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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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 male disorder, and even an over diagnosis of schizophrenia in black males, right? And so, so there's, there's all sorts of societal factors that also affect whether or not somebody is going to be diagnosed with schizophrenia or not,
Nick Jikomes 51:40
right? And I would imagine, you know, when they do a lot of these association studies and these GWAS studies, these twin studies and stuff, if there is a systematic relationship between the rates of schizophrenia and things like sex, males versus females, and things like race, you know, and what sort of lineage you belong to, and it's only 1% of the population, you know, if you have to sort of keep sub slicing the groups like this, the statistical power goes away quite quickly. And
Jibran Khokhar 52:06
you know, to be honest, we haven't done a great job of having diverse data sets. Yeah, like we what we know most about in neuroscience is the white male brain, white male adult, healthy brains, right? Like, that's what we have studied the most. And then every sort of additional cut that you add just gets it further and further lower. So even when it comes to genetic studies, we don't have a lot of genetic studies in populations outside European Americans and then African Americans, that would be the second and then beyond that, we don't have much at all. And so even the genetic association that I'm telling you about today, they only are in one racial group or two, maybe. Yeah.
Nick Jikomes 52:54
So one thing that I know, that there is a decent amount known, is the effects of THC in males versus females. Can you start to talk about that a little bit? Look, give us a bird's eye view to start with. How does THC impact men versus women differently? Is it more potent for one of the sexes
Jibran Khokhar 53:13
than the other? Yeah, so I think there's different layers, right? So potency, the technical definition when it comes to pharmacology is how well that molecule, the THC molecule, interacts with the receptor in the brain that is a part of your endocannabinoid system, but interacts with these exogenous cannabinoids, and that would be the CB one receptor, for example, the cannabinoid receptor one right? So there are differences there between males and females, and that's related to both expression level, but also, because it's the gbcr, it's a G protein coupled receptor, all of those downstream mechanisms that are activated, they also have sex differences, and so that's the pharmacodynamics,
Nick Jikomes 54:03
but the key molecular component that is responsible for the psychoactive effects of THC, the CB one receptor right out of the gate, tends to vary systematically in terms of where it's expressed and how much is expressed in males versus females. Yeah,
Jibran Khokhar 54:17
and there are, there are differences. They're not huge differences, but there are differences there. But importantly, it's not just how the drug interacts the brain. The other piece of it is how much drug gets into the body, and how that drug is distributed in the body, and how your body gets rid of the drug. And that's the particle kinetics piece, and that's just as important, if not more important,
Nick Jikomes 54:41
I see because even if everything in the brain was identical between males and females, they had the exact same CB one receptor profile. They consumed the exact same dose. You're saying one person's body might clear it more quickly than the other, for example,
Jibran Khokhar 54:54
yeah, or metabolize it from that THC compound to another. Compound, which is, for example, the 11 hydroxy THC compound, which is also an active drug, partial agonist at the CB one receptor, just like the parent and women make more of the 11 hydroxy THC compared to men. And so when it comes to edibles, not only might they have differential effects from the parent, but because they make more of the 11 hydroxy THC, which is a longer lasting metabolite in the body. That effect may last even longer, especially with an edible that goes through significant first pass. Effect goes through the liver and get a lot of it gets metabolized, I
Nick Jikomes 55:34
see so. So when it comes to 11 hydroxy THC, the metabolite of THC, how much of it is inside of someone depends on how they consumed it, whether they ate the THC versus, you know, inhaled it, and whether they're male or female, yeah,
Jibran Khokhar 55:46
yeah. So that those are important factors, but then there are additional layers to it as well. You know, in women, we know of the telescoping effect, and so while they might not use as much, they end up progressing through the stages of the addiction cycle faster than men. In addition to that, we know that there are differences in how quickly men develop tolerance to the effects of teaching, which is a very important part of THC, that of cannabis and THC action that we maybe don't see as much with other drugs. And so the tolerance women become more tolerant to THC faster than men do, for example. And so it's at multiple layers, and it's again important. And so even you know, the studies which then give THC to male and female rodents, or like they will just give the same dose to both sexes and then say it all, males are more likely to have skin so many Well, God, they were processed very differently, and they did different things. And I think that's why it's really important to be considerate of the multiple places that each of these compounds can be at.
Nick Jikomes 57:02
Yeah. Well, let's, let's, let's think about a two by two grid here. So males females and then inhaled THC and edible THC, if we give everyone, if we were to give everyone the same exact dose of inhaled or edible THC, males and females exact same dose, and they all have the exact same use history, which which quadrant of the square is going to have the strongest psychoactive effects? Would it be the females eating THC
Jibran Khokhar 57:27
depends on what time you're asking right. Like, how many hours after taking it right? Because that peak right. Like, if you what you might call a visual analog scale, measure of how high are you right? Like you just ask somebody to draw on a line from zero to 10. How high are you when they drive that already scales Right. Like so you see, so try to draw a graph of my hands, x and y axis. Time after taking it, it's how the peak is higher plasma concentration is higher when it comes to inhale TC, and that peak might be higher, and then it comes down quickly, whereas that one doesn't get up to the same way, but then lasts a whole lot longer. So are you looking at area under the curve, how long that effect lasts, or what that peak height is, or and then on top of that, add the differences between what you might call volume of distribution, right, like more fat in the body versus less fat in the body versus women. So then TC quickly, even though it enters into your bloodstream, gets redistributed to those fatty tissues, and then it slowly reaches out over time. And so then it's possible that somebody who has more fat tissue, it goes there quickly. And then your plasma level may not be as high, but there's enough of it stored in your fat tissue. And then it's you're gonna keep, like, feeling that effect. You're gonna keep testing positive on a urine test. You're gonna so there's, like, I this is why. Well,
Nick Jikomes 59:00
instead of thinking about blood levels, what if our measure, what if we just have a behavioral measure of intoxication? Yeah,
Jibran Khokhar 59:08
but then tolerance, tolerance. Are you saying? This is a first time user? Say, everyone's first time. Okay, see, so then that's where, this is where, like, I, you know, people, all of these companies, especially when I was first starting the lab in Canada, who legalized, can legalized cannabis, they were coming to me like, we want to establish a roadside test for cannabis. I was like, here in lies the problem, right? Like you actually there's this really cool thing called the cannabis reverse hysteresis effect. It sounds like a cool name, but again, looking at a graph. And so on the y axis is exactly what you're asked, what you're mentioning, right? Visual analog score. Have score, how high do you feel? Yeah, and on the y axis is plasma THC concentration. So now you know you actually see a circular graph. So where, when the plasma concentrations have. Come down again, your VAs still stays high, and so that's why it's really hard to then. So even when you're setting up the question, you said, Let's ignore plasma. So
Nick Jikomes 1:00:10
in other words, you're saying people, when people report that they feel the highest, it's not when their blood levels are the highest.
Jibran Khokhar 1:00:16
No. Well, there might be a point where it is the highest in both cases. But there are points when the blood levels have come down and you're still feeling really high, yeah, and there are other points when you were feeling just as high and your plasma levels were actually higher. And so the plasma levels are not indicative of high, how high you feel, right,
Nick Jikomes 1:00:35
right? And I guess the natural interpretation of that would be that when your blood levels are high, you know the drug is, you know, circulating at high levels. It's probably binding to CB one receptors and things like that. But even after it goes down, there can be long, lasting effects that have already been triggered, that linger beyond the blood levels. But
Jibran Khokhar 1:00:52
also because of the redistribution, right? So it's already gone into the fat, but also because your brain is pretty fat heavy, your brain may have a very different amount of TC that you've
Nick Jikomes 1:01:03
Yes, so you know, if someone, if you get a blood draw to measure your blood THC levels, it's, you know, venous blood from your arm that might not be indicative of what the brain blood levels of? THC, yeah,
Jibran Khokhar 1:01:13
yeah. So that's what? So that's where I I'm not trying to avoid your question, but I think, I think, and it'll also differ on which subjective effects you're talking about, euphoria, versus sleepiness, versus impulsivity. And there's even within it, there's something called the nesbits paradox, right, where you have less locomotion, but you have more impulsivity, and so you end up doing, wanting to do more, but able to do less, right? So there, so I think there's, depending on which you which of those subjective effects you think about, it will differ based on males and females.
Nick Jikomes 1:01:55
How common is it for there to be fairly substantial measurable differences in the reaction that males versus females have to psychotic drugs or psychoactive drugs generally.
Jibran Khokhar 1:02:08
Again, they differ both on the pharmacokinetics and pharmacodynamics. And again, it's really important that we consider that, and that's why you know what might be considered an average drink for a male is different from an average drink for a female, or a number of drinks allowed for a male versus female is different. And so both of all of those factors play into each psychoactive drug with their individual nuance in receptor expression, metabolic enzyme expression, volume of distribution. Is it a fat soluble drug or a water soluble drug? Water Soluble drug will might get cleared out faster in one sex versus the other. So I think there are clear differences in across psychoactive drugs, in how male and females receive them.
Nick Jikomes 1:02:57
Are there any genetic differences that affect people's sensitivity to the psychoactive effects of things like THC, for example, I don't know, do people have different alleles of liver enzymes that metabolize it differently?
Jibran Khokhar 1:03:10
Now we'll see depends on who you ask me, like they there's like companies that have popped up that basically will be like, do you want to know how you would respond to cannabis, we will genotype you for these four genes, and that, we think you know, that captures all of SIP 2c 19, or SIP 2c 11, which is the liver enzyme that metabolizes THC. They all genotype that, and they might genotype catecholamino methyltransferase gene. And they there's a gene that we're working on in the lab called Cat m2 cell adhesion molecule two. It's one of the only hits that's repeatable in GWAS studies for lifetime cannabis use. In our own work, we've also looked at it with the frequency of cannabis use symptoms, so it's a it's probably contributing, and we've now started to model it in animals and see that it does affect how the pharmacodynamics of THC in that animal model. But what's really interesting, what's important is that it's not just one gene. One gene is not going to impact it's not like warfarin, right? Like where you can do, like point of care pharmacogenetic testing, you know you're going to bleed out versus it's not going to do anything to you or or codeine. Codeine is another one coding, I call it a choose your own adventure drug, right? So codeine is a pro drug that's metabolized by sim 2d, six to heroin. And so when your dentist gives you codeine for a wisdom tooth removal, somebody could be high as a kite all the analgesia in the world. And that would be what's called a an ultra rapid metabolizer, or an extensive metabolizer. And then on the other side you have a poor metabolizer. He's popping all the especially in the Caucasian population, you actually see both Ultra rapid. Metabolizers and poor metabolizers And so really, like it's a choose your own adventure drug.
Nick Jikomes 1:05:05
So for a drug like codeine, there are genetic differences that affect enzyme metabolism of this drug, such that one person takes codeine, they're essentially getting high on heroin, and another person it's not very effective at all. Yeah,
Jibran Khokhar 1:05:17
yeah, because it stays at the parent, but that's because it's going from an inactive parent to an active metabolite. In the case of THC, you're going from an active parent to an active metabolite, so no gene is going to set you off in one direction or another.
Nick Jikomes 1:05:34
Interesting. So, you know, you mentioned something earlier. You mentioned that you've done studies more recently with inhaled THC in animals, whereas classically, you know, going back years and years, there's the majority of studies in rodents and experimental animals usually involve injecting THC into the animal's body, and this is going to lead to very different levels of THC and how long they last, and all of that. What are so? So it's become more common fairly recently for people to do things like inhaled THC vapor and rodent studies. Can you give us a sense for how those studies where you're looking at inhaled THC have started to change the picture of what we think of in terms of what this drug does. So I'll start
Jibran Khokhar 1:06:14
off with it's not perfect by any means, and I'm by no means saying that the people doing the injected THC studies are not doing something, right? We're all trying to, you know, model a uniquely human phenomenon and experience in our animals in some way, shape or form. So we're like, if it walks like a duck, talks like a duck, vapes like a duck, then maybe it's not a bad model for the duck, right? But we're all going to miss something in one way or another. For example, TC, when injected, produces very different plasma levels of Tc. But also that metabolism is very different, and it's going to differ based on how it's injected, as well, as well, versus inhaled. But you know, with the one problem with inhaled roots is the animal actually still has volition, right? An Egyptian, you know, the entire amount is getting
Nick Jikomes 1:07:10
Yeah, you can't control if one mouse is breathing 12 times versus 14. Yeah.
Jibran Khokhar 1:07:15
And then so you'll see some of them will actually go and stick their nose right where the port is, and another one's gonna go to the other side and, you know, stick their noses in the bedding so they don't inhale as much. Yeah, right. So that differs how much they breathe, how deeply they breathe, how much their body weight is, body fat, all of that. So that really changes things. And so then you need to, then have an anchor, something like you're measuring, measuring plasma. You're measuring a behavioral with cannabinoids. It's easy. There's a something called a cannabinoid tetrad. It's a it's a telltale sign. You look at their body temperature, you look at how much they're moving around, you look at how much motor rigidity or catalepsy they have, and you look at anti nociception, how quickly they perceive a painful stimulus, and that tells you if you have cannabinoid action, anything that acts as an agonist at the CB one receptor shows this classic Tetra and so then you need to be able to anchor it to something real, like plasma or brain levels and some behavioral outcome to know how much of it is affecting. So this is just to give you that no way of doing it is perfect, and I'm not advocating for one over another. I'm just saying that both of these we should be remembering the caveats when it comes to drawing conclusions from these things, right? But you know, and Hill has its benefits. So for example, for the longest time, and it's not for the lack of trying. We have 5060, years of people trying to get rodents to self administer cannabis intravenously, and we haven't been able to do that. The only model that we've been able to have that in is a squirrel monkey. Squirrel monkeys will self administer intravenously THC. But when you give it via vaporized drought, the animals will self administer it. When you inject THC into an animal, and you look at what's called condition place preference, do they want to spend more time in the room that they got the THC, or in another room where they didn't get the THC, and you always saw a condition place aversion with injected THC, but when you gave it via inhaled vapor, you saw preference, in fact, in our own studies, like with Joule vapor, with nicking paper from a e cigarette, at doses, At plasma levels that are like in the 100 and to 200 nanograms per million. If you ever gave that to a rodent in an injected form, they would not they would have be gasping for air and find it really aversive when given inhaled via e cigarette vapor, they. Short condition, place preference, right? So the root of administration makes a difference, and it matters. And it matters it affects how much they like it, but also how much of it they'll take and how much of it will then get into the brain and then have its effects, and what that temporal dynamics are. Those temporal dynamics are going to look like, also change right? Like inhaled through the lungs. This is one of the fastest way, aside from IV, of getting something into the brain, right? But along the way, we are obligate. The animals are obligate nose breathers, and we breathe through our depending on how stuffed up we are. We can breathe through our mouth and through our nose, and then you can do a French inhale, where you let it out through your nose and take it back through your mouth. And you can do all sorts of ways of smoking. But then people will raise concerns like, well, the animals are taking it in through the mouth or it's getting deposited in their nasal cavity, and that's not how humans take it. So they there are, like, I will be the first to tell you the all the problems in the way I do things. It's just a problem when other people don't. I think that's what I think we need to have more humility with our science, but also not be so dogmatic. Like My way is the right way of doing it, and your way is the wrong way of doing it. And that is not, if you know, the listeners get something out of this is that's their injectable versus vapor. There's no one right or wrong way. We're all there. We're all the we're these are all paths to that equal final goal of trying to understand what these drugs do on the brain and body better.
Nick Jikomes 1:11:47
Yes, it's a red flag if someone can't articulate the shortcomings or the method. What about, I want to ask you a little bit more about nicotine vapor so you've been experimenting with that in animals and stuff. What do we know? Can you just let's, let's again, start at a very high level. What do we know about the differences in terms of the drug effects between vaporized nicotine versus smoked nicotine? Yeah,
Unknown Speaker 1:12:12
so
Jibran Khokhar 1:12:16
probably I'm not giving you a straightforward answer for anything, and I'm sorry, but there again it various factors come into play. Cigarettes are tobacco that's been cured that has a certain amount of nicotine, but it has all of those other things, tobacco specific, nitrosamines, and also things that FDA asks the cigarette manufacturers to put in accelerants to make the cigarette burn, irritants to make it feel irritating when you take too deep of a puff of it, right? So that's that. And so you're limited to the amount of nicotine that the plant can produce that can be cured and then to convert it into a cigarette. E cigarettes, synthetic nicotine in a propylene glycol glycerine mixture is not the same and does not have the same limits. But also you can then change the form of nicotine and change the salt that's there. So benzoate salt will now make nicotine more likely to cross biological memories. Me, right, like and that's why you see some differences in how cigars are versus cigarettes are. And it's because the the the salts end up being different and the ionization ends up being different, and so nicking can cross things better or worse, depending on so. So you cigarettes give you a lot of rule to experiment. And so that's why, when something like Juul comes out with a 59 nanograms per mil, 59 milligrams per mil, or
Unknown Speaker 1:13:58
the
Jibran Khokhar 1:14:00
5% as they called it, of jeweled e liquid that, at that time, became the highest possible nicotine level that you had in any e cigarette. That changed the game, because everybody else in the E cigarettes were selling six grams, milligrams per milliliter, or up to 30 milligrams per milliliter. Then they also change the salt that was it, was it, and so that also significantly changed how much of the nicotine would get into the body. So some of the work we've done, like even a 10 minute exposure to a jewel e cigarette, vapor produces massive levels of nicotine in the plasma and in the brain, right? It's higher than it even. You know, they've done studies where they take a marble red versus a jewel e cigarette and an anesthetized animal they're just pumping right into the nose and. And the levels of nicotine are much higher with the Julie cigarette than the Marlboro red. And so that, I think it's again important, it how the product is. But then if the other part that becomes important is smoking topography, right? With the indoor smoking bans, it meant that maybe every hour, whatever your workplace allowed, wherever you were, you took a smoke break. You had one unit of a cigarette. You had a pack a day, 20 packs, whatever that was the unit. Vaping changes the game when it comes to you don't have a unit, right? Like you don't have a cigarette that you're going to smoke. You're not going to light up another one before you come back in, alright, like that. That was a cigarette. You had your smoke break. You'll go back in. You can hit the vape as many times, however many times discreetly, without the scent, without all of that, wherever you are and so and I mean, you know, any behavior that you repeat becomes habitual, right? And the more often you repeat it, the more context you repeat it in, right? Like cigarette might be a context specific activity. You have to step outside, and you're only in that context using it. Vaping changes that I've had schools contact me and tell me to, ask me to come talk about vaping at their school because they're having plumbing problems because of how often the kids, middle schoolers, are vaping in the bathroom and then flushing it down the toilet, right? So there's, it's, uh, they, I think, I think there is, there is a lot of difference in the ways that and there's the perceived safety as well, right? Like, but cigarettes are a low bar, right? Like, Nothing's worse than cigarettes. It's a single largest preventable cause of death worldwide, so anything would be safer, like exhaust fumes on the car. But
Nick Jikomes 1:17:01
I guess, you know, I guess, to step back for a second, you know, one of the, one of the features of the E cigarettes that's used to market them is that, well, you're not getting all of the nasty combustion byproducts and carcinogens that you find in smoke, and you can titrate the dose better, etc, etc. But what you're basically saying is the E cigarettes are very capable of getting your blood levels of nicotine higher, and because of the form factor, your frequency and pattern of consumption is probably going to go up. Yeah. And
Jibran Khokhar 1:17:30
what you see is that most people end up being dual users anyway. So even the ones that were using it to quit smoking combustible tobacco end up becoming dual users now they're using their cigarettes, and they're also hitting the big so that the troughs and the so you're basically with cigarettes. You were playing this peak and trough game, right? Like nickname levels drop. You bring it up for a little bit, then they drop again, and then you bring it up. So you're trying to maintain it in that sweet spot throughout the day where your nicker, Nick acetylcholine receptors are maximally occupied by nicotine. Right now, you can sort of hit it in the middle and get a little bit of that nicotine hit. And that's what I most people end up being dual users. And the problem is the people that were going to be never users in the first place, that were never going to take on cigarette smoking, but now vaping ends up bringing them there.
Nick Jikomes 1:18:28
What about so I want to ask you about the E cigarettes in particular, the the propylene glycol, the the the other stuff in these e cigarette fluids, besides the nicotine. What do we know about those things? Are they problematic in any way? Are they relatively inert?
Jibran Khokhar 1:18:45
We haven't had a long enough run time with them. Probably glycol and vegetable glycerin. Yes, you know with those posters, that you find that it can produce dangerous chemicals, and it's true. When you heat propylene glycol or vegetable glycerin up to a certain point it can produce some number of harmful chemicals. Yes, that number is still much lower than the harmonic chemicals in cigarette smoke. And yes, as time goes on, we might see effects overall, and yes, it affects lung volume, and yes, it might increase or change risk for emphysema, and yes, it impacts, you know, lung function and surfactant amount and all of that like that is all true, but we just, we can't draw a straight line between that and lung cancer like we Could with tobacco specific nitrosamines. But the other thing that also is important to consider with
Speaker 1 1:19:48
this is that
Jibran Khokhar 1:19:54
it may actually have rewarding effects of its own as well. Which. Animals, animals will readily self administer propylene glycol. Oh,
Nick Jikomes 1:20:04
propyl is like, Excuse me, propylene glycol without any nicotine. Yeah,
Jibran Khokhar 1:20:09
right. So, so they it's a it's not inert in
Nick Jikomes 1:20:14
so propylene glycol vapor, animals will self administer that,
Jibran Khokhar 1:20:18
yeah. And then you add flavors on top of that, flavors that interact with and we already know with menthol and nicotine and how that interaction happened, and how that affects it. But then other flavors, how they interact, both at the level of just the fact that it's a flavor and it's gonna have its effects on making it more likely that you use it, but also how it interacts with the pharmacology of nicotine. So I think there's multiple sort of layers in how that gets affected. What
Nick Jikomes 1:20:48
are some of the active projects in the lab right now?
Jibran Khokhar 1:20:52
Yeah, so I think one of the things that we're doing, so one goal that we always have in the lab is this is probably why I can stay pills. Causation points off the top of my head up is to try to get at causality right. Take things from human genome wide association studies or human imaging studies, reverse, translate them into the animal models and begin to get at that causal influence of whatever the factor is, right? Like if a study is showing that vaping changes brain function and connectivity in this way in the human study, for example, they're doing the ABCD study 12, 10,012 year olds that they've recruited. They're scanning them every two years. And so there's data, real nice data coming out from it, from a large data set. But again, there are compounds, and it remains associational, right? So, so what we're doing is actually taking animal models where we're exposing animals to vaping or nicotine, or cannabis or edibles, for that matter, or even have a model, an animal model, right now, of accidental and cannibal and cannibals cannabis edible overdose, because that's another thing that we've seen since legalization has happened, is kids, pets, even older adults, will eat too much of a pack of gummies or a Chocolate Bar or and then end up in the ER with acute cannabis poisoning. And so we have an animal model of acute cannabis poisoning that we're trying to both establish ways of reducing the armor impact, but also seeing what are those long term consequences of an acute edible poisoning incident. But then, on the reverse translation side, we're taking findings from human neuroimaging studies, trying to bring them back into the animal model by using similar methods of exposure and similar methods of studying the brain. So using preclinical Mr. Imaging, magnate resonance imaging, functional connectivity and structural connectivity, we can then see, okay, that's what the signal was in the humans. This is what the signal is in an animal. So this component of is probably causally related. And just like with the neuroimaging studies, we're also reverse translating findings from genome wide association studies like that, 2018 Passman paper, there's a gene there called the cat m2 the cell adhesion molecule two gene and so we took those findings, brought it into an animal model. We have an animal model where that gene is knocked out, and now we can begin to see if that gene is no longer there. How do these animals react to THC or cannabis? How do they like it? Do they not like it? And to again, begin to establish causality. That gene does causally contribute to risk for cannabis use. And in addition to that, we're we're doing a lot of studies looking at social drug use behavior. So for a long time, cities that have done drug intake or drug exposure end up singly housing animals, and that can be a confound by itself. You know, when no, aside from the people that drink by themselves in their living room, not a lot of substance use in humans happens in your lonesome, right? So, so we've established methods where animals can be together and they can drink in the at the same time, and you can know exactly how much each animal is drinking in a social context. And then we can look at whether, if one of them drinks more than the others, how does that affect the others, or if one of them also is exposed to cannabis or uses or exposed to nicotine at the same time, how does their drinking change, versus how does the drinking of everybody around them change? How the stress affected. So those are some of the, you know, in a in a 32nd whirlwind tour of the type of work that we're doing,
Nick Jikomes 1:24:49
I also want to ask you a general question about animal models for human mental illness. So depending on your perspective, you know, you can get very different answers. Users to to a question like this, you know, SSRIs were developed in the 80s and early 90s. We don't really have new versions of SSRIs. Yeah, I mean, there's, there's some new ones, but they're all just sort of still the first generation SSRIs, and it's sort of the best we can do in terms of giving people a pill to help with depression, as you know, right? Most of the anti psychotics were, I think they around for decades and decades. We don't really have new ones that have been developed, and they work for the positive COVID Five,
Jibran Khokhar 1:25:26
the ones that FDA just approved, yeah,
Nick Jikomes 1:25:31
we can come to that. And they work for the positive symptoms of schizophrenia, but they don't work for many other aspects of psychosis. And then, of course, you know, if you know, if you just think about the difference between a human being and a mouse or a rat or whatever, you know, you can, of course, model these things in rodents to some extent, because we're all mammals. We all have neurons in our brain. We all have dopamine receptors and so forth. But at the end of the day, how well can you model something like schizophrenia in a rodent? They don't have language, they don't have the types of complex cognition we do, and those are very much the core, at the core of what's disrupted in a human schizophrenic. So what are sort of the limits of these animal animal models? In your view? I
Jibran Khokhar 1:26:12
think you captured a lot of them, right? The best model for something is the same, like the best model for a cat is the same cat, or at least, preferably a cat, right, like and so that remains the case. These conditions are uniquely human conditions with all sorts of social, genetic, developmental, social determinants of health, all of these factors impact the value in which these conditions happen, right and so. So I think it's important that we recognize that, and we again, have humility around the models that we do use. But there are ways to try to bridge that translational gap that exists as well. In fact, you know, the drugs that you mentioned are actually evidence of the success of rodent models, antipsychotics, antidepressants, ADHD medications, even things that are used for varenicline for Cigarette smoking, like all of these came from rodent models and and they work, and we've gotten them to a place where we are able to use them in patients. So I think that, by itself, is a great testament to the utility of the models, but then also a cautionary note on the limitations of those models as well, when you mentioned SSRIs, we've established that these were the SSRIs and then we established some behaviors for swim test and tail suspension test and during like, maybe elevated plus maze. And these were like, Oh my gosh. These are these predictive, valid assays that tell you whether an antidepressant is going to work or not. And then we spent our whole life trying to come up with metoo drugs, the drugs that are similar to the other drugs, and just testing them on the and somehow we convinced ourselves that a mouse or a rack swimming in a vat of water was a model for depression, and that's where it became from, right? And so while it was had utility and some screening ability for a drug that was not depression. And so I think we need to keep questioning ourselves with any models that we have, whether there is theoretical validity. Is it based on a theoretical basis of that condition? Is there predictive validity? Does a drug that work in humans also work in alleviating whatever it is in this mom? And then the third one is face validity, with whether it looks like, you know, you're not usually putting somebody who has depression into a swimming pool and asking them to swim, right? So that right? So that, does it look? Does the Anhedonia look like? What it is looks like in humans? So I think those are the three. But I think I'd add a fourth dimension to it, something I I, I call diagnostic ability. I don't know what others call it, or
Speaker 1 1:29:23
that if the way you study it in humans,
Jibran Khokhar 1:29:29
and then you try to study it in animals in the same way. Could be with MRI, could be with EEG, it could be with biomarkers, it could be and those also look the same. Then you're one step closer, right? And then you can try to bridge that gap by using techniques that are used in posts, and then adding the techniques that you can do in animals, but also mimicking the roots of administration a little bit. And so I think that that is one place that you can get to, but I think an important. Other place that is really important to
Speaker 1 1:30:02
to consider is, yeah, we started
Jibran Khokhar 1:30:06
with this, and I think maybe coming back to it at the end is important as well. All of those overlaps that we mentioned between the diagnostic criteria for DSM also apply in animals, right? Like behavior for an animal, it's most of the times it's going to do something, it's going to be through its movement, right? So, so it's locomotion is going to affect how we perceive its cognition, or how we perceive its positive symptoms, or how we perceive its negative symptom. And so it's so, so I think, stepping back from having a model of I have a rap model of schizophrenia, depression, bipolar disorder, whatever. Instead we can have in this model, we are testing this transdiagnostic construct of impulsivity. In this model, we're testing the transdiagnostic construct of anhedonia, which shows up in depression, which shows up in bipolar disorder, but chosen for schizophrenia, and so that then also de risks it a little bit, because you're not going to have one model of a disease that's going to capture all facets of it. And then you can use genetic tools, right, like where you can then take findings from genome wide association studies, bring them into animal models, or use the genetic diversity that exists in an outbred rodent population, for example. And then you can see, these are the animals that are the most impulsive, and these are the animals that are the least impulsive. What are the differences between those two? And so there, I think there are ways of I think science is evolving enough, but I think we're also and then, you know, for a large part of neuroscience, we're often studying things that are largely conserved, breathing circuits and circuits for thermal regulation, circuits for Okay, so I think there is, there's a lot of room and a lot that We haven't figured out about the brain, that we still can use rodents. Yeah,
Nick Jikomes 1:32:05
yeah. I mean, I guess you know, when I when I think about something like schizophrenia, and I think about the mesolimbic dopamine system, it's going to hook into lots of other systems, including systems that are highly divergent between rodents and humans, like, you know, parts of the association cortex, the so called higher parts of the brain. But some of that core, some of that core dopaminergic circuitry, is itself very, very conserved between mammals. So even though it hooks into other things that lead to different manifestations in humans versus rodents, we talk about different forms of psychosis. Say there still is, to some extent, a common core that's highly evolutionarily conserved. So served, what's um? So let's like just another general question here that's a little bit more practical for people. Genome sequencing is cheaper than ever. Um. You've got every you've got tools out there, like 23andme you can get your full genome sequence now for relatively cheap. There's different platforms that enable people to do this. Are there cost effective and easy ways for people to see if they've got risk factors, genetic risk factors, for psychiatric illnesses, and if so, do you recommend those, or are they maybe risky to use? Like, what is your take on using some of these genome sequencing tools to assess one's own risk of psychiatric illness? Yeah,
Jibran Khokhar 1:33:24
I think, I think the data governance
Unknown Speaker 1:33:25
piece is an important piece there.
Jibran Khokhar 1:33:29
Who owns the data, holds your genetic data, and what they do with it, right? Like, are they patent filing patents on drugs based on your genetic data, right? Or is it for profit, or is it not? And all of that, I think, is an important factor to consider, and it's an important caveat. I personally wouldn't do any direct consumer for myself. I haven't done it, and I haven't done it for my kids, and I wouldn't do it, especially now that one of the big ones is about to go under and who's going to buy out that data? Where is it going to end up? What is it going to get used for? And so those are the important questions there. But I also think it's too simplistic to then be able to say, Oh, this one gene, you are a variant in it. This is, like, it's genetic determinism. I think is reductionism on that front, is one piece right, like, there's no guarantee that just because you have a variant in this that you're going to now go on to develop that right, and and so. So I think, I think probably the closer thing is, if you have a family member who has cannabis induced psychosis and then develop schizophrenia, then probably exercising caution is, is
Unknown Speaker 1:34:46
is
Jibran Khokhar 1:34:47
anchored on something more real than a data driven approach that's going to be impacted by all sorts of things, right? Like, what are the training data sets that they have? If you're you know from some part of the world that. They just didn't have a lot of data on then those genetic determinations may, in fact, be completely inaccurate. Yeah,
Nick Jikomes 1:35:07
yeah. So, like, if you have something like 23andme and they're saying you've got this allele, therefore you've got this risk, it may or may not apply to you as an individual based on the training data set that led them to put that element in their UI. Yeah. Interesting. So, so, I mean, basically, it sounds like what you're saying is, yeah. I mean, you can get genome sequencing done, you can buy 23 of me or whatever, and you can get, you know, data that is about you and your genetic risk profile, but at the end of the day, it's not that much more informative than knowing who your family risk history,
Jibran Khokhar 1:35:37
yeah. And I feel like we're we are starting to lean on one way more over the other. We don't know people anymore. We don't know family members anymore. We don't talk to each other anymore. But we put a lot of weight on a piece of paper that came out that you know, you know, if you think about something like Theranos, maybe some of the data isn't even based on anything, yeah, maybe what the report they sent back was just completely made
Unknown Speaker 1:36:04
up. Yeah,
Nick Jikomes 1:36:09
we've covered a lot already. Is there anything you want to reiterate, or any kind of things you want to tie together from all the topics that we covered today?
Jibran Khokhar 1:36:16
I think, I think it's important that we recognize that comorbidity or poly substance use is the rule and not the exception. And I think, as scientists, what I'll make is a is a case against purity, where, you know, like, where do we? What do we do our clinical trials? We do test these drugs in unicorns, right? Like, you cannot have any CO morbid comorbid condition, you can't have a substance use disorder, and you can't have mental health condition, you can't have a metabolic disorder, and you can't and then we expect it to go out into the real world, into the real population, and then we have to put on a black, black box warning on the drug because, oh, it's associated with increased risk for suicidality. This happened with Vernon MCLIN, for example. But then, when they actually did the test and actually included people who are actually the smokers, you know, 90% of cigarettes are used by 10% of the population, those with serious mental illness, there wasn't any higher risk of suicidality or any other psychiatric complication when they actually test it in a representative population. So we should? We need to stop testing unicorns and studying unicorns. I think, I think we need to study real people with real conditions, and I guess a case against purity and a case for diversity in our research setups and even in the animal models, right? Like outbred strains, heterogeneous rat strains, like mouth strains, I think there's, there's benefit in embracing messiness and diversity,
Nick Jikomes 1:38:01
all right. Professor. Jibran Khokar, thank you again for your time.
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