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Ep #42 Transcript | Steve Laviolette: THC, CBD, Omega-3 Fatty Acids, L-Theanine, Opioids, Pregnancy

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Steve LaViolette, thank you for joining me.

Steven Laviolette 3:00

Thanks for having me.

Nick Jikomes 3:01

Can you start off by telling everyone a little bit about who you are and what your lab does?

Steven Laviolette 3:05

Sure. So I'm a professor in the Department of anatomy and cell biology and the Department of Psychiatry at the University of Western Ontario, and I've been here since 2006. Our lab is focused on quite a range of different neuro psychiatric disorders, mostly using preclinical models, animal models, to look at the neurobiological mechanisms associated with things as diverse from, you know, neurodevelopmental effects of drug exposure, opioids, nicotine addiction, PTSD, anxiety disorders. And we take a range of different approaches, we are now moving a little bit more into the clinical side of things. So so doing some human clinical trials as well, in addition to some of our preclinical animal work. So quite a broad range of research we're doing right now.

Nick Jikomes 3:55

Interesting. I wanted to start off by talking about cannabinoids, and some of the effects and the interactions between different cannabinoids before moving into developmental questions. So to start out with, I've done several episodes to do with different cannabinoids, so many people listening we'll have some background here but let's just start off by giving people some context around THC and CBD. Can you describe what those cannabinoids are and what their key differences are in terms of how they affect the brain?

Steven Laviolette 4:24

Sure, so they're the largest phytochemical compounds that you find in most strains of cannabis. But they have very divergent effects both pharmacologically and what they do in the brain. So THC and CBD have been the the main focuses of our research and cannabinoids over the past 15 years or so, THC is believed to be the primary psychoactive compound in cannabis. So THC binds primarily with cannabinoid receptors, not as strongly as synthetic agents, but it interacts primarily with the cannabinoid receptors. is believed to underlie most of the rewarding effects of cannabis. And it activates things like the brain's dopamine pathway, which is believed to be responsible for its dependence producing properties and some people. Now CBD on the other hand is a lot of our research has shown that it has almost the exact opposite effect from THC in a lot of different brain areas. So we found that CBD can actually inhibit dopamine. And it can actually block a lot of the effects of dopamine, activating drugs like amphetamine, which is interesting, because you've got these two different phytochemicals in the same plant that are actually producing opposing effects on various neurotransmitter pathways. And we even see this at the molecular level. So for example, THC will activate certain molecular pathways that are associated with pro psychotic effects, and CBD will actually block those effects of THC or will actually produce the opposite effect on the same pathway. So it's really this interesting sort of push pull relationship between THC and CBD. And it's quite, it's quite fascinating from a neuroscientific point of view.

Nick Jikomes 6:12

So when you say that something when a drug can cause a pro psychotic or psychotomimetic effect? What does that mean, basically?

Steven Laviolette 6:19

Yeah, I mean, so it means quite a range of different things, sort of depending on how you're framing the question. So from a neurodevelopmental point of view, exposure to THC has been shown to increase the risk of developing symptoms of psychosis and schizophrenia in some individuals that are that have certain predispositions to the to those disorders, but acutely as well. It's been shown both in human studies and in animal models that THC can basically mimic a lot of the psychotic symptoms of schizophrenia, most of the sort of the positive symptoms of schizophrenia. So things like feelings of paranoia, anxiety, hallucinations, in some cases. And it really sort of depends, it's sort of a dose dependent effects. So the stronger the levels of THC, the stronger the activation of that cannabinoid system, you get sort of stronger activation of these schizophrenia related symptoms.

Nick Jikomes 7:19

I see. So is that is that common for a drug to have that kind of dose dependent effect? And what do we know about sort of the dependence of teachers effects on dose with respect to things like, like anxiety or like memory impairment?

Steven Laviolette 7:31

Yeah, well, actually, it really does depend on the drug. So THC and cannabinoids in general are quite interesting because they're generally by phasic. So some of our research has shown that the effects of CB one CB one receptor activation, which is the major brain cannabinoid receptor, has a very strong by phase of effect. So we've shown that if you activate CB one receptors in an area of the brain called the prefrontal cortex, there's sort of this this dose range where you can produce hyper activation of the dopamine system. So that's through a pathway going from the brief prefrontal cortex down to the midbrain, which controls the dopamine system. But if you go much higher, if you can sort of flood that cortex with cannabinoid receptor activation, you actually blunt that response. And you can lead to this can lead to symptoms that are associated with anhedonia, or blunting of emotional processing, and sort of a shutdown of the dopamine system. So there's definitely this there's sort of this by phase a dose response curve associated especially with THC, we haven't really seen that with CBD. Which is interesting, because CBD acts are a different receptor pathway than than THC. But, but THC most certainly seems to have these sort of BI phasic effects on how it modulates dopamine, for example, and then how it can modulate you know, sort of going from producing side effects like paranoia to to relaxation, it really depends on the dose. And it also depends on the individual's history with candidates. So how, how much history have they had with a drug? What is the state of their, their central cannabinoid receptors have they been sort of desensitized after years of use and exposure to cabinet drugs that can also determine what your initial reactions are going to be to do cannabinoids in general?

Nick Jikomes 9:29

So how does that work? The development of tolerance to something like THC and is that is that reversible?

Steven Laviolette 9:35

Well, yeah, well, I mean, so the the CB one receptors is sort of a classic G protein coupled receptor. So like most G protein coupled receptors, they can engage in different sorts of desensitization mechanisms. So the membrane of the neuron and those receptors that bind to THC, for example, can go through various different states of desensitization. And so the cell might respond to Continue continuous exposure by actually producing few the receptors, or the receptors can sort of shut down their ability to bind the login or they can actually become internalized into the cell. So there's a variety of different ways that desensitization can happen. It's not just cannabinoids, that that's things like amphetamine or nicotine is a great example of that as well. Nicotine nicotinic receptors are also very prone to desensitization phenomenon, especially with continued exposure to tobacco. So we seriously similar types of phenomenon going on throughout the brain are different.

Nick Jikomes 10:34

So So I think one way, one way of translating that could be that if you're consuming a product, a cannabis product that contains THC, the effects could could be different, potentially even dramatically different at two different doses. And what those two doses are going to depend on on the individual and also what your history is, because you might have some level of tolerance.

Steven Laviolette 10:55

Exactly. Yeah. And and of course, the, the purity of the THC is also a factor. There's a lot of individuals now that are extracting THC, they're producing things like shatter, which is sort of that that purified extract of cannabis. And that can contain up to 90% thc. Whereas most strains of cannabis, even the high THC content strains go up, you know, 20 25%, maybe 30%. But there is definitely much purer forms of THC isolates and extracts that are now available, either commercially, or people doing it themselves.

Nick Jikomes 11:34

Yeah, I want to talk a little bit more about this sort of interactive effect between THC and CBD. First thing I want to ask is what, you know, Is it surprising that a plant would be capable of producing two drugs that have these kinds of opposing effects? Or is that something that's actually commonly seen in nature?

Steven Laviolette 11:53

I'm, I'm, I can't speak too much about other plants. But I mean, from my perspective is coming from the neuropharmacology point of view, we were quite surprised at those sort of competing effects and how, how consistent they were. So I mean, it was almost like, we'd see THC exposure, activating this, you know, five or six specific, very specific molecular signaling pathways. And then we give CBD either before the THC or by itself, and we'd see literally either a blockade of those effects or the reverse phenomenon on those same pathways. The sort of the evolutionary reason for that is, it's I don't think anyone really knows I mean, there, there is some speculation that THC is sort of the plant's natural defense mechanism, because unlike humans, most animals don't enjoy getting high, this sort of, you know, they it's not, it's not, it's not safe, really, you want to be sort of at especially if you're an animal, in the natural world, you need to have your wits about you, you don't want to be sort of dissociated from reality and whatnot. So there's some some arguments that THC sort of evolved as a defense mechanism for the plant to keep animals from, you know, eating the plant, a lot of plants have those sorts of, obviously poisons and other sorts of anti nutrient compounds and whatnot. But CBD, it's really hard to say why they're opposing effects. There's over 100 distinct phytochemicals within cannabis. And at this point, we're really only scratching the surface, I mean, some of the some of the lesser cannabinoids, like cannabichromene, or canavese, you're all we're only now beginning to get a grasp of what they're doing, pharmacologically, and sort of from a psychiatric point of view, but there's a lot more to, to, uh, to understand. And then of course, there's the terpenes as well. So there's all the mono terpenes that are associated with cannabis as well. And we're only now beginning to understand sort of how they interact with THC and CBD, they call it the entourage, the entourage effect. And given the potential for different combinations, and how different strains of the plant might have different profiles of those phytochemicals, we, we could expect pretty dramatically different effects depending on just you know, what type of cannabis you're you're consuming, what the growing conditions might be, so are they grown inside? Are they grown in nature, all of these different environmental variables can can have a huge impact on the sort of the final chemical profile of a cannabis type product. So which is quite interesting.

Nick Jikomes 14:41

So what do we know so far? In in humans or animals but but especially in humans about, you know, what's the difference between giving someone a given dose of THC and then giving that same dose of THC in conjunction with CBD? What are the effects that CBD is actually modulating there?

Steven Laviolette 14:58

So there have been some interesting clinical study is looking at using imaging studies that have looked at how CBD and THC produce different effects both in terms of sort of psychological cognition processing, emotional processing, and looking at different brain areas. And they they're also consistently showing that THC and CBD can produce different effects. So one good example of that is studies that looked at imaging in the striatum, which is sort of a an emotional processing center in the in the forebrain. And they show that CBD and THC can produce opposing effects on sort of the activity states of neurons in that those tribal areas. And whereas THC was producing cognitive impairments, CBD was able to block block a lot of those negative psychiatric side effects without producing effects in and of themselves. So it's trickier to do those studies in humans because, well, first, first of all, you need to you need to, you know, get the ethics approvals for those sorts of studies, which can be tricky, but but then sort of finding the ideal dose range as well can be difficult. So one advantage of the animal studies is that we can sort of control in a homogenous population of rats, for example, the the exact dosing, the timing and all of these different tests that we want to perform. And given the the natural variations in how people respond to cannabinoids, this can sort of be a bit of a confound with human clinical trials. So it's really important to sort of converge both the clinical and the preclinical evidence together to get a better understanding of how THC and CBD are really interacting, right.

Nick Jikomes 16:43

As a general rule, HC and CBD do seem to have opposite effects. And if you were to ingest pure THC, versus in just THC with CBD, the presence of CBD at least at a sufficiently high dose will mitigate some of the effects of THC.

Steven Laviolette 16:58

Yeah, exactly. And that's largely because CBD can counteract a lot of those central effects of THC. That hasn't been the the exact mechanisms in the human brain through which they're actually interacting with each other at the at the sort of the receptor of the molecular level. That's not really well understood at this point. But if you look as as I was talking about previously, some of the imaging studies, they are consistent with the idea that CBD can block a lot of those unwanted side effects of THC.

Nick Jikomes 17:33

But you still have the primary psychoactive effect, nonetheless, is that true?

Steven Laviolette 17:38

Well, that's a good question. Um, certainly in the animal studies, we seem to be able to completely block all of the effects of the psychoactive properties of THC. So we published a study in the Journal of Neuroscience a few months ago, we looked at an area of the brain called the hippocampus, the ventral hippocampus, which, which feeds into a lot of emotional processing centers. And what we found was that THC, in that area of the brain produced a lot of the sort of the cognitive, the memory deficits, the emotional processing abnormalities, the, the changes in reward sensitivity, through modulating the dopamine system. But when we when we administered CBD with THC, all of those effects disappeared, we were literally able to block all of those effects of CBD. And it came down to a single molecular pathway that seemed to be really important for that. And that's called the the extra cellular signal related kinase pathway IRQ, one or two, so that that pathway is getting a lot of attention in terms of THC. It's basically a cell signaling a very sort of ubiquitous cell signaling molecule in the brain that's involved in a lot of different neuronal homeostatic mechanisms. So we don't we don't even know exactly why this particular pathway is so critical for sort of those those those psychiatric side effects of THC. But what we do know is that CBD seems to block the activation of those pathways through through THC. So that's sort of where our research is now trying to get sort of dig down a bit more into exactly what's happening at the level of the single neuron, for example to to regulate that, that circuitry in

Nick Jikomes 19:28

the brain. I see. So you give animals a dose of THC, you see some abnormalities in a particular part of the brain. You can give them the same dose with CBD, and it completely you don't see any of those abnormalities anymore. What's the relative dose there? Is it an equal dose of each compound?

Steven Laviolette 19:45

Yeah, we just we did use equal doses. I mean, we we've been doing this for quite a few years. So we've sort of worked out different dose response curves. These are of course, our primarily central infusions. We do do systemic injection or we've even moved on to edible administration. as well, and we see similar sorts of effects. But these studies were looking at Central infusions into the brain. So they're they're very small doses. But in terms of their sort of relative content they were they basically equal molar doses. And but what's important to note is that THC and CBD act through different pathways. So CBD is a really sort of messy compound, it interacts with a lot of different receptors in the brain. So there's evidence that it interacts with that it might be an antagonist of CB one receptors, which is sort of the opposite of what THC does, interacts with certain certain elements of GABA receptors, opioid receptors. Nuclear power receptors, I don't want to I don't want to list too too many too much nomenclature, but it was a lot of stuff. A lot of stuff. Yeah, but the most important one seems to be the five HT one a receptor which is a subunit of which is the serotonin receptor, basically. And the five HT one a receptor is quite interesting because it's, it's very highly distributed in a lot of brain areas that are important for controlling emotion and cognition areas like the prefrontal cortex, the striatum, the amygdala, and it's able to control the presynaptic release of serotonin and, and other pathways as well. So it's sort of a ubiquitous receptor. But but pretty much at least in our hands, all of the effects of CB the we've seen, were dependent on this five HT one a receptor, which is radically different from what T THC is doing, pharmacologically so so that's quite an interesting distinction between CBD and THC in terms of how they're producing their effects at the level of the self exam.

Nick Jikomes 21:53

So there's this interesting connection between CBD and this serotonin receptor serotonin one A, so that would be So serotonin two A's is what people call the psychedelic receptor that a lot of compounds like psilocybin interact with. So this is a similar but distinct receptor. And is this related to CBDs apparent anti anxiety effects?

Steven Laviolette 22:12

We think so um, we do have some emerging evidence that CBD can interact with a with a benzodiazepine binding site on the GABA a receptor. And that's pretty exciting, because a lot of people are, you know, the clinical, the clinical evidence isn't too great at this point, because there hasn't been enough research on but a lot of people will sort of anecdotally report that CBD produces anti anxiety effects. And we've certainly shown that in animal models that CBD can produce anti anxiety effects as well, either acutely or even if you've had chronic stress, CBD can can reduce a lot of those long term stress related effects. And and that, that also, in addition to acting through the five is to one a receptor seems to interact with this benzodiazepine subunit on GABA a receptors. And that's really exciting because most of the the commonly used benzodiazepines have a lot of unwanted side effects. They produce dependence, addiction, withdrawal, they're associated with long term cognitive side effects, sexual dysfunction, all kinds of unwanted side effects. So it's kind of exciting that that CBD might be able to interact with a similar sort of anxiety related receptor substrate in the brain, which which raises the question, does that make CBD a safer anti anxiety alternative from classical benzodiazepine? So that's, that's very early going research. But that's I think that's an exciting area for future investigation.

Nick Jikomes 23:54

Interesting. So CBD might be having anti anxiety effects. And it might be doing it by at least partially tapping into some of the same mechanisms as other drugs that we already know work really well for anxiety, but it doesn't have potentially as many downsides as some of those drugs.

Steven Laviolette 24:09

Exactly. Yeah. And to that point, the fact that the fact that CBD actually can reduce dopamine, that would be sort of the opposite from an addictive type drug, would you expect to do the opposite. So that that's quite interesting, as well just sort of based on its it's known functions.

Nick Jikomes 24:27

So I'm interested in talking about some interactive effects between THC and other compounds that are showing up in cannabis products that are found another consumer products that people are probably using fairly often. Can you first start off by summarizing what the, you know, what do we know about the effects of chronic to THC exposure in the brain, either in the adult brain or the developing brain?

Steven Laviolette 24:49

Yeah, so we've done studies where we've compared exposure to chronic levels of THC, either in the developing adolescent brain or in control group. We're all basically mature adult animals. So these are all animal studies. We've also moved now towards prenatal studies as well, I can, I can touch on that in a minute. But just just comparing adolescent versus adulthood exposure, when we gave the exact same sort of escalating doses of THC to adolescent cohorts and adult cohorts, we saw dramatic differences. So for so in adolescent exposure, we had these long term changes that were very much indicative of a schizophrenia like phenotype. So, for example, they had this hyper sensitization of the dopamine system. So we actually went in and recorded the dopamine neurons within the midbrain. And they were hyperactive all the way up until early adulthood. So this is after just 10 days of exposure during adolescence and 10 days in, in sort of rats, Adolescence is actually quite a long time, because they obviously have a much, much more condensed lifespan. But it was quite remarkable that these hyperactive dopamine phenotypes lasted all the way into early, early to mid adulthood. And that was associated with all kinds of behavioral abnormalities. So they had cognitive disturbances, they had emotional processing disturbances, memory problems, sensory filtering problems, all of which are sort of classic phenotypes for schizophrenia. And, and also activation of molecular pathways. Pathways like the GSK three pathway that was dramatically reduced in the the frontal cortex of the adolescent exposed animals, which is exactly what you see in postmortem brains from people with schizophrenia, and other pathways as well, similar sorts of analogs following the adult exposure for the exact same period of time, and the same dose range. But after the brain had already gone through those adolescent developmental windows, no effects at all, I think we observed one sort of minor memory impairment, I think, a social memory impairment following adulthood exposure. But other than that, they look perfectly fine. They had no hyperactive dopamine system, they did not have any of these molecular changes. They didn't have anxiety, they didn't have any major cognitive problems. You know, no changes in sensory filtering. So it really sort of underscores just how vulnerable the adolescent brain is, during that period of development to something like THC.

Nick Jikomes 27:45

Yeah, I recall a study from a few years ago now, where they compared the effects of chronic THC exposure in, in adolescent mice to older adult mice. And my my memory is that, you know, the adolescent mice tend to perform quite well in various learning and memory tasks. You have chronic THC, and then you test them after the THC is gone, and they perform worse. So they have a deficit. Whereas the old mice are basically the opposite. They actually perform worse at baseline, because they're older. And yet, when you gave them chronic THC, and then tested them, subsequently, they saw an improvement, they looked more like sober adolescent mice in their performance. Is that Is that surprising to you? Or is that common that you'd see that kind of developmental distinction between two different age cohorts?

Steven Laviolette 28:34

No, sometimes uncommon? I'm not familiar with that study. So I'm not sure what what if the, if the windows of time were sort of corresponding to what we were doing in our studies, but that's not that uncommon. You know, the brain is sort of this plastic and very dynamic structure, especially during prenatal development, and during adolescence. And those are the two windows of time that we focus on. And, of course, it gets much more static after the age of 25. But there's still, you know, it's still obviously an evolving organ. And it's subject to, you know, the problems with aging. So, depending on the age at which exposure takes place, you can either see, you know, potentially an improvement in some symptoms, versus a worsening. And a lot of that's also going to depend on if there's any comorbid conditions associated with aging, that that might be relevant to the individual that's taking the cannabis. But there really needs to be a lot more research done in human populations to get a better feel for how cannabinoids can either help or hinder certain symptoms associated with the aging brain at different periods of the lifespan.

Nick Jikomes 29:51

So so you get chronic THC to adolescent rodents for a good chunk of their adolescence it might cost onto I don't know, probably weeks or months of of a human consuming THC. Have you done the study where you would co administer THC just like you did, as you previously described in the adolescent rodents, but you co administer it with another compound?

Steven Laviolette 30:14

We have? Yeah, so we've tested a couple compounds. So the one that we most recently worked on was L theanine. So l theanine is it's quite a quite popular amongst the various internet discussion groups and whatnot is sort of a cognitive enhancer. It's an extract, it's also found in green tea. Okay, so it had a lot, I was getting a lot of attention a few years ago as sort of a pro cognitive molecule. So but what it also does is it modulates levels of various chemical precursors for glutamate and GABA synthesis in the brain. So it modulates glutamine levels, modulates glutathione levels. And these are really important chemical precursors for the production of GABA glutamate in various brain areas. One of the the major, well, just a step back, and the reason we chose that compound was because we had another study where we showed that adolescent THC exposure caused a loss of GABA in the prefrontal cortex, which and GABA is the major inhibitory neurotransmitter. And you see that in the brains of people with schizophrenia, that loss of inhibition in the prefrontal cortex leading to dysregulation of those neurons. And they also have hyperactive activity. So hyperactive glutamate signal, so basically an imbalance between excitation and inhibition in this area called the prefrontal cortex. So there's a lot of sort of complimentary literature showing that l theanine can normalize levels of GABA and glutamate in specific brain areas. And so we thought, well, let's try l theanine, we administered l theanine in conjunction with a THC and we blocked virtually all of the effects of THC. And, and so so essentially, what we found was that we had a normalization of the dopamine system. So we didn't see that hyperactive dopamine phenotype. We didn't see the hyperactivity of the prefrontal cortex. So that suggested that the L theanine. And this wasn't a hugely high dose in humans centers is about 10 milligrams. And l theanine is taken off in much higher concentrations in a lot of the human studies as well. So it was a relatively modest dose. But it was sufficient to reverse or sorry, not reverse, but block almost all of those negative side effects of THC. So we what we're doing now is looking at how that's happening, what is it doing what is L theanine doing to prevent some of those negative side effects of THC?

Nick Jikomes 32:55

So on what exactly is L theanine? Well, yeah, so it's basically

Steven Laviolette 32:59

an amino acid precursor. And it's again, it's it's found in natural compounds, like like green tea, for example. And it modulates levels of glutathione, which is again, a precursor for the production of a lot of different neural chemicals, especially GABA glutamate, the GABA glutamate pathway. And so the idea is that and this has mostly been shown in in vitro sort of biochemistry studies, l theanine can modulate the levels of those pathways. So we're now trying to actually look at what it's doing in terms of glutathione and glutamine levels in the in the prefrontal cortical areas of these rats that are getting the THC. So our hypothesis is that it's preventing that dysregulation of glutamate in the prefrontal cortex. And that is, what is causing the reduction in the the THC related symptoms.

Nick Jikomes 33:56

I see. So so just just to summarize some of this. So in the animal models you have where you're giving THC for an extended period to adolescent, Rodin's they develop, they develop symptoms, behavioral characteristics, molecular characteristics, that looks a lot like an animal model of schizophrenia. And somehow it has to do with this idea that the level of excitation and inhibition in certain parts of the brain is off. And it's fair to say that's why like, that's what we would think about to explain why, you know, when you observe someone with schizophrenia, or another form of psychosis, they're often right, talking out loud, or vocalizing, or doing something that a normal person wouldn't do that a normal person would inhibit themselves from doing is that due to the sort of literal disinhibition or imbalance it's going on in the brain?

Steven Laviolette 34:42

Yeah, there's a lot of competing theories about that. So sort of the classical schizophrenia model was the dopamine hypothesis when the idea was that you get this hyperactive dopamine system that leads to dysregulation of emotional processing and for example, You pay, you're unable to properly process the salience of incoming sensory information. So for example, someone with schizophrenia is watching their television set, and they believe that the newscaster is speaking directly to them, for example, and this gets blown into some elaborate, you know, paranoid hallucination. And it comes down to the inability to, you know, sort of properly attend to relevant sensory information. And this has been linked to everything from the dopamine deform receptor, which is a subtype of the dopamine receptor. That was some work we did quite a few years ago. And also, this idea that there's this imbalance between GABA and glutamate. So you get this hyperactive output from the prefrontal cortex down to those sub cortical dopamine neurons. And that hyperactive, so it's sort of like a, an abnormal circuit, as opposed to just one area acting in isolation. You've got this hyperactive glutamate input to the dopamine cells, and that's causing that hyperactive dopamine drive, and then you're getting these positive symptoms of schizophrenia. And so, so another paper we did, looking along those lines, we actually were able to infuse a GABA agonist drugs, so activating GABA directly in the prefrontal cortex. And when we did that, we were also able to reverse a lot of those negative side effects of adolescent THC exposure, which provided further support that is this GABA glutamate imbalance that leads to these cannabinoid related abnormalities. Now, the extent to which that's the case and in schizophrenia, independently of cannabis, that's not entirely known at this point, because there's, as I said, there's a lot of competing theories, and a lot of different Some patients will respond differently to different medications that interact with different pathways. So and there's even debate as to whether or not we should think of schizophrenia as sort of a homogenous entity, or is it sort of a combination of different disorders with different underlying pathologies? Which really, which makes it even more complicated to address from our research?

Nick Jikomes 37:19

Okay, but but in the animal models you have, you give THC you see these various brain abnormalities, you have THC, same dose, same timing, but with L theanine, and it blocks most of those abnormalities from developing and it sounded like you said that you're not using like an astronomically high dose of L theanine you're using something that's comparable, perhaps to what a human would ingest with with with a product that has it? That's right. Yep,

Steven Laviolette 37:45


Nick Jikomes 37:46

Interesting. Is it in anything else besides green tea that's that's commonly consumed?

Steven Laviolette 37:51

Well, you can actually just pick it up at the health food store. So there's there's healthiness Ltd and extracts that are, um, as I said, a few years ago, we have been sort of getting a reputation as being a pro cognitive, natural supplement. And, you know, there's there's very little controlled evidence for that, in terms of the human literature. There's some evidence that, for example, there's some evidence that l theanine, in combination with certain medications for schizophrenia can improve the efficacy of those compounds. But those are sort of few and far between. But yeah, basically, it was sort of a modest amount of Elfine that we were giving. And we gave it sort of it very close in time to the THC. So they were sort of being the brain was being exposed to both of them at the same time. So the idea was that whatever, whatever l theanine was doing, it was doing it in a preventative manner. I assume it was blocking sort of those acute and long term effects of THC. But they had to be together at the same time. So it wasn't as though we I mean, we did not demonstrate that taking l theanine after the damage is done, can necessarily reverse it back. That's a really interesting question in and of itself. And that's something that we're, we are going to be looking at that in the future, but we haven't, we haven't done that yet. So that's the next big question.

Nick Jikomes 39:19

Can you take too much l theanine, is there a risk of overdose?

Steven Laviolette 39:24

Um, I'm not too much of an expert on sort of the physiology of L theanine itself. I mean, we were sort of using a translated dose range from the human literature terms of the right size, but I've seen papers where people were taking up to 800 milligrams, for example, without any reported negative side effects, but of course, you know, it is it is a stimulant as well. So I mean, anyone considering taking out the union would want to consult with their, their appropriate physician to meet and also you want to make sure that it's not going to interact with any other medication. If you're taking if you are going to take it sort of as a supplement beyond, you know, drinking green tea, for example,

Nick Jikomes 40:07

I see so so it does tend to have a stimulating effect. Yeah, for sure.

Steven Laviolette 40:11

Yeah. And some individually again, this, some some people like it sort of like, you know, how you respond to caffeine, some people get no reaction, some people are wired for hours after. So a lot of it depends on the individual and their own sort of genetic makeup, how they respond to it.

Nick Jikomes 40:27

I know that you've also done some research looking at the relationship between CBD and omega three fatty acids, so So what have you done around that area?

Steven Laviolette 40:37

Yeah, so we've been looking at how CBD combined with omega three fatty acids can have synergistic effect. So this I mentioned briefly before that CBD is quite a messy compound, it interacts with a lot of different receptors. And one of those receptors is, is a nuclear receptor, called the P par family. And there's a lot of different P par receptor. So it's Grokster zone, proliferate proliferative activated receptor in the nucleus, and it's related to once once the P bars get activated, is involved in a lot of basically cell metabolic actions, it helps regulate what what sort of metabolic state the cell is in, how different proteins are produced, etc. So it's a complicated system that we don't fully understand. But long story short of omega three fatty acids, and CBD both converge on P power receptors. So we've been looking at how combining those together, how might that improve the efficacy of CBD? So we have, we've got some preliminary evidence suggesting that the combination of omega threes plus CBD can improve its function at the p bar receptors, and can improve the ability of CBD for example, to block dopamine. So that might have some implications for the use of CBD as either an anti anxiety medication or something for treating psychosis, if you can improve its efficacy. And well, let me step back a minute. So I mean, one, one of the clinical issues with CBD is that a lot of the trials out there, were using these really, really high doses of CBD, sometimes up to a gram per dose per bolus dose, which is a really huge concentration. Now most of those studies didn't find any major negative side effects from taking doses of CBD. One issue that has come up, and you may be familiar with a study that came out, I think it was last year or a year and a half ago or so in pediatric populations with pediatric epilepsy. And they were giving them pretty high doses of CBD. And a lot of those kids were having some unwanted digestive problems and nausea, and unwanted peripheral side effects from those high doses of CBD. So if we can improve the efficacy of CBD, add those receptors, that sort of the goal is to get more bang for your buck. Right? Right. Oh, it goes to CBD.

Nick Jikomes 43:17

Yeah. And that's like, literally, that's important, a very literal way. Because, you know, when you're talking about hundreds of 1000s of milligrams of CBD per day, the average person is not going to want to spend that kind of money.

Steven Laviolette 43:29

Exactly. Yeah, it's it's absolutely, it's an economic issue as well.

Nick Jikomes 43:32

So So to summarize this area, so there's these things called P par receptors, and you said their nuclear receptor so so instead of a serotonin receptor or a cannabinoid receptor sitting on the outside of a cell, it's actually in the nucleus of the cell. Does that mean that when something like CBD or omega three fatty acid interacts with this receptor, it's more directly influencing the gene expression in that cell?

Steven Laviolette 43:57

Yeah, absolutely. So it's sort of interacting at sort of the, the command center of the cell as it were. And that's going to have impacts. And again, we don't really understand exactly how this these pathways work. But it's involved in things like cell metabolism, the activation of different protein synthesis machinery in the cell. So it's not just going to be switching a cell on and off, for example, or controlling the presynaptic release of a neurotransmitter, it's actually going to be sort of getting into the Master the Master Control of the cell and, and regulating and from a more centralized position.

Nick Jikomes 44:34

I see. So before moving on to another topic, I was really intrigued by a preprint that came out some months ago. I don't know if you saw it. I don't think it's been published yet. But it had it had to do with SARS, cov two replication in vitro, at least half the study. And without getting into the details of that particular study too much what they basically showed as CBD in vitro was able to change gene expression patterns within the cell. And based on what you just said, it sounds like there's there's a plausible molecular mechanism for why that would be. But But I guess the sort of interesting observation, just as a as an interesting molecule is CBD can actually change which genes are coming on and coming off inside of a cell.

Steven Laviolette 45:16

Yeah, absolutely. And it's such a, you know, it's a really, it's a sort of a nice lipophilic compound that can really get into the cell, and produce those sort of centralized effects. I didn't unfortunately, I didn't read that paper. But it's, you know, that could certainly be a mechanism through which you can can modulate different metabolic processes within the cell itself by getting to that sort of command center in the nucleus and regulating it that

Nick Jikomes 45:39

way. Um, I want to talk about earlier phases of development now. So you know, if you were to, you know, thinking about thinking about the human side of this, right, if a woman is pregnant, and she's taking a cannabis product that contains THC for any length of time, what do we know about the the exposure of a fetus to exogenous cannabinoids, like THC? And so I want to, I actually want to, I want you to talk about two sides of this, what are the effects on brain development of a developing fetus? But also, why would or why are some pregnant women actually taking such products? What are they treating?

Steven Laviolette 46:18

Yeah, that's, that's, that's really becoming a very important issue. So I mean, there are there's some, some evidence that, you know, depending on the population, you know, anywhere from 15 to 20%, of pregnant women in some jurisdictions are using some form of a cannabis product, largely because it can produce two things it can it can relieve anxiety associated with pregnancy in general. And it can also have anti nausea effect. So it's great for morning sickness. So I mean, there's even anecdotal reports of pediatricians prescribing and have annoyed products to pregnant women to alleviate morning sickness. You know, my concern as a developmental neuroscientist is that we don't really know what's going on with cannabinoids in these early stages of brain development. So my lab is taking two different approaches. We're looking at both the prenant the effects of prenatal THC exposure on the on developing mammalian brain. So we're using animal models, in this case, rat moms basically pregnant rats, and we're giving them THC. And we're seeing some rather disturbing effects, long term effects in the offspring of these pregnant rats that are exposed to THC. So we're I mean, this is pretty early evidence, but it's consistent with another study that came out. From a colleague of mine, Miriam, Dr. Miriam Millis, in Italy. She published a study in Nature Neuroscience, I believe, where she showed that prenatal THC exposure again, using an animal model leads to a lot of the same phenotypes that we see following adolescent exposure. So they get hyperactive dopamine, they get cognitive and affective problems, we're seeing the same thing. We're seeing hyperactive dopamine, we're seeing abnormal levels of GABA and glutamate and various brain areas like the hippocampus, the prefrontal cortex, we're seeing a lot of behavioral cognitive problems. And we're seeing some interesting sex differences as well. So male versus female offsprings tend to be differentially impacted, following maternal exposure to THC. Why that is, we don't know the trends that we're seeing are that male developing male brain is more vulnerable than the female brain, there seems to be some protective elements in the female brain prenatal.

Nick Jikomes 49:01

So the effects are there, they're in the same direction. They're just, they're just more strongly expressed in male brains. That's

Steven Laviolette 49:08

what we're seeing so far. Yeah. And for a longer period of time, at least. And keeping in mind, this is very preliminary. So these are ongoing studies. But that's what we're seeing at this point in time. There seems to be some sort of neural protection in the female brain. And that's not to say they're not affected, they are affected, but in different ways, and in ways that are not quite as severe from a neuro psychiatric perspective. I

Nick Jikomes 49:34

see. So, so obviously, it must be true that these cannabinoid compounds are able to clot cross the placenta and get into the fetal tissue. Yeah,

Steven Laviolette 49:43

absolutely. And it is also very high. It's highly efficient in crossing into breast milk as well. So if you continue smoking while you're smoking cannabis, or or ingesting cannabis, while you're breastfeeding, you're also going to be transmitting the cannabinoids to to a child that's breastfeeding.

Nick Jikomes 50:02

What about CBD looked at CBD? And is it safe to suppose that it would likely have a very distinct effect based on what we talked about previously, we're starting

Steven Laviolette 50:11

those studies now or so we're looking at the effects of CBD combining CBD with THC, it's really too early to tell the data is still still very preliminary. We, one of our predictions is that CBD, if it's acting similarly to what we see in the adult brain, then it in theory should be protective against the effects of THC. But it's a little bit too early at this point to know for sure whether that's going to happen. But that's sort of the hypothesis we're working on at this point. Yeah.

Nick Jikomes 50:41

I see. Um, so we've already talked about anxiety, a fair amount. And it sounds like just to kind of summarize my understanding of THC and CBD with it with respect to anxiety in general. It sounds like THC can actually be anxiety promoting or help with anxiety, depending largely on the dose that someone would take THC. And CBD generally has an anti anxiety effect, at least at a sufficiently high dose. But it doesn't really have that kind of BI phasic effect that THC has, is that a fair summary?

Steven Laviolette 51:14

Yeah, based on what we've seen, we don't really see that by Facebook. That's not to say, if we ran things a little differently, we wouldn't be able to pick it up. But that's a fair summary what we've seen so far.

Nick Jikomes 51:25

What about? Well, it sounds so it sounds so far like, like there is clear evidence, at least in animal models, that chronic THC exposure early in development, whether it's adolescence or, or a fetus, when a when an animal is pregnant, is going to have long lasting abnormalities produced in the brain. Is that also clear in humans? Is that you know, do we expect that to translate? How does that connect into the propensity to develop something like schizophrenia? We touched on that a little bit, but I don't think we dug into it too much.

Steven Laviolette 52:00

Yeah. And that's where the literature sort of gets gets a bit muddy, because we don't have too many really great sort of long term. follow up studies, the limited evidence that's out there does suggest that children of mothers that were taking large amounts of cannabis during pregnancy are more likely to have certain attention, cognitive type problems, problems with impulse control, problems with emotional regulation. But I'm not really aware of too many studies that have done like a long term follow up. And these are really difficult to do because, you know, people move away, they dropped out of the studies, it's really hard to do these sorts of long term sorts of clinical work. But the limited evidence would suggest that there is certainly some unwanted long term side effects in the children of women that were exposed to high levels of cannabis during pregnancy, similar, similar profiles to what we see from some of the evidence from mothers that were heavy smokers during pregnancy. So as prenatal nicotine exposure is also related to some of those side effects. We're also doing collaborations, we're looking at some of the physiological side effects as well. So we published some studies with some of our partners here at the University. Dr. Dan Hardy is one of our major collaborators, and he's finding some very interesting physiological issues as well. So there's abnormal abnormalities with placental development, there's abnormalities with, you know, liver function, intrauterine growth restriction. So the idea is that the, the, the fetus is exposed to THC, prenatally it's not just the fetus that's affected, but it's also the reproductive physiology of the mother as well, putting the uterus and, and even the, the maternal fetal, placental circulation seems to be modulating as well. So it's this really sort of holistic phenotypes, you know, beyond the brain, then that seems to be at play here with prenatal care animals, because obviously, it's having all sorts of physiological effects beyond the brain in the body.

Nick Jikomes 54:26

Yeah, and I suppose that's not surprising given just given how widespread the CB one receptors are.

Steven Laviolette 54:31

Exactly, yeah. Yeah. And people often, you know, sort of, and I'm guilty of this myself, I mean, we're, we're laser focused on the brain, but the CB one receptor system is everywhere. I mean, it's a ubiquitous system. It's one of the most ancient receptor systems in invertebrates. So I mean, it's it's really critical for a range of physiological functions well beyond just what's going on in the brain. So it's one of those really ancient, primordial risks. After systems that can have impacts on a wide range of physiological processes in the body.

Nick Jikomes 55:06

I'd like now to start connecting the dots between cannabinoids and opioids. So there's a few things. A few things I want to mention before before we get to talking about this. So you mentioned briefly previously that CBD had some interactions with opioid receptors. We haven't talked about this yet. But But many people and there's some literature on this have talked about the kind of synergistic effect between cannabinoids like THC and opioids for pain management, the idea being that you can administer a lower dose of opioids with THC, and then maybe decrease the odds of say, an opioid dependency developing. And I also know I've had Yasmin Hurd on before she's she's done research connecting CBD to addiction in the sense that it can be used to treat addiction or prevent relapse. So you know, starting starting wherever you want to what's the connection between cannabinoids and opioids in the context of an addiction treatment?

Steven Laviolette 55:58

Yeah, I mean, so so I'm very familiar. I know. I know. Dr. Hurd very well, she's she's a she's a great friend. And she she's done some really fascinating work looking at how adolescent THC can and it sort of Prime's the opioid system in the reward centers. And she's shown it in animal models that this can increase the sensitivity to the rewarding effects of opioids. So we've shown that for example, a paper I was referencing before about the vendor campus. If you expose the ventral hippocampus to THC, you can increase the reward salience of opioids, so morphine, for example. So we've shown that in some of our animals, and CBD blocks that effect, again through that, er k, that herb pathway, and through modulating the dopamine system as well. So very conversion types of evidence. And Dr. Hurd published a really exciting paper, I think, was about a year and a half ago, a clinical study where she showed that CBD can blunt the appetitive effects of opioid related imagery in patients that are basically exposed to images that evoke opioid reward related memories and induce craving. And so can have an eye sorry, CBD can reduce craving for all goods. And that was really exciting. And from our perspective, that really plays nicely into our findings that CBD can modulate the dopamine system itself. So we showed a couple years ago, that CBD can block the effects of amphetamine. So an impediment of course, is basically ramps up the brain is dopamine system. And we show that CBD directly in the brain in this area called the striatum, can can blunt all of those effects of amphetamine. And of course, opioids, and amphetamine and cocaine and nicotine and alcohol all, almost all drugs of abuse really have that common action on the mesolimbic dopamine system. So by by CBD, blunting that drug related activation, I think that has huge potential for CBD as a potential treatment for not only sort of blunting the addictive properties of a lot of drugs like opioids, but also in preventing relapse. Because if it can prevent the ability for drug related cues to invoke that, you know, craving for those drugs, which is really the main reason people fall into relapse, they get they experienced this, these very intense cravings, especially for opioids. That's really exciting. And I think I'm sure I'm sure. Dr. Hurd is following those studies up. And that's an area that that needs a lot more attention, I think, from a clinical point of view.

Nick Jikomes 58:57

I see. So it sounded like on the one hand, CBD can help prevent relapse or sort of make the opioids less potent in driving the effects they do. But that THC, more or less did the opposite. It could actually make someone more sensitive to the effects of opioids.

Steven Laviolette 59:13

Yeah, exactly. And probably, again, through a similar mechanism through sort of priming the dopamine system. So and, again, our study with the adolescent and the prenatal exposure to THC, that the common theme was this hyper drive of the dopamine system that lasted for a long, long time after the initial exposure. So it seems to be priming the system for drug dependence essentially, because because as soon as you've got, you know, sort of the dopamine pump is being primed to respond to any sort of psycho stimulant drug or an opioid, for example, that is going to produce dependence through overdrive of the dopamine system. Then then that's where I think you again, you've got these opposing effects of CBD and THC.

Nick Jikomes 1:00:09

Interesting. What can you tell us about? Can you describe the effects of opioids themselves? How are they similar? And how are they different from something like THC? And then I'd love if you could go into what we know about the developmental effects from opioids.

Steven Laviolette 1:00:23

Yeah, so I mean, our our research on opioids is has look mostly at sort of the long the chronic effects of opioid exposure. So we develop, we expose, again, test test animals, to to chronic heroin, for example, to get them basically dependent on opioids. And then we look at what changes in the brain. So there actually are some common pathways that opioids and THC for example, act on. And again, one of those pathways is the earth pathway BRK one two pathway. So we published a paper a few years ago, showing that chronic heroin can induce this addiction switching mechanism in the amygdala, which is dependent on hyper activation of this birth pathway. And interestingly, that's what THC seems to do acutely as well, it activates that pathway. And so that's one common substrate that we don't know exactly what that relationship is in terms of mechanisms, but they definitely have shared pathways in addition to their their, they both have this common ability to sort of overstimulate the dopamine system. Our research suggests that, in the early stages of opioid dependence, the dopamine system is not even really an issue for getting someone hooked on on on heroin. But after chronic exposure, you get this over sensitization of dopamine, and then the brain sort of switches on this dopamine dependent addiction pathway. So this is where I think CBD again might be really exciting, because if we can sort of throw that addiction switch off by switching off dopamine, that might have some real, some really important implications for controlling both the process of addiction, and then reversing some of those long term adaptations in the brain that are induced by opioid exposure, or nicotine or cocaine or amphetamine.

Nick Jikomes 1:02:24

What about nicotine? So as a drug, how does it differ from the drugs we've been talking about so far in terms of how it acts in the brain? And what do we know about the developmental the effects of nicotine exposure during development?

Steven Laviolette 1:02:37

Yeah, so nicotine, of course, interacts mostly with the acetylcholine system. So the brain has a ubiquitous numbers again, similar to cannabinoid receptors, the nicotinic acetylcholine system is also very ancient and primordial in the vertebrate, nervous system. So there are excitatory receptors, they control, you know, excitatory, ionic transmission in various brain areas. So that's different from the CB one receptors. So yeah, so they're sort of cat ionic receptors. They're found throughout the brain, but they also impact dopamine. So are some of our research on nicotine, shown that sort of similar to opioids, the early phases of exposure to nicotine does not necessarily cause an acute response in the dopamine pathway. But if you're chronically exposed to nicotine, that you slowly get this ramping up of the dopamine pathway, and the dope the dopamine pathway gets hyper stimulated following chronic nicotine exposure. So again, and that is very similar to what we find with opioids. So it's a sort of a similar mechanism. And nicotine is also highly highly addictive. I mean, it's, some people argue that the dependence they experienced with nicotine, it makes it almost as hard to quit as much harder drugs. Probably not certainly not in the in the, in the same league as opioids. But certainly the ability to quit. tobacco dependence is really challenging for a lot of people. So it's similar in that sense. We've been looking at the effects of adolescent nicotine exposure. And we've seen some some interesting similarities and some interesting differences between nicotine and THC. So they both cause this long term hyper activation of the dopamine system, but the nicotine seems to induce a long term anxiety and mood related phenotype, whereas the THC seems, seems to appear as a much more of a schizophrenia like behavioral phenotypes and molecular phenotypes. So that's consistent with a lot of the clinical evidence suggesting that adolescent nicotine exposure is associated with an increased likelihood of mood and anxiety disorders, not so much more severe psychotic, like disorders like schizophrenia. But it seems to be associated with mostly with anxiety if you actually look at some of the more clinically relevant studies. So and what we've seen so far is that, um, there's a different array of molecular pathways that are activated by adolescent nicotine. But some of the neuronal effects are very similar to THC. We don't know exactly why that is. But the end result is a very different psychiatric phenotype. So as opposed to sort of the sort of the psychotic sort of predisposition to schizophrenia, like symptoms following chronic THC. Nicotine produces this long term, increase in anxiety and mood related disturbances.

Nick Jikomes 1:05:52

I see. So chronic THC, chronic nicotine are both going to have long lasting effects on brain circuitry. But the the details of what that looks like are just very different. They're very distinct kinds of effects. Exactly. Yeah. What, I'm not sure if this is your area, but like, while we're on the subject of development and prenatal exposure to things, you know, we've talked about cannabinoids, we've talked about nicotine. Now, I think everyone has probably or most people have a pretty good intuition that you probably don't want to be ingesting those things as a general rule. If you're pregnant, alcohol would be another one where I think, you know, people probably have a pretty good intuition that that that's what you'd want to do you want to avoid alcohol ingestion, if you are pregnant. What about something like something more innocuous say, What about caffeine?

Steven Laviolette 1:06:40

Well, yeah, I mean, that's a great, that's a great question. Um, you know, some some, some women certainly do not drink caffeine during pregnancy or cut down on significantly. Caffeine, caffeine is, is certainly the dependents producing compound I can I can attest to that. Personally, I can't start my day without a strong cup of coffee. So but obviously, again, we're talking about vastly different pharmacology and different receptor system. So you know, caffeine, caffeine has been shown to activate dopamine as well, not to the same extent as something like nicotine or opioids or, or THC, but it does interact with the dopamine pathway. And you can get pretty nasty withdrawal. If you know, most of us who've gone through that and had to go a few hours without it without a coffee and you can start start getting a bit grumpy and certainly nothing on in terms of severity that you would expect from nicotine or opioid opioid withdrawal. But yeah, I mean, I don't think there's been too many preclinical studies looking at pre natal caffeine exposure, per se. I'm not I'm not familiar with that area. If there are there probably are some studies out there, but I'm not personally familiar with them. But yeah, I think it's I think it's an open question. I think most pediatricians advise, I think the official recommendation is no less than a cup day. I'm don't quote no more than a cup. No more than a comp a day. I think. When my kids were born, I think that was the recommendation. But But But yeah, I think I think there needs to be more preclinical research into that as well, because I don't think there's a full picture exactly on what the effects of caffeine are.

Nick Jikomes 1:08:31

Um, you mentioned a little bit some of your ongoing research, I'm sure you have quite a bit more what what are some of the exciting problems that that you guys are working on today? Well, we're

Steven Laviolette 1:08:39

really excited, we're moving now into brain organoids. So this is, this is an exciting new technology, it's it's quite, quite novel. It's only in the past few years, that has been sort of gaining traction in the field. And this is basically where you take an IPSC cell. So a stem cell basically, from a fibroblast developed from a fibroblasts from from a human, you know, usually taken from a skin biopsy of fiberglass, and then you, you reprogram the cell into into a pluripotent stem cell. And then you can transform that in in vitro, and it develops in this three dimensional matrix into basically, what they call mini brains. And so you get this sort of Roset like structure, and you put it into this gel matrix. And because it's in a three dimensional structure, it starts evolving into an what we call a brain organoid. And a lot of the preliminary sort of the primordial structures of the brain are in those organoids. So like, you start seeing the cortical layers developing, you start seeing like a primordial hippocampus developing, you can move them in different or you can get them more midbrain, so you can look at dopamine developments, you know, striatal development, that sort of thing. So you can take these Sell samples from patients, for example. So we have samples from patients that had schizophrenia. And we have cell samples from these patients. And we're comparing them with samples from healthy controls. And looking at how exposure to compounds like THC or nicotine during this very, very early period of human brain development. Obviously, it's an artificial system, of course, but we're looking at how exposure to those compounds during what roughly corresponds to about the first three to four weeks of prenatal brain development. And the great thing about this is that these are, you know, these are real human brain samples, human brain tissue, that we are basically recapitulating in a dish. So we're able to, you know, draw much stronger parallels between the effects of these early exposed drug compounds to what they're doing to both sort of the healthy brain and brain and brain brain tissue samples from people that have suffered from very serious psychiatric disorders. So it's a really exciting technology. And we're just getting that off the ground now. But we're quite excited to see how how some of the biomarkers that we've developed in our animal models might translate into what we see in the human samples as well. So it's really about convergence. Translational convergence, because I think is really important too. Despite all the advantages of using animal models, there's there's limits, of course, to what we can infer, based on what a rat brain is doing and what what's happening in the human brain. So the organoids give us this nice controlled environment to model these early stages of, you know, neurogenesis and cell migrate neuronal cell migration, for example. And, and look at how these different developmental project trajectories might be impacted negatively by exposure to things like THC or nicotine. I see.

Nick Jikomes 1:12:06

So effectively, you've got a method in the lab where you can take some human cells and put them in a special environment, and they start to sort of kind of develop into something that looks like the brain. And so now you've got this proxy for human brain development, where you don't have all of the the operational and ethical restrictions that you have with an actual intact developing human brain. And you can do the more invasive, more mechanistic experiments you might want to do to understand human cells developing. Exactly, yeah. Interesting. Um, one of the things I mean, you mentioned this early on, and it's been at least implicit in a lot of what we've been talking about. But this idea of an entourage effect. Generally speaking, that would just mean that multiple compounds have an effect when they're, they're given together that they wouldn't necessarily have on their own. This is a very big idea in in the cannabis industry and in the cannabis research world. The idea being that if you've got, you know, different ratios of THC, CBD, other cannabinoids, other terpenes, that could actually greatly impact the effect that they have for someone. And what you've told us so far is that at least with THC and CBD, there is clear evidence, they do have these interactive effects. And you know, having both together, it's going to have a very different outcome than having just one in isolation. One of the, you know, one of the areas of research that I'm involved in, has to do with this. So what we did a few months ago, and there's a preprint on this as we basically mapped out the full phytochemical diversity, at least with respect to cannabinoids and terpenes for commercial cannabis in the US. And we use some algorithmic techniques, techniques to define what the different sort of profiles are, that you see in different cannabis strains that people are actually out there buying and consuming. And long story short, there are different kinds of strains that have different terpene profiles and these different compounds found in different ratios. Would you say, you know, we don't know the answer yet. We don't really have the clinical data, one would want to know for a fact what the different effects these these different profiles might have actually are. But would you say that, you know, based on all of the the preclinical work that you and others have done that it's plausible that you have this kind of entourage effect where you have distinct profiles giving you noticeably different psychoactive or medicinal effects?

Steven Laviolette 1:14:18

Oh, absolutely. Yeah, I'm we're quite convinced of that. And we have a lot of compelling evidence to suggest that the combination of certain terpenes with Knapp, CBD, for example, improves the efficacy of CBD in various behavioral measures. These are things that we're still working out and working on, but we hope to have some publications out early next year, that look at CBD combined with certain monoterpenes and how those might improve the efficacy of CBD by itself. So I'm quite keen, and there's actually quite a bit of literature, looking at some of these terpenes by themselves. Things like little linalool, for example, or limiting their heart, there have been some preclinical studies looking at exposure to those by themselves. And they've been shown to have, for example, zeolitic properties, which is quite exciting. And so it stands to reason that there would be some synergy between different phytochemicals and terpenes. Whether it's happening at the exact same receptor substrate, we don't know. But there is certainly evidence for synergy.

Nick Jikomes 1:15:35

What the studies aren't out yet, so So I won't ask you for too much detail. But what terpenes are you guys looking at in conjunction with CBD?

Steven Laviolette 1:15:43

So we've been looking at mostly linalool and limonene. A few other ones, as well, you know, but but they definitely seem to have some interesting, entourage like properties. So these are so we're actually presenting some of this evidence of this Society for Neuroscience meeting coming up. Unfortunately, it's not in Chicago, it's all it's all virtual online now. So not going to get as much exposure. But But yeah, so again, we're still working out some of the, the details of that, but very exciting, preliminary evidence.

Nick Jikomes 1:16:22

Interesting. Um, I know that there's other people working on this as well, one of the things that I think is kind of exciting is, and I guess the question will be, the question is ultimately going to be how are you actually administering these things? But one of the things I'm interested to see some results come out from is these new like inhalation chambers that people are using. So instead of just doing you know, IP injections or something in an animal, making it more ecological, I guess, compare, you know, me, you know, because people are often inhaling these things. And I know that they've developed at least some labs chambers, where rats are really inhaling vaporized cannabinoids and terpenes. Is that, are you guys doing that at all? And if so, or if not, how are you administering these things?

Steven Laviolette 1:17:02

Yeah, so we're not doing vapor at this point. Um, we do hope to set something up in the near future with some collaborators or vaporize formats. We are, we're mostly doing edibles. We're moving more now towards edibles. And to be honest, I think that's where the market is going. In terms of administration, I think edibles are ultimately going to be sort of the preferred method of ingestion in the future, because a lot of people don't necessarily enjoy the sensation of smoking, the compounds and whatnot. And this and the respiratory side effects, for example. So we've been looking at edible administration of some of these different compounds, and the effects are very similar. So there's, you know, I think it's important to look at it from different angles, obviously, giving injections is much easier, from a preclinical point of view. And it also gives you the advantage of actually targeting specific brain areas as opposed to giving it systemically where you don't, you can't necessarily pinpoint where the actions are, and we're in such a worse, we're at such a ground level of research right now that I think we're still at the stage where we need to be working out, mapping out these brain circuits that are responsible for the effects of these different phyto cannabinoids, and terpenes and what have you. But having said that, we so far are seeing remarkably similar effects, regardless of whether these drugs are administered intraperitoneally or through an editable format. So I think that's that's quite validating, in terms of the preclinical models in general.

Nick Jikomes 1:18:46

I see. Any final thoughts you want to leave people with just on sort of the general topic of cannabinoids or other drugs and brain development and interactions between all those things are anything that you want to point people to? That's that's sort of outstanding questions that you think we might answer in the near future?

Steven Laviolette 1:19:03

Well, I mean, I think we've really been shifting more towards neurodevelopmental models and I've been quite well in many cases, very surprised at just how severe some of these negative side effects can be following on neural developmental exposure both to compounds such as THC and nicotine. You know, the the mature mature brain has over 125 trillion synapses. And that those synaptic connections are very, they need to be very finely orchestrated during these early periods of brain development. So I think a take home messages that you know, really look after your brain during these, these windows of vulnerability because if anything has impressed me over the past decade or so, it's just how sensitive the developing mammalian brain is to a lot of different things. external compounds, and I think there needs to be a lot more care and public awareness given to some of those potential side effects, and more importantly, increasing funding for this sort of research so that we can identify biomarkers and maybe have a better idea of understanding who's more vulnerable, who's more likely to be vulnerable to potential side effects from developmental exposure? That's really the million dollar question because obviously, not everyone is going to suffer side effects from exposure during the certain periods of brain development. So I think the onus is on on us to figure out who's at risk, and, you know, developing more streamlined ways of identifying people that might be at heightened risk of developing unwanted side effects if they do happen to expose their developing brains to things like THC or nicotine.

Nick Jikomes 1:21:02

Well, Professor Steve LaViolette, thank you for your time.

Steven Laviolette 1:21:05

Thank you very much for having me.

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