With cannabis now legal in Canada and GLP-1 agonists reshaping how we treat obesity and diabetes, host Fiona sits down with are asking the questions patients - and the public - most need answered.
Are two of the most talked-about drugs in our culture today quietly reshaping how we understand the brain? Host Fiona Sanderson sits down with two researchers exploring the intersection of metabolic health and neuroscience - including how cannabis impacts the nervous system's ability to regulate blood flow to the brain, why GLP-1 drugs like Ozempic work brilliantly for some people and not at all for others, and what this could mean for the future of personalized medicine.
With cannabis now legal in Canada and GLP-1 agonists reshaping how we treat obesity and diabetes, these researchers are asking the questions patients - and the public - most need answered.
Featured guests:
Dr. Alexandre Caron, Associate Professor in the Faculty of Pharmacy at Laval University
Dr. Michael Tymko, Assistant Professor in the College of Biological Science, Department of Human Health Sciences at Guelph University
This work is supported by the Azrieli Foundation and the Heart and Stroke Foundation of Canada.
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Alex Caron 00:05
It’s important to push the boundaries. I’ve always found myself between disciplines. I mean, 16 years ago, I remember presenting a poster and someone told me, “Why do you work in the brain with obesity? Everything happens in adipose.” But now the conversation has changed, and we know that the brain is important. So, I think it’s really important to stick to your conviction and really do what you like.
Fiona 00:35
This is Bold Minds: Future Leaders in Canadian Brain Research. I’m your host Fiona Sanderson. I work at Brain Canada, where our mission is to bring together funders and researchers to enable health innovations for Canadians. The Future Leaders program is made possible thanks to an anchor gift from the Azrieli Foundation and matched by Brain Canada through the Canada Brain Research Fund. Come along with me as we journey into the bold minds and labs of researchers who are redefining our understanding of the brain. [music continues then ends]
[rousing music] 2018 doesn’t seem like very long ago, and yet a lot has changed in Canada since then. 2018 was the year cannabis was legalized in Canada. It’s also the year a new drug for diabetes entered the Canadian market under the brand name Ozempic. Since then, the popularity of both drugs has skyrocketed. Cannabis was around for a long time before being legalized, and GLP-1 agonists, like Ozempic and many others, have gained a huge following for their off-label use for weight reduction.
These drugs are now so culturally significant, they really need no introduction, but we still have yet to discover what these drugs mean long-term for public health. Their uses are many: recreational, medicinal, life-saving, life-changing. Inside Canadian labs, researchers are mapping the brain in real time to understand how these drugs work. Today, we’re delving under the influence, figuratively of course, to discover not just what these drugs do, but the changes they might be rewiring in our brains. This is Bold Minds. [music ends]
Today I’m joined by....
Alex Caron 02:24
Alex Caron, associate professor at Laval University.
Fiona 02:28
His team is studying the brain regions and pathways that GLP-1 receptor agonists target in order to develop and refine the next generation of obesity treatments.
[whooshing] And I’m also joined by....
Mike Timko 02:40
Mike Timko, assistant professor, University of Guelph.
Fiona 02:44
His team is investigating how inhalation of THC, the active ingredient in cannabis, affects blood flow regulation and brain and nervous system function to provide a clearer understanding of how cannabis affects brain health, and the longer-term risk for stroke and other brain diseases. Alex, Mike, thank you for joining us on Bold Minds.
Alex Caron 03:04
My pleasure.
Mike Timko 03:05
Yeah, thanks for having me.
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Fiona 03:09
So, let’s delve right in. Mike, your project, funded through the Future Leaders grant, is focused on cannabis, THC in particular. But your research program looks at the impact of many environmental factors, cannabis being one, but also things like brain injury, high-altitude exercise, on the health and function of blood vessels in our brains. Can you tell us about that? What do these things have in common and why is the effect on brain blood flow so important?
Mike Timko 03:36
Yeah, I guess my primary interest has always been on brain health and what affects the brain and how do our brains regulate blood flow. So, that’s really the common theme between all of those. I guess my first kind of love and passion was actually related to brain health and high-altitude acclimatization. That’s how I got into research. Was how does the brain respond to being in a low-oxygen environment, such as being up at high altitude? And then sometimes, you know, in research you get dealt a lucky hand. And when I came over to the University of Guelph, that was certainly the case. It’s really tough to do cannabis-related research in humans, and University of Guelph is one of the few places that I’ve known that we can do this type of research. We can bring healthy participants in the lab, get them to smoke THC or a CBD oil, and we can measure the physiological effects of those responses. So, there’s been very, very little research done on brain health and brain blood flow, the effects of acute cannabis inhalation on those things.
Fiona 04:46
That’s amazing. Alex, GLP-1s, semaglutides, Ozempic, it seems like not a day goes by on social media without mention of these, like, medical buzzwords. What was developed as a diabetes treatment has ballooned into an extremely popular weight loss drug. As a neurometabolic expert, you study how the brain is involved in both obesity and diabetes. Can you tell us a bit about what you do? What exactly is neurometabolism? Why is it important?
Alex Caron 05:15
Yeah, that’s a good question. So, I will say that I’ve been working in the neurobiology of obesity for the last 16 years, trying to understand initially how the brain controls metabolism in general, how it controls behaviors such as food seeking and appetite and also peripheral metabolism activity. When I was an undergrad, I really became interested in these neuroendocrine axes and how the brain can—and in particular the hypothalamus, can send, you know, information to the pituitary, which then releases these hormones that control peripheral metabolism. This is really what got me into this field. I remember this professor one time came from France to teach us a class in physiology about a hormone called leptin, and leptin is this hormone that’s produced by adipose tissue largely in proportion to how much fat mass there is. The more fat mass, the more leptin is produced. And one of the functions of leptin is to tell the brain about this energy storage and to suppress appetite. And I thought this was really fascinating, that adipose tissue had this ability to produce something to tell the brain, “We have energy,” and then in turn the brain could send all these signals to modulate the activity of the organs.
When I was looking for an internship, I started working on another protein called DEPTOR, which at that point was just being discovered as a regulator of mTOR signaling pathway, which is a very important pathway in diabetes in particular. And the way I really became more focused in the hypothalamus was that we actually first didn’t know anything about DEPTOR. So, we mapped its expression in the brain, found it was really, really highly expressed in a particular part of the brain called the medial basal hypothalamus, and then we overexpressed DEPTOR in this particular region. We found that mice were protected from diet-induced obesity and diabetes. And so, it’s really at this point that I realized how important the hypothalamus was and how, in my mind, it became the common center of metabolism. And then I kept working a little more on how the hypothalamus-controlled periphery metabolism, as well as appetite, and finally started working on leptin.
And how I really became—back to this GLP-1, is that while we were looking at, you know, receptors expressed by some of our favorite neurons, we realized that some of them were expressing high levels of GLP-1 receptors and were actually sensitive to GLP-1. So, I will say that’s really what got me into this field of GLP-1 pharmacology now.
Fiona 07:29
So, you know, you both study substances that are part of this, like, cultural zeitgeist, albeit for very different reasons and purposes. So, what do you think your research findings will mean for real people, for the public, Canadians all over the world? What’s the impact?
Mike Timko 07:45
With cannabis, because—it’s a bit of a shame of how difficult it is at times to do this type of work in humans. And I guess some—a little bit rightfully so, because there are some real considerations in terms of kind of safety risks with doing this type of work, and, luckily, I think we have a really good kind of protocol and system in place. But the biggest concern that we found was this landmark paper. And this study was published, I think, the year that I joined University of Guelph in 2023. And what they did was they measured sympathetic nervous activity by sticking a little tiny electrode, which is about the width of a human hair, into a peripheral nerve. And the nerve that’s most commonly used for this type of work is in the leg. It kind of runs on the outside of your kneecap almost. It’s called the peroneal nerve.If you stick that needle just right in the right spot, you can get a really nice measurement of sympathetic nervous activity directly. It’s commonly referred to as your fight-or-flight system, right? It is a neural activity that is a primary component that helps you maintain your blood pressure.
So, what we found was after just smoking cannabis in young and healthy people, nervous activity drops by about 50%. We can’t find anything else that does this. So, this has some real concerns for a few reasons. What I’m particularly interested in is, how does this affect the brain blood flow? There’s a few different mechanisms, about four or five, that are kind of the primary contributors to how blood flow is regulated in the brain. You’ve got blood pressure, you have, you know, levels of arterial blood, oxygen, carbon dioxide, you’ve got metabolism. And then another one is nervous activity. And it’s a really tricky area of research because in healthy humans, you can’t really measure nervous activity directly in the brain. You know, we’ve got a big skull in the way, so we have to be kind of creative on how to do this. But if we assume that this drop in a nerve activity that’s occurring in the leg is kind of global, if it’s across the whole body and it’s also happening in the brain, how does this affect blood flow that is regulating in the brain? Is it better? Is it worse? I mean, it might not all be a bad thing. Maybe the brain is totally fine and there’s other mechanisms that can compensate for it. So, that’s kind of step number one with this study. Is how is the brain regulating blood flow when one of its primary mechanisms is essentially abolished?
Secondly, the way that we regulate our blood pressure. So, I’m sure Alex and Fiona, you’ve had this before, but if you stand up from your chair super quickly and you feel a little lightheaded and, you know, things start to dim down and then you’ve got to catch yourself and sit back down, well, that’s because your blood pressure is reduced and really acutely. But you have these mechanisms in place to return your blood pressure back up to where it should be, and these mechanisms are an increase in heart rate and an increase in neural output to signal for all your blood vessels to vasoconstrict. To kind of push more blood back up to your heart and thus your brain.
So, if cannabis basically knocks out one of those mechanisms, which is the neural component of blood flow regulation, does that make people more prone to passing out? If you were to just stand after smoking cannabis or whatever, which is widely used—it’s one of the most, you know, widely used drugs in the world—does that make you more prone to passing out and having a fall? And we’re going to test this in healthy people first to see if it does reduce their ability to maintain their blood pressure. I guess the biggest thing is cannabis, it’s widely used, so we need to understand, how does that affect how we regulate our blood pressure? How does that affect how blood flow is regulated to the brain?
Fiona 11:42
Blood flow regulation, so you talk about how, you know, it could affect your stability and things like that. We think about blood pressure as being important for things like, you know, preventing a heart attack or a stroke. What about less severe but still very important other brain functions?
Mike Timko 11:58
For sure. I mean at the crux of it, our brain has no ability to store energy as opposed to other parts of our body. So, you know, there’s no adipose tissue, there’s no fat there. So, if blood flow is reduced in the brain, you have no energy there. So, that’s why brain blood flow is so important, and there’s so many different overlapping mechanisms that kind of control blood flow to the brain. You know, let’s say that you went into a Brazilian jiu-jitsu gym and the first thing that they do is they put you into a chokehold and they reduce blood flow from the arteries in your neck going up to your brain, you would pass out in about five seconds. You have basically under a second of energy storage available, so that’s why brain blood flow is so tightly regulated. So, if that’s being disrupted, yeah, for sure, like, cognition could be impaired, the brain’s ability to respond to changes in metabolism. So, we are doing those tests as well. That’s part of the protocol—part of the experiment that we got funded through Brain Canada. An arm of it is to look at, how does cannabis potentially change the impact of how blood flow is being regulated during changes in brain metabolism as well?
Fiona 13:11
And I think that sets us up perfectly for Alex. As we’re talking about brain metabolism and energy, what do you think your research findings will mean for, you know, the general public, for real people?
Alex Caron 13:23
Yeah. So, I want to say first that we often hear that, you know, these GLP-1 agonists were developed for diabetes and used off-label for obesity, and that some sort of genius in the marketing department saw that people were losing weight, ran to the CEO and said, “Hey, I think we’re sitting on a goldmine.” But in reality, we’ve known for a very long time that GLP-1 was actually suppressing appetite and reducing body weight. And actually, early in the 90s, people had shown that if you infused GLP-1 directly in the brain of mice or rats, this suppresses appetite. And likewise, people have done intravenous infusion of GLP-1 in patients at the end of the 90s and showed the same thing. The problem back then is that the half-life of GLP-1 is so short, there was no way we could believe that this could be used for treating obesity or inducing weight loss. Half-life is actually the time required for a drug to reduce to half of its initial value. So, it’s basically how long a substance can live in your body. And when I talk about half-life of these GLP-1, I think what’s important to understand is that GLP-1, the indigenous GLP-1, which is the hormone produced by the gut, has a half-life of three minutes. So, it means as soon as it’s produced, three minutes later there’s no more of it. What people have done to improve these—I mean, improve the structure of GLP-1 to make its half-life longer, is that they modified the different sites in the amino acid chain to prevent it from degradation but also to be a better binder to some circulating proteins that will just, you know, cargo them around in the circulation. So, basically, what people have done is just prevent their ability from being degraded by enzymes that will normally just cut them down. And so, I just want to put it back in perspective that scientists have known for a very long time this potential of losing weight.The problem was that the molecules we had at this point were not good enough to reach it, and so now we got to this point. And so, the question that really drives us around this is, how does the brain really decide how much energy your body should store? Because one of the problems is when you lose weight, you have all these feedbacks that will make sure you kind of try to maintain this weight. And evolutionary speaking, it’s important because the brain has evolved to prevent us from starvation, not to manage Uber Eats, or anything else that is easily accessible. So, I think what’s important to understand is that the brain is really good at defending our energy stores. But now that we live in this modern, so-called “obesogenic environment”, where everything is accessible easily-- we don’t need to cook and even we don’t need to hunt or harvest anything if we want to eat. We can just use an app and call something, or just go to the restaurant, and I think it’s really that evolutionary mismatch that drives this chronic disease. And the reason GLP-1 drugs work is because they really tap into these survival circuits.
And so, one of the things that our research is trying to push is first to really understand the biological basis of it. Because we know these drugs work and often people say, “Well, why do you care about the mechanisms? We know they work.” And I always say, “Well, we know they work, but they don’t work for everyone.” So, there’s people that respond really well. There’s people that do not respond at all. And one of the biggest issues is that about 50% of people that will start taking medication for weight loss will actually discontinue within one year. So, there’s really a limited adherence that it is largely due to side effects.
And so, one important part of my research is trying to dissociate, what are these circuits that drives appetite or suppression of appetite versus the circuits that drive nausea? Do they overlap? Do they diverge? And can we make better therapies by better defining how exactly these drugs are working and how we could maybe target particular pathways in the future? We know GLP-1 drugs work, what we’re trying to do is really understand how exactly they work in the brain and how we can make them better in a way that potentially we can have precision medicine that will, you know, eventually expand access and equity.
Fiona 17:11
And so, you mentioned how, you know, these drugs work for some people and then they don’t work for others, or maybe some people experience more severe side effects than others do. I’m curious, like you can have two people, similar body types, maybe they’re experiencing obesity. They change their lifestyle in the same way, diet, exercise, one person’s able to lose a ton of weight, the other person isn’t. Is that a brain effect? What do you think about that?
Alex Caron 17:36
Yeah, that’s a very good question. I mean, my bias will be to say it’s probably something in the brain. We have to understand that obesity is a very heterogeneous disease. The etiology is really different. Some people will have mutations leading to obesity. Some people will have anxiety or depression that’s responsible for them eating more food or having propension to go towards highly caloric food. You know, some people will have change in their microbiome that will predispose them to absorb maybe more the energy that they consume. So, there’s all sorts of mechanisms. So, I think we always refer to obesity as a single disease or as a single condition, but I think that every single individual that lives with obesity has a reason behind it, and this is what we need to understand better.
And actually, there’s been a lot of work over the last few years showing that there’s actually different phenotypes of obesity. There’s people—I remember this story from Mayo Clinic where they actually tried to separate patients based on their phenotypes, and then they tried to adapt a pharmacology based on this phenotype and they were able to actually double the efficiency of the pharmacology. And one example was they found that there were some people that had this hungry brain. Others had a hungry gut. Others were called these emotional eaters. Others really were the slow burners. And, really, when they took time to adapt pharmacology to each of them, they could improve the response and the ability to lose weight. So, yeah, I think for some people, you know, dieting, exercise works well. But for others, they’ve tried everything and it doesn’t. And potentially it’s because there’s some sort of brain circuits that are altered, and that’s exactly what we’re trying to figure out.
Fiona 19:09
Sounds like your work could really help a lot of people. So, you know, there are big question marks, I think, for both of you in your areas of research about the long-term impacts of these substances in the brain. So, what kinds of predictions can you make about that based on your current research? Is there anything you can share with us?
Alex Caron 19:26
So, yeah, I mean, one of the major issues, and we always hear about it, is that if you start taking a GLP-1 receptor agonist when are you going to be able to stop taking this drug? And the answer is we don’t know. Potentially your whole life. Because if you address obesity as a chronic disease—and I like to make the analogy to hypertension. When you have hypertension, at some point we will give you drugs to lower your blood pressure. But if tomorrow you decide to just stop your drugs, well, your blood pressure comes back up. And it’s the exact same thing when you take drugs to lose weight. As soon as you will stop them, the chances are you’re going to go back up. So, what’s important is that when people will take these drugs, they will also have a very good follow-up with their physicians, but also it will be important to improve the way they eat, the way they exercise, ideally have some psychological support. So, I think we don’t know yet because those drugs—I mean, they’ve been on the market for about 20 years for diabetes and 3 to 5 years for obesity, so we don’t know in the very long term what the effect is going to be. But I think that we have to keep in mind that if we undergo treatment, the chances are at the moment that people will regain. But also there’s patients that can just stop and they do fine, but, again, it shows how heterogeneous the biology of obesity can be.
Mike Timko 20:46
I have a hard time kind of thinking long term for this type of work because we’re in its infancy in a way, right? So, we need to understand the mechanisms from just acute inhalation first in order to potentially understand the long-term effects. How does the brain respond to different kind of stressors? After smoking THC, what happens to brain blood flow regulation during exercise? What happens when you walk up a flight of stairs? What happens during emotional stress? All those things are pretty unclear and unknown. And the really nice part is there’s been a big advancement over the last 10, 20 years in just imaging techniques. So, back kind of in the late 90s, early 2000s, of course we can measure brain blood flow, but we’ve come such a far way to be able to measure brain blood flow dynamically. So, on a beat-by-beat basis, moment-by-moment basis. So, I think we’re in a real exciting time for this type of work.
Alex Caron 21:39
A lot of people don’t appreciate, but the endocannabinoid system was once one of the most promising drug targets for obesity. And we’re talking about 20 years ago, actually, there was a drug called rimonabant that came out in the market, which was approved for obesity and related cardiovascular risk. I think this was around 2006, but it was rapidly withdrawn from the market due to high risk of depression and suicidal ideation.
And so, it’s quite interesting to see that—I mean, cannabis was once, like, a very interested circuit for obesity, but the problem there was all these side effects. So, I think what we learned from this is that the brain was a good target for weight loss, but when you target the brain you need to be cautious on where exactly this thing will work. And so, this was just a little thing I wanted to say. Just to ask you a question, Mike, because we often hear about, you know, the munchies with people taking cannabis. But then at the same time, we see that guys like Snoop Dogg, which we know have been smoking weed for a long time, they are pretty lean. I don’t know if you have your input on this, whether taking cannabis is good for weight? Is it inducing body weight loss? Is it promoting food intake? I don’t know if it relates to what you do.
Mike Timko 22:52
I think very, very similar and probably a kind of a cop-out answer, but very similar to kind of GLP-1 agonists it’s so variable. Because you’re right, as a performance enhancer, taking THC, whether it being in an ingestible form or smoking it, and then going to the gym after. And they find that it helps them with their exercise. Maybe it’s all cognitive at that point. They think it helps them from a creative and cerebral standpoint. Varies from person to person, but it’s, yeah, I find that very interesting as well.
Fiona 23:24
So, you know, on that vein, what do you think your findings and, you know, that of others who are in your field, mean for public health awareness? So, people who are using these drugs typically because of the beneficial short-term effects, be it alleviation of obesity-related negative health effects or alleviation of pain, for example, with cannabis. So, how should we be framing our mindset and our choices when it comes to short versus long-term effects of these things that we’re, you know, putting in our bodies?
Alex Caron 23:52
Like I mentioned, I mean, these drugs have been on the market only since 2005 for diabetes. So, it’s already been 21 years but only recently we’ve seen this boom in the number of people taking it. I like to say we’re living into a living lab where we have to see what’s going to happen. And so far, I mean, the side effects with GLP-1s, even if they target the brain, there’s nothing really big I’ve seen. I mean, the more people take it, the more rare events we start seeing. But other than, you know, nausea, vomiting, GI discomfort, which were expected because of the function of GLP-1, we don’t see that much. So, I think in the long term, these drugs are here to stay. They’re going to become probably better. Again, I think we need to better understand who should benefit the most from them and try to adapt it to these patients. So, in the long term, I think it’s only the beginning. I mean, there’s—I was looking at the report recently. There’s over 173 drugs for obesity right now being in development. So, that’s a lot. I teach pharmacy to pharmacy students, so I teach them, you know, drugs for obesity treatment., and every year I need to remake my entire class because it’s going so fast. I like to say if you didn’t read yesterday about GLP-1, you’re already late. You don’t know where the field is at this point and that’s quite exciting and worrying at the same time.
Mike Timko 25:13
Yeah. And likewise, like, cannabis is here to stay. It’s been around before it was legal for a long time, right? [chuckles] So, from a global perspective, it’s going to continue to increase in popularity. And with that, I think other psychoactive drugs such as psilocybin, LSD, I think those are kind of also on the table as potentially being legalized at some point. MDMA, and those might—not even just for recreational purposes, but for potential treatment strategies for things like depression. You know, cluster headaches is another big one for psilocybin. So, if those start to open up and we’re allowed to use those as potential treatment options, we need to understand how they might affect young and healthy people. And it doesn’t even have to be limited to the brain. It’s whole body. It’s just, how does this affect, you know, your entire body? And for me, I mean, obviously, as soon as those things jump on board, and if we do get availability to test them, yeah, I’ll be all over it as well to learn how that affects brain function and brain blood flow regulation. You know, those are kind of the bare bones, the basics that we need to understand in order to make informed decisions to the public, or in order for physicians to read this type of work in order to make informed decisions to the public on how we should be using these type of substances.
Fiona 26:30
Okay. And I guess, you know, to finish off, like, so for better or for worse, you both study extremely popular hot topic areas. You know, Alex, you were talking about, “If you didn’t read about it yesterday, you’re already behind.”So, you know, and people seem to have pretty strong opinions about these. So, if you could explain one insight from your work that you wish everybody understood, what would it be?
Alex Caron 26:53
We’re shifting from weight-centric focus, I think, to more brain-centric focus. And I think the future is not just about making better weight loss drugs, it’s also about understanding better how the brain integrates. I spoke a lot about metabolism, but also reward and stress and inflammation. So, those are all things that altogether can impact the brain and how it motivates us for food seeking. And so, we need to learn to modulate these networks in a clever way, and that’s exactly what we’re trying to do with our research.
Mike Timko 27:23
For me, I think it’s just to remind people that even though this work is done using THC and CBD oil, the results from the project are not just going to be restricted to people that are smoking cannabis and THC. Essentially, we’re using these drugs as a tool to alter a mechanism. The big question here is, we know that cannabis is reducing neural activity, how is that reduction in neural activity affecting brain blood flow?
Well, there are a stack of different types of pathologies and drugs that modulate neural activity. So, these results can be applied to a lot of different conditions and scenarios. It’s not just limited to people that smoke cannabis and THC every day. It’s applicable for just overall brain function and that’s what I think is really exciting for this type of work.
Fiona 28:18
Well, Alex, Mike, thank you so much for joining us today on Bold Minds.
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Alex Caron 28:22
It was a pleasure. Thank you again for having us.
Mike Timko 28:23
Yeah, thank you for having me.
Fiona 28:27
Bold Minds is a Brain Canada production with support from the Azrieli Foundation. Our executive producers are Jillian Donnelly and Kate Shingler. Our lead producer is Jess Schmidt, with editing by Morgane Chambrin. Thanks for listening.
If you enjoyed this episode, we’d appreciate it if you could send it to a friend. If you want to learn more about Brain Canada and our Future Leaders program, please visit our website at braincanada.ca. [music ends]