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S2E5 - The Endocannabinoid Researcher

What is the endocannabinoid system?  Did you have that friend in high school with the hemp shirt who told you, "The body was designed to smoke pot, man!"  That is not as crazy as it sounds.   Trevor and Kirk talk to Dr. Robert Laprairie.  He is a pharmacologist who studies the endocannabinoid system.  Your body produces its own cannabinoids and has receptors that can accept external cannabinoids like  THC and CBD.  But just because cannabis is natural doesn't mean that it shouldn't be used with caution.  Dr. Laprairie also discusses interactions with prescription medications and other thing to watch for.  But in general Dr. Laprairie is very positive about cannabis research in a post-legalization Canada!


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Episode Transcript

Kirk:  Trevor, we're back. You just spoke to a researcher after legalization.

Trevor:  We did. And he said happily that research after legalization has gotten better. And he thinks Canada is going to be well positioned to be a world leader in cannabis research.

Kirk:  Right, Doctor Laprairie.

Trevor:  Dr. Robert LaPrairie from the University of Saskatchewan and he's in the pharmacy department. He's a pharmacologist in the pharmacy and nutrition department.

Kirk:  So we should warn our listeners that this is this is a conversation with a researcher discussing the endocannabinoid system.

Trevor:  Which has come up a lot, even just I see on social media a lot lately like it and about what these the endocannabinoid system. So I don't think this is going to be too esoteric for most people.

Kirk:  No, I don't think so either. Some of the things that came up in in the conversation that I want to emphasize is the concept. First of all, research is easier. Reefer Medness is all about the research. I truly hope our listeners take note what we're saying. Cannabis is legal. We are health care professionals. When you are talking to your doctor, when you are talking to your health care professional and if you are using cannabis medicinally or recreationally, make sure you inform your doctor of it, because we just discovered that cannabis will affect the lipids in your body. And what.

Trevor:  Yeah, well, that one is brand new to me.  I think I've mentioned in passing before that there are some interactions between cannabis and some medications. The one I keep pulling out is warfarin of common blood thinner. It will make it work better than we thought. So, we might have to reduce your warfarin dose so you don't bleed more than we thought.

Kirk:  That's pretty serious for those people out there on warfarin.

Trevor:  And yeah, even if you do using it recreationally, call your doctor, call your pharmacist, say, you know, I'm on this, do we have to do anything? And it's not don't be scared. It's not that bad. Usually what it's going to involve is we're going to do a blood test, both in your blood is and we might just have to adjust your dose. So, it's manageable, but we just need to be in the loop.

Kirk:  Yeah, exactly. And this is another reason why I get frustrated with the Medical Association of Canada. They need to encourage their members, our family physicians, to be more involved with cannabis.

Trevor:   All I think all health, from pharmacists, to nurses to, you know, physiotherapists, when, you know, whenever it ends up being a year from now when CBD oils are going to be as common as anything else for rubbing on a sore leg like that, it's great that all the stuff is becoming easier and easier to get a hold of. But just keep your health care professional in the loop. And. Yeah, and what you were talking alluding to earlier, Dr. Laprairie was talking about some theoretical interactions between cannabinoids and your cholesterol lowering pills. So, yeah, I'd never heard of that one. So learning new stuff all over the place.

Kirk:  So, people that are taking statins, you know, for common heart issues, these are common medications that you dole out daily.

Trevor:  Absolutely.

Kirk:  So and there are as we're discovering now that after legalization, I can't tell you how many people on the street I've discussed cannabis with.  People that I have never dreamt would be involved with cannabis, discussed cannabis with me. So we know that people are coming out of the closet. You mentioned to me in our last episode of Cooking with Cannabis, you made a note. Well, it's kind of normalized already. I said has for me. I think it has for others as well.

Trevor:  Yeah, no, lots of people. My wife again, just she's not interested in using cannabis at all. Her sister made fun of her for that. But that's just not her thing. But what is my wife discussing at work with her colleagues now? Cannabis. Are people using it? Who's using it? You know, should you throw a cooking party with Strainprint? And we did.

Kirk:   We should talk about Strainprint. So, exit stage left. Let's talk about Strainprint. We have a sponsor.

Trevor:  We do. And we've given them some free advertising up to now because honestly, we really think this is a fantastic product. Strainprint, Kirk what is Strainprint?

Kirk:  What Strainprint is an app that you can download onto your phone. What makes Strainprint so interesting is that it objectifies your cannabis use. It allows you to track your use. It tracks the strain. How many puffs or tokes you take of the strain or how many you eat or how many you rub on your arm. It tracks it. It's almost like a diabetic log, but a it's a log for cannabis use It's a free download. Now, what makes this an interesting app and why we're promoting it in Reefer Medness is because it allows us now to take all that anecdotal evidence, all that subjective evidence of you using cannabis and get the hundreds of thousands, I think they had seven million hits, and that was six months ago.

Trevor:  Yeah, and they've got tons. So, from a personal, you know, as a personal user's point of view, you get to, because honestly and patients are bad for this and it doesn't matter Cannabis user or not, you know, how bad is your pain? Oh, I think I got better after I took that Tylenol 3, three weeks ago, like you don't remember. And then that's what the app does, is it reminds you, you know, whatever it is, 10 minutes, 20 minutes after you used. How was your pain before? How's it now? So that's about as good objectively as we're going to get. So it really helps you decide if this strain is good for you. So that's fantastic. But they've got lots of other options out there that they actually have clinic software that a doctor could use to help manage all of her patients on cannabis. So they've got just so many wonderful products.

Trevor:  So welcome back to Reefer Medness. It's Trevor here. And I've got Dr. Robert Laprairie from the University of Saskatchewan. Dr. Laprairie, introduce yourself to our listeners.

Robert:  Good morning. So my name is Robert Laprairie.  I am an assistant professor here at the University of Saskatchewan in the College of Pharmacy and Nutrition. I wear a couple of other hats too, I am also the chair for Drug Discovery and Development here at the University of Saskatchewan. And I'm the director of Trainee Growth at the Canadian Consortium for the Investigators of Cannabinoids, which is a national research group that kind of brings together all of the different cannabis researchers across the country.

Trevor:  Well, I think that makes you an excellent person to talk to on this podcast. So and just a little bit more about your background. Were you, I know you're working in the College of Pharmacy, are you, were you originally a pharmacist or did you come from another discipline or how did how did you get where you are now?

Robert:  Great question. So I actually I did my undergrad here at U of S, in Biochem and then I did grad school at Dalhousie University, my Master's in neuroscience and a Ph.D. in Pharmacology. So, I am a pharmacologist I think is how I refer to myself. And then I did a post-doctoral fellowship at the Scripps Research Institute in the US and I was also in pharmacology.

Trevor:  Again, eminently qualified. Thanks for giving us some time. So, because we've been hearing about it a lot lately and even like people like Strainprint on their sort of community when they're sort of handing out information out to the people that follow them. Everybody's been talking lately about the endocannabinoid system. And I hear that's something you're a bit of an expert on. So, you can tell us what endocannabinoid system is?

Robert:  Yeah, absolutely. So, the endocannabinoid system is a system that's present in all of our bodies, and it's really what our body is used to respond to cannabinoids. So, we have in us two major receptors. They're called CB1 and CB2. The Type 1 and the Type 2 cannabinoid receptors. And then we also have a number of endogenous cannabinoids. So, these are molecules that our cells naturally produce that really mimic or mirror the effects of THC found in cannabis. So, the two main ones are called Anandamide and 2-arachidonoylglycerol (2-AG).  And they work to activate or turn on those cannabinoid receptors. And then we have a number of different enzymes. And those enzymes are in charge of making the cannabinoids and then and breaking down the endocannabinoids.

Trevor:  Thank you. Now, CB1 and CB2, they are located in different parts of the body, is that right?

Robert:  That's right. So CB1 is what we usually refer to as a neuronal cannabinoid receptor. So, this is the receptor that present on most of the neurons in our body, in our brain, as well as in our spinal cord and in the neurons CB1's job is actually to inhibit neurotransmitter release. So, we can think of it like a cellular brake mechanism. So it slows down neurotransmission, that slows down neurotransmitter release. And that's what CB1 primary goal is.  CB2 on the other hand, is mainly expressed in cells that modulate inflammation. So, when we have something that's inflammatory in our bodies, CB2 is going to get turned on and when CB2 is turned on, it's going to act to limit or inhibit that inflammation. Turn the inflammation down.

Trevor:  OK, and as we know, sir, from traditional pharmacy world, especially in the inflammation end of things, that  leads into a whole bunch of different autoimmune and other diseases, everything from MS to arthritis. So, if you influence the CB2 receptor, I assume that we think that's where a lot of the we'll call them medicinal effects of cannabis come from.

Robert:  So that's probably where a lot of the anti-inflammatory effects of THC come from. So, the effects that we associate with, you know, decrease swelling, decreased inflammation, decreased pain in the periphery. So, like on our limbs, those are where the anti-inflammatory effect comes from.  If we think about a lot of the effects in the brain, things like increasing hunger or decreasing anxiety, these sorts of effects are probably happening through CB1in the brain.

Trevor:  OK, and a little bit more of an esoteric question, but my co-host, Kirk and I have a debate about this constantly. So, if we have an endogenous endocannabinoid system and we have the, you know, a plant out there, the cannabis plant. If we've been co-evolving for years, did we evolve to use cannabis? Like, why is there a plant that produces stuff that works so specifically in the little lock and key mechanisms in our body? Do I know that's getting a little bit out there, but we have this debate all the time.  Do we have any idea of how we ended up co-evolving with this plant to have some of its cannabinoids worked so well at our body? More of a fluke than anything.

Robert:  So, I think I would trend towards the more of a fluke than anything camp.  The endogenous cannabinoids that our body produces are very much lipids that are similar to fat in most respects, oily substances. And it would make sense from a biological perspective that we would evolve to need receptors that respond to certain types of lipids and fats. So in the case of cannabinoid receptors, we end up with these endocannabinoids and kind of sheer coincidence, we also happen to encounter in nature these cannabinoids produced by the plants that are also lipids, they are also oil, and they also happen to bind to these receptors. This isn't unique in any way. So, we can think about opium morphine. Our bodies have endogenous opioid systems that respond to endogenous opiates, but we also encounter morphine that comes from the opium poppy that activates the same receptors.

Trevor:  Thank you, I think well, that solves our debate for the moment. So Kirk just handed me another note, which is so the different receptors, CB1 and CB2, do all the cannabinoids hook on to all the receptors like this THC do more CB1 or CBD do more CB2 So the CBD cannabinoid, does it hook more onto the second receptor or do the different cannabinoids affect different receptors more? That's what I'm trying to ask.

Robert:  A great question. And so I'm a drug discovery person. It's kind of like my bread and butter. So THC, Deta9-tetrahydrocannabinol. This is like the most abundant cannabinoid in most strains of cannabis. It is a partial agonist, so it partly turns on both CB1 and CB2 equally.  Similarly, Anandamide and 2-AG are endogenous cannabinoids. They are partial agonists at both CB1 and CB2.  Cannabidiol is a much more complicated thing. So cannabidiol seems to partially turn on CB2, but cannabidiol does not activate CB1. Cannabidiol seems to have some indirect inhibitory activity CB1 but cannabidiol also activates a whole slew of other non-cannabinoid receptors. So cannabidiol is a little bit more complex in that way. And that's an important distinction because it's the activation of CB1 that is the thing that mediates getting you high. So, THC turns on CB1 gets you high. Cannabidiol does not turn on the CB1 does not get you high. If we look on beyond THC and cannabidiol, the plant actually produces upwards of 120 other cannabinoids. Historically, these have been really hard to isolate and they're still considered controlled substances, and so they've been hard to study and we know very, very little about their pharmacology, about how they work on the endocannabinoid system. And then we have a whole host of synthetic cannabinoids commonly referred to kind of colloquially as Spice or K2. And these are cannabinoids that are made in a lab setting or are made illicitly. And these tend to be full agonists at CB1 and in addition to producing intoxicating effects can be quite dangerous.

Trevor:  OK, and I'm sure we'll swing and swing on back to that, but before I forget.  You, have lots and lots of things you're associated with but one of the ones that I, sort of caught my eye because it's right next door to us here in Manitoba, you're involved with something called the Cannabinoid Research Initiative of Saskatchewan. What is that and what do you guys do?

Robert:  Yeah. So thanks for bringing that up. So CRIS, Cannabinoid Research Initiative of Saskatchewan, is an interdisciplinary research group here at the University of Saskatchewan. And our goal is to conduct research on cannabinoids and cannabis in order to provide an evidence base for where and when cannabinoids are effective in a medicinal context and where when they are not effective. Because right now, a lot of the literature that exists is, I would say, still in development, a work in progress, and so we want to be able to have the tools to conduct the studies, to get an evidence base from where and when cannabinoids are useful or not, and then act as a public conduit to present this really cool and exciting research to the public, to educate the public, to provide good resources.  So, we can move this field forward and hopefully help people. So right now, at the U of S, we are, I think, 40 faculty from all across the university. So, I'm in Pharmacy and Nutrition, but we have colleagues in medicine, agriculture, veterinary medicine, law, public policy, et cetera.

Trevor:  So, and maybe it's not up yet, but if the public or health care professionals like myself wanted to get access to what it sounds like you're developing is something akin to what we have in the rest of pharmacy world, things like clinical practice guidelines. Do you? Is there somewhere that the public or health care professionals can look at what you guys are recommending it, or is that kind of a work in progress?

Robert:  So, it's for us personally right now, it's a work in progress. We do have an active website where you can see some of the resources that were pointing people toward and also just to get a better idea of who we are as a research group. And then we've also we are in favor or we are promoting the Canadian Pharmacists Association has recently come out with guidelines for pharmacists, continuing education modules that can be accessed through the CPA website. So, I would encourage any pharmacists to check those out. They're really a great resource. Very much up to date.

Trevor:  Yeah, and I'll try not to go down too much of a tangent, but yes, our national advocacy body, the Canadian Pharmacists Association, seems to be all for using cannabis safely, medicinally in patients. And yet our provincial licensing body just a couple of weeks ago sent, a for goodness sakes, don't have anything to do with cannabis note out to all of us to the point of that one of my colleagues said she was scared to talk to talk to a patient about cannabis because what if they told the college that she was talking about cannabis? So, yeah, we need to we need some more reasonable information out there for people. So, they're not they're not scared to talk to patients about cannabis.

Robert:  I am all for and all about education.  I think no matter where cannabis is being used, be it medicinal or recreational, it is a drug. And that means it's going to interact with other drugs. That means that it will have effects on the body on its own. And so, the pharmacy has a really good opportunity to be able to counsel patients on it. It's safe and well-informed use.

Trevor:  You know, thank you. And I think that's what we're all shooting for. So as a pharmacist, I've got to ask about drug interaction. So, I came across a nice thing by the CBD, what do they call themselves?  The put out a list of cannabinoid drug interactions. It's not a complete list, but it was a nice little 35-page document. The one that always leaps out at pharmacists is warfarin. So, what can you tell us about what we know about cannabis interactions with medications and if you know anything specifically about warfarin, because so many people are on that blood thinner. What do we know?

Robert:  So I don't know much about the interactions with warfarin specifically. I do know that many cannabinoids, including cannabidiol, interact with the CytochromeP450, and that includes the common like the big players CYP3A4, CYP2C9, CYP2C19.  And so, a number of drugs are metabolized by 3A4, including very common antifungals. And then for 2C9, and 2C19 these are the same CYP enzymes that are going to metabolize opioids. So it's important to just consider and be aware that there is a common mechanism of metabolism that could affect drug availability when multiple medications are on board. The other important thing to consider is that many cannabinoids are substrates for cholesterol metabolism. A lot of the plant cannabinoids are very structurally similar to cholesterol. And so, there's a potential for interactions with statin-based drugs that inhibit HMG-CoA reductase. 

[00:21:11] Well, that's interesting. I've heard of the Cytochrome P450 before and I'll throw in my little plug about the Warfarin case study basically said it might make warfarin work better than it did before. So just careful, watch the INR and you might have to reduce warfarin dose, it's basically the long the short of it on this case study, but tell me more about cholesterol, statins and cannabinoid.  Do we think it makes the statin work less well because of statins the HMG-CoA reductas are working to break down the cannabinoids or what do we think is going on?

Robert:  So I've only ever seen theoretical data, so not even case reports on this. But it would be a similar mechanism where the predicted effect would be that the statin might be more effective because the metabolism of the statins by other enzymes would be inhibited because the system is basically gummed up by your cannabinoids. Right. You might also have to modulate dose or reduce dose in order to maintain your therapeutic window.

Trevor:  Well, that's fascinating, though. We don't usually think of statins as being a narrow therapeutic index, drug or drug that we really have to worry about, but that there's definitely some people with some heart conditions where we worry about things like QT interval prolongation or sort of causing a heart arrhythmia that, you know, statins might have a tertiary role in. So, no, that's again, and not just to plug my profession again, but there's a really good reason to have pharmacists involved in medicinal cannabis, no matter what my college thinks. So no, thank you for letting me go on that little tangent.

Robert:  And that's not just medicinal cannabis, but, you know, patients are using recreational cannabis and they're prescribed all the other drugs they should just something to think about.

Trevor:  No, absolutely. Ya, no, I completely agree. So drug design and discovery, like that's your bread and butter. So what have you been working on lately that's sort of been interesting in the we'll called the cannabinoid zone. What's new coming down the pipe that we can hear straight from the researcher?

Robert:  Sure. So, two big projects underway here in my lab, and I'll start just by giving credit where credit is due. So as a principal investigator in a lab now, I have the luxury of talking to find folks like yourself. But it's my grad students that are doing all the heavy lifting, so they should get credit for that. The first project we're looking at, I alluded earlier to all these other cannabinoids that are in the plant. So on beyond THC and cannabidiol. So working to isolate those compounds that are also present in the plant and involved in cell culture setting looking at how those how those cannabinoids work, what do they do? What receptors do they work on? Where should we exercise caution in terms of their pharmacology? Are there potentials for new drugs hiding in there? So that's the first project. And then the second project is actually looking at positive Allosteric modulation of the cannabinoid receptor. So typically, when we think about a drug like THC, THC is going to turn on the receptor or Anandamide might is going to turn on the receptor. In the case of cannabinoids coming from outside the body like THC, we know that THC gets you high, but what if there was a way to modulate the activity of the receptor without turning it off? So now thinking of a receptor not as an on and off light switch, but more of a dimmer switch. So these compounds that we're trying to develop called positive Allosterics modulators, they bind somewhere else on the receptor.  Allo meaning other in Greek. And when they bind to that somewhere else on the receptor, they make the receptor more available for binding endogenous cannabinoids. And by doing that, they kind of turn that dimmer switch up so that the base setting of the receptor is elevated and the tone of the system is elevated. And by doing this, we can produce all of the therapeutic benefits that we associate with cannabinoids. So, whether that's reduction in pain or reduction in anxiety, without producing an intoxicating effect. So, developing some of these new drugs, we can kind of liken them to the benzodiazepines of the cannabinoid receptors. That's another project that we're pushing into right now.

Trevor:  Well, that's fascinating. So, if you hooked on to, let's say, for example, the side of the receptor, had it worked better. So now the endogenous anandamide, I'd say hooks on to it better and does it does its thing of relaxing you more than it would have otherwise. Something along those lines.

Robert:  Exactly. Yeah.

Trevor:  Wow. I had no idea that that was even a thing. So that's very cool. Yeah.

Robert:  That's exciting.

Trevor:  And I'm just going to lean over here to Kirk as he is scribbling down a couple of notes. Oh, this is a big one. A good person to have is. So, we're as of October 17th, we're legal here in Canada. So, we're hoping the answer to yes is this. But first question is, did legalization change the research opportunities now in Canada now that hopefully it's easier to get access to product?

Robert:  Yeah, so the answer is a big yes, but I'll break it down at a couple of different levels. So here at the University of Saskatchewan, I can't say enough nice things about U of S, they have been very supportive to our CRIS team in helping us get off the ground and get working on this. So that has been wonderful. It's been good as a new researcher to come in and know my grad students are supported and that's going to go well. So that's locally. Nationally, we see that the Canadian Institutes of Health Research CIHR, announced a Catalyst grant competition specifically tied in to conducting more research around cannabis and cannabinoids. So that granting program launched this summer. The grants were due October 1st and I think we'll see some really amazing science coming out of this. The hope being that Canada will be the leader globally in cannabinoid research. And I think that we're well positioned to do that. And then also on kind of a federal level, we do see the regulations changing so that this research becomes easier in a in a bureaucratic sense, so easier to apply to hold controlled substances. More straightforward in terms of how the research can be conducted. So, it's all good.

Trevor:  Good. We were really hoping for yeses on all of those. And because, you know, we've got a growing batch of listenership. Is there anything that the general public can do? You know, we've got lots and lots of people out there interested in cannabis. Is there anything the general public, our listeners can do to sort of make researchers lives easier? Is it anything you're as a researcher you'd like the public to do to either, you know, from lobbying MPs to, you know, signing up if there's ever clinical trials? What can the public do to help the research long?

Robert:  So the first thing that I think is really helpful from the public is I would encourage patients, whether they're using recreationally or medicinally, to make sure that your health care provider is in the loop, because we really you know, now that we are in a legal status, we have an opportunity to understand where and when and how cannabinoids are being used by the public that we haven't necessarily been able to grasp fully before. So just being able to make that knowledge available is really important and also for the patient's own health and well-being. But then in terms of the research itself, I would say, if you see events in your area, you know, I know me and my colleagues personally, we often go out and we do public speaking events where we talk about the research and we try to get the public engaged, go out and learn. This is this is like the cutting edge of research right now in Canada. And I'm biased because I'm a scientist, but I get super excited about it. If you see opportunities like that, go out and learn and make sure that if you do have an opportunity to talk about, you know, research priorities in your area, in your community, in your province, that you do talk about those and why it's important because, like I say, we have this great opportunity to really lead in this area. My colleagues all across Canada who are in this field and there are a lot of us, would just really like to see this work out well.

Trevor:  Oh, and we love the idea of Canada leading the cannabis research world. We think that's fantastic and we're glad we're so well positioned. So we're getting close to the end of our time. Is there anything else that I forgot to ask that you were just dying to tell the listeners?

Robert:  I think I would just maybe reiterate cannabinoids are drugs. Just because it's natural doesn't mean it's 100% safe. We talked about drug interactions. We should think about these things as drugs and that they have a time and a place. And then I think I just end off by saying, you know, this is a great opportunity. The research is a great opportunity. If there are people listening to think, oh, maybe I want to get into research as a career option, this is a good opportunity for them to in terms of conducting research. There is so many stones that haven't been turned yet, so many unanswered questions. And it's been an exciting place to be to do the research.

Trevor:  Well, it's always great to hear someone excited about their job. That was really good Dr. Laprairie thank you very much.

Robert:  Awesome. Thank so much Trevor.

Trevor:   It was another good one. I like them all, but I love the researchers one I liked hearing from the.

Kirk:  I like the science nerds and again.

Trevor:  Nerds were good.

Kirk:  All right. So, Trevor for the music today is a is this gentleman has roots in Dauphin Gary Procyshyn. He has roots and Dauphin here. His family, I believe, still live here. He doesn't, but he's put out several albums. He's known as a blues player. This this song Gone comes from his CD called Gary P.

Trevor:  I Love the Blues. Let's listen to Gary.