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E134 - Hilal Kalkan - Statins, MicroRNA and Cannabinoids

 The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun for the discovery of microRNA. It’s too bad we at Reefer MEDness don’t know anything about microRNA. But wait…We do! Hilal Kalkan, a post-doc at Laval University, talks to us about how microRNA and cannabinoid receptors are involved in the side effect of a common cholesterol medication. Come dive deep into the molecular workings of the endocannabinoid system with us!

Episode Transcript

Trevor: Kirk, we are back.

Kirk: Hey, Trevor, How's it going?

Trevor: I am doing well. So this talk is a little ways in the making. So I first read about this paper. So I first and I'll say that this did not end up being the paper. You know, these are not the droids you're looking for. This was not the paper I thought I was getting. It was very interesting. But what I thought I was getting was a paper about, so and we'll get much more into this, but, statins. Statins are a drug that are very commonly used. They reduce cholesterol. Very safe. Very effective. I'll even say some nice things about them in a second because we're going to spend the majority of the time here beating up on statins. And I don't want people to get the impression they are not good drugs, they're fantastic drugs, but they do have side effects. And we're talking about one of the side effects. But when I first read this preprint, it was late 2022, early 2023, and I started emailing with the team involved with this paper and it was eventually put in contact with Hilal. And she, you know, we were setting up time to do the Zoom. And then February 6th, 2023 happened and there was an enormous series of earthquakes in Turkey, in which more than 50,000 people died. And unfortunately, as I found out shortly thereafter, that included over 50 members of Hilal's family. So, you know, a few emails back and forth. You know, I don't think I can do this. I might be going to Turkey. A bunch of my family die there. Of course, you know, that's way more important than a Zoom call. And so, you know, basically that was kind of the end of it in, you know, February 2023. Honestly, I thought that would be the last I ever heard of Hilal because, you know, this interesting paper, but then enormous tragedy and all went away. And then in July.

Kirk: I remember you discussing this actually that this just triggered and you may have even in one of the episodes you might have even discussed this, that you were trying to search a story because I just had a huge I just had a boom, I remember this story. 

Trevor: So, who says old guys don't remember stuff, so in July 2024, like a year and a half later, I suddenly get this email from Hilal saying, Hi, you ready to do that Zoom call now? Yeah. Yeah I am how are you? So she is out of Quebec now. Laval.

Kirk: Well, I got her. I've got her on LinkedIn here as a post-doctoral fellow at the University of Laval. She's in cutting edge research, neurobiology, cancer, genetics, diseases, using various molecular and cellular techniques such as recorded gene assays, gene expressions analysis and drug screenings. I got to tell you, I know we're going to get into this. I read the paper. Oh my God, man. That is one of the most dense papers. I couldn't get past the acronyms. I couldn't get past the biology terms that I don't think I've ever used in my life. I know it's a pretty dense paper.

Trevor: She is a phenomenally bright person. She's a postdoc. And like all the things she listed, I think she used every one of those tools in this in this paper because they they were very thorough and we won't even get through how thorough they were. But just trust us. They went and we'll post the paper. People can read it.

Kirk: Yeah, yeah, yeah. Well, this is. This is another one of Trevor's richly dense scientific episodes, but this is definitely for those that are practicing, prescribing, using cannabis in their profession. This is probably.

Trevor: But interesting.

Kirk: I got to tell you. It's incredibly interesting. I'm going to let you go, but I'm going to bow out here because I truly got lost. I had a tough time following her because I like the way she speaks and she speaks in science.  Anyways, Trevor, I just want the audience to know hugely, deeply, very scientific episode. So go, buddy.

Trevor: So I'm not going to do it justice, but I'm going to just. Because I think it'll be easier before we get into the interview to just try to dumb down, simplify what the experiment was looking at. What the paper was looking at. So and if you read the paper, you're going to see murine a lot. So we'll just start with that murine means mouse. So they use a lot of mice. And so they started with some mouse muscle cells and they gave these mouse muscle cells some simvastatin, the cholesterol drug. And the first thing that happened was the cannabinoids that our body produces that produces a bunch of them. But the two most famous ones, an anandamide and 2AG. The first thing does is those levels shot up, which is interesting. Wonder why they did that. And then something called micro RNA. So sidetrack already. I'd never heard of micro RNA before this paper. So back to cell biology. Normally something called RNA goes into the nucleus. Hooks on a part of the DNA. Sort of gets a piece of a copy of that, goes to the ribosome and then we make proteins off of that RNA. And almost everything in the cell is proteins. So that's how that works. If you remember messenger RNA or mRNA from the Covid vaccines, they also work that way. RNA usually causes proteins to be made. This micro RNA don't do that. And in this case they were like suppressing parts of the of the DNA from making stuff. And in this case, they were suppressing the genes that made the CB1 receptor. So they literally, so after Simvastatin showed up, there were literally less CB1 cannabinoid receptors on the cell, which is wild. And then the simvastatin reduced how well those CB1 receptors sent their message to the hey anandamide is hooked on to me. And now you have to send a chemical message to the rest of cells so something happens while they slowed down that signaling. And so they found these two sort of completely different ways that Simvastatin changed the endocannabinoid system. The CB1 receptor and that through some other things before the study they found actually leads to some muscle weakness. They use Muscular Dystrophy and a few other things we won't get into of what. So they found that just at the cell level, then they did the similar things on an actual mouse. Now, I love to picture this. They did grip strength testing on mice. So picture those tiny, tiny little things. No, my understanding is they sort of have them hang on to something.

Kirk: You've seen mice are pet gerbils while they swing. They give them those swing things.

Trevor: Yeah. So but they do grip strength testing on mice. And they found that the simvastatin treated ones had weaker grip strength. And then they went to actual human muscle cells and found that the Simvastatin affected the endocannabinoid receptors and caused the muscle damage there, too. So, a very deep thorough paper about how a little bit of Simvastatin, a little bit of a really good drug does some, leads down this whole complicated endocannabinoid system to have muscle damage. So that's kind of my overview of of what they were doing.

Kirk: Okay. I agree. I agree. I got that. Let's get into in the interview.

Trevor: Yeah, Let's listen to Hilal explain this to us. And be happy that there are smart people like her around to make science go forward. All right.

Hilal Kalkan: So I am Hilal Kalkan. My name is Hilal. My surname is Kalkan. I'll come and I'm working in University Laval in CNR - ICB specifically as a postdoctoral researcher under Professor Vincenzo Di Marzo, who is the person actually the main person in cannabinoids and biology. And on the other side I am working with Professor Nicolas Lamont, whose expertise is in inflammation and again in biology. So these people are the top one and top ten people in the world and they are the best in cannabinoid biology. And that's why I work with them and I'm proud to work to be working with them and so yeah, this is my background basically. And I mean, I'm in Canada right now.

Hilal Kalkan: So yeah, no, thank you. And we really appreciate the fact you agreed to talk to us. So just for the audience that we're going to be talking about Simvastatin, which is a cholesterol pill. As a pharmacist, I deal with that all the time. But just in case people aren't aware, tell them why you picked simvastatin and sort of why it's so important.

Hilal Kalkan: Okay, so why did we choose Simvastatin is because it's the most commonly used statin for lowering cholesterol levels. And it's also the most use drug for cardiovascular diseases. And that's why we wanted to investigate the simvastatin benefits in, of course in cardio biology is different, but what happens in muscle, especially in the as skeletal muscle and muscle disorders which cause toxicity, so on one side, it has important benefits, like it's the most important drug in lipid lowering. But on the other side, it has so much damaging effects in different organ, in muscle. So that was our beginning to investigate studies and especially simvastatin. That's the reason.

Trevor: No, good. And like in pharmacy we talk about simvastatin the other statins being relatively safe. Actually very safe. We use them, we use them in millions of people. But like you said, depending on where you look, somewhere around ten percentage of people who take a statin might get anywhere from, you know, mild sore muscle to the much more rare, but the much more serious rhabdomyolysis, which is really, really bad. So these are all sort of muscle problems that can happen when we use statins. So how do you think how in this paper what are you looking at with statins and simvastatin toxicity? How what were you looking at?

Hilal Kalkan: Okay, so what we looked is that first of all, has simvastatin is inducing the toxicity, especially in muscle. And we included in vitro samples and in vivo sample also included the donors from human primary myoblasts sample and we investigated the effects, the mechanism and the clinical context a bit, but just in writing. Not that we have a binding to any medical center for any test, but we just made a general context in medicine fields by comparing cardiovascular diseases and muscle diseases and very similar to studying especially Stans. So what we found in this study is that, the simvastatin is inducing a muscle toxicity involved in murine more than and also in human primary myoblasts. How it is doing this is through the mechanism that's linked to downregulation of Endocannabinoid signaling system, which is a specifically CB1 Receptor, which is cannabinoid receptor one type. And this is mediated through the expression of some specific microRNAs. And how they induce the changes in the specific gene, cannabinoid receptor one gene. And our results are showing that simvastatin impairs the cannabinoid receptor signaling pathways and it is specifically inhibiting the protein kinases and also the several other pathways like ERK signaling by inhibiting both protein kinase and ERK signaling their phosphorylation. And this inhibition is not entirely reversible. And by direct CB1, by the use of direct CB1 agonist like ACE1, but it's modulated by positive allostatic modulators and these positive allosteric modulator, they are only a little bit different than agonists because agonists are directly binding to the receptors, but positive allosteric modulator, they are binding to different sides of this receptor and they are enhancing the response of the receptors to the endogenous molecules, endocannabinoids or their agonist. So basically this is the main idea and finding of the paper. And there a clinical context in this paper too, as I mentioned. And so what is it, if you ask me, is that the use of statins normally they are, yes, they are very good in some diseases like cardiovascular diseases and maybe other diseases that are related to cholesterol. So I understand that point. But despite these benefits, they also cause the major toxicity based on my paper that we are talking right now. And that includes a range of muscle disorders, including myocarditis. We don't know that, how the exact mechanism of studying murine exist or happens. Lets me know that there is for sure there is an involving of disruptions in several cellular processes. That includes cannabinoids signal.

Trevor: Okay. I want to go back to micro RNA. So because honestly before your paper, I don't think I've heard of micro RNA. So I'll tell you what I think I figured out and you jump in and correct me. So they are RNA, but they don't encode for proteins, which is what I usually think of the RNA doing. They're actually affecting how genes are turned on and off or modulated. And in this case, do I have it right that the micro RNA is making the gene for producing the CB1 receptor not work as well, so we get less CB1 receptors. Do I sort of kind of have that right?

Hilal Kalkan: Yes. So if you are in your exactly the right path, but just to let you know and that microRNAs are actually non-coding RNA molecules, that's why they don't have the effect on protein. They play a crucial role mostly in the regulation of gene expression. And that's what's actually we are also saying in the study that micro, there are specific microRNAs. Like microRNA 152 is suppressing CB1 receptor activities. So yes, you are right.

Trevor: So the simvastatin is is causing there to be literal less CB1 receptors and the CB1 receptors we have are signaling less so there's less of them there. And when they do get activated, less signal happens all because of the simvastatin.

Hilal Kalkan: Yes, exactly.

Trevor: Okay.

Hilal Kalkan: So simvastatin inducing that myotoxicity in these muscle and it's true the dysregulation of these microRNAs. Especially as I mentioned that microRNA 152 which is causing the decreased expression level of cannabinoid receptor one and this in turn affects the PKC/ERK pathways, downstream pathways that I mentioned in the beginning of this top like protein kinase and signaling pathways. And they are they're contributing basically to muscle toxicity.

Trevor: Okay. So can we use cannabinoids or cannabinoid agonists or allosteric agonist we use anything to. So if we're going to be using simvastatin because it does a lot of good things, can we be using any cannabinoid agonists, antagonists? Can we use anything like that to make the toxicity better or go away?

Hilal Kalkan: Let's say if we can, can we use, for example, CB1 receptor modulators for this study and we are seeing that the antagonist that they worsen the muscle toxicity and the agonist didn't have much effect but allosteric positive and the positive allosteric region, yes they have some effect. So can we use that? Yeah, because targeting the CB1 receptors with these specific allosteric modulators such as these positive allosteric modulators especially, they might be offering a productive effects against simvastatin induced myotoxicity but the efficacy of this CB one agonist as we saw in my paper, I mean, you know, and I know it was limited in reversing the toxicity, which indicates to us that it's a multi phase process and that includes CB1 motivation and microRNA targeting. They thought might be necessary because as you know the microRNA involvement and also the and the cannabinoid system in movement. So by combining the antagonist antago-miRNA  and CB one and modulator specific modulators that can yes that can that can give a protective effect basically.

Trevor: Okay. So just to mention two cannabinoids that people will be familiar with. So THC is a direct CB1 agonist. So like the agonist that you used in your trial, we wouldn't expect it to have much effect on the toxicity. But CBD and I really don't know the answer to this, so I'm asking. I know it's a it's a negative allosteric CB1 agonist. Would a or could a, I know he did test CBD so I'm out. Theoretically would could a negative allosteric CB1 agonist like CBD be protective against simvastatin toxicity or or we'd have to test it or we don't really know.

Hilal Kalkan: In this study I do not know, but I know that positive allosteric modulators that we saw the protective effect be positive allosteric modulators. So that tells me that's I'm not sure about.

Trevor: Okay. Fair enough. So and I know this is not a clinical trial. You're not, the idea behind this was not to get you necessarily a way to treat or prevent simvastatin toxicity. But do you have any ideas after this about where you might be looking for something to treat or prevent simvastatin muscle toxicity?

Hilal Kalkan: I will come to there Trevor, but just before that, since you mentioned THC and CBD, I really want I just want to add something is that, you know, that THC is mostly use in like chronic pain or like nausea and appetite stimulation and in wasting diseases. But CBD because in that lab that I was working and I'm still working and we also work on epilepsy, and we used CBD and we saw the positive impacts of CBD in epilepsy and anxiety. But in this murine toxicity. Why I said that, I'm not sure because like normally I would expect CB1 agonists to have a greater impact, but I didn't see that right in my paper. So that's why I couldn't talk in this aspect. But there are a lot of important and beneficial effects of THC, CBD or different cannabinoids in different diseases. So any kind of cannabinoids or cannabinoid system for the audience just to explain them. What it is, is that it's a lipid signaling system, basically has their own receptors, their own syntax is their own, a number of metabolic pathways. So they have all different important roles in our body. And it depends on is it being peripheral, is it in the brain, for example? CB1 is mostly studied for in brain. And CB2 is mostly studied in inflammation or in immunity because their expression varies between organs, tissues and so on. So we cannot generalize one mode, which that to me has two general aspect of different diseases. That's why I couldn't answer your question, because I do not know. And other side. On the other side, your question was, so what is it from now on?

Trevor: Yeah, it's from this this paper where we're looking at simvastatin muscle toxicity. Is there anything in the, what do you think the road forward or what do you think we should look at next for ways to treat or prevent simvastatin muscle toxicity?

Hilal Kalkan: I think the study should definitely discover the effects of firstly different form of simvastatin to evaluate the CB1 and the sector and its modulators and also investigate the broader therapeutic targets that are related to microRNA regulation and also be hit in the broader impact. We should understand that all these findings, might influence the development of safer starting therapies or a need to put treatment approaches for studying using toxicity. For example, the clinical trials in the future. Potentially they could test to CB1 receptors modulators or microRNA inhibitors for studying treated patients and we have to manage these patients. So the patient management should be one of the most important criteria because they should be monitored and also they should see if they are having muscle, any muscle, and complication. For example, if the physician can hear from the patient, okay, I started to have some impact or some different feeling in my muscle. I'm not feeling mad. They should be monitored carefully and they shall start from low doses and they shall not increase unless it is necessary, unless they are knowing that these people are that they have cardiovascular disease. Either through inheritance from family or they all they have a cholesterol, enormous normal level of cholesterol. So then they have to use statins like there is no other way. So,  I think in the future, the most important part is that. These studies show that the how beneficial simvastatin or statins are. But on the other side it shows what they cause actually. How they can cause a different disease like my fixing wrong disease which is muscle toxicity. And think if somebody has a predisposition to the muscle disease just think how quickly that could be progressing. Right. So patient management that's why is, I think it's very important for the people who prescribe statins. Or the people who is using statins, they should be really informed carefully and they should be educated about statins.

Trevor: No, that's fair enough. I just maybe as an aside, but I just it never occurred to me because, you know, I've been a pharmacist a lot of years and we've, you know, just heard this muscle toxicity. And, you know, I've even ran into a couple of patients where, you know, we have an obvious I ran into the, you know, the really serious rhabdomyolysis. But, you know, I have sore shoulders or sore trapezius. And we basically we took them off the statin and we put them on something else. Maybe we gave them some CoQ10. Although in your paper says the coated CoQ10 probably doesn't do anything. But you know, we've tried all those things and usually if we take them off the statin in a month or so, all the muscle pain goes away and they, they carry on. It just never occurred to me that the endocannabinoid system, the ECS might be involved at all. So I was, I was really interested to read that, that, yeah, even when you just give somebody a statin and the first thing that happens is the, the Anandamide and the 2AG level start going up and, and how that all might be related or tied up in the expression of the CB1 receptor and the how the CB1 receptor signals. So the fact that the endocannabinoid system which I know sort of has its tendrils everywhere, is involved in how a very common medication has, it's not so common side effect and how the endocannabinoid system was involved in that was was fascinating.

Hilal Kalkan: But as you see it, as you see in this paper, there are there are actually it's very clear paper because we are showing what does Endocannabinoid system receptors, CB1 is doing in this process, in the toxicity process. How it is being affected and if it is affected how is this happening. We are not just showing the micro picture, we are showing the micro picture by finding the microRNA CB1 downregulation CB1 by different pathways that all been effective and that cause the toxicity in the muscle. And we used agonizts. We use antagonist and we use positive allosteric modulator and we are showing what each one of them is doing. So, yes, and endocannabinoid system is involved and the endocannabinoid system is really important for many diseases or disorders. And so like if you see a 24 hour, we have higher levels of anandamide and we don't have the effect 2AG but actually at three hour we have effect on 2AG. So, you know. Yeah. So it's like,

Trevor: I read that. But honestly, it kind of went a little over my bald head. Why was or maybe we don't know why, but why was different things happening at different times with with anandamide and 2AG. Do we know? Do we know why things were released at different like. Yeah, you mentioned that it was at different times different endocannabinoids were release. Do we know why? Or is that just something that happens or so.

Hilal Kalkan: Because anandamide and 2AG are the original two lipid mediators. They are the ones. They are the ligands of CB1 and CB2 receptors. Of course, now you want to know what's happening to cannabinoid system. There are two ways to do. One, first, to understand what is happening to endocannabinoids in the body or in the plasma or whatever you are looking. And then you have to look there are receptors and there are enzymes because endocannabinoid system is a big lipid signaling system that has mediators, receptors, enzymes for the degradation for their anabolic mechanisms. So it's a big system, and that's why we wanted to understand first whether if  simvastatin is having an impact on endocannabinoid system activity. And that's why we started this study. And we use this in-vitro model and then we ran to new ones. We check the different concentration of studying first in myoblast cells and myotubes cell. So myoblast cells are the original muscle cells, when they differentiate, they become the myotubes. So that's why we check these two cells. And then so then we expose them to 30 micro molar of simvastatin to understand their effect, the concentration levels. And we found that both anandamide and 2AG levels, they are both significantly increased compared to our untreated group. And so the only after three hours this was happening. And now we take after 24 hours what is happening and as you've seen the picture in the figures that we are having, at 24 hours on my level goes almost tenfold. And then the 2AG levels doesn't changes. But we also found the receptors, their enzymes that they are also deputed to their synthesis. They also show the same impact as their ?. So that's how we understood that, okay the endocannabinoid system is being altered by simvastatin exposure. And as you see it again, if we could do more time for experiments, but since we get our results with 24 hour and 3 hours, we just remain there. And we continued to do our experiment in myoblast cells because they were more sensitive than my myotubes. And that's how study was structured actually.

Trevor: No, and that's great. So I think you've answered well most of my questions. Like I said, I'm a pharmacist, not a not a biochemist or or geneticist or you got a lot going on in your very big brain there.

Hilal Kalkan: I am jealous

Trevor: The audience whether or not they take statins. What do you think sort of our general audience should take away from this about how you know the medications they take and the endocannabinoid system interact? What do you think is an important takeaway for people to come away with after your study?

Hilal Kalkan: Okay, so for me, I think it's the most important take home message right now. Is that, we need a needs for balance, which means that while we are using the statins for effective cardiovascular health, we have to not forget the side effects on muscle cells, and that needs to be in management carefully. My second message would be definitely the potential for CB1 modulation of the endocannabinoid systems targeting the Sydney one receptors or just its signaling pathways that might offer away to reduce the statin induce muscle toxicity and that microRNAs are important because understanding the role of microRNAs in regulating cannabinoid receptor one expression, it's open the new avenues for therapeutic interventions for us and the importance of this study is that we need to and we need to enhance study safety. So we have to provide insights into mitigating one of the significant adverse effects of statin therapy. Therefore improve the patient compliance or outcomes and also for advancing new particle approaches. We are highlighting the potential for targeting endocannabinoid system and microRNAs in the prevention for muscle toxicity.

Trevor: So here's my pharmacist duty. I have to say, statins are not bad. They are very, very good. So one of the papers I pulled out, five organizations suggest using statins to prevent cardiovascular disease. In 2013, it was the American College of Cardiology, the American Heart Association. In 2014, the United Kingdom's Institute for National Institute for Health and Care excellence or NICE. In 2016, the Canadian Cardiovascular Society, the US Preventative Task Force did it same year and the same year The European Society for Cardiology and Atherosclerosis have all said that statins are good for you and even if you don't currently have heart disease takes, it can make sense to take statins to prevent heart disease. So they are very, very good recommended by everybody. If a doc has you want to statins today, please don't stop taking them because of this paper. Okay. Now let's talk about the damage that statins can do.

Kirk: I would imagine that our listeners have come this far into the episode and listening to us. They know what statins are. So I would bet that if they've come this far, they know that statins are a class of drug used for cholesterol to lower the cholesterol levels in your body. Right. But what I want to understand a little bit more about is that there is this statin induced myopathy, myopathy is that happen to the muscles. Right. And it happens to 1 in 10,000 people that use it. So. Right. Approximate.

Trevor: Well, that's the really that's the really, really bad one. The mild maybe my shoulders hurt could be as high as 1 in 10.

Kirk: When I say 1 in 10,000 or 1 in 10 people. 1 in 10 people.

Trevor: Well, but that's for the mild stuff. I don't have the numbers in front of me, but the that rhabdomyolysis, the really, really bad one is also really, really rare. Okay.

Kirk: So as a wellness nurse. I completely get it that statins are important. Okay. But however, as a wellness, I would also encourage you to change your diet. Go for a couple of walks, live a healthier lifestyle, and try to get yourself off of Better Living Through Chemistry. Right. But we're not there. So if someone's here. So I would like to know a little bit more about what we, but going to the paper, what I pulled out of the paper was that what makes this very important is the fact that statins are number one used cardiac medicine out there. Right. So it's very important. It's very important that they do this paper, do the studies. What I also want to pull out of the what I pulled out of the paper was that was that how an unbalanced endocannabinoid system is associated with a plethora of pathologies. And they're learning now that if your endocannabinoid system is not balanced, then you can have chronic, you can have chronic issues. And one of them, of course, is diabetes. They've talked about the consequences of diabetes, liver and kidney dysfunction. And those are all out there. So I get it. But like I said, there's so much in that paper I didn't understand. And I'll gladly let you sum up your conversation with her. I'll walk away from it now.

Trevor: No, no. And that's fine. And my apologies if, if we left some people in the dust of too many acronyms.

Kirk: But I think that's important. I think it's important that we have these kind of episodes because I want people out there to know that we don't just do the fluff stuff like, you know, Kirk going into a Rec store and talking to people. This is heavy duty, cutting edge science. This is important.

Trevor: Well, and as I mentioned, the front I think it's worth mentioning again, I really thought this was going to be a simple and interesting one in that, you know, we have this muscle problem with certain cholesterol pill, the statins. And I thought the answer was going to be, okay, take some CBD and that fixes that. You know, 20, 30 years ago, we'd say take some CoQ10, which a B vitamin that fixes that. A, her group says no, that CoQ10 stuff doesn't really work. Well that's too bad. And B, THC and CBD also probably don't at least by themselves don't, it's a multifaceted thing. So I think my takeaway now is not that suddenly CBD can fix muscle problems from statins. It's I just you know, we see it all the time. And, you know, Dr. Russo's quote is, you know, the endocannabinoid system is the master regulator of the body, but like, the tendrils are going down to the how simvastatin affects how CBD receptors show up on the surfaces of mitochondria. Like the depths, we literally cannot be separated from the endocannabinoid system. It goes down to the chemistry and the receptors of our individual cells. It's, you know, it's just a fundamental, fundamental part of how our bodies work. And this is just another paper that goes, wow, that's that went a whole lot deeper than I thought.

Kirk: Well, seven years we've been doing this podcast and six and a half years ago we learned how the theory was the endocannabinoid system is involved with our homeostasis and we always thought it was the endocrine system. Right. But you know what keeps you equal and balanced? Well, we've got this little system called the endocannabinoid system. And throughout this entire exercise of doing Reefer Medness The Podcast,  found at reefermed.ca,  doing this whole project. We've learned so much about how, you know, the bliss, the bliss molecule, how really people need to be in touch with the endocannabinoid system. And the Western medicine needs to be in touch with it because it truly is what keeps us balanced. So I appreciate this paper as much as I will admit to the to our listeners that I really understood 60% of what was going on in that conversation. I really had a tough time. I tried to listen to it several times. I read the paper. I even I even went off and did some my own research. And I just I got lost in them. I got lost in it. And it got to a point where it was it was as a pharmacist, I think this is important for you to know as a registered nurse who doesn't prescribe. It's a little deeper than I want to get, but it was nice to have. So I'll put that out there.

Trevor: So no. Hilal, We really appreciate you talking to us and trying to educate our bald heads a little bit.

Kirk: Thank you very much for getting back to Trevor. Thank you for doing that. Right.

Trevor: Like, seriously, a year and a half after an enormous tragedy, like we're not we're not making light of your families. I just, you know, something horrible happened, and I just kind of assumed that was going to be the last we chatted and it wasn't. And I can't believe you got back to me and agreed to do the interview anyway.

Kirk: Very good. Trevor, I, I think I think I'm going to have an interesting time transcribing this one. Maybe as I transcribe it, I'll understand better and I will come back the next episode and go, Hey, Revelation, Epiphany, you got it.

Trevor: We all we all need an epiphany once in a while. So I'm Trevor Shewfelt I am the pharmacist. 

Kirk: Kirk Nyquist the Registered Nurse, sometimes confounded we are found at Reefer Medness - The Podcast. Check us out. We're on social media. Tell a friend, Did you get to music from her?

Trevor: No, we did not claim music from Hilal. We'll leave this one up to Rene.

Kirk: All right, man. That's another good one. Talk to you later.

Trevor: See everyone later.