Pod Insights Psychiatry & Psychotherapy Podcast Cannabis and Psychosis: The Link Between THC Use and Mental Health Risks About this episode Dive deep into the connection between cannabis (THC) and psychosis in this enlightening episode with Dr. David Puder. Explore cutting-edge research on how cannabis impacts neurodevelopment, particularly during adolescence, and discover genetic and environmental factors that can amplify psychosis risk. This episode provides valuable insights into recognizing cannabis-induced psychotic symptoms, understanding the importance of early intervention, and implementing effective strategies for treatment and prevention. Essential listening for mental health professionals, educators, parents, and anyone interested in the nuanced relationship between cannabis use and mental health.
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Link to blog. https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-240-cannabis-thc-psychosis-risk
Link to YouTube video. https://youtu.be/cHez9-uS-8I
Transcript 11,827 words · 4 speakers
Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.
0:13 David Puder? All right, welcome back to the podcast. I am joined today with Daniel Suevas. He is at MS4 at La Malinda, Liam Browning, and Christopher Campbell, both back for more. And we are going to be doing a deep dive into cannabis and psychosis, marijuana psychosis, THC. We'll title this Reefer Madness 2.0, just kidding. And we will be treading the line into as close as truth as we can. We have no conflicts of interest. If you're listening to this, we are not paid by Big Cannabis
0:52 David Puder? or Big Pharma. We have received no dollars from either of them, which is nice because we don't have a stake in the game. I get these emails all the time for people who have a real large conflict of interest. They want to shell out their specific thing that they get paid for, and I'm not interested. I'm interested in only bringing you the closest thing to the truth possible. So yeah, welcome, welcome to the podcast. Welcome, guys. And this will be part one in a, what, three-part series, Liam?
1:23 Speaker 01 Yeah, one or two, or two or three parts.
1:25 David Puder? Two or three parts?
1:26 Speaker 01 Depending on how much. We've got like 60 pages of notes from all the different subfields of this, this field. So yeah, we've got a lot to talk about.
1:36 David Puder? Today, we really wanted to focus on cannabis and psychosis. This is something that if you are practicing psychiatrists who have spent time inpatient in the ER, if you've spent time seeing clients in the outpatient even, you see, you have seen this, people who are heavily smoking and then get psychotic for the first time. ER visits have increased, and it's very hard to treat someone with psychosis if they continue to smoke heavily. I've also seen that quite a bit. So we will be getting into the details on this. Where do you want to begin, Liam?
2:09 Speaker 01 Yeah, I just wanna, uh, thanks for opening up for us. I just wanna say like, uh, this is a really polarizing topic. So like you mentioned, we wanna try to tread the line and talk in the middle ground and really try to approach this really critically and try to really look at what the literature is having to say about this topic. And to your point about seeing inpatients who use cannabis regularly, I'm from Detroit, so working inpatient, you see, you'd be pretty hard pressed to find some patients who don't use cannabis if they have schizophrenia. I think Detroit has some of the highest dollars spent per capita and the whole country.
2:53 Speaker 01 Uh, so it's, it's really common in Detroit and I've seen how things have changed since legalization where every other billboard is assigned for a dispensary. So the culture around it here is pretty favorable and it's pretty ubiquitous now, especially with people using incredibly high potency cannabis. So, and I do think it plays into a lot of the presentations that we see with, with patients having relapses and worsening of their symptoms. So I really wanted to address this topic from that perspective and from a clinical perspective as well as looking at what the research has to say.
3:29 David Puder? Yeah. Okay. So who wants to take us through the intro? Christopher?
3:34 Speaker 02 Yeah, I can get us started. So yeah, one reason why we are revisiting this to such an extensive amount is be in large part because of the increased accessibility and the increased utilization of cannabis that is really, when you look at it from a historical perspective, it is fairly unprecedented just in, in human culture and society. And to kind of illustrate that point, we can look at historical data where only about 4% of Americans had ever tried cannabis in 1969, and that is compared with 47% who have tried it today.
4:14 Speaker 02 So we've just seen a massive increase in the amount of people who have ever tried it. And then furthermore, we've seen massive increases in the people who use it daily. So the amount of people who use cannabis daily now surpasses that of the amount of people that use alcohol daily. And that correlates with about a 15-fold increase over the last 30 years. And kind of continuing with the comparison of cannabis use to alcohol use, which we think is important because alcohol has been such a fixture for millennia now of culture and society for worse, probably if not than anything else. But if you look at the median cannabis user,
4:57 Speaker 02 they tend to use cannabis about 15 to 16 days per month, whereas the median alcohol user only uses alcohol about four or five days per month. So we see really different use patterns with people using cannabis much more frequently. And on top of that, when you look at daily cannabis users, you see that on average, they smoke cannabis or use cannabis about 3.2 times per day. And this kind of correlates to a more or less consistent intoxication during waking hours. So this really is a pervasive issue in substance use.
5:37 David Puder? Yeah, it's kind of like obesity has increased. And we know it's not entirely genes, right? Because it's not like only people who are obese are procreating. Likewise, marijuana increase has increased in our culture and the potency has increased. It can't just be genes because, you know, people who are marijuana users are not the only ones procreating. Yeah, but it's a substantial change in the potency of even the flower, right? We're going from like 2% to like 20% potency.
6:17 Speaker 02 Right.
6:17 David Puder? Within decades. That's, that's an incredible shift. I mean, think about how many tens of thousands of years probably cannabis has been used to some degree by some people. And now it's like 10 times the potency. And, and now people are using 90% THC as well. Right.
6:39 Speaker 02 With the concentrated forms.
6:41 David Puder? Yeah.
6:42 Speaker 02 Right. And so that is a really crucial point is it's not only that the presence of cannabis use has skyrocketed, but simultaneously the potency has skyrocketed and it's become really easily accessible for a variety of reasons. Most people can access some form of cannabis. It might be in a different, different molecular structure, but so we really have easy access to it nowadays. And then to your point about potency, it, it is just so much more potent as we'll look at further down in this document that these, these higher potency forms can have more significant effects. And, you know, an additional point to raise is the oral and edible forms of cannabis.
7:28 Speaker 02 These can also be, you know, they can be in the form of something like a gummy bear. And so they're very easy to consume and they're delayed onset of action, which can take up to two hours to see the effects. Can result in people, you know, taking a dose and then not experiencing the effect they thought they would. After the hour mark, let's say, and so then they take, you know, eat another dose or two. And next thing they know, they're, they've consumed a far greater amount than they initially meant to. And then one additional thing is in regards to the THC vaporizers. These are a concern as well because like you mentioned, they can be 90% THC. So not only is it highly concentrated, but you quite literally have it at the push of a button.
8:13 Speaker 02 And so it really kind of enables this pervasive compulsive use that might not have been as easy to achieve if you were using the more traditional form of the plant.
8:24 David Puder? Right. You don't have to light it up. You don't have to make a big stink.
8:28 Speaker 02 Right.
8:28 David Puder? With, with, with the pen, you can just take a quick hit when no one's looking. I mean, this can be almost like hidden. I've had people in my office pull out a vaping pen. I'm like, whoa.
8:40 Speaker 01 Yeah, I've seen it inpatient, like patients who are hospitalized, they have their vape pen with them somehow.
8:46 David Puder? Yeah.
8:47 Speaker 02 Yeah, it'd be interesting to look at a study and see how, what percentage of hospitalized patients just in general are accessing things like this, this way.
8:56 David Puder? Another big thing is CBD has decreased as THC has increased, right? So the percentage in the average marijuana plant of CBD has gone way down, especially in relation to THC. And that's CBD can potentially be helpful for someone in psychosis.
9:17 Speaker 02 Right. And the effects of CBD, at least partly, can help to kind of modulate the effects of THC and keep it in check, so to speak. So having this mismatch can just exacerbate the, whatever issues might arise from THC use.
9:34 David Puder? Okay. So is cannabis distinct from alcohol and other drugs and how it hits the brain, how it stays in the body?
9:44 Speaker 02 So it certainly is. And one reason for that is the fact that it is highly lipophilic. So it's really readily absorbed in fat tissue, both in the body, but also in the brain. And it can be present for up to several weeks, even after cessation. And it's been shown that people who consistently use THC at least twice per week essentially have amounts of THC in their brain at all times. And then furthermore, you know, if you look at other drugs like alcohol, for example, compared to THC, the fact that THC is consumed in this plant form so often, there are really, quite literally, hundreds of other bioactive compounds that we just simply can't isolate
10:29 Speaker 02 the effects of all of them. So there's a really wide range of effects occurring when you use cannabis.
10:37 David Puder? Yeah. I had a patient who, the family got so tired of him smoking and staying in psychosis. He was on risperdal, four milligrams, not budging. And the psychosis was such that he would get angry and have a lot of conflicts, family, wife would have to leave for several days with the kids. And so they tied him being able to drive a car to having progressive decreasing blood cannabis levels. And he was motivated for his car. And you know, this is, this is
11:18 David Puder? an adult, right? And yet financially, he was tied so strongly to the family because of his continued psychosis and cannabis use. And so we checked his blood level probably every two weeks for six months. And if he had any bump, they would take away, you know, basically his ability to drive. And it worked. And now the guy is doing awesome. He's going back to college. He's succeeding in so many domains of life. And we're working on his, his obesity and working on, you know, first world issues now, rather than the psychosis. He's no longer psychotic. Okay. So let's, uh, let's go into, is there anything about
12:02 David Puder? the endocannabinoid system we want to touch on? I think one thing we should mention is that it does impact fetal development because it crosses the placenta. Do any of you want to speak to that?
12:15 Speaker 02 Right. We can, um, you know, we can, we go into great detail about this in the document that we will release with the podcast. But yes, we absolutely want to say that during times of neurodevelopment, the cannabinoid receptors, specifically CB1 receptor, tends to be more highly expressed. And this is both in fetal development as well as again in adolescence. And because of the fact that THC can cross the placenta, uh, this can have, you know, maternal use of THC can have significant effects on the neurodevelopment of the fetus. And it should be noted that because of this fact, the American Academy
12:55 Speaker 02 of Pediatrics does advise against the use of THC in individuals who are either pregnant or breastfeeding. So that is a salient point we need to, to make at this time.
13:07 David Puder? Yeah. And tell me a little bit more about this. We have an endocannabinoid system, right? That helps us regulate mood and anxiety. Tell me about that.
13:17 Speaker 02 Right, so this is an evolutionarily conserved system that is responsible for kind of maintaining the homeostasis of a wide range of functions, including appetite and sleep and learning, as well as some mood and emotion regulation as well. And how it works is it essentially helps maintain homeostasis between different neurons. So, for example, if we've got neuron A that is exciting, neuron B too much, neuron B can release these compounds called endocannabinoids in order to suppress the activity on neuron A and thus weaken the synapse between the two neurons.
13:59 Speaker 02 So this is an innate system that exists within us and it just so happens that THC can exert really powerful effects on this system.
14:10 David Puder? Okay, so let's get into the schizophrenia. We have three hypotheses.
14:19 Speaker 03 I can start us off on that discussion.
14:21 David Puder? Okay, thank you, Daniel.
14:23 Speaker 03 So there's a general overview with the three different hypotheses that we should mention is that first one, cannabis causes schizophrenia. Second one, people with schizophrenia use cannabis to treat their symptoms, consistent with the idea of reverse causation. And the last one is that cannabis increases the risk of schizophrenia, but only in those with other genetic and environmental risks. I'll start off by discussing the first hypothesis, which is that cannabis can cause schizophrenia. That's a debated topic, but what is known is that cannabis can cause psychotic-like symptoms, even in those people who do not have psychosis at baseline. There is a case report that I came across that really exemplifies this presentation. It was a young adult male who'd been using cannabis since his early teens
15:08 Speaker 03 and he was brought to the ED by his brother because of worsening paranoid behavior over the past month. In the prior two weeks, he reported not being able to sleep and he was being hyper vigilant. He believed to be being followed around by people in a black truck. And of note, the patient said that over the past month, he had started dabbing, which is... A way of consuming cannabis that gives you a very, very highly concentrated form of THC. In older studies, like even like as early like, you know, early 2000s and like a little bit before that, high concentration of THC would be like, you know, 10%, but dabbing can give you sometimes upwards of 80%, so it's a very, very highly concentrated form of THC. And so they noticed the timeline like, oh, let's change this a bit.
15:51 Speaker 03 So he underwent some voluntary hospitalization, they got him off of the high concentrations of THC. They started him on some antipsychotics and he was stabilized very quickly. It was like a black and white difference night and day. So that was a pretty typical case of psychosis induced by THC in that there was a high degree of paranoid behavior, but there wasn't agitation and there wasn't as much hallucinations, especially visual hallucinations, which you can see in other substance-induced psychosis.
16:24 David Puder? I think that's a really good, let me just pause there, that's a really good point to kind of sink in. A lot of the other things like meth, coke, PCP, even alcohol can have visual hallucinations. Alcohol you should be after withdrawing from heavy use, whereas meth, coke, PCP is when you're actively using it. Those can have visual hallucinations, whereas THC psychosis doesn't have that as much.
16:51 Speaker 03 Yeah, it's a very, very key differentiating factor between cannabis-induced psychosis and psychosis induced by other substances, so it's good to harp on that point.
17:01 David Puder? Good, okay.
17:02 Speaker 03 But considering all this, it is worth noting that experiencing psychosis due to cannabis is exceedingly rare. Only about half a percent of people who use cannabis have ever experienced psychotic-like symptoms, which is in line with the rates that we see with other substances as well.
17:19 David Puder? This is, this is where kind of like, you know, we could make this episode into Reefer Madness 2.0. If we're like, every patient will have psychotic symptoms. It's like, nah.
17:29 Speaker 02 We're trying to stick to the truth.
17:30 David Puder? We're trying to stick to the truth. It's how, it's like, out of 200 people that use one will have psychotic symptoms. That being said, it'll be higher for higher potency, right?
17:40 Speaker 03 Yes. And there are other risk factors that go along with having increased risk for these psychotic presentations. Namely, having a diagnosis of a psychotic disorder that can give you a relative risk of about 14. Bipolar disorder can give you a relative risk of about four, anxiety close to three, and depression about two and a half when compared to those individuals who don't have mental health diagnosis.
18:03 David Puder? Right. So you're much more likely to have a psychotic episode on THC if you already have a psychotic disorder, bipolar, anxiety, depression.
18:13 Speaker 03 Yeah.
18:13 David Puder? If you already diagnosed and then you use THC, you're much more likely to have a psychotic event. Okay. Okay, keep going.
18:20 Speaker 03 Generally, we advise against THC, but in those populations, we really advise against THC usage. As other risk factors include being younger age and of course, using high potency forms of THC.
18:33 David Puder? Yeah, I would say the younger age is, is, is really crucial. That, that's kind of like one of the big, one of the big risk factors. Okay, keep going.
18:44 Speaker 03 Yeah. But there is evidence to suggest that cannabis-induced psychosis can transition to a full-blown psychotic disorder at higher rates than psychosis induced by other substances. There was a number of studies that looked at a cohort, a population cohort from Ontario, Canada, from 2008 to 2022, included about 22, or included about 10 million people. In the first study published in 2023, they identified cannabis-induced psychosis as a drug with the highest risk of transition to schizophrenia in a three-year follow-up period, having an adjusted hazard ratio of 84.9 comparing to amphetamines,
19:26 Speaker 03 which had 22.3, cocaine 16.6, alcohol 16.3, and polysubstance use being 48.8.
19:35 David Puder? This is, this is a wild number for a hazard ratio, right? Usually hazard ratios are like, if you, you know, exercise at the, compared to someone who doesn't exercise, your, you know, hazard ratio is like 0.3 of what it was before, right? So, but this is like 84 times more than the general population, right? Than the general population that isn't in the ER with a psychotic episode due to the substance. Correct?
20:10 Speaker 03 Correct, yeah.
20:11 David Puder? So, yeah. The other thing that's really fascinating about these numbers is that the hazard ratio is so much higher for cannabis than it is for other things that also cause increased risk of psychosis, like amphetamines, like cocaine, like polysubstance use. The polysubstance use surprised me, it's only 48, whereas the cannabis is much higher. It's like-
20:35 Speaker 03 Yeah, it surprised me too. It kind of lends some credence to the concerns that mental health providers have about cannabis specifically.
20:42 David Puder? Specifically, yeah. And the psychotic stuff, when I think of psychotic stuff and someone who uses methamphetamines, you know, it's, it's like a different breed. It's like I have bugs crawling on me. I once had a patient who came in and that was his big issue. And I think it was the third session, I realized this guy's using methamphetamines, like on a daily basis. And he had been to dermatology, you know, at the university I was at, he had been, he had, he had done the rounds, you know, people trying to investigate, help this guy. And finally, I'm like, you know, this is really from the methamphetamines. He never came back.
21:22 Speaker 03 It's amazing what you uncover by doing a thorough drug use history.
21:26 David Puder? Yeah, and sometimes they don't tell you the first time around. They have to like, trust you somewhat before you before you get to the truth. Okay, keep going.
21:34 Speaker 03 All right.
21:34 Speaker 01 So can I make a can I make a point on this?
21:37 Speaker 03 Of course.
21:38 Speaker 01 Yeah, one, one thing that I wanted to raise in this study specifically, they had 10 million people. And they found that about 400,000 or 4% of that sample was the sample that presented to the ED due to substance use. And then of those 400,000 people, only 3.4% of those 400,000 people presented due to substance-induced psychosis. So that equates to about 0.1% of the total population. Uh, so you're looking at a very extremely small subset of the sample. And I think given just how much cannabis, how differently it can affect someone.
22:16 Speaker 01 If you're looking at, say, 0.1% of the people who have that proclivity to a negative response to cannabis, more of a psychotic sort of spectrum. Uh, then that can explain a lot of the the hazard ratio that we're seeing here. Compared to some of the other substances where alcohol more consistently is going to affect people the same. Uh, methamphetamine probably as well.
22:37 Speaker 03 Hmm.
22:37 Speaker 01 So that that's just one point they wanted to make.
22:40 Speaker 03 Yeah.
22:40 David Puder? It take it takes a lot for someone to get so psychotic that they go to the ER.
22:47 David Puder? Right? Because like, I mean, lesser degrees of psychosis, someone's paranoid. Homeboys are just gonna be like, calm, man, let's just watch them. Let's just, we're gonna be calm here with you, like chill out, you know? Like, how bad does it need to be to actually go to the ER, right?
23:04 Speaker 03 Yeah, there's a great chance it's probably missing a lot of the psychotic presentations in the general population because they're just not going to the ED.
23:10 David Puder? Right, but if there it's bad enough to go to the ED, then the risk jumps to transitioning to schizophrenia.
23:19 Speaker 03 Yeah.
23:20 David Puder? Okay.
23:20 Speaker 03 Yeah. Well, it is worth noting in this study that there can be some residual confounding, um, effects because they adjusted for a lot of variables. But the from the population that did present to the ED, they are more likely to have already received acute mental health care in the past. Or treatment for substance abuse, and they were also likely to be younger and more likely to be in the body in the bottom socioeconomic quartile, which can introduce a whole variety of confounding variables. So it's worth noting that as well, just, you know, for the sake of being accurate and truthful.
23:50 David Puder? But did they control for those things in the adjusted hazard ratio? Did they control for the socioeconomic status in those numbers?
23:58 Speaker 03 They do control for sex, socioeconomic status, primary mental health treatments.
24:02 David Puder? Okay.
24:03 Speaker 01 But the thing is with epidemiological studies, no matter how much you control, if your samples are wildly different, like they are in this case, there's only so many confounding variables that you can control for in an adequate way where it doesn't affect your outcome that you're interested in. That's what residual confounding is because you can't possibly control for everything. And that's where the limitations of epidemiological studies come into play and why randomized controlled trials are the better choice for looking at causality.
24:34 David Puder? Yeah, and we're not making an argument for causality. We're making an argument for if someone is ill enough to have a psychotic episode that leads them to the hospital, then there's a very high risk of them transitioning to schizophrenia. This is a very high-risk population and take it very seriously. And actually, first-episode psychotic, you know, treatment pathways, where they treat first-episode psychosis, they're, you know, coaching them to not use marijuana, to realize that this is a huge risk for this specific population is a big part of the treatment.
25:13 David Puder? Okay.
25:14 Speaker 03 It is worth noting that there were two other studies published at a later date that looked at the same cohort. And they had some differences in their methodology that are worth bringing up. In these two studies, they claim that cannabis use disorder is linked with a greater risk of all-cause mortality. And they also claimed that the percentage of schizophrenia cases due to cannabis use disorder increased significantly following the legalization of cannabis in that region. However, they define cannabis use disorder as someone presenting to the ED due to cannabis use. And this sample of patients, you know, they had a much greater of being more socioeconomic disadvantaged. They used other drugs more and they had more mental health disorders.
25:57 Speaker 03 And these models and these later studies did not control for these factors. And so although it's worth noting that although ED visits attributed to cannabis use did increase following legalization, the schizophrenia rates did not increase. This is a bit of a mismatch. If it could be all attributed to cannabis use, then you would expect to see the schizophrenia rates go up as well, but they just stay constant.
26:22 Speaker 01 Yeah, this study, they, I don't want to say marketed as like saying that post legalization more schizophrenia has gone up, but that's kind of the field that I get from it because they talk so much about post legalization in Canada and they use what's called the population attributable risk factor. And that is based off of hazard ratios. And then obviously, if you have some confounding that goes into those hazard ratios and you also assume causality, then that's where you can get a high PARF, that statistic. And they looked at this statistic after legalization, I saw exponential increase, I think from 2020 or the early 2020s.
27:04 Speaker 01 And they attributed, yes, after legalization, we see a greater risk for cannabis use disorder being related to schizophrenia. But then again, if you're looking at a specific subset of people who are at a higher risk for psychosis in general due to socioeconomic factors and higher mental health comorbidity, then you're going to expect to see that anyways with more people going to the hospital due to cannabis use. So they really show this graph like going up exponentially, but then they also show schizophrenia at the same like flat line, so not increasing. So I think, I think it'll be really interesting to see in the years going ahead, if we do see increased rates of schizophrenia with how much we've seen use increase.
27:47 Speaker 01 So I don't want to say that this study, because they don't see an increase of schizophrenia with an increased use of cannabis, that it's completely negating the fact, or negating any possibility that cannabis can lead to more schizophrenia. I think we just need more data on this topic. And I think, I just think that this study is a little bit premature in terms of like how much hype it's built up, because it's published in JAMA Psychiatry and a lot of people have picked it up in the press.
28:17 Speaker 02 It will be really interesting to see in the years ahead because if you look at the kind of use rates, they have really reached their peak in the last year or two. So seeing, you know, 10, 20 years down the line, how the schizophrenia rates change or don't change will really kind of give credence or take away credence to these assertions.
28:40 David Puder? Yeah, I think this is an interesting finding, like, why haven't the schizophrenia rates jumped up, right? Or why haven't there been really well-done studies looking at the rates before and after population-wise in every country where they've legalized, where the percentage has increased? You know, I haven't seen a study like that where they looked at each country and the data and really hashed that out. And I think that this is still a topic of debate, whether cannabis use and schizophrenia are linked, how linked they are. And long-term, large-scale studies are still needed to fully understand the relationship between cannabis legalization and schizophrenia rates. The other thing
29:25 David Puder? is there's a lot of things going on simultaneously that impact schizophrenia rates. Socioeconomic status is one of the big ones, actually, that I've looked at, like, the percentage of schizophrenia in low socioeconomic versus high socioeconomic status is substantially different. And so there, you know, there's a lot of things simultaneously going on in society. So it's, even if there was a jump up, you could argue that, oh, is it this or is it that? Or is, you know, like, what's causing what, right? It's really hard to tease out.
29:58 Speaker 03 That was kind of a constant theme I came across during a lot of the research, is that everything is polyfactorial. It's never a, you increase one thing and you automatically see an increase in the outcome, you know?
30:11 David Puder? Yeah, keep, keep going though. Keep going, Daniel.
30:13 Speaker 03 All right. And this kind of does get to some of the limitations with regards to research into cannabis use and psychosis in that a lot of the research is epidemiological in nature. There's this one very famous study that happened in 2019. It attributed about 12 to 50% of first episode psychosis due to high potency cannabis usage. However, the study attributed causality to correlational findings, which is problematic in epidemiological research.
30:42 David Puder? Yeah, and I think I wanted to mention here, there was a 2022 meta-analysis, Robinson and colleagues, which addressed a key gap in the literature by quantifying the risk of psychosis across five distinct levels of cannabis use frequency. And this offered more detailed insight in the dose-response relationship. So they analyzed over 7,000 participants from 10 studies, and they found no significant increase in those who used cannabis yearly or monthly, but identified a 35% increase in psychosis risk with weekly use
31:24 David Puder? and a 76% increase with daily or near daily use. Okay, so these results were, you know, the most robust in their flexible nonlinear model. So it's not like, you know, there's a linear relationship between cannabis use and risk of psychosis. Instead of a linear relationship, it's like the more cannabis, the higher the risk. It goes up higher and faster with the higher potency, highly frequent use of cannabis. Okay, so I think that's important to think about as well. Because when we were talking about before, like, oh, you know, these people that came to the ER, much higher risk of converting to psychosis.
32:09 David Puder? But actually, there's also a dose-response that you can see in studies.
32:13 Speaker 03 Yeah, there's another really good study that we'll get into in a little bit that also it saw a dose-response effect, particularly pertaining to frequency. But we'll address that a little bit later in the talk. But continuing back to the idea of epidemiological research versus randomised controlled trials. Because of much of the regulations surrounding cannabis use and cannabis research, a lot of the literature is epidemiological in nature. And so it presents some form of, you know, challenge with regards to ascertaining causality. But what can be useful in assessing whether or not a relationship is causal is the Bradford Hill criteria,
32:55 Speaker 03 which are a set of criteria that can, again, assess causality. But it's not going to be like, you know, if you meet so many criteria, then it's going to be definitively causal. It's more just like to ascertain, you know, what is like the chances that this is causal, like with more criteria, your chances will go up. And dose response is a big one. You can also include temporality in which cause precedes effect. There's nine criteria in total, so we don't have to get into every single one. But it's just really important to know that Bradford Hill criteria are very, very useful in assessing epidemiological studies.
33:34 David Puder? I think that's really helpful. I think I've talked to one of my mentors, a great statistician, and he kind of thinks that people are too stuck on this, like randomised controlled trials, the only way to determine causality. Because he said in more advanced statistical models, you can make those linkages. But most people, if you say anything like this on Twitter, they'll say, "That correlation doesn't equal causation." It's like, have they heard of the Bradford Hill criteria? Probably not. Okay.
34:09 Speaker 03 There's a lot of things that the Twitter mob is generally ignorant of.
34:12 David Puder? I found out the most recent one. I posted a picture of me eating kale, and I didn't know there was an anti-kale Twitter mob.
34:19 Speaker 03 Oh, they have an agenda?
34:21 David Puder? There's people who are like the kale police. They're like, "People against kale."
34:27 Speaker 03 What did...
34:28 David Puder? They must have had a bad batch. Oh my god.
34:31 Speaker 01 No, this this kind of raises the point, though, like with epidemiological studies, I'm sure they're citing these studies that are saying kale increases risk for cancer because there is a famous statistician, I think out of Stanford in epidemiology, and he published a book, it's like the epidemiological cookbook, and he looked at just random ingredients and found links to cancer with everything, like lemon, doesn't matter, like lemon, vanilla, apples, bacon, like you can pretty much find a study that will support a claim with epidemiology just based on correlation causation, which is why we need to address the quality of the study that goes into it and not just look at, you know, these numbers devoid of any context.
35:14 David Puder? Let's talk about the Bradford Hill criteria a little bit more. It's like, does the cause precede the effect? Okay, so with here it would be like, does the use of heavy marijuana use precede getting psychotic? Okay. The next one is, is the association consistent with existing knowledge? So is there like a mechanism that makes sense? Is there, you know, multiple different studies that have shown this this linkage? Have similar results been shown in other studies, right? So there's a consistency across studies. Is the strength of association between the cause and the effect? So like if it's a point two correlation,
35:59 David Puder? it's like, ah, maybe, maybe not, right? But if the odds ratio is like 90, it's like, okay, wow, let's pay attention to this. Does increased exposure equal increased effect? Like, it sounds like I'm almost making up this criteria for marijuana as I'm reading these off, right? Does the increased exposure of marijuana increase the risk of psychosis? I just talked about this study. Does the removal of a cause decrease the risk of the effect? So if I remove the cause,
36:29 David Puder? Marijuana use, if I remove marijuana reuse, does it decrease the risk of psychosis? That's one I'm curious if we have that one. Is the evidence based on a robust study design? Is the evidence based on a robust study design? And this is where Liam's tying in, like, was it a well-planned study? And if you, if you're doing a shotgun approach to epidemiological research, shotgun's approach would be like, let's just look for what's correlated, right? We don't know what, let's just look for all the correlations. But that's different than going into like, we're looking at this specific thing. We're gonna look at, we're thinking through what are all the confounding variables? We're planning the study accordingly, right?
37:14 David Puder? And then how many lines of evidence lead to the conclusion is the last one. So I think that that's a pretty cool set of criteria.
37:23 Speaker 03 Very, very cool and very, very useful.
37:25 David Puder? Yeah, and I think that would be like a good CME question. To kind of like up, up the, up our understanding of like, you know, there are things that lead to us being more likely to think that this is a correlation. Other than doing research, which is potentially like, we can't research something that we think has a high possibility of causing someone to have lifelong psychotic illness. Yeah, that's not a fair randomized control trial.
37:55 Speaker 03 Ethical boundaries for a good reason.
37:57 David Puder? Yeah, okay, so keep going. What is, what is one of the best studies that addressed these criteria?
38:04 Speaker 03 All right, there is a really, really good study that addressed dose response and temporality. And it was based off of a cohort of Swedish military conscripts. So it studied followed 97% of the country's male population from the time that they're from the ages of 17 to 18 up until 26 years or later. And the intensive military screening process was able to control for a lot of variables, such as pre-existing psychotic disorders, severe mental illness. They also collected information on drug use patterns and social background. And the study observed an increased risk of developing schizophrenia with lifetime cannabis usage.
38:49 Speaker 03 And the odds ratio was 1.5.
38:53 Speaker 03 There was also a dose response effect associated with frequency of usage in that the odds ratio for those who used cannabis more than 50 times was at 3.1 compared to the general population. There was a limitation with the study, given like the nature of like the screening process in that the baseline study that was, the baseline population that was studied had a relatively low percentage of people with schizophrenia, it was about 0.7, and that was due to controlling for psychiatric disorder at baseline. But of the about 1,700 subjects who'd ever used cannabis, only 1.1% of those went on to develop schizophrenia, with 5.7% of them having used cannabis over 50, over 50 times.
39:38 David Puder? I think that's, that important last statistic is worth repeating. So of the, the subjects who were using cannabis, who had used it greater than 50 times, 5.7 of those went on to develop schizophrenia.
39:54 Speaker 03 5.7%.
39:56 David Puder? Yeah.
39:57 Speaker 03 I believe the overall number was five out of 70, so you know, percentage wise, it's about 5.7%.
40:03 David Puder? This study is great because it's huge, it's a massive amount of people, it's only men, which is maybe a limitation, but the, the fact that they were able to control for so many things like psychiatric diagnosis at conscription, IQ score, personality variables, concerned with interpersonal relationships, because sometimes we'll have someone with the kind of pre-morbid sort of pathway to schizophrenia, who's a little bit more socially awkward, socially, kind of not as engaged in relationships. I used to have an attending who would say, like, ask about their relationship history,
40:46 David Puder? because they usually weren't in a lot of, like, romantic relationships pre-morbidly.
40:52 Speaker 03 And this study too, they also along that line, they also like assess the number of prior relationships with girlfriends. So that's there's truth to that, too.
41:00 David Puder? Yeah. Disturbed behaviors in childhood, history of alcohol misuse, family, history of psychiatric illness. They controlled for all these factors and still had an odds ratio of 1.5. And then when they increased it to the dose response relationship, the odds increased to 3.1. Okay.
41:19 Speaker 02 And one additional point, too, is when these conscripts were first evaluated, this was, I believe, 1969. And so one thing to remember is the potency of cannabis back then was between four and 10 times less than what it is today. So perhaps if the same study were to be repeated today, we could see an even, an even greater effect.
41:44 David Puder? Because the dose, we would, we would expect that. We'd be surprised if we didn't see it.
41:49 Speaker 02 Right.
41:50 David Puder? It would be in line with our gut instinct here. But yeah, the Bradford Hill criteria would be further met if that was the case. Cool. Liam, any thoughts on the study?
42:02 Speaker 01 No, I think you guys hit every point that I wanted to make. And I guess one discussion point is about that dose effect. I hear a lot of people talk about how people self titrate their dose, where in the 60s, 70s, 80s, with a lower potency cannabis, that people would smoke an entire joint, whereas nowadays, people maybe take one or two hits. But at the same time, you have to realize the patients that we're discussing today, they tend to be using cannabis at much higher rates. Like we mentioned, using 90% cannabis. Like no matter how much, how much you titrate your cannabis use or your consumption, you're
42:42 Speaker 01 going to have a much higher dose. And they see plasma concentrations and patients using 90% in these concentrates, it can be tenfold higher than that of using flour. So that's one thing to keep in mind for people making that argument for self titrating.
43:02 David Puder? Okay, I found this other study that kind of fit here, I think. It was a prospective, population-based study, Vans Oetall 2002, where they followed 4,000 adults in the Netherlands who were free of psychosis at baseline and found the baseline cannabis use predicted later development of psychotic symptoms, including symptoms severe enough to require mental health care. And the odds of developing pathology-level psychosis were over 24 times higher in those who had used cannabis at baseline compared to non-users, even after controlling for a ton of factors. And importantly, the study showed a dose-response effect.
43:46 David Puder? Greater cumulative use was associated with progressively higher risk. And I might add furthermore, those with existing vulnerability to psychosis at baseline, cannabis use led to dramatically higher rates of poor outcomes, with 80% of psychosis cases in this group attributable to the synergistic effect of cannabis and baseline vulnerability. And so these findings address several of the Bradford Hill criteria for causality. You have temporality, dose-response, biological gradient, and strengthen the hypothesis that cannabis may play a causal role
44:30 David Puder? in the development or exacerbation of psychosis.
44:35 Speaker 01 Yeah, I think one of the things that this study does well is it does address dose-response relationship, but it doesn't do the best at looking at temporality, where they're looking at baseline consumption of cannabis. So someone who's more likely to use cannabis at baseline, they have other factors that go into why they're using cannabis at a young age. And that's kind of leads into the third hypothesis that we're going to discuss later, which is there are predisposing conditions, environmental, genetic, like adverse childhood experiences that will increase the risk for cannabis use and schizophrenia, both independently. And then also looking at the someone's genetic proclivity for developing cannabis use disorder
45:19 Speaker 01 that may also predispose them to developing schizophrenia. So it's still, I think it's a good. Study to look at a dose response relationship and really show that there is something there. But you still have to keep these other perspectives in mind.
45:37 David Puder? I think that the unique thing about this, and we talk about temporalities, they did have a structured psychiatric interview conducted at three time points, which the military study didn't have. So that's kind of like one of the unique things.
45:52 David Puder? Military screenings for mental illness are much more like, you know, brief, I think, in general. Okay, let's talk about the adolescent cannabis use and how it may affect brain development.
46:05 Speaker 01 Yeah, so a lot of people will say that cannabis use in adolescence will lead to chronic deficits in brain development and to cognition, and that this could be one of the ways that you could explain cannabis's effect on later psychosis. So, based on rodent studies, chronic exposure to THC in adolescence, these studies tend to show atrophy of dendritic spines and cortical glomerotergic neurons, and they also observe morphological changes in different GABAergic interneuron subpopulations. So essentially, glomerotergic neurons are the ones that project from parts of the cortex to other parts of the cortex, so different
46:47 Speaker 01 brain regions, that's how they connect. And then these GABAergic interneurons are the neurons within the layers of the cortex that modulate the activity of these glomerotergic neurons. And differences in morphology have been seen in patients with schizophrenia and these different neuronal subtypes, as well as in depression and chronic stress. So, chronic THC exposure probably has some impact on the morphology of neurons with, if seen during adolescence. Next, for looking at structural MRI studies in humans, they tend to show some commonalities between chronic cannabis and schizophrenia. And the most consistent finding
47:29 Speaker 01 that I was able to see was a reduced rate hippocampal volume. But a lot of these studies, they don't control for the effects of early life adversity, which as we've talked about on the ACEs podcast, that this is independently linked to hippocampal volume as well. Also, some studies, when they controlled for alcohol and other substance use, this effect also diminished to where there is no difference. And one recent meta-analysis in 2023 of 16 studies, they found that heavy cannabis use during adolescence or young adulthood, they couldn't find any consistent deficit in subcortical or cortical gray matter volume or in white
48:10 Speaker 01 matter integrity. But as you've pointed out to me, Dr. Peter, that there was a slight trend for a decreased prefrontal cortical volume or thickness. And I think one of the best studies that addressed this, since the publication of this meta-analysis, they looked at 800 adolescents from age 14, before they started using cannabis, and then they looked at them multiple brain scans up until age 19, and saw the patients who began using cannabis after age 14, they saw a greater reduction in their prefrontal cortical thickness. You know, usually during adolescence, you have synaptic pruning and a reduction of gray
48:53 Speaker 01 matter volume up until, I think, the age of 30, and then it kind of like flatlines a little bit. But you see this accelerated reduction in gray matter volume that was accelerated even more so in patients who were using cannabis. And this also correlated with the brain regions that showed the highest expression of CB1 receptors. So I think this is a pretty strong study to make that claim that cannabis can influence brain development.
49:18 Speaker 01 And then in terms of fMRI studies, I'm not as excited about this literature because there are so many different methodologies that people use. But you will consistently see changes in attentional control networks, which is the prefrontal cortex, anterior cingulate, posterior parietal cortex. These studies tend to show either increased or decreased activity, depending on the methodology that they're using. And then some other studies suggest that there are changes in reward responsibility in adolescents who use cannabis heavily. And I think given any drug that increases dopamine in the limbic system, that you're going to see some changes in someone's reward responsibility, greater risk for anhedonia.
50:01 Speaker 01 But I think the, some of the findings in these studies are a little bit inconsistent, but I think that's a topic to, to keep in mind as more studies come out.
50:10 David Puder? I think there's a, there's, there's one study that I found that's not in our, our notes yet. It's 2025 study by Palan Yapan, I'm probably pronouncing that wrong, et al, in Jama Psychiatry, where they used neuromelanin sensitive MRI to show that young people with cannabis use disorder have an abnormally high dopamine activity in the midbrain. And they observe blacker spots of neuromelanin in the substantia nigra and VTA in heavy cannabis users, equivalent to, to someone a decade older. And this indicates excessive dopamine release over time,
50:52 David Puder? since neuromelanin is a byproduct of dopamine metabolism. Strikingly, this dopamine elevation was present even in cannabis users without schizophrenia and was similar in magnitude to first episode schizophrenia patients. So.
51:13 David Puder? I think that that was significant because it's kind of like this other link to between cannabis use and schizophrenia. Have you seen this one or is this one?
51:21 Speaker 01 No, that's that's new to me, but it kind of goes along with some of the critiques that other authors have made like of the meta-analysis. There's the claim, okay, what are the predisposing factors that people who use cannabis, like what do they already have? Are they already more impulsive? Do they have higher like reward-seeking behaviors? And that kind of plays into that increased dopamine potentially. So there are other preceding factors that could explain some of these effects. But I think that's a pretty interesting study. I haven't heard of that methodology before.
51:56 David Puder? We'll add that one in to our ever-growing handouts here. Okay, let's keep going. So thinner prefrontal cortices on MRI compared to non-users. There's also adolescent mice studies that have shown THC shrinking dendritic arbors of neurons and altering synaptic genes. I think that's important because you can't really just, you know, in a human, you can't just open up their brain and look at the the arbitrarization of dendrites, right? Whereas you can harvest the mice after exposure and see how it's changed the brain compared
52:35 David Puder? to mice that haven't been exposed. So, okay, let's let's keep going here. Reverse causation. So people with schizophrenia use cannabis to treat symptoms. Could this be the reason? Could this be what is going on, right? Who wants to launch in about this one?
52:55 Speaker 01 Yeah, I can I can take it. So, you know, for any epidemiological study, you see increased hazard ratio, you always have to think about reverse causality. Could someone? With schizophrenia, just be using more cannabis compared to someone without. And it's found that nearly half of people with schizophrenia develop a cannabis use disorder in their lifetime. So that's a higher rate than the general population. And, you know, some reports or some patients report that it helps their negative symptoms more. So the symptoms related to volition and affect, poverty of thought. But the systematic review and meta-analysis found no difference in negative symptoms between patients who use cannabis and those who did not.
53:39 Speaker 01 So I don't find this argument very convincing, but I do find the argument, which is the third hypothesis, that there are genetic and environmental factors that increase the risk for both cannabis use disorder and schizophrenia, and that these environmental influences can overlap with each other.
53:58 David Puder? Okay, let's get to that.
54:01 Speaker 01 Yeah, so in talking about the genetics of cannabis and schizophrenia, there are a lot of studies in the early 2000s looking at the catecholamine methyltransferase gene. And these were studies that looked at polymorphisms in this gene and in adolescents who use cannabis, they found, I think it was a fourfold increased risk of later developing schizophrenia. But a lot of these studies, the single gene studies, they weren't replicated very well because most single gene studies, they can't exert that much of an effect. Any phenotype, especially mental health phenotypes, they are polygenic in nature. So you need to look at the effects of multiple genes.
54:41 David Puder? And to which I would say, a lot of people online will say, therefore, these are not biological diseases at all, because you can't show me the gene that makes it a biological disease like sicko cell anemia is.
54:57 Speaker 01 I mean, yeah, for for some disorders, it is just one gene and it and that can explain the entire disease state. But for mental health disorders, where there are so many different factors going into it. You know, we're meant to be shaped by our environment as well as our genes. So our brains and our personalities and our our behaviors, they're all flexible in in terms of what the genetics that we're given to be, you know, in accordance with the environment that we need. But that's not to say that there aren't genetic factors that will increase your risk for having a deficit in your functioning. So that leads to a mental disorder.
55:37 Speaker 01 But with these polygenic risk scores, so looking at multiple genes together in what are called GWAS studies, a lot of reports will look at these polygenic risk scores and say like, okay, if someone has a high polygenic risk score for cannabis use disorder, they are also more likely to develop schizophrenia compared to people with without without a high polygenic risk score for cannabis use disorder. So then they make the claim, okay, people who are genetically predisposed to cannabis use disorder will develop schizophrenia, therefore cannabis use can cause schizophrenia. But then you also see other studies in the opposite direction where you see a polygenic risk score for schizophrenia can also predict cannabis use disorder.
56:22 Speaker 01 And then they make the argument that there's an overlap for cannabis use and schizophrenia. And I think it's important to note that studies that rely on this Mendelian renitization for these two different disorders, I I think it's not the best methodology to use in this case. Because these genes can predict behaviors and traits and you know, biological abnormalities that are common to schizophrenia and cannabis use that can independently explain their effect, like the gene's effect on those disorders, like impulsivity, lower conscientiousness, higher neuroticism, a higher emotional reactivity, maybe changes in their neurodevelopment.
57:04 Speaker 01 So you're you're looking at all these genes that affect all these different traits. And these traits will then predict both of those disorders. So it's not really the best methodology to infer causality like you see a lot of researchers using.
57:19 David Puder? Did you see this 2024 cross ancestry genome-wide study by Johnson at all? And because I think they looked at this, they looked at specifically, and they were using 1.2 million participants, right, over multiple ancestries. And the author found that cannabis use disorder and schizophrenia are significantly genetically correlated, 0.37 in European ancestry and 0.61 in African ancestry, with strong overlap between schizophrenia and tobacco use.
57:58 David Puder? Though the methods adjust for something that I think you were speaking to, which the fancy word is horizontal pleiotropy. So essentially, what that means is that they're trying to adjust for these things that you're talking about, like neuroticism, or, you know, these things that maybe lead to both issues, but maybe not in the same way that it's like there's a causal relationship between the two, right? So, for example, executive function, okay? So would executive function potentially lead to both of them being linked genetically, right?
58:43 David Puder? So if someone had genetic markers for low executive functioning, they might be more likely to develop schizophrenia and cannabis use because of decreased ability to stop impulsive action. So they controlled for that, actually, in this study, which I found fascinating that they're already, that they're doing that. So importantly, they identified 200 pleiotrophic loci. Now, remember, we can only really hold three things in our working memory at once. So identifying 200 links between these two things is pretty significant and pretty hard for us to comprehend at once, right? So some of them were things like executive dysfunction, increased risk for other psychiatric
59:27 David Puder? disorders like bipolar, PTSD. Notably, though, shared variants between cannabis use disorder and schizophrenia were enriched in brain tissue.
59:40 David Puder? Suggesting biological plausibility pathways for comorbidity. So they looked at both shared genetic predisposition and reciprocal causality. And they they thought that this may contribute to the link between cannabis use and psychotic illness. So a couple of chromosomes that they found, which might be interest. This one, CHRNA2 on chromosome eight. These genes code for nicotinic acetylcholine receptor, which affects cognitive function and reward systems. This was previously linked to smoking and cannabis use, but in this study, it was most
1:00:22 David Puder? strongly associated with both cannabis use disorder and schizophrenia. And so this was implicated in the positive symptoms of psychosis, cognitive deficits, possibly explain comorbidity. Another gene that they found specifically was EPHX2, also chromosome eight, codes for an enzyme involved in neuroinflammation, has been linked to schizophrenia, Alzheimer's, and pain. It interacts with FAAH, which metabolizes endocannabinoids, our brain's natural cannabis-like chemicals. So I'll just mention those.
1:01:06 David Puder? There was another one on neuroplasticity that they also found a link. So, yeah, does this change your perspective at all? Or does it, do you still kind of think that this is not a good thing to show linkage?
1:01:20 Speaker 01 No, I think it's a great thing to show linkage because you're looking at genes that have biological processes that are predictive of both cannabis use and schizophrenia. That explains a lot of the overlap there. So I think I think it's a great example of the study that shows pleiotrophic genes, both, you know, the shared genes are there. And one point that I did want to mention too, that I forgot to mention is that there's some studies that suggest that the relatives of patients with schizophrenia, the relatives have a greater reward responsibility and sensitivity to cannabis. So this kind of leads into the idea that, you know, maybe.
1:02:03 Speaker 01 There are genetic traits that predispose someone to liking cannabis more than others. And we know this for alcohol, too. So you'll see like family trees of people who just consistently use alcohol. And again, there's environmental factors that go into it as well. But I think the magnitude of reward that you get from a substance, a lot of that is biologic in nature and genetic.
1:02:27 David Puder? So there's some linkage, right? There's some common genes, but it's not a hundred percent correlation, you know? There's some linkage, but this doesn't say that if you didn't have any genetic stuff, that if you smoked high enough amounts of THC that you wouldn't be at risk. That's not what this study says. I hope that was clear. It's like, it's like someone made this point on Twitter the other day that there's no amount of trauma that will lead you to develop PTSD unless you're genetically having some predisposition to develop PTSD.
1:03:10 David Puder? And I was like, I don't think that that's how it works. I think that there is a significant, like, if you take the dose up far enough, you will have a mental health issue, even if you had perfect genes. I don't know. Liam, isn't that what we found in the ACE study?
1:03:25 Speaker 01 Yeah, yeah, with four more ACEs, far more likely, I think. I forget that the odds ratio is off the top of my head, but you do see this step up where it's an exponential increase in someone's likelihood of developing a psychiatric disorder. But that also opens a discussion for, I think it's called multifinality, where with an exposure to some sort of event, either that's trauma or heavy drug use, the way that someone will express a disorder after that is going to be different. Like, people, that's where the genetics probably interact as well and the individual's coping strategies and just how biologically predisposed they are to developing PTSD or schizophrenia
1:04:07 Speaker 01 or, you know, depression with increased cannabis use. I think that's an interesting point to bring up as well. It's not automatically going to cause schizophrenia and someone who uses high potency cannabis daily, they're going to have other deficits that could be expressed.
1:04:26 David Puder? Yeah, this is kind of what I think. It's like, what is the first organ system to get hit by a specific stress? It's like, maybe your genetics predispose you to have migraines that first hit, you know, when you have lots of stress. You know, what is, what is that thing for each person? I think it's, it can be different based on genetics. Is that what you're saying?
1:04:48 Speaker 03 Yeah, exactly.
1:04:50 David Puder? Okay, so the next big sort of category is cannabis worsens schizophrenia.
1:04:56 Speaker 03 I can talk to the, I can speak to that a little bit. So much of our discussion up to this point has been about the working hypotheses of the connection between cannabis users and schizophrenia. And so there are hypotheses, so they're being, still being worked out, but what we can say definitively is that cannabis use can make the clinical course of schizophrenia much worse. And I'm pretty sure we've all come across patients that have, you know, a long-term psychotic disorder. And we're thinking to ourselves, if they weren't using all the weed that they were using, things would probably be, be better, especially when it comes to, you know, immune resistance and paranoia. I've come across patients that they would just refuse to take any oral medications, any oral
1:05:38 Speaker 03 antipsychotics. And so all their antipsychotics had to be intramuscular, to the point where they had to, you know, rotate spots because you couldn't use the same spot over and over again to give them the medication because it would just fall up. So yeah, I think that if the guy wasn't using all that weed, it probably would have gone a bit smoother for his own well-being.
1:05:58 David Puder? Yes, I've, I've, I've seen this play out so many times, so many times. I could, it's, it's like, it's not like a couple cases for me. It's like, I've been doing this for more than 10 years. It's like, I could, I could think through the faces of these different individuals. And when they stopped the marijuana use, how much easier it was to control the, the positive symptoms and to lower the severity of the negative symptoms. So both. So, and the cognitive symptoms too, where it's like they could get back into life. They could like, Okay, keep going.
1:06:36 Speaker 03 Yeah. Of note, there was a 2022 meta-analysis and review of studies by Raltz and colleagues. It showed that cannabis use was not associated with worse psychotic symptoms or increased psychotic dose requirement. Or what, and it also was not associated with poor symptom evolution. But it was shown with an increased rate of relapse into psychosis. Specifically in two of the studies and one of the studies was by Scheffler and colleagues. It was a perspective and longitudinal single site cohort study of 98 patients. With first episode schizophrenia. They were giving a long acting injectable antipsychotic and followed over 24 months. Abstinence was ensured using periodic urinary drug screens throughout the study.
1:07:21 Speaker 03 And after the 24 months of treatments, psychotic symptoms decreased equally in both groups. With similar remission rates for cannabis users and non-users. However, cannabis users did relapse to a higher percentage. And the number of positive urinary drug screens for cannabis was correlated with the increased relapses. And it is also worth noting that the two groups did not differ in their psychotic symptoms at baseline. That was measured through their PANS scores. But the cannabis users did have poorer, poorer social and occupational functionality at baseline.
1:08:00 Speaker 03 With this particular study, it addressed ensuring compliance to the use of long acting injectables and controlling for baseline symptoms. As non-compliance and poor baseline symptoms could each independently lead to more relapses.
1:08:15 David Puder? Great. And I found this other article, it was a 2023, so it came out of, it came after the one that you brought up here. And it was a meta-analysis by Argoti et al. Using the PANS score on 3,000 individuals. With schizophrenia spectrum disorder. And I think it offered a more nuanced view specifically on the different symptoms of schizophrenia and psychosis. So after adjusting for co-founders, they found that cannabis users had higher severity of positive symptoms. They had higher, greater excitement symptoms. They had lower severity on negative symptoms compared to non-users.
1:09:02 David Puder? And no association was found with disorganized or depressive symptoms. So this kind of supports this idea that there is a higher paranoid ideation and hyperactivation. But also it seems to attenuate the negative symptoms, which is interesting to me, like the evolution or affect of flattening, probably because it's increasing the dopamine somewhat. There may be some self-selection effect that's here that we need to pay attention to. So this study really highlights and strengthens the idea that cannabis use worsens positive symptom trajectories and highlights the importance of differentiating symptom clusters when assessing cannabis impact.
1:09:46 David Puder? And I think also it may speak to like some patients really, really hate the negative symptoms and maybe they're trying to get out of the negative symptoms. Now, it wasn't a huge change in the negative symptoms, like effect size 0.5, but still the positive symptom increase is significant and that's what I've seen.
1:10:05 Speaker 01 Yeah, a couple of points I want to make first about the negative symptoms. You mentioned the self-selection effect that could lead to more substance use. So essentially you imagine a patient who has such severe schizophrenia that they have zero avulsion, they don't even want to get up out of the house to go to the dispensary or contact someone. So you can make that argument as well, someone with less negative symptoms, higher functioning, better able to plan how they're going to get the substance. So that could explain some of the effect. But one of the reasons why I really like the study that Danny mentioned, the 2022
1:10:45 Speaker 01 study by Scheffer and colleagues, is that it really controlled for, you know, someone is definitely taking the dose because they're on an LAI. So that controls for maybe some of the functioning of patients who use cannabis and have schizophrenia, saying that if patients use cannabis, then they're less likely to take their oral medications. So that definitely controls for that in this other study. And then also, you know, controlling for the baseline psychotic symptoms, where someone with worse schizophrenia, they may, maybe they are just more likely to use cannabis more because they have less, less functioning in their daily lives. So there's a couple of different arguments that can be made there, but I really like this
1:11:29 Speaker 01 Shuffler and colleagues study because it controlled for a lot of these factors. And I'm not quite sure to what extent the, that study that you mentioned controls for some of these factors.
1:11:41 David Puder? I think, um, I think the big takeaway from this is kind of what I've seen in practice is that cannabis worsens schizophrenia, worsens relapse. I think it worsens the positive symptoms. And I think that those things are pretty common sense from what I've seen.
1:11:59 Speaker 01 Yeah, I want, one other point that I did want to make is there's one argument for cannabis potentially reducing the plasma concentration of antipsychotic, especially the peens that rely on the CYP1A2 activity because cannabis can induce the cytochrome P450 system, specifically 1A2, along with tobacco smoking as well. So patients on clozapine, alentipine, if they presume cannabis use, then they might significantly reduce the plasma concentrations of these drugs.
1:12:34 David Puder? That's a good point. So this is the end of our handout, which is amazing. We've got, if you're listening this far, congratulations. You know more about cannabis-induced psychosis than probably the average person. What are some of the key takeaways and maybe some of the messaging that we should have from this, coming from this? Christopher?
1:12:55 Speaker 02 I think one key, one key takeaway is kind of again, going back to whether or not many of the Bradford Hill criteria are met. And I think it is certainly safe to say that there is a wide range of both epidemiological studies as well as other studies that seem to meet many of these criteria in different ways. And that there does appear to be a dose response relationship. And this is something that patients should absolutely be mindful of. If they choose to use marijuana, that the frequency and amount that they use it. Is is a very serious consideration. In terms of either exacerbating their current illness they may have.
1:13:40 Speaker 02 Or predisposing them to develop a psychotic illness.
1:13:45 Speaker 03 A takeaway that I had is generally avoid using cannabis, especially because it's kind of the wild, wild west and you can't really control for what's in it. And you can't really control for the um, for the concentrations of THC or the concentrations of CBD. So you really are taking a lot of risk by using cannabis recreationally. And you just want to definitely avoid the stronger and more concentrated forms of THC.
1:14:12 Speaker 01 Yeah, just echoing what you guys said, avoiding strong concentrations of THC. Especially in patients with a history of psychosis or family history of psychosis, it's not worth the risk and. Yeah, you should, if you have a patient who's treatment resistant and they're still using cannabis. Uh, yeah, definitely try to get them off of cannabis as much as possible. And we'll kind of talk about some of the strategies in the next episodes leading up to this. But I hope a lot of people took something away. Uh, from this episode to to think critically about what the research is saying because. Like I said, it's a polarizing topic and there are political narratives behind each perspective. Uh, saying that cannabis is helpful for psychiatric symptoms. Or people on the other end saying that it causes every psychiatric symptom under the sun.
1:14:56 Speaker 01 So I think to really, I I hope that people. Can listen to this episode and have a better understanding of how to go through some of these epidemiological studies that are coming out.
1:15:08 David Puder? All right. First of all, I really appreciate all three of your contributions to this. This handout is amazing. If you want to check it out, it's going to be on psychiatry podcast.com. You can go check it out for free. If there's new studies that you feel like we're missing here, shoot me an email. We always like to, you know, challenge our understanding, deepen our understanding of things. And I think, I think that one of the things I've, I've had since I've posted on this before is I've had parents reach out to me and be like, my kid was a heavy cannabis user. They got psychotic and it has, it's, it's changed the trajectory of their life. And so I think there's this sobering aspect for me, having been in the trenches, having talked to parents, having seen this
1:15:50 David Puder? firsthand. And, um, you know, if at all possible, delaying onset of cannabis use. In Canada, they're trying to, they're trying to delay it. They're trying to keep it for the weekends, not every day, stay away from high potency use. So in some of their sort of public agendas, specifically it's called the lower risk cannabis use guidelines. They're trying to push for those things. I think this is very important, especially in first episode psychosis events, to have this discussion with the family, to have it with the patient. There's some patients I've had it with 10 or 12 times before they get on board. If, if I post
1:16:31 David Puder? anything on this online, people are always like, oh, who's funding you, Big Pharma? I'm like, no, that's not the case. Actually, I mostly do psychotherapy, lifestyle stuff, and, uh, you know, medications for severe mental illness. And then they're like, severe mental illness doesn't exist. And then I'm like, okay, I don't know if I can have this conversation. So yeah, we're here 2025. We'll probably come back three or four more years and see some of the new science that has come up, come out on this topic. And I'm looking forward to part two and maybe part three on this. And we'll continue to dive into the science. So, thank you guys.
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