[MUSIC] So I just want to thank you again, Sachin, for taking the time to do this, I know you're super busy. >> Sure. >> And I mentioned to you earlier, I think the students are really going to love hearing from you. And the challenge in terms of our conversation I think is sort if narrow down or talking about, because your research is so broad. It's honestly amazing how much stuff you're able to do, I was looking over some of it earlier today. And you going from the basic neuroscience all the way to the clinical land is pretty amazing. From you work on endocannabinoids and endocannabinoid system and functioning of the amygdala all the way up to the clinical side, it's just really cool. But we just talked recently, we had a module on cannabis and psychosis and mood disorders. And there as you know it's fascinating because we both worked on that at National Academies, Academy of Science Committee. Of course, it's a really important area of research in terms of the link between schizophrenia and cannabis. Maybe not the mood disorders and depression and cannabis has not received the same level of attention, but I think also an important area. >> True, yeah. >> And also, I think just because you understand it from a very basics of neuroscience level, but you also see the things in the clinic. I thought it would be awesome if I start there and ask you about your thoughts about schizophrenia and cannabis. And also maybe in terms of, again, sort of a chicken and the egg kind of thing, right, which comes first or can we really even know that at this point. >> Yeah, the relationship between cannabis and schizophrenia, there are sort of two ends to that discussion. There's one discussion about what are the effects of early life cannabis use or cannabis use at some point in life. And then the subsequent risk of developing schizophrenia or other psychotic disorders. So that's one discussion I know a lot of people have been very interested in. The other is about simply, how does cannabis affect people that have schizophrenia? So people that have schizophrenia, for example, that might be using cannabis. And what is the impact of that on their mental health and their disease trajectory and things like that. So those are two separate sort of questions, the latter one is a little bit more easy to answer. In terms of what is the effect of the acute intoxication using cannabis or cannabis products on people that have schizophrenia. We know in many cases that can actually make symptoms worse acutely. So we know this from human experimental studies where people have been given, for example, intravenous THC, which is sort of active component of cannabis. And when you give people that, especially at high doses, they'll report transiently experiencing some symptoms that might be, related to psychosis. For example derealizations, some perceptual changes, maybe even some delusional thinking, that can occur when people get high doses of THC. And the dose for the most part of transient while people are intoxicated, and those go away after the sort of drug gets out of their system. And the same is true for acutely for people that have schizophrenia. If they use enough cannabis, especially high potency, high THC containing cannabis. It's not surprising that some people can have an acute worsening of their psychotic symptoms. Now, that could be balanced to some degree by maybe some of the anti-anxiety effects. Or the benefits that those people perceive they're getting when they use cannabis. Which might underlie a sort of high rates of cannabis use in a lot of psychiatric populations. Including people with schizophrenia that also smoke a lot of nicotine, more than the general population. So the acute effects of cannabis, a lot of people with schizophrenia will use cannabis. We know that in some patients, that use will actually exasperate their psychotic symptoms. Yet a lot of people will at least anecdotally report that they get some benefit from that. That might be reductions in their stress level or their ability to cope on a day to day level. But in a long term, I think there's a fairly ease of consensus that using cannabis actively with schizophrenia, is probably not a good thing. It can interfere with medication compliance and may have more detrimental effects on long term trajectory. Although that's not conclusive, the acute sort of psychosomatic effects of cannibals can be seen. And even healthy people at the right doses that they are using enough of that. So that sort of one discussion that's a little bit more straight forward. The other one which is probably a little bit more controversial and a lot of people are talking about these days. Is your dose using cannibals especially may be when you are younger affect your risk, or does that lead to getting schizophrenia when you're an adult? There's a lot of differences of opinion on this, and a lot of strong feelings on both sides of that for a few reasons. But, I could talk a little bit about the data's, from contributing to the review we did several years ago. Is that there's strong and conclusive evidence that there is an association right between using cannabis, especially early in life when people are teenagers, for example. And the subsequent risk of being diagnosed with a psychotic disorder like schizophrenia, schizoaffective disorder. Or even having symptoms of those disorders without a formal diagnosis, the risk of both of those is higher. And that increase anywhere from 20% up to several hundred percent depending on the study that you look at. And the subtleties of the end points that that people are are looking at. As well as different sub populations that are being analyzed depending on genetic risk and things like that. So those associations in my opinion are fairly strong and they're compelling in several ways. There have been many different independent studies using independent cohort analysis that have been done as you know. And the directionality of that association has been fairly consistent among studies. And so things related to, or data that are consistent across time, generally show same directionality. Heparin replicated and independent cohorts, lead myself as well as others, to I think at this point, feel that association or the data supporting that association are pretty solid. Another important point and one of the most recent meta analysis is that there seems to be a dose dependence to that association. So in studies where people were able to, again, mostly retrospectively classify people as using sort of a little, a middle amount or a lot in some way. Either in terms of the frequency of their cannabis use or the amount of their cannabis use. Those studies that have been able to do that suggest that the highest risk is associated with the most use. So when you see sort of a dose dependent relationship like that again, it strengthens at least at a minimum that association. And it leads to the causability that there might be some causal relationship, although that's really where the most controversy is, right? So the association, I think, I don't think there's much argument in terms of there, there is an association to cannabis use and people, not all people, some people having a higher risk of developing schizophrenia when they're an adult. The problem is we don't know which population that is. You take all comers, the risk is still higher, it's just not as high. If you start subdividing based on sort of genetics, and other risk factors, that might go up to fourfold or more. That means we don't all know our genotypes. And so conservatively, we want to say that there is an association at the general population level, and people need to be aware of that. The controversy arises when people say that you're using cannabis causes schizophrenia. And there's clearly not conclusive evidence that that's the case. There are many people that believe that. And there is evidence if you look at some of the biology that we talked about earlier in terms of, or not biology, but acute effects of cannabis being able to mimic some of the effects of schizophrenia. There is that sort of underlying physiological effects of cannabis, that might suggest there's some causality there. But that has not been demonstrated at a population level. And there's always counterarguments, such that maybe people that go on to develop schizophrenia later might be more prone to using cannabis before their symptoms develop. Or there might be some common genetic risk that leads to both cannabis use and schizophrenia. That would then, at a population level, be manifested as an association between the two. So we don't know the answers to those conclusively. It's a high area, a lot of people are very interested in getting that answer, especially as more people use cannabis. So I think the jury's still out on whether cannabis causes schizophrenia. But clearly, there is an association between the two, and I don't think that there's that much debate anymore in the literature about that >> No, I totally agree, it seems very strong, this association. The thing is it's an interesting academic debate in some ways about the causal interpretation of that. From a public health perspective, I mean, it seems like everyone should be able to agree, and I think we all do agree, right? That adolescents using cannabis is not a good idea, and especially not if you have some kind of familial risk- >> Right. >> And I think that's a very clear public health message that is, and hopefully, and should get out there, regardless of the academics sort of debating the causality of that. >> And I agree. Some of the studies have shown that the highest risk is associated with early use during teenage, early teenage years. Some studies have shown that, so clearly getting that message out to people, schools, from a public health perspective, that's really important, even if the risk is only 10 or 20%. At the general population level, it's still something that people need to know about and doing due diligence in terms of limiting access to cannabis in places where it is accessible, hopefully to people that are past that window. I think we need to be aiming for that, although, clearly that's not going to always be the case as accessibility is. As we know for nicotine, accessibility is clearly there for people under 18. But at least getting that public health message out, I agree with you that that's important, regardless of whether there's causal, conclusive causal relationship between the two. >> Yeah, it makes sense. Well, just a quick digress for a second here, because one of the things I think is fascinating about this is maybe all of this work highlights the importance of the endocannabinoid system. Maybe the development of that early on, for example, psychosis, right? And if you look at this at all in terms of your research, if you find that kind of interesting too, but maybe if you have a comment, it'd be- >> Yeah, so the interaction between the two, the subjective, but more likely the long-term effects of cannabis use have to be a product of the interaction between the cannabis components. And what's going on in the brain, in terms of your endogenous signaling system, which includes the same receptors that things like THC bind to. So from a developmental perspective, we know very early on, for example, cannabinoid receptors and their endogenously produced ligands are very important for brain development. We know this because they're involved in the targeting of axons to the right place in the brain. They're involved in the division of neurons, as they're dividing and populating the brain. So clearly there's a significant role for this system in the growing, developing, and the wiring of the brain that happens. In humans, quite late in terms of age relative to other laboratory animals, like mice or rats. I mean, people's human brains are developing into their late teenage, and even early 20s. And so although we don't know the details of how the endocannabinoid system contributes at those later points, certainly early during teenage years. It's not too much of a stretch to think this system is playing important roles in how the brain is continuing to develop and learn. And we know that this system is involved in neuroplasticity, for example, things like long-term depression of synaptic strength and changes of synaptic weight. As well as those are well established to be important for things like learning and memory, which we know cannabis affects. So I don't think it's too much of a stretch to think that the effects of cannabis need to be thought of as being an interaction, not only between the drug and the target, but also the drug and the endogenous system, and what it's normally doing. And the ligands that are naturally produced by the brain and the body to act on those receptors, and then how THC affects that. And the most concrete example of that is, how it's not been shown that THC can actually down regulate the cannabinoid receptor in the human brain. And so that's a really sort of tangible example of how using cannabis is going to affect that endogenous system that's supposedly balanced and working normally with the right amount of receptor, and the right amount of ligand. If you layer on top of that cannabis use, especially heavy cannabis use, we know like many G protein-coupled receptors, those are going to down regulate. And when you don't have cannabis on board anymore, you have an imbalanced system. And so maybe some of the effects of withdrawal, or maybe some of the longer term consequences of cannabis use to outlast the acute intoxication are a result of that imbalance that somehow needs to get renormalized after a period of abstinence. So there's a lot we don't know about sort of how cannabis interacts and exerts a long-term consequences, like in the context of schizophrenia risk, right? That's a long-term risk. But certainly, from a biological perspective, it could have to do with the interactions between cannabis exposure in the endocannabinoid systems brain development, and learning and memory, and synaptogenesis, and all those types of things. >> Absolutely, no, I think it mainly just highlights just as an importance of the system, especially early in life, which you spoke to already, but- >> Okay, right. >> So I'm going to go back around for one quick thing here, because the fascinating thing too about cannabinoids, and schizophrenia, and psychosis is the recent data on cannabidiol methanol adjunct, right? So because again, when we talked in class about how it's very complicated, right? You have THC, but you also have other cannabinoids, many of them. >> Many of them, right. >> Very different effects, and so it's fascinating. We just covered a couple of those papers that came out recently on CBD and schizophrenia. So what do you think about that? Is this a promising area of research? >> So I'm not an expert in schizophrenia. I mean, it's not a patient population that I specifically focus on. And so I know there was a smaller positive study published recently on some therapeutic effects of cannabidiol. But you can correct me if I'm wrong. I also thought there was also a sort of a negative study that was published recently also or maybe not as positive. And I'd have to go back and look but I think one of the interesting things about cannabidiol is that we really still don't have a good idea from the biology about what it does. And I think in many ways, certainly in the epilepsy therapeutic spiel, they now may be even be psychosis therapeutic spiel. I'm looking at the effects of cannabis on disease or cannabidiol on disease processes and disease outcomes, has sort of outpaced our knowledge on what this compound is actually doing in the brain, or in the body and other places. So unlike THC, we still don't, in my opinion, have a good answer as to what is, for example, the receptor target for cannabidiol. There are many things that have been proposed but from my sort of reading of the literature, I'm not necessarily convinced that any of those are really have been proven to be that molecular target for this particular cannabinoid. And I think that's true for many of the other biological constituents, bioactive constituents of the cannabis plant that may do certain things, we don't really have a good idea how they work. I mean, as you mentioned, there are hundreds of component constituents of cannabis, although THC and cannabidiol are sort of the making or the largest constituents. And certainly cannabidiol can have biological and psychological effects in animal models as well as in humans. It's certainly not nearly as psychoactive if at all as THC. Yet there seems to be a lot of interest in, for example, maybe even anti-inflammatory actions of cannabidiol or effects on psychotic symptoms or on epilepsy. But how those work, I think, is really still, in my mind, still a mystery. And I think I'm going to reserve judgment as to whether I believe the therapeutic benefits of cannabidiol. But certainly, the public interest in cannabidiol has outpaced, I think, the scientific sort of literature. And I know even here in Tennessee now, you can buy cannabidiol containing products. And they're advertising that for all sorts of things from skin psoriasis to cancer in some cases. And I think that there's danger in that of course, in terms of people not really understanding really what this compound is all about. And the lack of sort of regulatory requirement around proving some of these claims. I think if they're marketed as nutraceuticals or herbal supplements, they are subject to the stages of scrutiny as traditional therapeutics are. So I don't know, I'm a little skeptical. I would be ecstatic if there were sort of a novel treatment approach for schizophrenia as those are quite limited and efficacy of current available therapeutics are suboptimal to say the least. So if there were something that could be derived from the cannabis plant that would truly be effective, I think that would be amazing. I think we would probably need larger-scale studies and things like that to really convince ourselves, as the psychiatric community, that this is something that's going to move forward in a meaningful way. >> Absolutely, no, I think it's so true that the hype has so far outpaced the science, right? And I think even in the scientific community now we're seeing like you said, we're seeing the studies without really a lot of knowledge in terms of the target, right? What exactly is the mechanism or the dose, right? I think this is the thing too, we mean, if you look at low to the doses range, that's just like an enormous range in terms of the doses that people use. >> Yes, yes. >> And scientists have used which basically have very little resemblance to what people are actually using when they go and buy it at the health food store [LAUGH]. >> Exactly, so the amount of cannabidiol you get as when you smoke or use cannabis products is probably a fraction of what people are using in some of these clinical trials, right? So at the epilepsy trials and other trials are using very, very large amounts of cannabidiol that are being ingested orally. Relative to what people would generally get if they're using cannabis, either smoking marijuana or using other oral cannabis products on a more recreational basis or even medical basis. I think the amounts that some of these clinical studies are using are still quite high relative to that. >> Absolutely, no, they are very high, yeah. But it is it is interesting because you look at the story with epilepsy and seizures and every dialect. I mean, clearly there's something there that, obviously, the FDA approved it. You had to cross a pretty high threshold in terms of evidence and so yeah, it's a very fascinating area, but yeah. >> Yeah, I mean, I think there's opinions on both sides of that, too. We may I don't know whether we've had this discussion, but I've certainly had it was some other folks and some of the GW folks too. And I'm still somewhat skeptical about the epilepsy studies and I would like to see those sort of repeated. The unfortunate thing is once something is FDA approved there's little sort of role for additional larger-scale studies. I think once the initial efficacy studies pass the FDA bar, I think that's sort of what we have. I think, at this point, what's going to happen is clinicians are going to begin using it. And we'll know, we'll get that sort of anecdotal sort of feedback over the next three or four years from clinicians and neurologists that are treating these patients, to say is this actually working in practice the way we thought it would or not. And I think, like with most things, there probably will be a subpopulation of kids that probably respond and there probably will be ones that won't. And the clinical trial showed that, I mean, in terms that there were certainly people or children that didn't respond, and there were ones that did. I think what's important for us is understanding or as scientists is beginning to understand what is the mechanism, for example, of that anti seizure activity. How is that really working and how is it interacting with other medications and things like that. As you know this study included was an add-on study and so children were still taking their normal medications that they were taking and cannabidiol was put on top of those medications. And so how the interaction of cannabidiol with those other antiepileptics works is still something we don't really understand, either. >> Exactly, yeah. Well, listen, I think we've run over the amount of time I told you we were going to have. >> [LAUGH] Sorry, I've talked too much. >> I knew we were all right because there's so much to talk about and in your again the breath that what you do is amazing. So thank you so much for taking the time, I really appreciate it. And yeah. >> Yeah [CROSSTALK]. >> I hope we'll have a chance to catch up soon. >> Okay. >> Take care. >> Thanks. >> Good to see you. >> Bye.