Chris Casey:
In January 2014, Colorado became the first state in the nation to begin allowing state-licensed retail sales of recreational cannabis for adults over age 21. Since then, many states have followed suit, creating a major industry and one spurring myriad questions about cannabis' effects on both physical and mental health. Today, we'll look at cannabis and brain function, specifically how marijuana may impact a person's ability to perform basic tasks and its potential effects on working memory.
Welcome to another episode here of Health Science Radio, where we meet with scientists and clinicians at the University of Colorado Anschutz Medical Campus to discuss the many ways they are innovating and advancing healthcare. My name is Chris Casey, and I'm the director of digital storytelling. It's, again, my pleasure and honor to be joined by Dr. Thomas Flaig, our vice chancellor for research.
Thomas Flaig:
Always glad to be here, and I think a very timely and interesting topic today. Here we are in Denver on a very nice, warm spring day.
Chris Casey:
Oh, it's beautiful. It's beautiful. If only this could last throughout the month of March.
Thomas Flaig:
It won't.
Chris Casey:
Yes. It probably won't even last two more days, but we'll take it while we have it. Today, our guest is Joshua or Dr. Joshua Gowin, who grew up here in Northern Colorado and completed his undergraduate studies at CU Boulder. He earned a doctorate in neuroscience from the University of Texas Health Science Center in Houston and then worked at the National Institute on Alcohol Abuse and Alcoholism as a postdoctoral fellow.
He joined the Department of Radiology at the University of Colorado School of Medicine in 2018. Josh uses MRI to study brain function and mental health, focusing specifically on substance use and how brain function might recover during treatment. His team recently examined the effects of cannabis use on over 1,000 young adults aged 22 to 36 using brain imaging technology. The study, which was published just a couple of months ago in JAMA, was the largest of its type. Welcome, Josh.
Joshua Gowin:
Thank you. Glad to be here.
Chris Casey:
Thanks for taking some time out and filling us in on this very fascinating topic. There's a lot of interest in what cannabis does to people, especially their brains, so I'm just curious, what got you interested in this area of study?
Joshua Gowin:
Yeah, sure. So I have been interested in substance use for a long time, and I will say that some of... at least some of my initial interests in the topic did start because, in elementary school, I learned a lot about substance use through advertising on TV and also through the DARE program.
So people come to school and tell children what they might expect in their teenage years, what opportunity they might be exposed to chances to use substances, and they may have impacts on their development. And so that was my initial exposure to it. But then I also went through being a teenager and sort of felt like, "Well, some of the things that I heard don't match up exactly with the experiences that I had."
I sort of got this impression that maybe you use a few times and then your brain will be like an egg, and it'll get smashed or something like that. And that certainly didn't seem exactly what I was observing, so I wanted to learn more precisely what does actually happen when people use substances and how do they affect our brains and our behavior.
Thomas Flaig:
Yeah. Well, I think that the recent work you've done with the JAMA Network study and the size of that study looking at cannabis, cognitive impacts, and so forth, has really, I think, gained some interest. So what led up to that particular study and positioning you to do that work?
Joshua Gowin:
Yeah. So it really was a neat opportunity. A lot of the time, so I do functional MRI and you know you have to pay hundreds of dollars to do a scan, you have to do all the work recruiting people. And so there was certainly a period of time where if you got 50 people into your study, you were pretty happy.
That was a good study to have done. And a little over a decade ago, they started this study where they really wanted to get a much larger sample size and do imaging on over a thousand people. And I really think because they were trying to get so many people through the magnet for a scan, they completed this study in just a few years. So they were just scanning a lot of people quickly.
I think they probably made some choices that other studies wouldn't have, which is, "We'll allow people in the study if they have been using cannabis even recently, and we'll just have that variable available for people to look at." So what in other studies might've been a problem, for this study became an opportunity, I think, to look at one of the larger samples collected for brain imaging and actually get to look at how cannabis use was associated with the brain function.
Thomas Flaig:
So why don't you say just a few more things about functional MRI? So what is that, and how does it work?
Joshua Gowin:
Sure. Yeah, So MRI generally can take a high-quality picture of things inside of the body. And for me, the brain is the thing I want to look at. That's what I'm really interested in. And functional MRI, rather than looking so much at the high-quality picture, you can look at changes over time, especially with blood flow, like fluid changes.
And so the blood being a fluid, you can see where blood flow patterns are changing, and that tends to correspond to where the parts of the brain that are using the most energy are the ones that are active. So the blood is flowing to those regions, and you can use that to learn which brain regions are active during a behavioral task that they're doing inside of the scanner.
Thomas Flaig:
What was the primary scientific question you were probing with this study?
Joshua Gowin:
Yeah, so we really wanted to know... One of the other cool things about this data set is that, a lot of times, these imaging studies, they look at maybe one or two tasks at a time, but this study, they had seven tasks. They were really trying to get a really good representation of how the brain works across different domains.
And I had looked at some kind of neuropsychiatric work where they had looked at how cannabis affects various domains of brain, of mental functions. So they looked at learning, they looked at working memory, they looked at other types of things, and I thought, "That is so cool. I wish I could do that for the brain." And I felt like this – having the seven tasks – allowed me to get about as close as you could for a brain-imaging person to look at how different parts of brain function are affected by cannabis.
Thomas Flaig:
And then, in terms of the functional MRI, you had three groups: heavy use, moderate use, and non-use. So how did you come up with that, and how did you define those different things?
Joshua Gowin:
Yeah, that was another... probably one of the most important things that we had to decide about what to do with it. So they didn't design the study, saying, "We're going to recruit heavy users." What they did was they brought people in, and they just asked them a question, "How many times have you used cannabis in your lifetime?" And they had a few options that they could choose from.
They weren't saying, "Oh, I used 3,742 times." They were saying, "I used zero times, one to five times, six to 10 times." Then there was 11 to 100, and then 100 to 1,000, and then 1,000 plus. And we thought, we don't really think that there's a meaningful difference between two times and seven times, but once you start saying over a thousand times, that seems like a meaningful difference to us.
So we made some choices about how to kind of slice and dice the groups, and basically, we said, "Anybody that's used it less than 10 times, we don't really think that that's going to have a huge impact on brain function. But if they've used up to a thousand times, maybe that could start to do something. And then if they've used over a thousand times, well, that certainly seems like the group that is going to be where you'd see the most effect if there was one to see."
Thomas Flaig:
So you took that group of a thousand, had those three different groups, and just in a real rough sense, how big were the individual groups then? Were they mostly non-users, I would guess?
Joshua Gowin:
Most of them were non-users. I think that makes up about 80% of the sample. But then there were not quite 10%, but about 9%, of the sample had used over a thousand times in the lifetime. So a pretty decent representation there. And then there was maybe about 12% or 13% of the sample that had used 10 to 1,000 times.
Thomas Flaig:
And so the sample size of 1,000, 10% is 100 patients, so still a reasonable sample size. And did you have any aspect of most recent use? Did it matter if you'd used in the last month or something versus this was distant use?
Joshua Gowin:
Yeah, I do think that that's probably one of the more interesting outstanding questions. So the best thing that we have is we... on the day of the scan, they provided a urine sample and that was tested for whether or not there were cannabis metabolites in there. And so if they tested positive, then we knew that they had used somewhat recently, but we didn't know exactly how recently.
So they could have used that morning, they could have used four days ago. We don't know exactly, but we also wanted to look at that. If they had used recently, did that also affect the same brain processes? And then if you put both variables into the same model, so recent use versus lifetime use, which one is more important for brain function, too.
Thomas Flaig:
So you had a thousand patients to these three different groups – heavy use, moderate use, non-use, and then you had these seven cognitive tasks. Maybe just remind us of that again.
Joshua Gowin:
Yeah, sure. So the key one that we focus on in the study, because it was the one where we found the most interesting results, was the working memory task. And so for that one, what they're doing is they're looking at a series of pictures, and on the easy condition, they just say, "All right, here's a picture of a castle. Every time you see that, that same picture, you press a button and say, 'That's the picture that I'm looking for.'"
The hard condition where they're really taxing their working memory is when they are seeing the series of pictures, and they have to remember what they saw two images ago. And so they say, "All right, I saw the castle. Now I see the palm tree. Now I see the castle again. That's when I press the button."
Then, if the next picture is something completely different, it doesn't match the palm tree. That's not the right one. You have to constantly keep track of what you're seeing and what you saw in the past, and you have to keep updating your list. And so it's hard to remember and also hard to describe.
Thomas Flaig:
And just so I understand the study then, so someone's in an MRI machine, and they're looking at images while the scan is being done, you're looking at functional changes in blood flow to different parts of the brain as they're doing that activity.
Joshua Gowin:
Yeah, precisely.
Thomas Flaig:
And then, so what were the major findings of this study then?
Joshua Gowin:
Yeah, so of the seven tasks, only the working memory tasks showed a significant effect for the lifetime history of cannabis use. So what we found was that the people that had used over a thousand times, they had lower brain activation when they were engaged in that cognitively demanding working memory task relative to the people that had used less in their life. And so we think that that may suggest that they were less able to recruit the brain regions that are needed to perform that hard task.
Thomas Flaig:
And was there any correlation between those that had active metabolites or recent use of cannabis?
Joshua Gowin:
Yeah, there were. And that was something that was interesting as well. There was... So we weren't the first people to look at this data set, and there were other people. They had actually shown that there was a strong mediation effect where the recent metabolites were not only associated with the lower brain activation but they were also... that brain activation mediated poorer behavioral performance, less ability to remember things.
So they certainly had looked at that, too. And we looked at that and saw the same thing that the people that had the recent use, not only did they have lower brain activation, they also had poorer memory performance. And it did seem like the brain activation mediated the poorer memory performance.
Chris Casey:
Did your research show any certain activity or... parts of the brain where... that were more or less impacted, perhaps by the cannabis use?
Joshua Gowin:
Yeah, that is a great question too, and one that we did get lucky that we could look at that a little bit more carefully. So there were four major brain regions that have been associated with this working memory task, and it's a fairly well-characterized task. People know when you're doing this task, we expect to see these regions are active by this task, and so they tend to be in the frontal cortex.
There's one region in the anterior insula. There's one in the medial prefrontal cortex and then one in the dorsolateral prefrontal cortex. And then there's another region in the parietal cortex that is also involved in the task. One of the things though that we thought was interesting is that you can look on PET scans, and in postmortem studies, you can look where cannabinoid receptors are more densely distributed, and they do tend to be more densely distributed in the frontal cortex relative to the more rear regions of the brain, like the parietal cortex.
And those were the regions where we saw the larger effects. So the frontal cortex showed greater decreases in the cannabis-using group relative to the parietal cortex. And that may have been explained. We couldn't test this specifically, but we speculate that that could be due to the lower density of cannabinoid receptors back there.
Chris Casey:
And I understand you employed a false discovery rate correction to parse out the data. Could you talk about that?
Joshua Gowin:
Yeah, right. So because there were seven tasks, we wanted to be a little more cautious. So we knew we were going to be doing seven different statistical analyses. And so therefore, we wanted to be a little bit more careful that whatever we were finding wasn't just due to random chance.
So you're doing seven tests, and you flip a coin seven times, you get a few tails, a few heads. You don't want to make any conclusions about that. So we didn't want that sort of randomness to be explaining our results. We wanted it to be a little bit more rigorous with our statistical approach and only interpret it as being significant if it met that higher threshold for significance.
Chris Casey:
And what about the whole issue of whether cognition gets disrupted in any way? For example, say a heavy cannabis user just goes cold turkey. Was there any look at... was there data to suggest what could happen in that situation?
Joshua Gowin:
So we did not have any data to look at that, but we do... that was certainly something that we wanted to think about a little bit more carefully as we were reporting these results. So we were aware that someone might look at this and think, "OK." And we thought about this too. This might suggest that if you're going to be doing something cognitively demanding, you may want to consider not using cannabis prior to doing that.
But there is also another issue that some people use cannabis regularly, and some people use it regularly and heavily. And because that... if you're doing that, you may develop symptoms of physical dependence, and if you do, then stopping something suddenly may precipitate a withdrawal syndrome.
So that could lead to irritability and other things that would also disrupt cognitive function and certainly just make you not feel well. So that would not be ideal if you're going to be involved in something cognitively demanding to just stop and then feel miserable during it.
Chris Casey:
Exactly.
Thomas Flaig:
Did you get into the route of administration of the cannabis in this – think about that aspect at all?
Joshua Gowin:
Yeah, that's a great question and one that we really were not able to look at closely because of this. So the data was collected mostly in the St. Louis, Missouri area, and it was collected, as I mentioned, between 2012 and 2015. So there's a couple of things to note about that. One is that that was not legal environment for using cannabis.
And the other thing is I do think that there was just less awareness of what people are doing. It was just, "How much did you use it?" It wasn't, "How many times did you smoke versus how many times did you consume an edible?" And I think that's really a question that a lot of people are getting interested in these days, is looking at how the route of administration may be affected with certain types of outcomes.
Thomas Flaig:
Another aspect of the conversation about cannabis use has been the potency increase over time, right. If you look more historically, in fact, some of the cannabis that's used in formalized clinical studies, it comes from a certain area. As you know, it's from a certain farm or distribution center, and that maybe doesn't have the same potency, for example, as what people are using more recreationally. So how many those ideas of changing potency of cannabis products play into this at all?
Joshua Gowin:
Gosh, I think that is a great question, and one similarly we weren't able to address with this particular study, but it's really, for me, one of the key reasons that I think it's so important to continue to study this. I think there's a lot of things that are going to be evolving. For example, the hyperemesis syndrome is something –
Thomas Flaig:
Maybe just define that for us.
Joshua Gowin:
Yeah, sure. Right. So cannabis hyperemesis is a syndrome that some people can develop where they're using cannabis regularly and it causes them to need to vomit repeatedly.
And really the only cure seems to be stop using cannabis, but it's really something that had not been documented well, really, up until just the past few years, and now there's more evidence about it, but it certainly seems like something that has been evolving as potency has been evolving as well, that the risks for these types of syndromes are changing too.
And so I do think that it certainly means that we just need to keep learning more as we're getting into these higher doses in concentrations that just weren't available before.
Thomas Flaig:
Colorado has a certain historical presence in this space because of some of the regulatory and legal changes that happened here over the last 10 years or so. I would say that context, it's great to see some really high-quality research in this field, which I think there's a great appetite to learn about some of these effects coming out. What was the biggest takeaway for you with this study? And additionally, what was the biggest surprise find that you maybe saw here?
Joshua Gowin:
Yeah, so I actually went into this. Looking back, it's easy to see working memory certainly seems like a good candidate for a place to find an effect, but I didn't go into this study looking for working memory. I went into it, looking at language processing. That was one of the things that was neat about this study was that they actually had a really well-developed language processing model for the brain function when you're listening to people speak versus when you're doing math functions, math problems. And I was expecting to see more of a difference in language processing.
We really didn't see any differences in language processing. I was also... The other thing I was a little bit surprised about is they have this task where people are doing, they call it a social processing or a theory- of-mind task. So what it is, there are shapes moving around on a screen. It's like a video you're watching, and sometimes the shapes are moving randomly, like a screensaver – just kind of floating across the screen. And other times, the shapes are interacting in ways where you might infer a mental function, so they could be doing a conga line. The big circle is moving in the front, and the little circles are moving behind it, and they're dancing, right.
So because you could infer that mental function on there, they used this task to probe cognitive deficits related to social processing, for example. It was used a lot in looking at autism spectrum disorders in the past, and we did see a slight difference in the brain processing of the heavy marijuana-using group on that task. As I mentioned, we... it didn't quite reach the threshold of the false discovery rate correction, but it was just below it. So it was certainly something enough that got us interested, like maybe there's something here, and it also fit with some of the other things.
There's a lot of thinking about psychosis and cannabis use where cannabis use might increase rates or experience of psychotic episodes, and sometimes people will go to the hospital having psychotic episodes related to their cannabis use. And so we actually saw that the heavy cannabis users showed slightly different processing related to this kind of social processing task that certainly to me seems worth following up on in terms of that possibility that there can be an association with psychosis as well.
Thomas Flaig:
I think this is a great example of using an existing data set, asking a really rigorous academic question and getting these results. If you were today to design a perspective study with more control over the inputs and the way data is collected, how would you do that?
Joshua Gowin:
Yeah, so one of the key things is we didn't know how recently they had used cannabis, and I think that really, for us, meant we want to do something where you can control that. You don't want to... You can't legally assign people to a cannabis-using condition where you say, "This is exactly what you want to take in terms of the products that you can purchase at a dispensary."
But you can use an FDA-approved formulation called Dronabinol, and we are planning to do that and get involved in some studies right now where you can actually assign people to either a placebo or an active dose, and then you can look at how the active dose changes their brain activation relative to the placebo.
Chris Casey:
And is there... How about studies? Have you looked into potential for studies that would examine whether somebody who's been a heavy cannabis user who maybe scored lower on the working memory if somehow they can perhaps regain that memory later, if that can be restored somehow?
Joshua Gowin:
Yeah, absolutely. Yeah, that's a big question, and it's also one that there certainly are good ways to study it. I have a colleague that one of her techniques is to just pay people to stop using, and you get some compliance with it.
You say, "We'll pay you this much to stop using for a while," and you can look at that, and you can look to see if cognitive performance recovers or if brain performance recovers. And that's something that we are also going to be engaging with coming up, too. We're going to be looking at how abstinence from substance use may be associated with recovery of brain activation.
Chris Casey:
And I have no direct experience with this, of course, but I've heard that many folks in, say, the creative fields find that perhaps cannabis use can in fact be used as an enhancement regardless of perhaps maybe some decline in working memory.
Joshua Gowin:
Yeah.
Chris Casey:
Is there any... Has that been looked into at all? That maybe a reduction in working memory is perhaps not such a bad thing if, on the other side, creative, more expansive thinking comes into play?
Joshua Gowin:
Sure. Yeah. So I don't know the answer to this one. I do know that there has been some research though into creativity where they, I think, were more experimentally minded, where they tried to give someone a pattern-finding task or something like that. I think they found that there wasn't a difference in people that use cannabis versus that didn’t.
I do think, though, despite maybe not finding it in this experimental task, there could still be something to it. I mean, one of the reasons why people might want to use cannabis is for anxiety management, and I would certainly suggest that for creative endeavors, anxiety is not helpful. So if you can even feel less anxious, even if it's a placebo effect or whatever, it doesn't matter, just the feeling of not being so anxious might help you get past some of those creative blocks.
But one thing also then, of course, to be careful of with cannabis is that it's interesting that in certain situations it could make someone feel less anxious, but there can also be certainly cases where it can make someone feel more anxious, too. So it wouldn't work necessarily the same for everyone.
Thomas Flaig:
Does the functional MRI, is there a creativity center, where you look at that specifically? I don't know that.
Joshua Gowin:
That's a good question, and I don't know that either, actually what might be associated. I do think that, and this really gets away from my focus, but it’s certainly fun to think about is that I know there are people out there that use MRI to study musicianship and things like that, like playing the piano. One of the things, this is kind of a fun opportunity.
It didn't actually end up happening, but we considered it for a while. UCHealth, they have an advertising campaign where they work with a guy named Harry Mack. He does kind of freestyle improvisational rap verses, and he relates them to patient stories. And so it is really interesting to see. And they... some people said, "Well, if we could do anything, what would you want to do?"
He said, "We would love to see an MRI of him doing this." And I thought, "Well, that would be kind of interesting to see how could... how does his brain work when he's doing stuff like that?" It's really challenging, though. You don't want people to be moving when they're in the MRI. You want them to be as still as possible. So we were trying to come up with a way to do it, but didn't quite make it happen.
Thomas Flaig:
Yeah, I just say that this is just a great example. Again, taking a rigorous scientific approach with the models you have into a question that's so translatable and approachable for people who may be using cannabis and thinking about the effects of that and so taking a rigorous scientific approach to thinking about it in that manner.
Joshua Gowin:
Yeah. Well, thanks a lot. Yeah.
Chris Casey:
Yeah, it's been a lot of fun to hear talk about this, Josh, and we very much appreciate you taking the time out today and look forward to hearing about your studies down the road on this topic, because they're pretty endlessly fascinating.
Joshua Gowin:
Yeah. Well, it was a pleasure to be here. Thanks a lot.
Thomas Flaig:
Thank you.
Chris Casey:
Thank you.
