there's some phenotype, let's say of people that exist out there. Again, we know there's a little bit we can learn from genetics. So like, again, that enzyme far I mentioned that metabolizes anandamide, we know there's genetic variants in that enzyme. And there are a cluster of individuals probably about maybe a little under 30% of the population that contain at least one of the two variants of that of the gene that can influence that. And if you are a carrier of this kind of anomaly in the fall gene, as a consequence, you just have less fog, and therefore have more anandamide. And this has been pretty reliably studied in this population, that people carry this gene variant in the fire enzyme. They just have more anandamide loans. And when we've studied those people, they do tend to in general, again, they probably wouldn't report it subjectively if anyone asked them but you challenge them and they tend to be generally more stress resilient. If you put them in a brain scanner, their amygdala doesn't activate as much of a threat or stress as someone who has the kind of normative level of FDA. Even in PTSD populations, they found that individuals that have this kind of higher anandamide have lower levels of arousal and some lower degree of some symptom measures. So it does and it does seem to influence brain connectivity as well. So there's a lot of kind of different things that we can learn from this one gene snip, we're really all it's done is given these people, a slight higher level of anandamide. So that's probably the best we could we could say at this point. Because it is hard to know exactly. We know this translates to the brain, we just don't totally know exactly how it translates to the brain.
Nick Jikomes 33:03
I see. So depending on genetics, if you have, you've got far the enzyme that breaks down anandamide, if you've got a mutation in the gene, so that you're breaking it down less, you've got higher baseline levels of Nanda mind. And in general, that basically makes you less stress resilience. So the HPA axis is less prone to turn on.
Matthew Hill 33:24
Yeah, I mean, we haven't done a lot of actual work in HPA axis with these people. Most of it's been more behavioral, and there's been some autonomic work. But certainly at a behavioral level, these people will show lower levels of anxiety and anxiety measures, they, they are less fearful when they do kind of fear tasks to gauge how you react to a threatening stimuli in front of you. And their brain activity patterns look like what you'd see if someone who has lower anxiety or lower stress. But interestingly, I don't think we've really done a fair amount of work on them in the context of HPA axis. But again, I just I, I'm primarily an animal researcher, and so I all the humans that we use through collaborative work. If I had my way and a certain questions, I would ask, but we work with what we get.
Nick Jikomes 34:07
So there's some genetic variation in the fall gene that leads to variation in baseline and of mine levels between individuals. In terms of variation within individuals, are there any things that can happen to an organism that change its general endocannabinoid tone in the brain?
Matthew Hill 34:26
Um, yeah, I mean, so we've done some stuff with for example, early life stress that seems to kind of do some reprogramming. So in animals where we've done or that they've stressed in early life, trauma exposure, they tend to have lower levels of CB one receptors, but as a consequence, they seem to have slightly higher levels of anandamide. It's almost like the system's trying to recalibrate itself. And there is some work in humans showing people with early life trauma do have higher levels of anandamide and circulation suggesting that what we're seeing in the animals probably translates to the humans relatively well, but we can't be 100% Certain there. There are others things too, though I mean even things like obesity. So we know that like the foods we influence endocannabinoid levels, our metabolic state will influence it. And so individuals with obesity tend to have higher levels of endocannabinoids. We know that giving drugs that block CB one receptors were pretty effective at reducing eating and bringing weight down. However, as a consequence, they also made people quite anxious and brought on symptoms of depression not surprising because of kind of what we know about the endocannabinoid system. So it's limited their therapeutic ability as anti obesity drugs, but yeah, the obese state is certainly another thing that can kind of reprogram your endocannabinoid system to some degree. Yeah, I think there's other things like inflammation again, we know inflammatory states can influence baseline endocannabinoid function as well. So some of these are for the worse. I mean, most of these tend to be on the worst side of things in terms of the kind of conditions that will have greater associations with things like anxiety or depression. And when we look in the brain, at least, we tend to see that endocannabinoid system doesn't quite function nearly as well in all of these states. And so we've actually started to conceptualize the idea that endocannabinoids might be a mediator of comorbidity of a lot of psychiatric issues with these other conditions. And so we know things like colitis or inflammatory bowel disease, for example, which is a peripheral disease, as most people conceptualize it yet does have a very high degree of comorbidity with anxiety and depression. And we have found that yeah, you know, you have chronic inflammation in the gut, it does cause a crash and endocannabinoids in the brain. And if we give these organism that has kind of inflammatory bowel issues and inhibitor to fondateur, to boost anandamide signaling, we can bring down that anxiety. Same thing with chronic epilepsy states, we've seen the same thing they ever seen the same with obesity. So we kind of think that a lot of these disease states or things that we view is, I mean, epilepsy is definitely a central one, but even peripheral as well like inflammation and an obesity they do have these consequential effects on the brain endocannabinoid system. And in response to that, we think that's what's driving a lot of the psychiatric comorbidities is that when endocannabinoid functioning collapses to some degree, that then pulls the brakes off a lot of this emotional regulation. And as a result of that, you just get greater incidences of of anxiety and stress sensitivity and things like that.
Nick Jikomes 37:24
What about the influence of plant cannabinoids, namely THC on endocannabinoid tone and things like this does does the acute or chronic ingestion of THC have have clear effects on the endocannabinoid system?
Matthew Hill 37:41
I mean, I wouldn't say clear outside of the fact that obviously THC is going to activate the cannabinoid receptors. But outside of that, I mean in terms of endocannabinoid tone, it's not clear I mean, we have not reliably seen changes in ligand in in kind of chronic cannabis users. There's some work that came out of Britain that looked at like non cannabis users to very light cannabis users to heavy cannabis users. And like, basically, the light and the heavy different from each other, but neither of them different from controls. And so the lights had a slight elevation, the heavies had a slight decrease, but both of them were pretty comparable with the controls, they were just different from each other. We do see like with the PET imaging of the cannabinoid receptor itself, we do see that CB one receptors, not surprisingly in like very heavy smokers, or users will down regulate. And that's a classic biological response to over stimulation of receptor system by a ligand like THC, the receptor will just down regulate. So we do see that individuals who are kind of chronic cannabis users tend to have lower levels of cannabinoid receptors. But we don't really see huge, huge changes in the ligands that are at least reliable we predicate in the animal stuff as well, and we just don't see it as consistently.
Nick Jikomes 38:59
You know, and when we think about the fight or flight response, or the HPA axis, we've got this natural stress response system, in the brain and body that, you know, turns everything on to allow you to say avoid a threat. That's only one type of stressor. You know, if you predator jumps out, you gotta get the hell out of there. There are other types of stressors that presumably activate the HPA axis in similar ways. One of them would just be, you know, if you've got to use your body, in some, you know, intense or vigorous way. So in the context of humans, exercise would be an example, if you're playing a sports game, you've got to be hyper vigilant. If you want to win the game, you've got to be able to detect, you know, all sorts of different things in your sensory environment. You've got to be able to mobilize blood glucose and use your musculoskeletal system in intensive ways. So does something like exercise also involve the endocannabinoid system, given that it's going to tie into the HPA axis and all that stuff?
Matthew Hill 39:57
Yeah, and it's interesting, it kind of there's something different than goes on there. So obviously exercise is will trigger a stress response like in the biological sense, because again, you need that mobilization of glucose, you need your blood pressure and heart rate to go up to be able to clear out, you know metabolites from muscle tissue and replenish them with glucose and everything. So obviously, it is it is a stress response on the body. But there is something different about exercise, in the sense that, for one, we only seem to see the elevation and endocannabinoids. We don't tend to see the crash the same way which is interesting. So we do see that across various forms of aerobic exercise, endocannabinoid levels do go up. And that's was a meta analysis that was was a part of, I think, two years ago that came out or a year ago, but kind of went through all the articles on this. And it's pretty consistent in both the animal and human stuff, it goes up to some really interesting work that's actually come out of France, from Frances shell off and joining Marcy Kanno, that has really shown that it's cannabinoid receptors in the that aren't on but that regulate the dopamine neurons in the brain that really mediate the rewarding effects of exercise. And so if you give an animal for example, a running wheel, they go crazy on them, because they just love running wheels. And so they'll start running and running like mad. And basically, if you take competitors steps away entirely, they just don't care about them as much, they don't run as much, they don't find it rewarding, they don't like it. If you go in and do really careful molecular work like they did, where they just take care of receptors out of like one part of the ventral tegmental area where they will regulate the dopamine neurons, when you take them out of that area that recapitulates the whole phenotype essentially, and so it seems like cannabinoid receptors in regulating dopamine neurons really are important for the rewarding aspects of of exercise and activity. But again, how so the thought is essentially that like the engagement and exercise and the release of cortisol, for example, will probably boost endocannabinoids. They'll then act on these cannabinoid receptors in the ventral tegmental area, which ultimately act to increase dopamine neuron activity. And that in turn then creates this kind of reinforcement, to support the rewarding aspects of exercise and enhance motivation to engage in exercise. And so I think that's a really kind of interesting concept, because historically, people for years thought it was endorphins that drove kind of runner's high, or the rewarding aspect of exercise. And that was, we learned a long time ago for one endorphins that are created in the periphery, because they're peptides that don't cross the blood brain barrier. So they don't actually get into the brain. And while they go up in the blood, people have looked in the CSF and the brain, they actually don't go up in the brain. So that wouldn't really make a lot of sense. And you can remove the new opiate receptor that act on animals was still love running. So it doesn't actually seem I mean, that idea still persists. And a lot of modern culture, people think endorphins mediate runner science, really, at this point, I would say the evidence is much stronger than it's actually ended up in adults that are doing this. But yeah, it's a bit complicated. There's something weird about exercise, I mean, just stress in general, because I think a lot of it is just how does it happen. And so for a psychological stressor, like, you know, oh, shit, this lines about to eat me or something in around my environment is bad, it's happening, your brain has to process that. So that's almost what I would call a top down stressor. When you're exercising, you engage in an activity, that triggers a response that tells your brain we need more blood sugar, because we got to keep going. So it's not threat base the same way. So the way that the brain is processing, that information is different. And so obviously, chronic exercise is a lot more health benefit, whereas chronic stress has a lot of health detriments, even though it's both ultimately engaging a lot of the same systems. We've seen this and some really interesting studies with it compared people who voluntarily run versus forced exercise and like military training, you get very different outcomes, even if they're both engaging in exercise, just over the nature of or whether something's volitional or forced. And so there is some like complexity to this. And I don't think it's really there to
Nick Jikomes 44:02
say for certain, but that people have observed that you get different physiological outcomes, whatever the details may be, for the same amount of exercise in two populations, one where they've chosen voluntarily to do it because they want to presumably, than other where they're forced to for some other reason. And so even though it's the sort of the same motor activity, it's happening about populations, whether or not you want to do it actually leads to a different physiological.
Matthew Hill 44:30
Yeah, I mean, I don't think it's been as well controlled as saying they've done equivalent amounts. Exactly. Okay. I think a lot of this is just comparison across different types of studies. But the consensus usually, from most of the literature that I've seen in hearing people who study this talk about is typically that yeah, voluntary exercise is a very different thing from forced exercise. And as someone who went from being super lazy and hating exercise into now loving exercise, I find it fascinating just the internal process, because you do Look at it like when it's not something you want to do. It's not that it's a threat, but it's certainly something you processes being aversive diversity, you don't enjoy it. And the idea of doing it is not motivating. And it's very daunting. And then like, once you actually get into this mindset where you actually enjoy exercise, it totally changes the whole framework of it. And like you look forward to doing it, you look forward to the benefit of it. Like you're like the clarity you get after going for a run or lifting weights or stuff. So I feel like it's very interesting. There's something complex here. And unfortunately, I just don't feel like there's no people studying and I don't know well enough to study even though it's something I find very interesting now. But yeah, that's I mean, we always say the same thing about sex. Like, that's, that's another example, because sex is, again, is physical activity and sexual wildly activates the HPA axis. But it's not an aversive thing, it's a positive thing. And you don't look at that as having adverse health consequences the way you would from stress. And so this is where we get a lot of the, you know, the issues when people start talking about cortisol is kind of this and this, and it's like, it's not always that clean. I mean, biology is just never that clean. It's always complicated. And it's always like, in this situation, I might do this. And in this situation, I might do this. And that's kind of what I would say we see with the HPA Axis typically, is that a lot of it is situational, where it's where it's detrimental, versus other times where it actually seems to provide benefit.
Nick Jikomes 46:20
Yeah, and I would imagine, there's something to do with the predictability to like, if you if you're expecting it to come, because you want it to come and because you're scheduling your exercise, but it's just going to have a different kind of input to all of this, then if it's, you know, if you're, if you're intermittently experiencing stressors that you can't control, just because you live in a poor environment, say, you know, that's presumably going to have some kind of very different effect on all of this stuff.
Matthew Hill 46:44
Yeah, I mean, predictability and controllability with stress are really the main things that predict negative outcomes. Like if you have no ability to predict and you have no ability to control it. The relationship that has two health, negative health outcomes is way higher. And again, that's not surprising, but then people have pointed out, and I guess this is true, there are some aspects of things where the predictability can still like, if you hate your boss, and you have to go into work every day, and you know, that you're gonna see and that's a very predictable phenomenon yet. It's still quite adverse. So yeah, there are there's the controllability outweighs the predictability but
Nick Jikomes 47:18
interesting. So So what was what? What changed for you? You said, you went from hating exercise to loving exercise, what exactly what type of exercise are we talking about?
Matthew Hill 47:28
Oh, I mean, it started for me, it was running. And this was just some way to not go crazy under COVID, because it was just not doing anything. But like, I hated it at first. And then I don't know, I can't really say exactly what a switch happened. All of a sudden, I felt like, I started to notice things I liked about it. Like, I know, my wife does a lot of yoga. And so when I've talked to her about, like, what it is about yoga, she likes people, her and others I know who do this often talk about how they get a lot of clarity clears their head. And I feel like was running I don't know, I always kind of look at things like a neuroscientist too. So I feel like somehow when I'm running, it separates the cortex and the straight, am I going a motor pattern. And I must release my cortex to allow it to just mind wander and process things. And so I feel like whenever I go one thing, I have this ability to just kind of freely think about things and let my body do whatever it's going to do. And I found that to be kind of very clearing, like almost what I feel like people would benefit from from yoga in the sense that they stopped thinking about other things. You focus on some things with weightlifting, I find, you have to focus explicitly on what you're doing. There's so much control you need to have over your body and the angles and exactly what you're doing so you don't hurt yourself or do something stupid, that like if you're dwelling on other shit, it has to fall out of your head, because you're forced to focus so attentively on what's in front of you. And again, I find that to be very clearing. So I mean, these are just like random anecdotes, I don't think there's anything sciency about that. But that's just what I've noticed in myself kind of going through the process of being very intimidated by exercise not enjoying it at all to actually like really loving it and looking forward to going to the gym. So yeah, I made people change. You just kind of got to get in the mindset. It's hard to explain to people, but I'm like, I feel like once you kind of get into the pattern of doing things and you realize what you gain from it and you like it more but yeah, or the to convince someone of
Nick Jikomes 49:18
the other thing I wanted to talk to you about is another kind of variation in the endocannabinoid system. So So we've talked about what the endocannabinoid system is, you've got enzymes, you've got endocannabinoids, like anandamide, you've got receptors like CB one. All of these things are going to vary somewhat from person to person based on their life history based on their genetics, you know, the density of CB one receptors will be a little bit different or potentially very different into different people in a given part of the brain. For example, one thing I wanted to ask you about was sex differences. So are there big sex differences between males and females in terms of the endocannabinoid system in any way, but in particularly, when it comes to the brain and stress response? Some things like that.
Matthew Hill 50:02
So there's there's definitely sex differences that exist in the cannabinoid system. Most of the seems to be at the receptor level, we've struggled to find differences in ligands. Like we don't see a lot of big differences between an animator today or at least reliable. We do know that anandamide seems to be estrogen responsive to some degree. And in, there's been some work mostly out of the Netherlands, it's really tracked women across the menstrual cycle. And they do find that right during ovulation peaks in estrogen, you do tend to see spikes in an antibiotic Co Op, we know that anatomy progressively increases in women's real pregnancy. And really spikes at the time of giving birth, which probably isn't surprising, because there's a lot of physical stress going on at the time there as well. But outside of that, we don't see a lot of differences in the ligands that we've been able to see certainly on the animal stuff. The receptor, though we do see differences in. And in humans, they've done like, depending on which ligand they've used, they've seen differences way in both directions. But the animal stuff really has suggested that there are certain parts of the brain where women have more females would have more CB one receptors than males would. And as a consequence of that, it might be on different neuron populations as well. And this may explain why there's somewhat different sensitivities. And so one of the things that we see if we just look at self report data, is that women more typically than men will report adverse reactions to cannabis, in terms of saying things like they had a panic or an anxiety like response when they use cannabis. And my thought on this has always been well, if there's just a slight greater abundance of receptors, the threshold between kind of having the right amount and having too much where it becomes an adverse response is going to become narrowed in women. Now, if we were talking about, you know, cannabis from 3040 years ago, when it was a lot less potent, that window is is a little easier to manage, because the amount of THC that hits the brain with consumption, can you have a wider range, because there's a lot less THC in the cannabis, because cannabis nowadays is more potent? Well, I would say a lot of people think that this means it's a totally different drug. And it's a lot more. There's more harms associated with the stuff, which is definitely possible. The reality, as we've seen is that most people, when they consume a more potent product, they just consume less. And so they tend to itself titrate a lot more. Now, the issue though, is if you have a narrow threshold, like women may have more than men, let's say that titration threshold between this is the right amount to this is too much, now I'm having an adverse reaction can be quite narrow. And so we've, my pet theory has always been this is one of the reasons why women might be slightly more sensitive to having adverse reactions, or at least having a narrower threshold than having an adverse reaction. And then the other thing we know, this is where Ryan vandrie and then West us and others in the states have done and we've done some here in rodents as well. But like Steve Mahler, and pmle and others have found this as well, Rhodes is we do see females make more 11 hydroxy THC than males do. And 11 hydroxy is a metabolite your liver makes from THC when it's first consumed. 11 hydroxy is at least as potent, although signs are saying it's probably slightly more potent than than THC itself is. And so if women are making more, and it seems to be a significant amount more certainly if it's through sheer saying
Nick Jikomes 53:35
for the same amount of THC Delta nine THC consumption, females will make more 11 hydroxy THC from that than males? Well,
Matthew Hill 53:44
yeah, they seem to either make it at a faster rate, so that it accumulates more as 11 hydroxy than it does is the parent molecule THC. Or there's some suggestion that there might even be different metabolic pathways that are preferentially expressed between males and females. So they actually end up making more
Nick Jikomes 54:00
than hydroxy. And you're talking about humans that's been measured in humans.
Matthew Hill 54:03
Yeah, so we definitely have seen in humans that you get more 11 hydroxy in women than you do in men. And we've seen this in rodents as well. Again, we don't know exactly the mechanism, those are the two theories, what they have is just that's just converting faster, and it may stays 11 hydroxy longer in females than it does in males, or it could be a different metabolic pathway. But regardless of what's happening, we do see more 11 hydroxy in females than males. And because it is a bit more of a potent agonist than THC itself as coupled with the fact that females seem to have more CB one receptors, those two variables together to me, I always think that's probably why females may have a again, this greater sensitivity to having an adverse reaction, or at least a more difficulty in titrating doses to not kind of reach into that range of not enjoying it.
Nick Jikomes 54:51
So so we know two things for sure one, when you ask females and males to self report things about their cannabis experience Do you tend to see higher rates of self reported adverse reactions to THC and females compared to males? Separately, we also know that there are sex differences and things like CB one receptor expression. So men versus women will have different densities of these receptors on average in different parts of the brain. And so it's plausible that the reason you see different rates of things like adverse reactions is because you've got different receptor levels, say, of CB one and two different parts of the brain. And that's going to change how wide or narrow the window is. For for what a, you know, what your dose is going to be that either gives you a good experience or triggers an adverse response,
Matthew Hill 55:40
basically, because yeah, I guess I've what I should have explained more is that we do know very clearly we have biphasic effects of THC. phasic, is that so we take something like anxiety, low doses or reliably the anxiety reducing high doses tend to be anxiety provoking, and that's true across the mammalian kingdom. That's every species that has been tested, we see the same effect in low doses reduce anxiety, higher doses to enhance it. The difference is that range of what produces low like will reduce anxiety before it triggers the high anxiety seems to be narrower in females than it doesn't males. It
Nick Jikomes 56:16
seems it's easier to go over the tipping point. Yeah,
Matthew Hill 56:19
exactly. Whatever the phrase is, I hate using the word overdose because that's obviously a very laden word. It's very charged with other things and people often associated with fatality. It's hard to figure out exactly where to use. That's why I just say adverse reaction. Yeah. overconsumption unintentional overconsumption.
Nick Jikomes 56:36
You're getting side effects. You're getting unintended consequences, but it's not a fatal overdose. Yeah,
Matthew Hill 56:41
yeah. And that that does. I mean, again, this happens more with with potent forms of cannabis than it does with weaker forms of cannabis. And it happens more women than a dozen men happens way more with edibles than it does with inhalation. And that's usually just because the time lag with edibles, you can't, can't properly titrate people will be like, Oh, wait 30 minutes, and I'm fine. And then like, I haven't done anything, I need more than that. And that's later shuts off. And they're like, oh, shit, what have I
Nick Jikomes 57:06
done? Yeah, well, I didn't, I didn't know what you mentioned before about women producing higher levels of 11 hydroxy THC from Delta nine THC. That would imply that for something like edibles, when you're orally consuming THC, the the risk profile is probably going to be higher for females, then compared to males in terms of how big of an effect you're gonna get forgiven amount of THC that you consume, especially given the the latency there from oral
Matthew Hill 57:29
consumption. I mean, and that's one of the so we've done some stuff in rodents with both vaping. And with edibles. And we both across we see an injection with compared to all the models of consumption, or at least administration. And we always reliably see females make more 11 hydroxy. And the majority of the human studies we've seen see as well, the effects might be a little more robust in rodents, they do metabolize drugs, slightly different in humans, but the signal is still there. And it's still the same general effect we've seen in human females as well. So it is something that and the thing is now is no one has really studied 11 hydroxy. Like we know so little about it. And so, you know, he tried to try talking to some people who do more screening based stuff to kind of do a little bit more work on this to figure out like, what is the actual potency differences? How different and when we look at CB one receptor activation is this. We also weirdly found that we don't know why this is the case. And I don't know how well this is seen in others labs. I've tried talking to a few people. But for some reason we found that 11 hydroxy THC sequestered into the brain easier than just THC. And this could be some kind of physio chemical reaction of how it gets pressed the blood brain barrier. But we generally found the ratio of 11 hydroxy between the brain and the blood was way higher for the brain than THC was. But no, I mean, there was one person pointed out to me that there's the possibility because there is some of these enzymes, they're mostly in the liver. Some of them exist in the brain. Maybe there's some local metabolism happening in the brain. And that's why we're seeing more 11 hydroxy there but we just across the board and everything we've ever run this in we always see more 11 hydroxy accumulate in the brain as opposed to be in the blood and we're not sure why that is.
Nick Jikomes 59:09
Another thing I wanted to ask you about is so we know that the endocannabinoid system is doing, you know, it's very evolutionarily conserved, it's very widely all of its components are widely expressed in the brain and body it's doing it's doing very critical things. How early in brain development in particular, do you start seeing, you know, CB one receptors and other components of the endocannabinoid system come up and interested in very sort of broad simplistic terms? Are, are these components of the endocannabinoid system playing critical roles throughout much of brain development in terms of how the nervous system is constructing itself?
Matthew Hill 59:44
I mean, definitely they do appear really, really early. It's kind of interesting though, because they seem to perform a totally different role. So as I was saying before, most of what endocannabinoids do in like a formed brain is regulate how neurons will talk to each other by gating release of neurotransmitters in fetal brain at least in the developing brain very early, certainly in the fetal and probably through at least the initial portion of, of following birth. Really what endocannabinoids are doing is much more acting as like a guidance cue for how neurons assemble themselves and find their targets. And so people are harkening, and Yasmin Hurd and a bunch of others have done some really wonderful work on this, where they really been able to show that as neurons are growing, and it kind of extending their axons to find their recipient neuron where they're going to synapse on to to form a connection, to basically wire the brain for the adult state, no could add right act is really important guidance cues that tell that neuron where to go, and where to form a synapse with. And so this is why we know some of the work on pronatalist is certainly suggest that that might mess up how some of the neuron the neuronal networks will organize themselves, because you bade the brain again and THC we know that it can influence this. I mean, we've done some work, and we definitely see, we were shocked. No one ever really done this before. But we wanted to actually understand how much THC got through the placenta into the fetal brain. And we found that it's actually about 30 to 35% of the THC you can detect in the mom's blood and is up in the in the fetal brain, at least in the role models where you're using with vape exposure. And so it's definitely getting in there. And what it's doing, we're not entirely sure, I'd say there's a mean, there's a lot going on. Now, there's not a lot published, there's a lot of work going on now looking at the kind of prenatal aspects of this and what it might be doing. But I mean, outside of that is also because endocannabinoids are also active on immune cells. We know that like immune cells are super important for circuit formation, because in the brain, these immune cells microglia. Basically, we'll start eating up synapses that aren't active or help refining networks so that neurons connect on to this one and not another one, or that this this, this connection isn't actually going to be viable, so it won't last. And so these immune cells, these microglia eat these up and pick McCarthy. We had worked with her a few years ago, basically, because she'd been looking at some sex differentiation that happens very early in response to hormones, and found that this process by which the microglia decide which cells to devour and eat, versus which ones get to survive and grow and integrate into a neural network. And Okinawans are actually a really important aspect of this. And really, they were being driven by androgen levels that were dictating this is this is the cell to eat, this is the cell mouthy and it was the androgen hormones that were mobilizing the endocannabinoids to do that. And that was relating to the sexual differentiation about there are a few. I mean, male and female brains, for the most part often look quite similar. But there are a few areas that are very sexually dimorphic. And in these areas that seemed like endocrine average, were quite important in dictating those differences.
Nick Jikomes 1:02:53
So a solid percentage of the THC we'll get into will cross across the placenta from the mother's bloodstream into the fetal blood supply. We know that CB one receptors and other things are very important for neuronal development. So it's going to have some kind of effect on brain development.
Matthew Hill 1:03:13
Yeah, I would say I mean, I'll be honest, I mean, a lot of the human stuff is really the effects are very hard to see, it's not clear, it's certainly not something like alcohol, like we're not seeing similar kind of very robust Tourette agentic effects, like we'd see facial dysmorphology and very noticeable. Early on effects. The the human cohort studies that have kind of looked at this had been quite variable, and I think a lot more compromised by the nature of them. Like, you know, one of them was done in Ottawa in the 70s. With like, essentially, a lot of a lot of them the mums that were in the study, were kind of like these barefoot, you know, kind of hippie style Earth moms, who were a different flavor than a lot of the general population. And one of the cohorts was done in like a really disenfranchised region of either Baltimore, Atlanta, and didn't really have good controls in that one. And then one of them was done in the Netherlands in the 2000s, which is probably the more kind of modern ish one, I would say. But they've all kind of come with their own problems. And all of them have found slightly different outcomes. And none of them have been that that clean. The one thing we do see, at least from the animal stuff that's quite reliable, is that for some reason, males seem to be more sensitive than females. And it really seems to have an impact on the developing dopamine system. And this I find interesting because stuff is starting to come out of some of these large cohort studies that are being done now in Canada with legal cannabis is also in the states two ABCD is that there does seem to be a slightly elevated risk for some neurodevelopmental disorders like autism and schizophrenia. Autism certainly has a male bias. Schizophrenia is maybe a slight male bias earlier on at least. And both these involve at least to some degree, some dysfunction and dopamine function. So there Some interesting, there's some signal there that I don't think we've fully seen yet. But if anything's gonna come out, my guess is it's going to be in that direction.
Nick Jikomes 1:05:07
I see. So the human data is pretty hard to interpret just because of how the studies have been done historically. But they're certainly going to be neurodevelopmental effects from exogenous cannabinoid exposure on the brain. And we're, I guess it's fair to say we're only just starting to understand exactly what's going on there.
Matthew Hill 1:05:27
Yeah, I mean, again, like, and I think there's the thing with with fetal alcohol exposure, it was a lot easier to detect, because at birth, essentially, a lot of those effects of certainly if it's significant alcohol exposure are immediately observable, because they are outwardly physical dysmorphology is that can be seen. That's not the end, I think that's so a lot of the thought is that this might be more of like, a latent effect that maybe, you know, as an individual who had been exposed to cannabis grows up, if they get exposed to various challenges, they might be more prone to various psychiatric conditions or neurodevelopmental conditions. Like, you know, maybe prenatal cannabis alone isn't sufficient to produce a phenotype, but you couple it to some kind of early life inflammatory event. And those two together now suddenly, dramatically increase the risk for autism. So something like that I could see. But again, this is going to be because it's just not a sledgehammer effect, it's going to be really hard to pull out. Because the other issue here is that like people are generally not honest about the cannabis use, certainly in the States, because the legal ramifications that can still happen on some of these. Yeah, that has also made it really difficult to track these cohorts properly.
Nick Jikomes 1:06:39
Yeah, and I would imagine to I mean, sort of the frequency of use would matter here. If, you know, if a woman is acutely using THC to mitigate, you know, her nausea, versus, you know, chronically consuming for the entire pregnancy. I mean, there's probably an analogy there with alcohol as well, right? Like, if someone's drinking alcohol every day of the pregnancy, that's obviously going to have much, much more dramatic effects than, you know, having an occasional drink here and there or something like that.
Matthew Hill 1:07:05
Yeah, I mean, there's certainly some weird stuff in the alcohol field that I've heard from people where like, very low levels of exposure still have dramatic effects, and other people have exposure and somehow didn't. But in general, I think, you know, I'm a pharmacologist, like the doses and the point, the poison is in the dose, that's always the way it goes. It's like, you could have some limited exposure. And this is one of the things that's interesting is, in the ABCD study, at least a lot of what they've asked women is like, because there's also a leg like if, if there's a woman is a regular cannabis user, she may not know she's pregnant, up until two months into the pregnancy. There's been like, Did you stop once you knew you were using CAT or when using Canvas when she knew you were pregnant or not. And the majority of women did stop, but there was still some incidental exposure. And so that they've been compared to, you know, women who use Canvas or the entire pregnancy, to see if there's differences. And we're on a paper right now, that was probably going to come out relatively soon, again, like white matter development, and the kids are like 10 years old now, who'd been exposed to cannabis. And there was some there was some subtle effects. But they're even seen in the ones that were had some exposure, even for just like the initial phase of the first trimester before the woman even knew she was pregnant. And so if the effects again, we have no idea what the consequences of these effects are, because a lot of the the behavioral stuff is really inconsistent. So it's hard to understand that this relates to things like attention issues, or impulsivity issues or aggression issues, as some of the literature suggested. But I assume as you know, we start studying this a lot more as we are now, we'll start to probably get some more definitive answers in the next five ish years, I'm thinking.
Nick Jikomes 1:08:42
And it sounds like you and quite a number of others are now doing studies where you're giving non human animals cannabis in the form of inhaled cannabis, you're exposing them to vapor. Why is this starting to happen more? And what are those experiments look like? And you know, why is it? Why might it be advantageous to to administer cannabis or THC that way as opposed to you know, injecting it directly into animals?
Matthew Hill 1:09:08
So one of the things that we realized pretty quickly was while the dosing that gets used to the injections is hard to understand in the context of cannabis use. So we've done some comparative work, as have others are one of the things we know is when you inhale cannabis, which is like still like the majority of people still inhaled cannabis. It's like 85% of people. They may also do edibles, but the majority of people will still inhale cannabis as the primary root of consumption. So when someone inhales cannabis, what we know is very quickly, that THC goes across the transfers from the lungs into the blood and very quickly accumulates in the brain. THC is a lipid molecule so it's going to want fatty substances to live in. It doesn't like the blood which is aqueous. So where does it go and accumulates and things like that on your body, your brain, your mail your testicles because water and fat tissue when they're with the steroid production, so you get these very clear areas where THC accumulates very, very rapidly. But the other thing is it also clears out relatively fast. And so I mean, if you track kind of neuro psychologically intoxication rates from someone consuming cannabis, you know, people feel it after about two to five minutes, peak around 30 minutes, and then they start to come down, they may still have some residual effects up to a couple of hours. But most people after about 60 to 90 minutes from inhalation, or basically, for the most part, won't score very high on any measures suggesting that they're actually intoxicated or high still. So when we do inhalation in animals, we see very similar we get the same blood THC levels. So you know, blood THC from inhalation usually falls somewhere between 50 and 100 nanograms per mil, so we want to kind of hit that spot. But it's only staying in that range for a short period, because it has this rapid spike, and then it gets cleared from the system pretty quickly. And so that's an important thing to think about. Because when we inject THC, we inject it either subcutaneously under the the fat layer of the skin, or into the intraperitoneal, like the abdominal cavity. And either way you go there, it's either going to sequester into the fat and then leak out, or it's going to go, if it goes into the gut, it usually almost always goes right into the blood brand and the liver. And what happens with that is it makes an insane amount of love and hydroxy. Even if we try calibrating the blood THC levels, which don't make a lot of sense, because with injection, they'll go up and stay at that. Let's say even if you match it at 50 to 100, they'll stay there for hours, because they're leaking out of the fat tissue. So instead of getting a spike like this, you're getting this kind of plateau function, which he is online for long periods of time. So not only your blood THC levels staying higher for longer, but your the amount of local hydroxy is being made because so much of this is getting chewed up from the liver is going up dramatically. So we see like five to 10 fold higher levels of 11 hydroxy from an injection than we do from inhalation. Use inhalation largely bypasses hepatic metabolism until it's on its way out. So you don't get our 11 hydroxy levels are very low with inhalation.
Nick Jikomes 1:12:04
So it just means when you're trying to compare or make differences from animal studies where they've administered THC through those routes. It's just truly apples to oranges. If you try and compare that to cannabis consumption in humans, which is primarily inhalational.
Matthew Hill 1:12:19
It can be I mean, I think if you use really low doses of THC injection, which most people don't use, there are definitely some that do, I think that can be a little bit more appreciable. I think that makes a lot more sense. But the problem is, I mean, like, let's just look at hypothermia. So this is a classic physiological readout of THC. So if you give an animal THC, their body temperature drops a degree or two, humans have some degree of hypothermia as well, I can go a little bit a little bit dropping body temperature, we consume cannabis. With inhalation, you see the hypothermia immediately when the animals come out of the vape chambers. If you measure body temperature, it's already down. And then over the next hour or so it'll recover. And that to me tracks the physiological timeline of how long someone's usually intoxicated for you inject them with THC, that hypothermia goes on eight to 10 hours. So it's like scales of magnitude orders of difference in terms of the length. And so again, I go back to being a pharmacologist, that I think okay, so if I think of what the biological consequence of activating a receptor on a neuron for, say, 30 minutes, well, that ligand is present in the brain versus eight hours, the outcomes of those effects are very, very different. Yep. Because one of them is going to cause a long term persistent change in the cell, one may not. So if we're talking about awakening, style smoker, or someone who all day is just consuming cannabis nonstop, which there definitely are people who are like this. Maybe the injections are going to be more representative of that we're we're looking at really persistent and chronic saturation of cannabinoid receptors, and whatever consequences is going to happen biologically from having that receptor driven that much of the time. But that's not how the majority of people consume cannabis who do. And so most people kind of have much more pattern to use, even if they're daily, a lot of people are more like nightcap errs will only use at the end of the day, the way that someone will have like a glass of wine or something at the end of the day. And that's a very different pharmacological effect. And so, again, it depends on what your question is. But if you're injecting THC, and then making inferences that are saying, well, this is the same as some consuming cannabis. That's where I'm like, I don't really think these are I don't know if I go as far to say apples and oranges, but they're definitely not the same. This is like a baby Apple to a fully mature Apple baby. Like they're very different. They may be in the same range, but we're looking at two different phenomenons for the most part, and the joke I always make the people they say Well, the funny thing is we look at the animal literature from injecting cannabis. We have managed to both cure and cause every disease known demand. Look, if you scour the literature in anything you look at, you know neurological diseases like MS or Parkinson's or even things like neuro inflammation, you give injected THC, it cures all these diseases like 100% They're all gone. And certainly in the clinical populations, there are people that derive benefit from this and have gotten, you know, symptom relief or improvement from using cannabis. But it's not a, it's not this, like, everyone suddenly gets better. And it's 100% improvement. It's like patches, and some people improve, and some don't. And even those that improve, usually the effects are relatively moderate. And then the same thing with the harms, you know, you look at the animal literature, and you inject THC and adolescent animals, and every single one of them has like permanent effects, because they've made it look like they've had all these impacts on developing brain. And there's always increased risk of, you know, behavioral measures indicative of psychiatric disorders. And yet you look at the human literature, and you're like, yeah, there's like a bit of the signal here. But it's not this. It's not like this. And I think basically, we've just kind of really overshot, what the effects of THC are both in the harms and the benefits by injecting it because we are just blasting the system to a level that was never happened in humans, inferences about what this relates to with cannabis. And I don't, I'm not convinced that it's reflective of what we're seeing in cannabis.
Nick Jikomes 1:16:04
I see. I mean, is it fair to say that a substantial part of the animal literature, but it's really modeling is something like chronic high dose use of an orally consumed cannabis product,
Matthew Hill 1:16:16
the pharmacokinetics of it would be far more similar to an oral product, but the difference is the oral products. I mean, if you smoke a joint of cannabis, there's like, I can't actually think you'd be able to 30% and gram, you're looking at a few 100 milligrams of THC in there. If you smoke, a lot of that philosophy drift. Not all of it gets in through the lungs, blah, blah, blah. Yeah, there's not a chance and how anyone would orally consumed that same level of THC and not be a zombie for 14 hours. People the majority of humans you get five milligrams of THC and they will feel that even somewhat seasoned users I mean, you know, you have to gotta go up the scale of people who have pretty high degree of tolerance and are using a lot but most people will feel five milligrams. And yet if you measure their blood THC with five milligrams, it almost certainly wouldn't even be detectable. And this is why you'll never get like a blood test for THC are a road test for people driving because you can be profoundly intoxicated off the edibles and basically have no blood THC. Whereas you could smoke a joint and only be moderately intoxicated and yet have blazing levels of blood THC. So it does make it really complicated because when you eat it, it also leaks out of your gut for hours. So there's no big spike if this progressive wave over like a longer period of time or it goes in your bloodstream. So a single snapshot in time doesn't tell you anything. But the problem is my view on it is always the injection studies are really modeling edible use but using doses seen in inhalation. And that
Nick Jikomes 1:17:47
I see. And so what types of things are you guys studying with your Rodin systems where you're giving them inhaled THC and are you giving them just pure THC vapor? Or are you giving them a vapor that more closely mimics the full set of things that you would see in say cannabis flour that a human is smoking?
Matthew Hill 1:18:06
Yeah, so we do both it depends on the question so so we have some stuff that's just THC distillate it's about 98% THC and it has like a little bit of CBG and a little bit of other things in there but it's really just THC we're looking at especially once we diluted down and that we do so we're doing studies we have a whole project running on the munchies right now I'm always fascinated by this with feeding like trying to understand exactly what is it that when you when you get an organism acutely intoxicated in cannabis, why is it that they consume so much food so you know we do the you put the you put it right in a vapor chamber for 15 minutes given like, few hits a cannabis vapor or this this this would be the THC distillate vapor, put them in their home cage, they go mad for food, I mean, they it is like, very is probably the most reliable if I've ever seen in science in my life. In males and females we repeat the day after day, we've been in like 15 cohorts, every single one. Every single time they get for the first 30 minutes after they're in their home gauge. They've been an insane amount of food. And so the question we're trying to ask with this is well, why is it that like, it's just disrupting a satiety signal. So we've pre satiated them in some studies where you get them, we give them access free access to sugar, they just eat as much sugar as they can, because they love it. So they're pretty full and pretty satiated. And if you take that animal and then put them back with their homepage food, they won't eat any. But if you get them stoned, they'll eat over their satiation. So we're like, okay, so is this disrupting a satiety signal? So things like leptin or CCK these molecules, our gut and our periphery sent to the brain to say stop eating. We know cannabinoids interact with those signals. So we're like, does it disrupt that? I'm not sure because that's not always the case. You can get munchies in the absence of study. So I think that can be a mechanism where you get overeating from cannabis, but I don't think that's what's driving it. What we're testing now what my pet theory is, is that what cannabis is doing is Thus inhibiting reward devaluation. And so if you think of the faculty, and you see a piece of pizza or like an ad for McDonald's, wow, that looks so good. And that first bite is just like the ship. Like, it's easy. And it tastes so good. And it's like sensory and rewarding, and it's very salient. And then like, if it's pizza, let's say you keep going, you get the fourth slice, not feels kind of greasy. Rewarding anymore. It's kind of gross. Right? And so this is a process we go through where we start to devalue. The rewarding aspects of
Nick Jikomes 1:20:35
what you're talking certainly seems to match what people report subjectively, when they get high, too, is like, you can tell that you are full. I mean, I've had this experience myself, like, I know I'm full. But my tongue is like, I want the taste.
Matthew Hill 1:20:49
Yeah. So this is, so as what we're explicitly trying to test now by using reward devaluation paradigms, where you appreciate them and then you look at how much they'll work to get food. And they definitely will work to get food even when they're when they're full. So I think this is probably the mechanism. But I think basically what cannabis does is it locks in the reward salience. And so you don't get this reward devaluation. And that is, so food consistently seems to have high levels of rewarding salience. And that's why people want to engage in consuming it. There's also probably some stuff that's going on with like, the feeding circuits in the hypothalamus, we definitely see they get activated, I'm sure that's a part of this as well. But it's going to be an interaction, I think, between the reward system, and the kind of homeostatic hypothalamic system. So that's one of the things we're doing. We're also looking at things like stress responses, or fear learning are kind of the basic stuff that my labs interested in. But using cannabis vapor and just trying to tease out what the effects are. And then there's the whole neurodevelopmental stuff. So we're doing the pregnancy exposures. And we're doing a really detailed adolescent exposure we're doing within subject brain scanning, pre and post to try and see if there is actually effects of varying patterns of exposure of cannabis use during adolescence on brain development and behavioral outcomes. And so we have like what I call like the weekend warriors, which are like once a week versus the nightcap errs, which are once a day versus waken Baker's which are throughout the whole day. And I mean, certainly I would say just from looking at the brain scan data we have so far it's not finalized. So I can't say anything confidently, but it does. We're seeing anything, it's only in the wake of neighbors, that seems to be the group where we are seeing some effects emerge. And that doesn't totally surprise me. Again, you're saying that's a very different phenomenon. They're just kind of like the brain is constantly bathed in THC at that point. So you're gonna see an outcome from that, I guess,
Nick Jikomes 1:22:34
is anyone you know. So, you know, I've worked for years in the legal cannabis industry. And you know, one of the most pervasive beliefs and something that drives a lot of the marketing of this stuff to humans, is this idea that it's basically the idea behind what Ethan Russo calls the entourage effect that you can get different effects systematically of a given dose of THC in the presence of you know, different sets of terpenes or other things. Are you or anyone else looking at different combinations of cannabinoids and terpenes cannabinoids and terpenes in inhaled cannabis vapor to see if there's any kind of behavioral or physiological difference at all.
Matthew Hill 1:23:11
Yeah, sorry. I think I've read that you said in the last thing was Yeah, so while all the things I was talking about before were just THC distillate are adolescents studies are all whole cannabis extract. So that does have all the terpenes and the phyto cannabinoids that are more than just THC embedded in them. We've dealt with that is just those are two separate studies. We've done one study in the context of pain, where we have compared pure THC versus pure CBD versus whole cannabis extract. And in the THC context, at least we've matched the THC levels, so they're the same. And generally the the kind of analgesic effect we see from THC looks similar regardless of whether it's pure THC or P THC with everything else from cannabis, except that the THC with everything else from cannabis, the effect lasts a little longer. That's the one thing we've seen there. So Ziva Cooper down at UCLA is doing some individual molecule interactions work. So she's looking at like, THC plus beta carry awfully THC plus limonene. Ryan vandrie is doing this at Hopkins as well. Ziva is looking at pain. Ryan's looking at more subjective measures like anxiety, and how high are you and things like this. But so there are people now who are starting to try and look at the individual interactions. The problem is, I mean, all you have to do is start drawing out the math of this and you can see how quickly this will become infinitely impossible to really test this the way we would need to to be able to say this interacts with this and this because every strain of cannabis has so many different things in it, as you know, I mean, I've seen some of the analysis you guys have done about all the different things that you see in the different cannabis strains and it's like, so maybe you need THC and limonene and beta caryophyllene at certain levels for that interaction to occur to be able to produce x effect Um, but I would say up until maybe three or four years ago, no one was doing so we really had no answers, all the stuff he talked about was all largely speculative and conjecture. And it made sense in the sense that I definitely think there is subjective differences across different kinds of cannabis. Obviously, I'm not a believer in this whole indica sativa thing for the most part, because, as we know, from looking at them, there's more variance between or within what's an indica with a Steven than there is between what's an indica sativa. But that doesn't mean that across various strains, there may be more, you know, accumulation of some terpene, or some minor, that might be more predominant in some strains of sativa, or some strains of indica other people are giving it credit for because there definitely does seem to be some strain differences. We just can't. Yeah.
Nick Jikomes 1:25:47
Yeah, I mean, essentially, what we found when we looked at the lab testing data is when you use clustering algorithms and stuff, to see how many statistically distinct combinations of these things there are, or if there are any, there are there's definitely different types of high THC cannabis with respect to terpenes. And other things. It doesn't, for the most part, it doesn't map onto the labels, they're given indica, sativa, whatever. But there are different constellations there. It's just it's just again, it doesn't map onto what human beings are calling these things and putting on the box. So now do those do those constellations actually do anything? Someone would have to like use those particular ones and in the vapor chamber do something like that? I don't know.
Matthew Hill 1:26:31
Yeah. And so I mean, like, because obviously a scientist role reductionist. We do one variable at a time. That's what Ziva and Ryan are basically doing. And I think it's very informative because like, if I remember correctly, from the stuff Brian's talked about there does seem to be like, if there's limonene on board that does seem to taper the anxiety of THC a bit more, I think, and beta carry awfully might amplify some of the analgesic effects of THC I can't quite remember, but beta carry awfully is a legit CB two agonist. The only other phyto cannabinoids that directly activates a cannabinoid receptor. It's just a question of is it in high enough concentrations, and Ziva actually intentionally did their studies where they actually vape pure beta caryophyllene. But at levels that are what would be found in kind of higher cannabis that's more enriched in beta carotene. So it wasn't these ridiculous levels where you see this really,
Nick Jikomes 1:27:21
you know, which it would be, you know, 1% of the dry weight would be a high high. Exactly, yeah. So it's
Matthew Hill 1:27:27
very few milligrams we're talking here. But even then they can start to see some stuff it looks like. So I think that was super interesting. I mean, that was the funny thing I would say about the ICRS meeting this year is we came out of it every year, you always get a flavor of the slightly different focuses, you guys get a feel like where's the field right now. And this year was terpenes. Like, presentations that were on like terpene interactions with trying to understand the biology of terpenes and terpene, THC terpenes CBD stuff was it accounted for like a significant amount of the meeting. So it's like this is definitely somewhere the fields at now. So I would say, within the next two years, we should start seeing a lot of publications rolling out that have this data and it will, we'll get a bit of a better feel. And that I think will then motivate the cannabis companies to start reporting more data, product labels about terpenes and minor cannabinoids that are present in the strains. And I think ultimately, that then may lead us to have a better idea of which ones are going to be relevant for these kind of entourage interactions.
Nick Jikomes 1:28:24
Well, Matt, I don't want to take too much more your time. Is there anything you want to reiterate from what we talked about about the endocannabinoid system stress responses or anything or any final thoughts that you want to leave people with?
Matthew Hill 1:28:35
No, I mean, it was it was a good chat. I feel like we went through a lot. Hopefully it wasn't overwhelming.
Nick Jikomes 1:28:39
No, I mean, yeah, you'd be surprised at how many people listen to the majority of these. Yeah, no, no, they're
Matthew Hill 1:28:46
great. I love the podcast here. So yeah, no, I think you've got a you got a lot of really interesting guests on so it's always cool to be on here.
Nick Jikomes 1:28:53
All right. Well, Professor Matt Hill, thanks for joining me.