Mental Illness & Substance Abuse: Genetics, Psychosis, THC, Dopamine & the Brain | Jibran Khokhar | #190

About the guest: Jibran Khokhar, PhD is Associate Professor of Anatomy & Cell Biology at Western University in Ontario. His lab studies the neurobiology of the co-occurrence of psychiatric illnesses like schizophrenia with substance use disorders.

Episode summary: Nick and Kevin discuss high comorbidity among mental illness, the dopamine reward system, antipsychotics & other psychiatric drugs; the relationship between THC (marijuana) and psychosis; sex differences in the brain; nicotine e-cigarettes (vaping) compared to smoking; and more.

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* M&M #113: Alcohol Toxicity, Vaping vs. Smoking, Tobacco, Nicotine, Marijuana, Cannabis Terpenes, THC, Toxicology, Health Effects of Vaping | Echo Rufer

* M&M #93: Marijuana, Cognition, Psychosis, Addiction, Cannabinoids, THC, CBD, THCV | Amir Englund

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Jibran Khokhar 3:06

So my name is Jibran. I am an associate professor and Canada Research Chair in translational neuropsychopharmacology at Western University in London, Ontario, and I am a neuropharmacologist by training, did my PhD at the University of Toronto, followed by a postdoctoral fellowship at Dartmouth College in psychiatry, and then started my first research program at the University of Guelph down the road. And now I've been at Western for two and a half years. The focus in the lab is around the CO occurrence of substance use and serious mental illness, and we're interested in substances across the board, from alcohol to nicotine to cannabis. And then we as far as psychiatric conditions go, we dabble in schizophrenia, bipolar disorder, and even some work in ADHD now, and we're really interested in cracking the chicken or egg question in that there are relationships that go in both directions when it comes to substance use and psychopathology. And so we're really interested in trying to crack that Yeah, and

Nick Jikomes 4:17

I think we're going to probably spend a lot of time talking about the CO occurrence and the relationship between substance use disorders and certain mental illnesses. But, you know, stepping back for a moment, even more broadly, you know, we there's a lot of comorbidities between mental illnesses, substance use disorders, all of these types of things, a sort of meta result in the broad field of psychiatry and mental illness is that, you know, even though we have a DSM four that categorizes, you know, all of these illnesses into discrete names and categories, you know, we've got depressive disorder, we've got anxiety disorders, we've got schizophrenia, you know, we have words and labels for all these things, and it's very easy to talk about them. Um as islands as these separate things, but you know, as you know, and as many people know, but not everyone appreciates these things. Co occur at a very, very high rate, much, much, much more than you would expect by chance, such that for almost any mental illness you can think of, you know, if you have schizophrenia or an anxiety disorder or substance use disorder. What have you? Your odds of having some other mental disorders, usually, multiple are much higher than they are for the average person in the population. Can you just talk about that a little bit, and how you start to think that, about that and unpack that as a neuroscientist?

Speaker 1 5:35

Yeah. So you know, let's think about it in a few different ways.

Jibran Khokhar 5:42

There's only one brain, and the brain is very much concerted network of networks that act together. And so if there's a pole in one place, there's going to have something's going to give in another place. And so we need to understand that, you know, we don't have meat bins in the brain that you can file things into. It's not like inside out, right? Like it's messy when it comes to the brain and so, so I think there it makes sense that there would be co occurrence, there's genetic overlap between a lot of conditions, both in the psychiatric space and the substance use disorder space. But in addition to that, there is network and brain connection and brain area overlap. The same brain region, the mesocorticolimbic dopamine circuit that we always talk about it with substance use also comes up with schizophrenia and so that there's that brain region overlap. But important that you mentioned the DSM five, right? Like, DSM five is only really good for charging codes for insurance, right? Like, yeah, comorbidity is the rule and not the exception, right? And even when it comes to substance use, poly substance use is the rule and not the exception. And even when you look at diagnostic overlap, right, when you look at across the different diagnoses, if you take each of those symptoms that make up the DSM five, right? Like there's 600 something symptoms that make up the DSM five. Now how many of those repeat across multiple diagnoses? I think over 202 30 symptoms repeat over 1000 times between those diagnoses. So it's not as if that now that we created these neat little windows or neat little bins and pockets, that there wasn't no overlap between them. In fact, the overlap even within the DSM is the rule and not the exception. So I think that probably captures a lot of the different levels where the comorbidity can occur.

Nick Jikomes 8:05

Yeah, it's not, you know, it's not as if there's a circuit in the brain that breaks with schizophrenia and a separate circuit that breaks only with anxiety and so on and so forth. And even for things like substance use, it's not like there's one circuit completely dedicated to nicotine and one completely dedicated to opioids and so on and so forth.

Jibran Khokhar 8:22

And it's because substance use isn't just one thing either. Even when you think about the addiction cycle, the euphoria is something else, and then the withdrawal and negative affect is something else, and the acute craving and the preoccupation is something else. And those are already three distinct domains with three different parts of the brain and very different outcomes and phenotypes. So really, I think it would, it would be far too reductionist to try to reduce any of these things down to one thing.

Nick Jikomes 9:00

And you know, I think maybe we can just start by talking about schizophrenia, because schizophrenia ties into many different related topics that that we can, you know, spend quite a bit of time on. So there's the the illness itself, which is very debilitating, and we can talk about, it's a serious mental illness. It's not, you know, I mean, not to belittle anything else. But you know, depression is often mild. It can be very severe. But schizophrenia is if you have it, it's typically quite debilitating, and can be completely debilitating. And then so there's the neurology and neuroscience to talk about. But also, as we'll come to there are sex differences with schizophrenia, differences between males and females in terms of how it manifests and when it manifests, there are developmental effects. You know, it tends to arise at certain times in the lifespan, and then there's comorbidities, especially when it comes to substance use disorders. So schizophrenia is sort of an interesting single illness to talk about, because it can also relate to all these other domains that are interesting. But let's just start very basic here. What is schizophrenia, and what is sort of the core? What's the core of schizophrenia in terms of what's going wrong in the brain?

Jibran Khokhar 10:07

Yeah, so before I get into it, schizophrenia is also probably not just one thing, right? So we'll talk about what Schizophrenia can generally be, but it's probably a spectrum as well, a psychosis spectrum disorder of soils.

Nick Jikomes 10:21

Would you say that's pretty common, like we talk about schizophrenia, we talk about depression, but each of these things are probably some number of distinct illnesses that we often can't tell apart because their sort of endpoints are similar, yeah,

Jibran Khokhar 10:36

and especially when you think about bipolar disorder with psychosis. Where does bipolar disorder with psychosis end and schizophrenia begin? There's probably not a clear line that's then a lot of people can draw, right? So I think it's important to to know that the there are overlapping boundaries, probably, and that the sorry about that, muted, that I think there is probably an important thing to consider in terms of those overlapping boundaries, but Schizophrenia is a serious mental illness, as you said, very debilitating, serious mental illness that affects nearly 1% of the global population, the three primary domains in which we see symptoms, are positive symptoms, negative symptoms, and then cognitive symptoms. And it's, you know, this is not that there are symptoms that are good and symptoms that are bad. Positive here means something that is added that wasn't there before. Negative is something that was taken away that was there before. In cognitive symptoms would be related to cognitive dysfunction. And so what is being added is now hallucinations, that might they might be auditory, they might be visual, they might be paranoia. There might be, you know, so those are the domains that we usually see.

Nick Jikomes 11:57

They're hearing voices or seeing things. Things are being added to your perception that would not normally be there, not have

Jibran Khokhar 12:02

been there, and then what's being taken away is feelings of pleasure. So Anhedonia is a symptom. It's schizophrenia where you don't feel pleasure anymore. You lose your ability to connect socially with others. So social deficits and dysfunctions also arise, and can be considered a negative symptom. Mood, again, as we were saying, non overlapping boundaries. You know, mood is also significantly affected. And then in the third space, that's the cognitive deficits, cognitive dysfunctions. That's where you see a loss of working memory, changes in ability to pay attention, changes in ability to you know, navigate complex tasks. But in addition to that, even at a more simpler level, things like sensory motor gating, like how does your brain respond to sensory stimuli? And you can understand that even in the positive symptom side, there are things that we usually respond to, sensory stimuli, what we hear, what we see, but then our responses shift, and they change and so so there the cognitive domains, and you can again, even within each of these domains, one can affect the other if you're not understanding the world around you in the same way as you were, it then makes it that much harder for you to navigate it or communicate with it, or right so the the negative symptoms and the cognitive symptoms might over overlap, or your now positive symptoms are now affecting your ability to you know, hear the person that is speaking to you right in front of you, so that might affect Your social symptoms. And so I think there is a lot of overlap even within these three domains, as Nicole

Nick Jikomes 13:48

and you know, schizophrenia sort of famously has an onset in early adulthood. And so, you know, I don't remember all the specific details here, but typically, you know, your early mid 20s would be when someone often starts to manifest the symptoms of schizophrenia, and I've always understood it as probably being tied with either sort of the end of adolescence or the beginning of the quote, unquote, adult brain being, quote, unquote, fully developed. What do we know about the developmental side of this? So the

Jibran Khokhar 14:15

18 to 21 is the average age of onset in men, and 21 to 25 is the average age of onset in women when there are factors. You know, there might be protective factors related to sex hormones, for example, but then there are also societal factors that impact that as well. But I think it is by definition, a neurodevelopmental disorder. They're across multiple levels, everything from prenatal infections to insults, developmental insults throughout life interacting with genetic risks. Are, then what give rise to the schizophrenia? And so I think there's really a solid neuro developmental component. And there are theories that, you know, Daniel Weinberg and others have put forward, and even those have been used to then trying to model schizophrenia in animals. And a lot of them will then use these neurodevelopmental insults to introduce circuit dysfunctions that resembles schizophrenia and animal bodies

Nick Jikomes 15:31

and how. How much do we know about the biological causes? I mean, I know that there's still much to be discovered here, but are there certain types of circuit deficiencies, certain types of biological dysfunction, certain networks in the brain that are reliably dysfunctional in a certain direction in most schizophrenics, yeah. And so

Jibran Khokhar 15:52

in patients with schizophrenia, you see hallmarks, right? So there's this imbalance between limbic and cortical dopamine function, right? And so that's something that's seen. In addition to that, in brain imaging studies, you see changes in the size of the hippocampus, for example, the anterior hippocampus, and that's one of the more robust meta analysis findings in the brain. But even at a cellular level, you see differences in synaptic pruning, for example. So one of the strongest hits that we have as far as the genome wide association study for schizophrenia is actually in the major here, still compatibility, complex like the immune related function, and that has been suggested that, you know, there is a normal going back to the neurodevelopmental disorder piece a normal trajectory of brain development right when, especially when you're young, your brain is trying to understand the world around it, and all of these branches happen at the level of your neurons, right? And then as you grow up, that refinement starts to happen, where you start to prune away at some of those branches and to get to that, what is like the fully formed adult brain, if there's such a thing. But you know, by 25 maybe you've gotten to some place, your brain still remains plastic. Your brain is still able to create new cells of all sorts, right? So there's still room for change. It's not like you know at 25 that's when your brain stops, but maybe that maturation process stops by then. And so one of the things that we do know is that there is aberrant synaptic pruning in schizophrenia as well, and that might be one way in which that circuit dysfunction manifests itself through neurodevelopment, yeah.

Nick Jikomes 17:43

So, so roughly speaking, as you develop after birth and you mature as you become an adult, throughout that whole period, there's phases of synaptic pruning that happens. You have many more connections to begin with. Many of those actually go away, and part of a big piece of brain maturation is actually the loss, or the pruning away of excess connections and the preservation of some important ones. Yeah. And so you're saying that there seems to be a pruning issue in people who develop schizophrenia, and this is actually tied to genes of the immune system,

Jibran Khokhar 18:20

yeah. So, and I think there's some really nice, compelling evidence in that, but then there's other genes as well, right? Like we have, it is a polygenic disorder. We have, you know, 80 different de novo mutations, and we have something that's actually called disrupted in schizophrenia, one a disc, one gene, and there are genes and catecholaminal methyl transferase genes, and don't mean the two receptor genes, and don't mean metabolizing and catabolizing genes. So there is like, it's a complex disorder, and it cannot come down to one gene, but it's that complex interplay between all those genetic factors, and then add on top of that, the environment. So things like immigration status is a risk factor. Cannabis use, especially during adolescence, is a risk factor. And again, even those relationships are bi directional, and we probably talk about it later as well, especially this relationship between cannabis and schizophrenia. But I think there is, it is it remains a complex disorder that we shouldn't try to reduce down to one thing causing it. Yeah.

Nick Jikomes 19:30

And so one of the networks, or neuromodulatory systems, that is tied to schizophrenia and psychosis more generally, is the dopamine system. And you know, I've covered this a lot in the podcast in different ways. People often talk about the the dopamine system, or the reward system, or the mesolimbic dopamine reward system. And as hopefully, many of my listeners, listeners have have learned at this point, it's too simplistic to think about dopamine as the same as pleasure. Dopamine does not equal pleasure reward. It's involved in. Learning, but it's involved in motivation and cognition. More generally,

Jibran Khokhar 20:03

it's involved in locomotion. Yeah, it's

Nick Jikomes 20:05

involved in locomotion. So we're much simpler than we

Jibran Khokhar 20:08

that, you know, reward cognition might be too complex. It's even, you know, that's why Parkinson's disease is dopaminergic in its etiology. Yeah.

Nick Jikomes 20:18

And then, you know, maybe one, one point of reference right here that could be useful to people is that is that what we call anti psychotic medications that treat that that can treat certain types of symptoms for things like schizophrenia, well, but not others, they're often acting on the dopamine system. Can you? Can you just talk about what we know there

Jibran Khokhar 20:35

a little bit. So most anti psychotics, most typical and atypical anti psychotics, are modulators of dopamine function, specifically dopamine d2, receptor function in the brain. They're antagonists of the receptor, and so the older, classic typical antipsychotics, like galore doll and others, were potent inhibitors of the receptor. But with that comes again talking about locomotion, the extra pyramidal symptoms that were there, so that would affect gait, for example, and the main the people using antipsychotics. And so that was a problem. And so that's why we've shifted from typical antipsychotics to more atypical antipsychotics. And the difference is really how potent Are they as an antagonist at the dopamine d2 receptor, and how broad their function is beyond the dopamine d2 receptor and so things like Clozapine, olanzapine, aryptome, these are the newer antipsychotics that are atypical, and they are usually associated with less of a potent antagonism at the domain D, u2, receptor, but also they have action at other receptors like the muscarinic and the serotonergic system in the brain. So serotonin versus muscarinic acetyl cholinergic system, even histaminergic systems. And so they have been a broader, Messier profile, but does not have the same extra pyramidal symptoms associated with the typical antipsychotics

Nick Jikomes 22:09

and so, so the dopamine system is gone awry in certain ways in many, many forms of psychosis, including schizophrenia. What are the anti psychotics typically good at treating and what are they typically poor at treating? When it comes to schizophrenia,

Jibran Khokhar 22:26

most anti psychotics are pretty good at treating positive symptoms,

Nick Jikomes 22:30

so hallucinations and things like that. Not a

Jibran Khokhar 22:33

lot of antipsychotics are all too great at treating negative symptoms, and a lot of them don't even touch cognitive symptoms and the you know, my favorite drug all of all classes that remains an anti psychotic. It's Clozapine, which is probably the most efficacious anti psychotic we have. But because of its black label warning and side effect profile. It's only used in the most treatment resistant of patients, but it is, in fact, the most effective antipsychotic we have, and that does a pretty good job with positive symptoms. Actually can even touch negative symptoms, at least in terms of Anhedonia and stuff. It may have some effects on cognition as well

Nick Jikomes 23:21

I see. So the movie A Beautiful Mind with Russell Crowe, where he plays a schizophrenic mathematician. It seems like it was probably actually a pretty good representation of how the treatments typically affect you. So it was taking care of his hallucinations, positive symptoms, but it left him sort of anhedonic and unmotivated, and sort of it had cognitive side effects as well.

Jibran Khokhar 23:43

Yeah, no. And you know, that's that remains a challenge for patients with schizophrenia in general, and and then the other thing that often also complicates things right? Like, there's already all sorts of reasons for treatment, non compliance, the the paranoia, mistrust of the medical enterprise, and all of that is there that contributes enough to treatment non compliance. But add on top of that some of the side effects that come from the anti psychotic medications themselves and excessive weight gain, metabolic disorder and all of these other things then also further worsen that treatment on compliance piece,

Nick Jikomes 24:22

yeah. I mean, that's, that's an important thing to emphasize is, you know, even though this is a mental disorder, even though these drugs are acting on dopamine, which we think of as a neurotransmitter in the brain, doing brain stuff very, very often with these things, these psychiatric medications, you often have metabolic issues that span the entire body. So these things aren't sort of limited to the linguistic domains that allow us to talk about them.

Jibran Khokhar 24:46

And man, you know, those effects are probably central as well as peripheral, right? And so this is the thing with the brain. Anything that's going to act in one part of the brain is also going to act on the other part of the brain, and that part of the brain is connected. To the other part of the brain, right? So, and that's where some of the problems start. So,

Nick Jikomes 25:06

so, as we mentioned, schizophrenia, typically you see the onset in, you know, young adulthood, late adolescence, your early 20s, basically, and famously, you know, you hear this often, that schizophrenia can be precipitated by some type of stressor at that time period in your life, people often talk about, you know, if you have a predis genetic predisposition, say, to schizophrenia or runs in your family, you should avoid psychedelics, because they can trigger schizophrenia to emerge. Or adolescent use of THC can trigger schizophrenia to emerge in someone with a predisposition. To what extent is that true? And what do we actually know there about these precipitating factors? So they

Jibran Khokhar 25:44

you know, we can think about precipitation in different ways. So let's talk about on one side, substance induced psychosis. That's a real thing. You see it with cannabis. You see it with hallucinogens, psychedelics, you see it with methamphetamine. And when you have substance induced psychosis, there's usually three paths that happen after

Nick Jikomes 26:13

and before you go on. So when you say substance induced psychosis, are you talking about the onset of permanent schizophrenia, or do you mean the onset of a temporary and reversible psychotic

Jibran Khokhar 26:23

an acute psychotic state induced by substances? And that's where I'm going to get into the what the potential outcomes are. In the first case, you actually do end up going from having an acute psychotic state to an organic psychotic disorder.

Nick Jikomes 26:43

So an acute psychosis precipitated by drug use can sometimes turn into a long, lasting psychosis. The

Jibran Khokhar 26:48

second one is that you stop using the drug completely, and you never have a psychotic episode again. And that's where, you know, there's some level of self selection as well that happens, right? And so even with cannabis, where most people be like, Well, I never experienced such a thing, or I've never had a psychotic episode, or I've never felt like, even though THC is a psychomedic, people are like, I've never experienced such a thing. Well, it's because the person that tried it for the first time and had a bad trip never tried it. Yeah,

Nick Jikomes 27:17

yeah. The person who takes the edible and has a temporary, acute, psychotic like state, probably doesn't try it

Jibran Khokhar 27:23

again, try it again, right? So there. So there's a selection bias that keeps in when people generally talk about this, and that's why nothing polarizes people more than cannabis, whether schizophrenia or not, whether it's a psychotic

Nick Jikomes 27:38

Oh, I mean, I'm sure, I'm sure we'll get into this. But as someone who worked in the marijuana industry, I mean, yeah, this is just a huge issue. You've got, you know, you've got one pocket of people that, you know, think cannabis equals psychosis, and you've got another pocket of people that says cannabis can't possibly cause psychosis, because I enjoy it

Jibran Khokhar 27:57

that. But also they'll say, Oh, well, cannabis has gotten gone up in potency. Why haven't we seen an increase in the number, the prevalence of schizophrenia? So and those are all real, valid concerns and questions. Like, I actually tend to find myself somewhere in the middle, and I think, I think we need more people in the middle. I have colleagues that who are preclinical scientists who swear that THC causes schizophrenia, and on the other side, I also have pre clinical colleagues who are like, THC does not cause schizophrenia, right? And so and I think the truth is still somewhere in the middle, and I think it's important to to have that nuance when we talk about it. So going back to the thing from the sort of three paths. So one is you develop an organic psychotic disorder. The other one is you never go back to it again. And the third one is, anytime you use the substance again, you do have that acute substance and do psychosis, but you don't have a chronic psychotic disorder

Nick Jikomes 29:01

I see So, okay, so let me summarize for people, because this is important, and I rarely hear people sort of bucket things this way. So there are a variety of drugs that are associated with the induction of psychotic states of different kinds. The big ones that often come up the most are methamphetamine hallucinogens, including certain psychedelics and things like THC, and there are sort of three ways that psychosis can be induced. One, it's temporarily induced, but then that temporary, acute psychosis transitions into a chronic form of psychosis, such as schizophrenia, in some cases. The second thing that can happen is there's a temporary psychosis, but then when the drug goes away, so does the psychosis. So it's just sort of a side effect of the drug in real time. And then the third is that someone will have that temporary psychosis every single time they try a substance, whereas someone else might just have it once if they try a lot, but they don't have it every other time they try it. Yeah.

Jibran Khokhar 29:56

So that's that basically captures all of that. And I think. So where you then see it in terms of precipitating and even when this relationship between cannabis use and schizophrenia, where there's probably real signal, is in two places, prevalence and age of onset, so there's a greater prevalence of schizophrenia in those that use cannabis during adolescence, from the Swedish conscript studies and others, and there's a lower age of onset. And so especially with higher THC or more potent forms of skin of cannabis, you do have a earlier age of onset of schizophrenia. So I think that those are the sort of places where you can see it show up. Yeah,

Nick Jikomes 30:45

I want to unpack the relationship between cannabis and schizophrenia a little bit further. I want to take a minute to sort of summarize what I understand to be sort of the state of the literature on this and why perhaps there's a lot of confusion and antagonism between people on this point. So the question is, does cannabis use have a relationship with schizophrenia? Is it causally related to the onset of schizophrenia? And you know, there's questions here related to onset of use. Do you start using it earlier in life versus later potency? Do you are using a relatively potent or less potent form of cannabis, etc, etc. My sort of bird's eye view of the literature here is okay. If we just look at the correlation between cannabis use and schizophrenia there, there obviously is a correlation there. Nobody disputes that. The question then becomes, okay, is this a correlation that represents a causal linkage, or is this a correlation without causation issue? And then there's a bunch of studies. There's a bunch of correlational epidemiology style studies. There's a bunch of twin studies out there, and they can try to control for as many confounders as possible. And some of them do that, and they come out saying, yes, indeed, there does seem to be some relationship that could be causal between early adolescent use of THC and onset of schizophrenia. And then there's other studies, twin studies, that control for various confounders, including genetics. By the nature of a twin study, and they say, actually, when you control for the right confounders, there is no relationship. This is probably correlation, but not causation. I suspect that, as you mentioned earlier, this is an issue where the answer is somewhere in the middle, and there probably are genetic and environmental factors that mean that there is a causal linkage for a subset of the population, but perhaps not for everyone. What is sort of your take on the causal linkage between adolescent THC use and schizophrenia and what the literature says in totality?

Jibran Khokhar 32:35

Yeah, so if it's okay with you, I'll get into a little bit of causation versus correlation, a little bit, where that comes from, and what that technically means. And then we can get into the cannabis in schizophrenia a little bit. Yeah, yeah. Okay, yeah. So, so there's this hill 1965 like Hills conditions for causation, right? And so some of the things that they talk about in it does an agent cause a toxicological response? And it was in the context of tobacco. And so the seven conditions, and I mean, there might be more, but they are the strength of the association. So whether there's a relationship between the independent and the dependent variable, the consistency of findings, the biological gradient, is there a dose response as the dose goes up, as the amount of THC gets higher, you see this temporal sequence you know, which comes first the chicken or the egg or the cannabis or the schizophrenia. Then there are the biological and theoretical plausibility and the mechanisms of action, and then coherence with established knowledge, and so there's no other competing hypothesis that might explain it. And then lastly, the specificity of association, so how closely the cause is tight is linked with the outcome. So those are you know, this is a OG causation, correlation, criteria that hill laid out. And so I think going through each of these kind of will help us see, figure out that piece a little bit. Yeah, there's

Nick Jikomes 34:16

multiple boxes to check here, and we want to see, like, How many does teach? How many

Jibran Khokhar 34:20

other boxes can we check, right? So, so then, if you look at maybe, there's 12 studies, you know, Arsenio, 22,002 1019, 90, zamat, 2011 McGrath, 2010 like and they all sort of show cannabis exposure, and then odds ratio for schizophrenia. And odds ratio for schizophrenia varies, and it's anywhere between two as the as the amount of cannabis exposure goes up, the odds ratio is anywhere between two to seven. And so there is so you know, the logistic regression puts like the odds ratio across as if you. Did a meta analysis across all of these studies around four and so yes, there is a strength of association. That's there biological plausibility. You take Cyril D'souza work where they gave intravenous THC to healthy participants and to those with schizophrenia, in both the healthy participants and those with schizophrenia, it increases what's called the pan, the positive and negative symptom score, which is used to assess schizophrenia, right? So it increases it and it's time dependent, you see increases in positive symptoms around showing up around 10 minutes. They last for an hour, and then by three or four hours there. So

Nick Jikomes 35:40

just to be clear here, for people so positive symptoms that would include things like paranoia. So if you think people are talking about you, even though you're not literally hallucinating voices, that's a positive symptom. Obviously, some people get that when they consume a lot of THC and schizophrenics,

Jibran Khokhar 35:54

but yeah, I agree with you completely. But that's just one symptom, right? But the scores that these healthy participants got up to were like 1011 so multiple positive symptoms and multiple negative symptoms showed up. So it wasn't just paranoia that showed up,

Nick Jikomes 36:09

right? I mean, the other thing I wanted to point out there for people too, is when we think about something like hallucinations, people often will think about like the visual hallucinations you'll get on a trip to mean psychedelic. Now, if you did something like THC, you're not going to trip in that way. It's not a psychedelic. But very often people will think they hear people talking about them in the next room, and that is a kind of auditory hallucination.

Jibran Khokhar 36:32

Yeah, so I and I that that I agree completely, and that makes sense the other one, and this is where it gets interesting, right? Like we talked about it earlier, the specificity of association, when one goes up, does the other. And so while you know the there's a paper by keel at all that talks about this considerably, and they said that they found no increase in the number of cases of schizophrenia. That that success, there is not even an increase in the incidence of schizophrenia to explain while cannabis use has gone up, it might not be the case, but there are some more recent studies, especially the Swedish they do a much better job of capturing some of these things, right? And so as far as incidence of schizophrenia per 100,000 is concerned, like you've actually seen ebbs and flows. But like in the 1970s it was around 20% it dropped down to around 15% in the 1980s and now in the 2000s it was around 30% or 27 30% and then I close above 30, not 30% sorry, I didn't mean 30% it's in 100,000 so 30 and 100,000 versus 35 and 100,000 but because it's such small numbers, right, that flutter doesn't show up. It might be a quarter of a percent or a half of a percent. And so there, that's where I think we probably don't see it as well. But I think, I think that the where it gets really interesting is genetics. So this is one of my favorite Papers Past mid 2018 I think, did I send it? Maybe I didn't send it to you. Pasmin 2018 it was the title of it is GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits and a causal influence of schizophrenia. So remember, this is a genome wide association study for lifetime cannabis use. This is not a schizophrenia study, okay, whether or not you have used lifetime cannabis use is not the most specific outcome, right? It's rather big. It's whether or not you've used it. So one or a zero, did you use it? Have you ever used it or not? Have you ever used it or not? You know, a lot of the population would fit under a cannabis user in that condition when you looked at the genetics. So this was 23andme and UK Biobank, the largest possible data set that we had at that time, some cool genes showed up, some of those genes we're studying in the lab right now.

Unknown Speaker 39:08

They showed that there is

Jibran Khokhar 39:12

genetic overlap with psychopathology generally, but a causal influence of schizophrenia genetics on whether you're going to use, like lifetime cannabis or not, whether you're going to try cannabis even once in your lifetime,

Nick Jikomes 39:25

what? How do you establish a causal link in a study like that? So this is

Jibran Khokhar 39:29

what's called Mendelian randomization. Our germline DNA does not change, right? Like, no matter what you use, no matter what your environmental influences, our germline DNA stays the same, right? You have a epigenetic changes, but the DNA season and so what you can do is kind of look at, okay, these are the genes that confer risk for schizophrenia. These are the genes that confer risk for lifetime cannabis use. If you were to look for the genes that confer risk for schizophrenia in the lifetime cannabis use, GWAS, how many of those show up? There versus the other way around. So you can get a unidirectionality or BI directionality. And so this is, you know, you're basically randomizing by chance. You would have expected a randomization of a Mendelian trait in one population versus another, but one one is selectively over represented in one population that suggests

Nick Jikomes 40:24

the plausibility that is driving. It's driving,

Jibran Khokhar 40:27

right? So that's, that's where the word causality is coming from there. And so Mendelian randomization is a wonderful technique, and I think,

Nick Jikomes 40:35

you know, so basically, yeah, if I'm hearing you correctly, maybe one way to think about this for people is. So I'm gonna imagine three buckets of studies. One is a purely associational study. So you're simply asking, is one thing statistically associated with another thing? The opposite sort of extreme would be a cause and effect experiment that you would do in like a laboratory animal. You can inject something into an animal or take something away and really look at cause and effect directly, and these Mendelian randomization studies that you're talking about are sort of in the middle, in a sense, where you can look to see if there is a directionality to the relationship. Do these genes always, or nearly always, or more than often, the chance predict the presence of something else, in this case, lifetime incidence of schizophrenia, but you don't see it in the other direction. And so it's not merely Association, but it's also not a functional test.

Jibran Khokhar 41:26

Yeah, it's not a function test. And so, but there are other studies that have done, you know, cannabis use disorder, GWAS and and actually also show, you know, an increased risk for schizophrenia, even in that and so, but then you also see it with there's a lot of overlap in traits, right? Like cannabis, you also see a higher rates of smoking, and you also see higher rates of alcohol use. And those also overlap, right? It's right, so it could be possibly explained by a third gene or some pleiotropy at the genetic level, right? Like where it's now the same gene is contributing to multiple outcomes and so but it at the very least, it suggests that it couldn't possibly be as causal, unidirectional relationship that we make it out to be, right? So that's on the genetic front. But I think also what's important is the high rates of cannabis use disorder in people with schizophrenia already, and so they're already predisposed to cannabis use in some way, shape or form. But also, I think it's important to recognize that some of these things, like even though that piece that I mentioned about temporal relationship, right? Like cannabis, teens use cannabis, and schizophrenia happens when you're 18, at the very least, if not later. So just because one came before the other does not mean that that one thing on the other, right? The time that those things happen.

Nick Jikomes 42:59

Yeah, right. So, schizophrenia typically has an onset in your 20s and teens typically do all sorts of stuff, including marijuana,

Jibran Khokhar 43:06

yeah, yeah. So, and then even those animal studies that you mentioned, right like so, somebody might come and say that, Oh, THC causes schizophrenia in rats, right? It, they also were giving a honking big dose of schizophrenia. Of THC injected into an animal. And so that point that I made earlier about cereal de Souza study that was an intravenous THC, and yes, at high at an intravenous dose, where it's 100% bioavailability, it will be a psychotomimetic. And then if you do that in an animal, and give a honking big dose, and you inject them, and inject them three times a day, and you keep escalating the dose and and then you assess some, you know, you put them in an open field, and you put them whatever measures that people come up with to say it's schizophrenia, maybe it does cause kids, right? But it's not representative of what use looks like. And so in our heads, for example, when we give vaporized cannabis every day to an adolescent animal, resulting in plasma levels of THC that are much lower, like a 10 to 50 fold lower than what you might give with an injection, you don't see that shift in sensory motor gaining in adulthood. Yes, you do still see changes in cognitive function and stuff, but the hallmark of schizophrenia you don't see anymore. So I think it's important that we we are nuanced and even how much weight we put on the animal studies that have happened. But importantly, I think it's really important that we recognize that that genetic bi directional relationship makes it very complex. So yeah, because the people that were going to go on to have a risk for schizophrenia anyways, were more likely to try out cannabis and possibly develop a can. Abuse disorder to begin with.

Nick Jikomes 45:03

And do we know why that might be fundamentally, is it because things like the dopaminergic circuitry that is involved in schizophrenia is also involved in things like motivation, reward learning, the very circuits that THC interacts with? Yeah. But also,

Jibran Khokhar 45:21

let's think about like all the potential hypotheses, right? Like there's a shared susceptibility hypothesis to what you mentioned, and this could be a genetic susceptibility, like we've been talking about, or it could be a circuit level susceptibility. It could be self medication, as it's called, and even though self medication hypothesis doesn't necessarily hold true. So Kantian was this, like psychoanalyst that first suggested it right in the context of depression, and then it's been sort of taken and applied to it. You don't not all of it holds up, right? Like if treatment non compliance is already an issue in schizophrenia, why would you use cannabis if you don't use your antipsychotics, the symptoms usually arise much or the cannabis use usually arises way before the symptoms ever come in. But also, you don't see a relationship between amount of cannabis use and symptoms. In fact, people who have the most severe negative symptoms are, in fact, protected against substance use, so self medication doesn't always check out. But that doesn't mean that somebody who watches some podcast or some YouTube video, or some friend somewhere who said, when I felt that I tried some pot and it made me feel good. And so you're going to try it, even if it actually doesn't medicate you, you're gonna be like, Alright, let's try it. And, you know, cannabis, especially CBD, ends up having, like, the best PR, right? Like, so we can talk about that later as well. The expectancy bias is real, and that's why a lot of things with cannabis clinical trials never come out of the wash, because it's, you know, the placebo group also shows a considerable effect, and so doesn't mean that people aren't, in effect, using it as self medication, even if it is, in fact, associated with worsened outcomes for them through its continued use, right? So I think there's multiple factors that that contribute to it.

Nick Jikomes 47:21

So So in your view, after looking at all the literature on this, you know, if someone just asked you, the regular person just asked you, point blank, okay, is there does cannabis use during adolescence potentially make you more likely to develop schizophrenia? Is there a clear yes or no answer to that question?

Jibran Khokhar 47:38

I say there is a link, there is a link. And therefore, if there is any chance that you have any genetic risk for schizophrenia, it's better to avoid it, or start low and go slow and stay low for as long as you can. And like, you know, wait until you're 25 like all of those things, like, just delay it, just enough that you, you know, sort of cross that, that scary period. But I would never say that cannabis causes

Nick Jikomes 48:14

so, you know, we talked about this age of onset issue with schizophrenia, and that, you know, certain things can precipitate the onset of symptoms. Is there? So is it when people develop schizophrenia in early adulthood? Is that a sensitive period in the sense that, are there people that have all of the hallmarks of a schizophrenia predisposition, a family history? They have the right genes that put them at risk, if you just sort of wait long enough, if you get past the age of 25, or 30, do your chances of developing it sort of go away.

Jibran Khokhar 48:45

Yes, sometimes you can see late onset schizophrenia. But that it's true, it usually just arises within that region. What's interesting is even that sex difference that you were mentioning earlier than we talked about those who use cannabis, there's a women who have an earlier onset of schizophrenia often use cannabis, so so it can even take away some of that protective effect, for example, or that delay that usually come you see it there, but, but I think it's also important to consider that even When you think about a family relative, a first degree sibling, for example, a first degree relative of somebody who has schizophrenia that does not have schizophrenia, you actually see much higher rates of cannabis using that population as well.

Nick Jikomes 49:31

So so if I have someone in my immediate family with schizophrenia and I don't have schizophrenia, even if I never develop it, I'm more likely to use, probably, drugs in general, but cannabis in particular, yeah,

Jibran Khokhar 49:43

yeah. So I think that again, making this picture that much more complex, I want to

Nick Jikomes 49:50

talk a little bit about sex differences in the brain here, and this ties into both schizophrenia and cannabis use, and how cannabis and th in particular affects males versus. Females. Let's start with schizophrenia. My understanding is it's more common in males than females. Is that true?

Jibran Khokhar 50:05

Yes, and the CO occurrence with the substance use disorder is also more common. So male dominance. 75% of dual diagnosis cases are males.

Nick Jikomes 50:15

How much more common exactly, is schizophrenia in males than females? Is it a huge difference.

Jibran Khokhar 50:20

It's not a huge difference, especially, again, it's because it's 1% right. So however you slice this, it's going to be a 6040, right. Like you're not going to get a big differential there.

Nick Jikomes 50:33

And do we? Do we know why that kind of sex bias exists?

Jibran Khokhar 50:39

I think it's important to then realize how societal expectations, but also help seeking behavior, but also how society views mental illness. And so there's all sorts of layers that complicate this. And then if you add things like race on top of that, it gets like, I don't know how, if you've heard of the protest psychosis, or the prevalence, the high prevalence of schizophrenia in black males, if, in fact, it's actually been referred to as a black mal