Episode Transcript

Trevor: We're back. 

Kirk: Hey, Trevor, how's it going, man? 

Trevor: Good. So I got to talk to a another really smart person, which always makes me happy. Dr Lindsay Anderson. And so the cool part, while many cool parts of the conversation, so she is originally from the US, trained in the US, is currently working in Australia. When we were first chatting via email, I thought I was going to have to arrange a... People in Australian, people in Canada are only awake at the same time for a limited number of hours of the day, so I thought the whole coordinating a chat was going to be hard. But it turned out she was coming back to the US so that that was easy. But we got to talk about drug interactions. 

Kirk: Yeah, yeah. You know, I immediately enjoyed this conversation. First thing, though, let's let's bring up the Lambert Initiative for Cannabinoid Therapeutics, right? This is the second time that we've gotten. We have received an interview from from this group. Yes. E64 - Driving Under the Influence.  I'm almost thinking we should just hang outside their door. 

Trevor: Well,. 

Kirk: And every time they have a study, we just interview them, which is become their official podcast. 

Trevor: Well, and you know, we should take a road trip down to Sydney and go visit. 

Kirk: Well, I think the more often we cover their stories because it is quite fascinating, the studies are doing. We just might get that invite. So I think there's an initiative for us to try to look for more they stories from the Lamberg Lambert initiative. I'm really I'd like to see if there's a Canadian equivalent so we can get some Canadian stories that are being studied because I mean, we're legalized as a country for recreation and medicinal, and there is no funding for it. It's interesting. So, yeah, I wanted to bring that out. Episode 64 - Driving under the influence, and maybe there'll be more in the future. 

Trevor: Yeah, no. They're they're a fascinating group doing lots of really cool work in the cannabis space. So now Dr. Anderson: does a way better job of this than I do. So I'm going to try to not do too much alphabet soup here, but I'm going to just real quick do my version of what cytochrome P450 is are and why we care. So completely unrelated to cannabis, pharmacists talk about the cytochrome P450 set up a lot because that's that's one of those common ways for drugs to interact with each other. And the reason is this is this huge number of enzymes that break down medications. And I think Dr. Anderson: even says the 2C9 and 2C19 might metabolize like 25% of all the prescription drugs we have. So when you have two drugs that both want to use this one enzyme to get broken down, in the liver, they're going to affect each other. One will probably get broken down a little slower, one a little faster. So we might end up with more or less drug in the system than we expected. And that's that's why they're looking at that one. And the other really cool part about the study is they didn't just look at a couple cannabinoids, they looked at 12. Now there could be arguably hundreds of cannabinoids, but they certainly did way more than THC and CBD. So looked at 12-ish cannabinoids and all these cytochrome P450 and threw them into a big chart and see what happens? 

Kirk: Yeah, just before the conversation, yeah, a couple of things came up to me. CYP she kept using CYP the CYP id C-Y-P. 

Trevor: Yeah, which is another short form of cytochrome. 

Kirk: Yeah, exactly so. So so the audience needs to know that when she's saying the word CYP, she's saying C-Y-P is in that.. What is an expression? What is when you use the word expression of a C-Y-P a CYP enzyme, what is that? 

Trevor: Well, it's we all have slightly different enzymes in us, so it's probably not a big surprise that our livers are all a little bit different. So you might have more of this cytochrome P450. So you might break down this drug faster. I might have less. So one that comes up once in a while is there are people who break down codeine, so you have to... Codeine is what's called a pro-drug going off into pharmacy location. 

Trevor: Oh hi, it's Trevor. Again, breaking into the conversation, I kind of completely mocked up my explanation of codeine and pro-drug said cytochrome P450 expression. So let's let me try this again. Codeine is a painkiller opioid or a narcotic painkiller that many people are familiar with. Often they're familiar with it being in the painkiller Tylenol-3. So codeine kills pain, but it does it because it's what we call it, pro-drug. So that means codeine by itself does isn't the painkiller. It has to be broken down by an enzyme into a drug that does the painkiller and codeine actually gets broken down turn to Morphine, and Morphine is what does painkiller. So codeine gets broken down to Morphine. Morphine does the painkiller. All right, the enzyme that breaks Codeine into Morphine is one of the cytochrome P450, as we've been talking about it. Cytochrome, P450 2D6.  Codeine broken down to Morphine by 2D6. Straight forward? good. Now here is what the expression part that I was trying to get across Kirk: was talking about. Some people have 2D6 that works really quickly, and some people have a 2D6 that works really slowly. So that means people who have a really slow or a poor metabolizer are 2D6, a really slow enzyme. Not very much of their Codeine changes into Morphine. And they say, Hey, this codeine isn't working as because their body actually isn't forming very much of the Morphine. And so they really are getting less Morphine to do the painkiller than we would have thought. On the other hand. There are some people whose 2D6 works really fast or works really well, and they actually get a higher dose of Morphine than we would have expected. So, you know, I think, hey, that's great. You know, get more pain killing. But in tiny people like newborns, that can actually be deadly because we could actually get them too much Morphine to the point of overdose and not realize that because they or their moms metabolize the Codeine too quickly. So again, so that's what I was trying to explain to Kirk: is some people, their enzymes, their cytochrome P450 is work faster than we thought, some slower than we thought. And that's the variation that I was. Or variation of expression that I was trying to get across to him. 

Kirk: All right. So here's another question narrow therapeutic window. 

Trevor: Yeah, so I'm glad you brought that up. I was going to try to remember, too. So when I talk about it, I talk about a narrow therapeutic index, she says. Narrow therapeutic window. I'm pretty sure we're talking about the same thing. So again, in drug world. So the the therapeutic index is, is the magic zone, the the the Goldilocks zone where the drug is doing something good. And if it's too high above that, that we're doing bad things. And if it's too low about that, it's not doing anything at all. So drugs with narrow therapeutic index, a traditional example, would be Warfarin. Warfarin is a blood thinner. So if we get it in its therapeutic index, what's is thinning the blood just enough that we don't get clots that will cause like heart attacks and strokes? Right? So that's good, right? But but if we go too much, well, then you bleed out your eyeballs. If we do too little, then you have a clot. Clot and a stroke and die. Right. So, you know, we have just this narrow, narrow zone where it's doing good too much and too little where we have other things like I'll use antibiotics, really a lot of the antibiotics we use in the pharmacy, you know, don't go do this, but you could, you know, penicillin, you could really, down gallons of it and you're just going to get a tummy ache. It's not going to poison you. And for most, the things that we treat in the community pharmacy, if you didn't get enough of the antibiotic while your body was probably going to clear it eventually anyway. So, you know whether you got too much or too little. Probably as a patient doesn't affect you much now. Now that said, antibiotics and you know, I should have just asked the pharmacologist when I had her there, I was trying to make a point that she talking about sulfonylureas and I call them antibiotics. And of course, that's completely not true. Sulfonylureas are most commonly an anti-diabetic. Medications will get Rene to edit when I call them antibiotics and make myself look dumb in front of the pharmacology. 

Kirk: all right. So other terminology that she uses and saying, I got a thank you that whenever you bring these heady conversations to the podcast, I'm in the papers and studying and and it's like, Geez, I haven't done this kind of studying since I did my ICU course some 30 years ago, but I'm drug to drug interactions DDIs. I found it fascinating. I actually went into the two papers from her introduction and started studying the The In America. What is it? US$528 billion. Yeah, five hundred and twenty eight dollars billion in health care system has spent on drug drug interactions. That's hug.

Trevor: and it's honestly a perpetual problem that's probably not going to go away because when you think about most of our older, sicker people, even in the community, they're off, they're often on five or more medications. 

Kirk: bingo. 

Trevor: It's just about impossible to give somebody five different medication for there not to be a interaction between them. So yeah, so it's often yeah, we know there's an interaction, but we kind of have to use these anyway that it's an interaction. But you know, we think it's going to be small and manageable. That's an interaction. But so, you know, so yes, as soon as we get sort of again in a community pharmacy, it's usually older, sicker people on multiple medications. Drug drug interactions are just there and we've got to manage them best, best we can. 

Kirk: So this was what motivated this study, right? An estimated five hundred twenty eight point four billion dollars was just 16 percent of the total U.S. health care expenditure in 2016. So they wanted to figure out because cannabis is being used more and more in the world. So what would cannabis? Is participation in these drug interactions be? So that's the whole premise of this study. And so I guess who this episode is. Who's it for, Trevor? Like part of our audience here? Why should our audience listen to this episode? 

Trevor: Well, because whether you use cannabis, if you use cannabis medicinally, odds are now not everybody, but odds are you're on other medications. You know, by the time you have, I don't know, lower back pain, just chances are you're a little bit older and you have some other we call it comorbid condition. You probably also have some blood pressure issues or you have some diabetes issues or you have a cholesterol issue. So you're treating your lower back pain, let's say with with cannabis, but you're probably on some or a good chance you're on some other medications that might interact. So that's sort of the first group as a pharmacist, I think about. But really, the next is just people, not the recreational person. So, you know, I may, you know, let let's make me me and almost 50 year old pharmacist. Maybe I like to use cannabis recreationally on weekends, but I'm on a... Pick one. I'm on a diabetes pill. What's this going to do to my diabetes? You know, if if this is some, you know, because we talk about it, we talk about how someone's alcohol use affects, how they treat diabetes, that recreational alcohol use. Well, this is now. How does your recreational cannabis use affect, for example, your your diabetes medications? 

Kirk: So, so once again, we're just trying to remind our audience that cannabis isn't benign, although although it's it, it's diminutive in, it's, you know, in its risk risk management and harm reduction, it can be used in harm reduction for specific things. But it's this is something to let you know that it's not benign. And we have said many, many times this podcast that I believe that recreational cannabis for some people is still being used medicinally. No matter how you, no matter how you define it, you're still you're still drugging yourself for a reason. Hence why we've talked often coming home from work and back in the 60s was having a martini at home in order to wash away the work. And we still do that today with alcohol. But but let's let's get into the conversation. It is heady, guys. There's lots of alphabets, there's lots of lots of terms here that that are going to throw you. But ultimately, what we're trying to figure out is what cannabinoids should we be concerned about when it comes to the drug and drug interactions? 

Trevor: All right. off to Dr. Anderson. Dr. Anderson, first, let's talk a little bit about your academic background before we sort of get into the Lambert initiative and your paper. So what's your Ph.D in and sort of how did you get there? 

Dr. Anderson: Yeah. So my Ph.D. is in pharmacology from Vanderbilt University. And during my Ph.D., I investigated the pharmacological and genetic treatments for idiopathic epilepsy using various genetic models of epilepsy. And then, following my Ph.D., I began a postdoctoral fellowship at Northwestern University and at Northwestern, I pursued a new project on pharmacogenomics of drug drug interactions, as well as continued my in vivo pharmacology work, which validated a phenotype platform in the one knockout mouse model of Dravet syndrome. Following my postdoctoral hosting, I moved to Australia to join the Lambert Initiative for Cannabinoid Therapeutics, which is where I've done the work they are going to be talking about today. Excellent. 

Trevor: So before we get into it and as a pharmacist, I'm always very excited about drug interactions and and epilepsy. So you're a great person to be talking to about this. But for us in North America, tell us a little bit about the Lambert initiative and the amazing things it seems to be doing for for cannabinoid research. 

Dr. Anderson: Yeah. So the Lambert initiative was established in 2015 from an unprecedented, unprecedented donation from Joy and Barry Lambert, who donated $34 million to the University of Sydney to support medicinal cannabis research. And this gift was the result of experiences that they'd seen with their granddaughter, Caitlin. Caitlin has a very severe form of epilepsy called Dravet syndrome, and she was having really great results with medicinal cannabis, and they saw the great results she was getting and decided to to donate this money to establish research into cannabinoid treatment for all illnesses, including cancer, inflammation, 

Trevor: a wide, wide variety of things that that cannabinoids treat. But it sounds like you, you were kind of the perfect person. You were already doing research into the Dravet syndrome and already doing research into drug drug interactions, so this sounds like a natural fit for you. 

Dr. Anderson: Yeah, it was. You know, the thing that I didn't know much about was cannabinoids. So I was able to learn a lot about cannabinoids there and kind of take my background with epilepsy, drug drug interactions and meld it with their knowledge on cannabinoids. 

Trevor: And that's that's perfect. So that leads us into this paper. So before we get, we'll here first, I'll read the name of the paper. So I get get it right at least once. So the paper we're talking about is: Cannabinoid Interactions with Cytochrome P450 drug Metabolism, A Full Spectrum Characterization. Now, normally at this point, my co-host Kirk: would ask me the pharmacist to explain what the cytochrome P450 system is, but because I have an actual expert here. Can you give us just sort of a thumbnail sketch about what cytochrome P450 system is? 

Dr. Anderson: Yeah, the cytochrome P450s are an enzyme system that is expressed throughout your body, but predominantly in the liver, and it metabolizes drugs that you take. So when you take drugs or medications or prescriptions, these enzymes metabolize them and help your body clear them from their system. 

Trevor: OK. And as a pharmacist, when I fill a prescription, my computer system often pops up big red boxes, saying, You know, these two drugs this patient is on have a cytochrome P450 interaction. So my it'll say things like your drug X will make drug Y get metabolized faster or slower. So that would be we'd have less of, you know, a drug in the system than you expected or more of a drug in the system than we expected, as that kind of the well, from a clinical point of view, I think that's what I'm concerned about is that the sort of things you're looking at, too? 

Dr. Anderson: Yeah. So that's exactly what we were looking at. So if you have a an enzyme that's metabolizing Drug A and drug B is also metabolized by this enzyme and you're taking both of them, we're going to start competing for this for the enzyme. So if Drug B kind of out-compete Drug A, your levels of Drug A are going to increase and that could be a concern if there's a very narrow therapeutic window. So if the levels get too high because Drug B is inhibiting Drug A's metabolism, you could have some, some adverse events as a result. 

Trevor: OK. And because I'm sure we're going to hear some alphabet soup shortly, cytochrome, P450 is not just one enzyme, right? It's a whole bunch. It's a system. And there's a whole bunch of letters usually attached 

Dr. Anderson: that is true. It is a it that cytochrome P450 encompasses a superfamily of hundreds of enzymes. The major drug metabolizing enzymes are what you will hear is alphabet number soup coming up and they're broken down into subfamilies. So the six that we focus on in this paper are the most prevalent enzymes for drug metabolism, which will be 3A4, 2D6, 2B6, 2C9, 2C19, and 1A2. 

Trevor: Very memorable. Every pharmacy student loves trying to remember those four tests, so we promise at the end we won't quiz the audience. But but yeah, so those are the sort of numbers you hear about. The other thing that I think we should just touch on before we get into the study is. So cannabinoids, our listeners are probably familiar with THC and CBD and might even just that might be the only cannabinoids that they are familiar with. That wasn't all you looked at here, was it? 

Dr. Anderson: No, it's not. So we looked at 12. 12 cannabinoids in the cannabis plant, there's probably there's a little bit unknown as to how many cannabinoids there actually are, but it's on the order of 120. 

Trevor: Wow. 

Dr. Anderson: We looked at 12 of these. Some of them are very minor cannabinoids that are not expressed quite a bit in the plant, so it's hard to get our hands on those. So we have the 12 that we were able to actually isolate and have have on hand. 

Trevor: OK. I think we've got a firm background of where where we've got the audience are of up to speed. All right. So we have this study. What did you guys do? 

Dr. Anderson: Yeah. So what we did is we took the six major metabolizing CYP that we've discussed earlier. I won't repeat the names for you. And then we took 12 of some of the major cannabinoids. CBD and THC being the the most common and most prevalent. But then some of the others that are quite major. Typically, the precursors to both CBD and THC. So we took 12. 12 cannabinoids, six enzymes and then just screened whether or not the cannabinoids inhibited these CYP. And so what we do is we would take for each cytochrome, we'd take a normal substrate. So for, for instance, 2C9 we used Tolbutamide a drug people would find in the pharmacy. And metabolized with CYP2C9 and then we just one at a time added the cannabinoids to the mixture and saw whether or not they affected the metabolism of Tolbutamide for the case of 2C9. So we did that for for the panel of the matrix of 12 by six, although CYP3A4 We also used two other substrates, so we did three substrates for CYP3A4

Trevor: So I'm picturing an enormous spreadsheet at the end of this. 

Dr. Anderson: It is. It's a big matrix graph. When we had cannabinoids going one way CYP going the other way and checking the box once they were completed. 

Trevor: Cool. All right. So before we get to the big reveal at the end, so for as I'm sure we'll have at least a few sort of analytical chemist types out there. When you said you put them together, what was actually sort of going on in the lab, what would you see if you were sort of in there, standing over a technician shoulder who's doing this? 

Dr. Anderson: Yeah. So this one is actually in invitro experiment. So you wouldn't see too much. You just see somebody adding adding a bunch of different liquids to a little tube. So we put the mixture mix everything together, very few components in the tube actually, then heat it up to 37 degrees like in your body, so that we're mimicking drug metabolism happening there. And then we stop the reaction. And then for the analytical chemists that are listening. Yes, we used mass mass spectrometry to analyze the formation of the metabolite. So once again, for the case of at Tolbutamide, we put Tolbutamide in and then monitored the formation of hydroxy Tolbutamide inside using mass spectrometry. 

Trevor: Cool. All right. So we have this huge matrix, this huge spreadsheet. What did you guys find about the cannabinoids and the cytochrome P450 system? 

Dr. Anderson: Yeah. So I think what we found is if you kind of summarize per CYP, we found that the cannabinoids largely had no effect on metabolism by CYP2D6, which that's consistent with what had been seen in the literature. So there had been other studies that had looked at the effects of CBD and THC on the CYP system, as well as a couple of studies here, and they're looking at maybe CBN and CBD. So that's it, really, that the cannabinoids didn't 2D6 little effect on 2B6. Some of the cannabinoids had minor inhibition here and there. But what the major finding was that the majority of the cannabinoids inhibited CYP2C9 and then as well as CYP2C19, but less potently. And so the kind of the important thing about that is that together CYP2C9 and CYP2C19 they're responsible for the metabolism of about 25% of prescription drugs on the market. 

Trevor: That's as a pharmacist that significant. So that's going to help it work into my interaction calculator. OK, and is this are these 25% of all drugs is too much to discuss in detail in one podcast, but were there any sort of standouts of things that were, what's the word I'm looking for, particularly clinically significant, like one of the ones that comes up in conversation is things for for epilepsy, things like clopazam, am and some of these other we'll call them things with narrow therapeutic index. If you have too much or too little of them in the body, it's a big deal any any sort of standouts that way. 

Dr. Anderson: Yeah. Well, so we're using the screen we just used, for instance, for CYP2C9 Tolbutamide  as our just example drug. But Tolbutamide to mind is my understanding you might know more bit as a pharmacist, I don't think that has a very narrow therapeutic window. 

Trevor: In fact, around here, it's not. In fact, around here, it's not used very much. I'm sure it's fine, but just not very common. 

Dr. Anderson: Yeah. So but we used Tolbutamide as a proxy. Warfarin is a standout that is metabolized by CYP2C9 and has a very narrow, narrow therapeutic window. And indeed, there have been some case studies where there have been some adverse events with the result of CBD or cannabis based products used with with Warfarin. But other other drugs that are metabolized by CYP2C9 and CYP2C19 that have these narrow therapeutic windows are, in addition to Warfarin, Clopidogrel, Phenytoin, Amitriptyline and the Sulfonylurea. So I think there is the potential for drug drug interactions now. We predict that these cannabinoids are affecting CYP2C9, and this might be some cause for concern. But we didn't look at these substrates and these drugs specifically, so a little bit more research would need to be done to say definitively, yes, if you are taking a Sulfonylurea and a cannabis based medicine, there might be a bit of cause for concern. 

Trevor: Fair enough. So no, this is this is really interesting. Anything else that kind of stood out from or surprised you from from the study that you guys did? 

Dr. Anderson: Yeah, I think what surprised me personally is the cannabinoids. Their structure is quite similar. So I was anticipating that the inhibition profile of the cannabinoids across the CYP would be quite constant and consistent and that, you know, if one cannabinoid inhibited, they all would. And that really wasn't what we saw. So that was, to me, a bit surprising. It depended cannabinoid to cannabinoid to CYP to CYP. I think one of the stand outs, which was an odd one, was for CYP1A2, CBN, was the only one that metabolized it that inhibited CYP1A2 and quite potently. So that was a bit of a surprise. 

Trevor: Oh, another story that reminded me another. So this has come up in, we'll call it clinical discussions, but obviously it's be great if it we have an analytical person confirm this. So we've been told or people are surmising that CBD is a much more potent inhibitor, or we'll call it effector of the cytochrome P450 system than THC. Do you find that true? Not true or way more nuanced than I'm making it? 

Dr. Anderson: Yeah, I don't think it can be, which put into quite a simple sentence like, 

Trevor: no, no. And and and that that that's fine. That's kind of what I expected. Usually when people actually look at these, you know, grand statements that as clinicians use, it's it's never quite that simple. It's always more nuanced. So. So CBD was not across the board, affecting the cytochrome p450 more. 

Dr. Anderson: No, not that I would would say. I mean, if yes, I guess with what we looked at, there was a bit of CBD maybe popped up a bit more than THC. But I think I think it'd be hard to make a blanket statement for all medications out there. 

Trevor: No, no. And that's that's perfectly fair. That's why we want to talk to you, to talk to somebody who's, you know, not just, you know, theorizing, but someone who has actually tested it and looked at it. So this has been really interesting for me. Anything else that I've missed? Anything else you wish wished? I'd asked. I've enjoyed this whole thing. I could keep talking about drug drug interactions all day, but probably people won't let me. Anything else you wish? I'd ask either about your research laboratory initiative? Cannabinoids, anything like that? 

Dr. Anderson: Oh, let's see. Now, I think I think what we're we were happy to do this study because, you know, medicinal cannabis is a bit of a unique one. So when medicines go out onto the market, they go through this very drug regulatory pathway that's very consistent and 

Trevor: and structured 

Dr. Anderson: and very structured. Yes, that's the word I was looking for. I think you were as a medicinal cannabis has kind of gone on a unique pathway. So its pathway to market has been very indirect and it hasn't really followed this regular drug regulatory pathway. So whereas any drug that's in the in the pharmacy behind you would have been looked at, its effects on cytochrome P450 as well as drug transporters and stop looking for the potential for drug drug interactions. Medicinal cannabis didn't go that pathway that route. So we're trying to gain the knowledge because people are using it, most mostly not coming from the pharmacy behind you. So some products are, but you're fine people just taking medicinal cannabis products. And so it's we're hopeful and thankful to be able to contribute some information to the to the knowledge base for whether or not drug drug interactions can occur. Now we didn't encompass everything. There's still a lot of work to be doing to be done, but it's a start. 

Trevor: Oh, no, that's great one. Maybe it's better just as you were talking. So I know it's going to come up and is probably going to ask me. So I think I know the answer, but we'll check. So would it matter the route of how the cannabis got into the patient, like whether it was inhaled, whether it was ingested or we actually have people using suppositories? Would the the route of cannabis getting into the patient have changed the whole interaction with the cytochrome P450? Or is that not exactly what you looked at? 

Dr. Anderson: That's not exactly what we looked at, but that's a really good question. So because we just did it in a test tube, we don't have a route to the administration. So we're just looking at if these drugs come in contact at these concentrations in the body of an enzyme, this is the effect that will have. So it's interesting because if you inhale or uses suppository form of medicinal cannabis product, you are bypassing what's called first best first pass metabolism. So when you ingest something orally, you it's absorbed into your system, and the first thing it does is it goes through the liver, in the liver, and it is the the gatekeeper. So a lot of drug metabolism happens there, so you ingest both your prescription medication and your medicinal cannabis product together, the kind of going to be hitting the system, hitting the liver at roughly the same time. Whereas if you're taking an oral prescription and inhaling you when you inhale, you're just a cannabis product, you're going to be bypassing that first pass metabolism so your concentrations have the potential to be a bit higher. 

Trevor: OK. Know that. Thank you. And again, more nuanced than I would have given. So that's it's again great to have an expert on the line. This has been really, a lot of fun. Wish you the best in the continued research you're doing with the Lambert initiative. And we're hoping when your next paper comes out, there'll be something equally fascinating in that we might touch base again. 

Trevor: Kirk. So I said, Alphabet soup, did we do a little alphabet soup, but more importantly, do you think we did it in a way that people are going to understand what we're talking about? 

Kirk: I have no clue. OK, because I can tell you now I can tell you, because because I was listening to this interview, I take my dog for a walk every morning and I was listening to his interview on a walk and I'm going, Oh man, again again, you're forcing me to reach back in the knowledge that I haven't tested myself on in in years. Now again, I appreciate that as a nurse part of my responsibility, you understand medications is this stuff, but I can tell you that very few of the nurses in my category would get into it as deeply. And if we did have a question, we just phone you. Yes, we just phone a pharmacist, right? 

Trevor: And I think, you know, we have a very smart audience, so I think it is good to give them what the researchers are working on. 

Kirk: Yes. 

Trevor: But you know, if if you felt this went straight over your head, just don't panic. I think the important bit is what one of the little bits Dr. Anderson: had was, you know, a couple of these enzymes in your liver are responsible for metabolizing about a quarter of the prescription drugs out there and they are affected by cannabis. 

Kirk: Yes. 

Trevor: It's not saying you can't take the prescription drug. It's not saying you can't take the cannabis, but it's just a let's keep your medical professional, your pharmacist, doctor, nurse in the loop that you're using cannabis. And if suddenly you know your level of your blood pressure pill goes through the roof, you can go, Oh,  I wonder if that's from cannabis use that I think for me, I think for your average person, that might be the take home message. 

Kirk: Well, it's another reason. It's another reason to talk to your doctor about you're using cannabis. What I did, what I did here is that I actually came home and sat down and and listened to this interview with the paper in front of me. 

Trevor: OK,. 

Kirk: So so that's what I did to try to understand and really capture what was being said. And and I guess if I want to, I want to remind people that we did an episode back when with with the researchers that we're looking at the liver and mice, right? And so this this this particular episode relates back to that particular episode in which one was that I think, you know, which one was it? It was, I 

Trevor: think it was thirty three. But more importantly, it had one of my favourite titles was liver let die, 

Kirk: liver let die. Yes, I and I thought it was witty to maybe, maybe our maybe our audience will think so. But I tell you what, I pulled away from it, and I think this is where I might be able to help our listeners to think about it here a little bit. And that is with CBN's right. 

Trevor: Okay,. 

Kirk: We know where we're learning that CBN is starting to become dubbed the sleepy cannabinoid. You know, THC as as weed, as cannabis, age's CBD, not CBD, THCa ages and become CBN. So when I looked at that study CYP1A2 and the effect of caffeine with it, and I'm thinking that caffeine is metabolized in the liver using CYP1A2. Well, isn't that interesting? What they found is that CYP1A2 also is involved with CBN. Now, if you think about how these drugs interact, if we take caffeine to become awake, right, we we how are you going on a long road trip, you drink coffee on the road trip, get up in the morning, you get your coffee. Many of us have a true addiction and acceptance to coffee, right? We can buy big mugs. We talked about this before. So now here, here, guys, here, listeners think about this. If caffeine ends up being metabolized by the same CYP program and you're doing CBN to fall asleep, but you're taking a cup of coffee at the same time, maybe two or expect the caffeine to work as well or the CBN to work as well, because they're they're working on the same system. Is that an interpretation. 

Trevor: Yeah, I don't know if they specifically looked at that. So, you know, 

Kirk: It in the paper

Trevor: Yeah, I know, but it did but what the caffeine part, whether or not that's but its short version is yes, that could absolutely be true. And I like the idea of because I don't after off my head, I don't know what else CBN is doing in the body. But if part of its sleepy effect, is it sort of kicking out some of the caffeine? 

Kirk: Well, well, here's here's here's what from the paper, caffeine has a large therapeutic window. Thus, inhabitation of caffeine metabolism by CBN is likely of little therapeutic concern, but that's because caffeine is such a large window. However, the CYP1A2 substrate and it goes on and on and on does have an effect. So but it can result from a communitive CBN effect, so again, as other components. But I just it's what do they say? However, media sources have dubbed CBN the sleepy cannabinoid. So there is an increasing demand for CBN isolates as a sleep aid. So if we start getting into a situation where we're LP, start isolating the CBN and creating an oil of just CBN, then you're going to have to be very aware that that high concentration of CBN may have an effect on the caffeine. So this is this is how I pull it. This is how what I pulled out of the paper. 

Trevor: So, yeah, no, I think everything you said is fair. So. So and like you said, a sort of a a chemical almost all of us put in our body every day. So it just sort of a. Even if you're not on prescription drugs, just say how your cannabis could affect other things and could affect the amount of caffeine. 

Kirk: So the other the other thing, I guess when I get to the bottom of this again, there's nothing that we were that's really out there as a concern, except some some medications that have a low therapeutic window. Yeah, warfarin, some of the some of the anti-seizure medications. Yeah. And we do know that patients are using cannabinoids for seizures. So you need to include your pharmacist and your doctor to talk about pharmaceuticals that have low small windows when you're using cannabis, because that's when there'd be an effect, right? Yeah. 

Trevor: And one of the things I like that came up in the conversation because I have said this, and I guess I have to stop saying this is I've said that CBD seems to be seems to affect your drug metabolism more. And and Dr. Anderson. Well, no, it's probably not that simple. So, you know, that's again, good to know that it's as usual, more nuanced and not that simple. But but yeah, it's. And the other one, as a pharmacist, I really like they didn't look at that on paper, but I like that she let me go a little bit down a rabbit hole was how the cannabis goes into your body is going to affect this as well. Because if you smoke or will inhale it, if you if it's inhaled, it goes through your lungs. And the fancy word we use in the pharmacy world is first pass metabolism, which means when you take a drug orally goes in your stomach and the first. So all the blood flow from your stomach, intestines, etc. first place it goes is the liver, so it goes to the liver. And then a bunch of it is broken down immediately before it goes through for your body. We call that first pass metabolism. Your liver sort of blows it up before it does anything. Well, if you inhale it in the lungs skip the liver. And if you do it via suppository, it gets more complicated. I think it's 2/3 skips the liver at 1/3 doesn't. But if you take it orally, it definitely goes through the liver. So all of 

Kirk: the medical cannabis. 

Trevor: So all the medical cannabis, how it goes into your body is also going to vary how the liver enzymes work on it. Now again, that wasn't the part of her paper, so I like that she let me indulge, but it's just more things we have to sort of be aware of is route of administration is going to matter

Kirk: be going back to when I told you, I read the two papers or I scanned the two papers that initiated this study in regards to the cost of drug to drug interactions. No surprise, but NSIADs, most frequently commonly involved in drug to drug interactions and NSIADs, are your ibuprofen and and lots of people using it for pain management. So it's something to be aware of that a lot of people don't realize that NSIADs aren't for long term use, right? They're there for short term use. 

Trevor: Yeah, but the complicated part and different podcast is. But what if you have long term pain? 

Kirk: Yeah, yeah. Got it. Yeah, that's for a different podcast. OK, mate, that was fun. I enjoyed that. A couple other takeaway things. I had notes here. I also found interesting that once again, cannabis still, it's still a mystery. Scientists still don't like this. This study ultimately didn't come out and say, Oh my God, stop using cannabis. 

Trevor: No, no, no. It really it really said, here's a start we got. We got more. 

Kirk: Do we got we got more to do, which is happening in a lot of our studies. The other thing that's interesting is once. Again, we learn and we've known this for a long time. Once again, cannabis just seems to be there and we're and everything's back assward, you know, we are basically learning about cannabis as it's already out there, whereas other medications have been studied and studied and studied before they are out there so again, we're just still we're still scratching the surface about this plant. 

Trevor: I think that's a good place now. Kirk: on this episode, did you have a my cannabis story and or music thing? 

Kirk: Yeah, I've got a couple. Well, I've got a couple. And here's here's what I hope to do. We've gathered so many stories over the summer when we went up to Alberta that I think we're going to. I'd like to just sort of put them in to every so often because we've been asking our audience for My Cannabis Stories. And the only way we seem to get them is by actually going out there and saying, Hey, give me your My Cannabis Story. And I did that. I did that this summer lots, and one of these is a very old friend of mine. We've known each other. God, almost 40 years now. Yeah, 40 years. He lives in Vancouver and he lives down by Stanley Park. Now, have you ever been down that area? Lots of apartment buildings. Beautiful, but lots of apartment buildings. Beautiful area, trendy restaurants. Whenever we go, visit our buddy there. We're always in restaurants, we're always walking in the park, all that sort of stuff. He has a story about living in Vancouver in an apartment, so that's his cannabis story. So we're just going to let my buddy here tell us his story about why it was like to live in Vancouver or what it is like to live in Vancouver during COVID. 

Apartment Dweller: First of all, it's prohibited by the landlord when you sign your lease to smoke anything inside your apartment building. And that's true of most, if not all, of the apartment buildings now and many of the condo developments to have that too. So you you are forced to smoke anything, including cigarettes or cannabis outside. So. But then you run into the problems that you're supposed to keep it away from children and away from public places. And that so basically you are confined to walking around on your sidewalk or going somewhere. You're not supposed to go to the park. But of course people do. But you know you're caught. If you're caught, you're your break. You could be fined. So basically, you 

Kirk: So you've chosen to live in an apartment building. There's nonsmoking. Right? That affects your your use of cannabis right now. There's also you live in a province where you are allowed to grow four plants. 

Apartment Dweller: Right. But in our lease, it specifically prohibits growing cannabis, growing cannabis on the premises of the building. So basically, yeah, it's it's prohibited and you've signed a lease with that in full knowledge of that. So you have a choice. The problem is there are no buildings that really permit it. And unless you've been grandfathered that you've been a cigarette smoker for 30 years, 20, 30 years and have lived in that same apartment. And so that was never mentioned in any new lease that comes up as basically. I've never well, I've never seen one when I was looking for my apartment that would actually allow me to grow. That would allow me to grow or to smoke. 

Kirk: So you're a medicinal user of cannabis. So is there any clause in your contract that allows medicinal uses to use cannabis in your apartment? 

Apartment Dweller: It's not mentioned. It's prohibited as a general thing in there in in the lease. So basically, if they wanted to and they had evidence and basically what has what has happened is we have had notes from the landlord reminding people that that tobacco consumption is illegal. Reminding that people people have been complaining about the smell of of tobacco smoke entering their apartments. 

Kirk: Ha ha. Thank you. 

Trevor: Thank you for that story. That was great. You know, as a non apartment dweller, I guess I didn't realize how and you know what I mean. I bet this is not a specific Vancouver story. I'm betting this is a across Canada. Any time you're in a multi what's it called a multi-unit dwelling? I bet it is not always that easy to find a place to consumer cannabis. 

Kirk: I think going, I think we're very fortunate people. You know, I'm often I'm often reminded how fortunate we are. We live in a we live in a small community where we know probably well, you probably, you know, 90 percent of the people I probably know about 75 percent of the people and we own our own homes. So we have our own property, so we've been able to live with space. I couldn't imagine what apartment dwellers, condominium dwellers, what they've had to go through when the lockdown. I can't imagine it. And I know that I know getting back to cannabis without talking, you know, getting into social studies. But I know that one of the big issues with with legalization of cannabis in Canada was Apartment dweller. Here's issue, you know. Yeah. What do you you know, I I think back years and years and years ago, decades ago, my brother lived in a in a high rise in Victoria. So we were sitting out on his porch, you know, enjoying an expensive whiskey and a and a cigar. And be damned if someone wasn't complaining about the cigar smoke. We're out. We're on a deck looking out over the ocean and some guy down a couple of houses could smell the cigar smoke. So my god, man, I couldn't imagine trying to, you know, consume your medicinal weed in an apartment. The next story I have you remember this fellow? 

Trevor: I do. This is he was a very cool guy. 

Kirk: This is a music guy. Yeah, very raspy voice, but also we met him in the smoking room at Expo and his story about being a 50 year old 60 year old man,. 

Trevor: I think he's like fifty fifty three,. 

Kirk: Fifty three fifty three. OK, so you're close to your age? 

Trevor: Very close. 

Kirk: Talking about talking about what it's like to smoke cannabis for the first time in a public place. Legally.

Trevor: Legally, 

Kirk: Yeah, legally. So there we are. You know and what we've talked about this already. The smoking room was. I don't know if we talked about this with our with our audience, but the expo and we have a story about this coming right now about how they organize expo in Calgary. But basically we were corralled into this chain link bound area. That was what. 

Trevor: But I think the important part of it was blacked out, so we couldn't see out of it. But more important than no one could see cannabis being consumed in the smoking area. 

Kirk: Nowhere to sit there. We were always diligent legally smoking, consuming cannabis to anyway. This is Emre, and I think we're also going to use one of his songs. So I think what we should do is maybe we'll get Rene to just blend right in Emre Cords. This is his story and his music, and I guess we'll just fade out and remind people that I'm Kirk: Nyquist. I'm the nurse, 

Trevor: I'm Trevor: Sheffield, I'm the pharmacist, and we're Reefer Medness. Thanks for being here. 

Kirk: Yeah, and please go to our web page reefermed.ca. All these all these episodes are on the web page transcribed, easily, easily searched so you can go in there and you can search for the alphabet soup that that our guest presented to us. So once again, people thank you very much for listening. See you next time. 

Kirk: So we're in in the smoking room. 

EMRE: Yes, we are. 

Kirk: And what are you doing? 

EMRE: I am smoking marijuana for the first time in public with a bunch of people completely legally,. 

Kirk: Completely legally. How long have you? Is this the first time you do this. 

EMRE: And this be the first time I've done this? 

Kirk: And how many years old? 

EMRE: fifty-three. So I've been smoking pot since that's 15, probably. And this is the first time. And as a side note, marijuana saved my life. 

Kirk: OK. 

I have severe depression and anxiety, and I have a lot of social issues and I'm, you know, I'm a little bit on the autistic scale,. 

Kirk: OK? 

EMRE: Marijuana calms me down and slows down my head, and it slows. 

Kirk: Were you doing? What were you doing that before when you were a kid? 

EMRE: Yeah. 

Kirk: As a kid,. 

EMRE: You know, ever since. So you know, I found out it stopped my symptoms. 

Kirk: Cool. 

EMRE: Yeah. But just never legally, you know? 

Kirk: So yeah, and here it is today. 

EMRE: Yes, and here it is today 2121. 

Kirk: And there's a guy in a uniform over there, you know, keeping track. 

EMRE: Yeah, I know. Let's go back to the smoking section to smoke marijuana. And I saw this. I'm like, What is this all this? Oh my god. Oh wow. yes I have to come here to smoke a joint just 

Kirk: for the guys setting up for rosin 

EMRE: people have pipes everywhere it's great, you know? It sure is different than alcohol and beer gardens. 

Kirk:  Well, the only difference is the only difference is we are definitely corralled and we're in a blind. If this is a beer gardens, we would have picnic tables. We have live music and we be watching the band. 

EMRE: We're still second class at least we're not going to jail 

Kirk: we're not going to jail. 

EMRE: My name is Emre Cordes. And you can find me on YouTube under Emrecordslive or EMrecordslive or on Facebook. It's actually it's day 544 of our pandemic. I started playing live on March 17th, 2020, so I've been playing everyday. so if you go on YouTube you'll find more than 600 shows me going live every day. 

Rene: All right. Well, that was another good one, guys. It's Rene back here at the studio. And as promised, we're going to have some EmreCords music here. I went to his YouTube channel and found a song called Before We Decided to Fall. Emre So it's E-M-R-E then cords. Yes. if you want to look him up? Thanks for listening to Reefer Medness.