Trevor: Kirk we're back.
Kirk: Yes, I'm Kirk the nurse.
Trevor: I'm Trevor's pharmacist.
Kirk: And my friend. You got a scientific, geeky, nerdy, medical based interview to talk about.
Trevor: I did. I got like three scientists all at once on a speakerphone.
Kirk: Your grin was touching each lobe?
Trevor: I think so.
Kirk: So, this is this is going to be a real geeky, deep, like I was listening in, there's a lot of words that my tongue would never be able to get around. But essentially, what have you brought?
Trevor: Well, Twitter is good for stuff. Cannabis Twitter kind of blew up with this Forbes article about CBD.
Kirk: I saw it on Instagram also. Yeah.
Trevor: And basically, the title was "CBD causes liver damage." And then everyone got all excited. Yes, it does. No it doesn't. You're an idiot. And that kind of stuff.
Kirk: People say you're an idiot on Twitter.
Trevor: Well, not specifically to me,.
Trevor: But I think most of the You're an idiot was aimed at the guy who wrote the Forbes article, which is unfair because without him, I wouldn't have realized these gentlemen in Arkansas. So we thought we'd send out a note and they said, sure, we'll talk to you about our study.
Kirk: Yeah, yeah. And these guys are these guys are world renowned specialists. Like this is a this is a quantifiable scientific paper that you read through.
Trevor: Yeah. And basically, on the toxicology end. And it's not as scary as it sounds, but basically these guys are and we do this for every drug out there.
Kirk: I was going to mention that. Right. This is what I got out of this. Every person that's on a chronic med and they're and I'm sure you can label them off, eventually you have to be monitored on the levels in your bloodstream and how your liver enzymes are affected by the medicine. Right. So name a few that people would know.
Trevor: Oh, well, the big one that every almost everyone is taking right now is Tylenol. Tylenol affects people's livers left, right and center.
Kirk: But you don't go to your doctor and get a Tylenol level.
Trevor: Well, then there's people who argue you should. But one of the more common ones would be an epilepsy drug called carbamazepine. It definitely affects your liver levels and makes it difficult to dose everything else because you take carbamazepine and that affects how your liver metabolizes everything else that you take.
Kirk: So if somebody is taking a CBD as medicine, this is a consideration that they should actually have their levels checked.
Trevor: Well, that is kind of what they were looking at in this paper. They'd found some; previous studies had found some increased liver enzymes when people took CBD. So these guys are kind of this is the beginning of the toxicology. What does CBD do in the liver? Because the liver affects so many different parts of the body? You know, it's a reasonable question. What does CBD do to the liver?
Kirk: Well, and again, as a nurse, you know, and we've just come into this into this cannabis game two years ago with this podcast. But cannabis has been legal in Canada for, I always mix this up since 2002, I think.
Trevor: About 20 years.
So I wonder now if GPs, if General Practitioners, if doctors out there are drawing liver enzymes and CBD levels, I wonder if it's part of their practice.
Trevor: I almost guarantee it isn't. And to be honest and full credit to these guys and I hope that there is more research like this, there's probably just not been enough research yet to draw up what we look at all the time, the clinical practice guidelines saying, you know, if somebody is on CBD, here's what you should do your liver then says it's like when we know right now, if I had a fungus on my toe and I wanted to take a certain medication to kill the fungus on my toe, the first thing the doctor would probably do is draw my liver enzyme. Then put me on it and three months later, check to see if it's changed.
Kirk: Because some of those drugs are very harmful to your liver.
Trevor: Or can at least affect them. So, you know, it's one of these things that we've got clinical practice guidelines. We don't have that about cannabis products.
Kirk: But these guys, essentially what I'm getting from this, these guys may be starting like here it is, guys, ground zero. If you are taking CBDs, you should approach your doctor and maybe suggest maybe you should check my liver enzymes. There's a study out there that suggests it might have an effect.
Trevor: It's at least worth the conversation. You know, if you're an otherwise healthy young adult on no other medications, maybe it doesn't matter. But, you know, if you've ever had any liver problems in the past or if you are on a butt load of other medications, yeah, maybe we should.
Kirk: So we should, I guess, get into the interview.
Trevor: Let's listen to smarter guys on us.
Dr. Gurley: I yes, I am Dr. Bill Gurley. I'm a professor of pharmaceutical sciences and the vice chairman for the Department of Pharmaceutical Sciences in the College of Pharmacy at the University of Arkansas for Medical Science.
Dr. McGill: Dr. Mitch McGill, assistant professor in Public Health and Pharmacology and Toxicology, also at the University of Arkansas for Medical Sciences.
Dr. Koturbash: I'm Igor Koturbash. I'm Associate Professor of department for Environmental Health and Director of the Center for Dietary Supplement Research here at the University of Arkansas for Medical Sciences.
Trevor: Thank you, gentlemen, and thank you for joining us. So I've read your paper. I guess my first question wasn't is what were you guys trying to find? What was the idea behind this? What problem were you trying to solve by doing this study?
Dr. Koturbash: Well, the first thing is that cannabidiol is really paving interest on the market. Price has been aggressively marketed for a whole host of different purposes. The problem is cannabidiol is that we literally have no idea about its safety. Right. And before something goes on the market, right, you need to know about its safety. So with the first study was actually to see that potential of cannabidiol to cause liver injury because that product Epidiolex, which is the FDA approved drug based on cannabidiol to treat epileptic seizures, it's major side-effect is elevated liver enzymes. It has been observed in about 5 to 20 percent of patients that receive Epidiolex clinically, so for the scope of the first study, to see how far you can push the envelope, whereas if they say safety, let's say borderline for cannabidiol. Right. So, you might argue those tests were quite high. But the idea for selecting those, was the maximum recommended dose of CBD in a Epidiolex, 20 milligram per kilogram. Than we used a very sophisticated approach, how to calculate the mouse dose. So, I will turn here to Dr. Gurley who can explain this better than me.
Dr. Gurley: Yes. So, the doses that we use are based on an approach called alometric scaling. And so, animals are have a much higher metabolism than humans do, so we often times like to refer to mice and rats as, livers with legs. And so it takes much higher doses on a milligram per kilogram basis to have an equivalent dose in a mouse than it would in a human. So we did, this is a standard procedure that the FDA and the drug industry utilize with regards to doing initial studies with drugs and animals and then translating those doses to the humans; the first time in human dose. So, there was an approach that standard and we utilized that for the doses that CBD, excuse me... Epidiolex had been recommended for. And then we just converted those to equivalent mouse doses and then just administered those. Now, the first dose we utilized was kind of a standard kind of the upper end of the Epidiolex, and then we just pushed it. So we're going we're trying, as Dr. Koturbash mentioned, we're trying to find what our limits are. And so we started off with what we called a one X mouse equivalent dose, then a three X and then 10 X. And so we're really pushing it with ten X and we fully expected to see you typically expect to see a lot of unusual things when you're really pushing the dose there. And we weren't surprised at all. And so we were more concerned about what we saw with the one X mouse equivalent doses. And we were, you know, the results were quite similar to what Greenwich Bioscience is found with Epidiolex. So it meant that our animal model was a fairly decent mimic. For what for Greenwich Bioscience is what they found when they were administering their drug Epidiolex to humans. So we were not too surprised with our findings at the lower doses. We fully expected to see much more exacerbated problems when we started pushing the dose in the other direction.
Trevor: I just wanna jump in quick, because you're answering some of the questions that have come up anyway. So that's excellent. But just to make sure everyone sort of catches what you were saying. So some of the criticisms that I've seen people write about this as you use just phenomenally high doses that would never be used in humans. But the sort of layperson's version of that is you need to use a much higher dose in a mouse to approximate what a human dose would be because their metabolism so much higher. Right?
Dr. Gurley: Yeah. So, you know, this is a very common mistake for people that are not familiar with how different species metabolize drugs differently from humans. And so if you look at the doses on a milligram per kilogram basis and you try to translate that to a human, it seems like an inordinate amount. But in reality, if you put into appropriate scaling factor, so, for example, if we had a dose of, say, we had a mouse dose of 120 milligrams per kilogram, well, that would to that basically equates to a 10 milligram per kilogram dose in humans, you know, so it's not a it's not a direct comparison. There is a scaling factor that has to be factored in there. And those are different scaling factors for different animals. The smaller the animal, the larger the scaling factor. As the animal gets larger, it gets more closer to humans. And as the animal gets much larger than humans or like horses and cows, the scaling factor gets even smaller than that.
Trevor: So and that's a no no, that's great. I think you explain that very well. The other one that's come up is, you know, why on earth did these guys use, you know, three times and ten times what we'd expect in humans? And I think I read in there and you can talk to this a little more because, you know, one of the things I assume you guys were looking into is what happens in the case of overdose. Is that the only reason you would pick such enormous high doses to go up to to see what would happen?
Dr. Gurley: Let me turn it back over to Dr. Koturbash that is his expertise.
Dr. Koturbash: Yes, so there are several things, of course, you think about our adults, right? Second, you think about the situations that some people can be poor metabolizers, some can be super metabolizer. You know, some sensitive populations. You know that people who can take just a little bit higher than daily recommended doses of Acetaminophen and they have really developed a severe liver injury. Right. So, you have to be aware of such a situation. Also, when you start working with a chemical any chemical it can be a drug or for example, something that's going to be used in the food industry. Technically, if you want to show that this dose is safe from the human, you have to show that about 10 x from that dose is safe for mouse, right? So, if we saw the effects of 20 milligrams per kilogram at 10x and we saw there a really significant effect on the liver that resonates with the data from just GW science is right where they clearly; that's what their reason, why the selected this is your maximum recommended dose because of the dose higher than that, you're going to start seeing probably really nasty affects. Right.
Trevor: Thank you very much. And I know I sort of jumped in the middle of Dr. Gurley's explanation, but thank you. And I think that leads us well into sort of the next part of. So we've gotten kind of on the why. So how about the how. It looks like this was sort of a, if I'm reading this right, kind of a two-prong study, you had sort of one huge dose, see what happens and then sort of a subacute doses. Can one of you talk about sort of what you guys did with the mice and kind of how that went along?
Dr. Koturbash: So another one reason for that acute study is that you are identified those for further some chronic and chronic standards. Right. So if you know that 20 milligrams per kilogram is a mouse equivalent, also 20 milligrams per kilogram is quite high. So actually, you can schedule your subacute and sub-chronic and chronic experiments with the lower dose. Right. So, we used a much lower dose for the sub-chronic study in order to mimic that every day ingestion. Right. So, you feel, for example, like to treat your arthritis or back pain or any other disease that CBD is marketed for and you take daily doses of cannabidiol. So what we saw is that if you need quite a high dose of CBD to cause liver injury after a single administration, actually substantially lower doses and needed to cause liver injury in regards to chronic congestion. Right.
Trevor: Oh, thank you. Thank you very much. So as a pharmacist, of course, we deal with liver injury. You know, the thing we give out in the pharmacy is that causes the most liver injury out there is acetaminophen. So that's, you know, something we talk about all the time. But you guys alluded to in the at the end of the study things that I guess clinicians will have to be worried about. So, you know, if people take really big doses of CBD or they take a dose for a long time, we might actually injure the liver. But there's also enzyme induction, which, you know, I'm interested in because that affects how other drugs work. Do any of you want to talk on what we think we might know about what CBD might do to induce enzymes to maybe affect other medications?
Dr. Gurley: Yeah, that's a great question. So that's been my area of expertise for quite some time. We've been doing our drug interaction studies, clinical herb drug interaction studies for over 20 years. And so this pretty much was a nice dove tailed nicely to a lot of the work that we've been doing with some of the more traditional botanical dietary supplements. So what we did see when we did the mouse studies, one of the other things that we did was to do a whole host of the hepatic enzymes assays to determine whether or not certain CytochromeP450 and certain transporters and certain transferases and a wide variety of drug metabolizing enzymes and transporters, whether they were modulated. And oftentimes what we found was several fairly important drug metabolizing enzymes in humans, at least the homologs in mice were dramatically induced. And so that kind of explains some of the drug interaction profiles that GW Bioscience has also seen with Epidiolex. Now, does that mean that we're going to see the same types of effects in humans as we saw with the mice? Hard to say, given the fact that several of these enzymes were induced. Many, many, many, many, many fold, I would suspect that we would see some similar effects in humans, but that's not always the case. There's a lot of different there's a lot of interspecies differences in how and how drugs and how certain drug metabolizing enzymes are induced or modulated. I do know that there has been some herb drug or some CBD drug interaction studies that have been conducted by GW Bioscience is looking at its effects on the very important drug metabolizing enzymes CYP3A4 in humans and at least based on their small pilot study, it doesn't appear to have a significant effect on CYP3A4. And that's kind of similar to what we saw with our mice studies. 3A4 at least the mouse Humalog didn't appear to be modulated to any great extent, but there were several other cytochromes that GW scientists have not investigated that do appear to be dramatically induced. So that's going to be a next study. In fact, I have some colleagues of mine at the University of Mississippi that we're going to start looking at a clinical study to see whether or not reasonable doses of CBD might modulate human drug metabolism.
Trevor: So, thank you. And yeah, and Dr. Koturbash actually sent me another one of the papers that your team was working on that was specifically looking at, I think it was acetaminophen interactions with CBD. So, I'm excited to see what else comes down the pike for that kind of thing, just to kind of address some of the other criticisms I read. So mice to humans. Now, obviously, mice is a good place to start for any kind of drug testing, just physically easier to work with and that kind of thing. But can you just tell our listeners in general, and you've touched on a little bit how like you said, it's an analog between the mouse liver enzyme and the human liver enzyme, but it's not, even though we find, you know... The quote is we've cured cancer so many times in mice, but never in humans. So it's not always sort of a straight line to what we find in mice to when we scale up to humans. Is it?
Dr. Gurley: Oh, no, not always. It's just it depends. It goes from drug to drug. And but as a general rule, there's always going to be some differences. But if you like, for example, who we're starting to see some hepatic toxicity that's quite concerning. Now, whether we're going to see the same magnitude of changes in some of the drug metabolizing enzymes, difficult to say. But nevertheless, at least we have some idea as to which particular enzymes, at least the human analogs to be looking for.
Trevor: Don't thank you. That that's great. So, I think that leads us nicely into well, frankly, what a lot of people are wondering about. We have lots of people out there who are using CBD right now for, like you said, everything from childhood seizures to, you know, their sore arthritic knees. As health care professionals or as individual patients using it, what should we what should we do with this stuff coming out of this study? How do we extrapolate this out to somebody who's using it right now, rubbing it on their knee or giving it to their child with seizures? What should they watch for or think about or possibly talk about with their doctor, pharmacist or nurse?
Dr. Gurley: Yes. So there's another factor that we haven't talked about that I think is very important, and that's the quality of the CBD products that are on the market. And to be quite honest with you, the quality of the CBD products on the market is virtually unknowable. We just recently did a survey of various CBD oil products throughout the state of Mississippi. And only, less than 10 percent of the products actually had the quantity of CBD in the product that was claimed on the label. Now, from a safety perspective, the vast majority of those were much less than what was actually claimed on the label. So those are certainly much, much safer. However, there were several products that had one particular product, had 23 times the amount of CBD in the product that was claimed on the label. So, that particular product in itself would be setting an individual up for potential overdose, even if they if they took the recommended doses.
Trevor: Yeah, that's a scary, scary dose altogether, isn't it?
Dr. Gurley: Yeah. And then so another thing that was very disturbing that we found was a lot of products also were adulterated with synthetic cannabinoids, which are much more toxic than CBD or any other cannabinoids, for that matter. So that's that as a pharmacist and as a pharmaceutical scientist, that's very concerning to me. So you know what you're what you think you might be what you think you might be purchasing as a consumer might not necessarily be CBD. I mean, if you're going to spend 40 or 50 bucks for a vial of CBD oil, you'd hope to at least have some CBD oil in it. And what we're seeing right now is that's not always the case, and then in some situations, there's a dramatically, much higher than what you would anticipate. So it sets an individual up for potential overdose. And so you alluded earlier to potential drug interactions. And we've also finished a study looking at CBD and acetaminophen. So we can certainly talk about that and much more detail, if you like.
Trevor: Sure. Let's talk about that now, because you just did the study and B, I don't I can't think of any people I know who don't actually take some acetaminophen. So I guarantee there's some people out there who are taking CBD with their acetaminophen right now. What should we be aware of?
Dr. McGill: That's what we found in the study was pretty surprising actually. So for listeners who might not be aware of it, at least here in the U.S., acetaminophen is by far the most commonly used drug. There is about 25 billion doses sold every year. It's really, really ubiquitous. Most adults take it. At least a quarter of the population is taking it about at least once every week. So there's a really high potential when you start talking about drug drug interactions or herb drug interactions, acetaminophen is kind of number one, you know, start there. And so, as Dr. Gurley had mentioned, we saw a lot of induction of these CytochromeP450 enzymes. And so the mechanism of acetaminophen toxicity really depends on formation of a reactive metabolite that is generated by some of those drug metabolizing enzymes. So our initial hypothesis was you're going to see a lot more toxicity due to induction of metabolism. What we were really surprised. What we found is that, in fact, although the expression of a lot of those enzymes was increased, for some reason, the actual sort of end product. The Protein binding (?) depletion that occurs as a result of that reactive metabolite wasn't really different between the different doses of between of acetaminophen alone in the different doses of acetaminophen combined with CBD. But instead, what we saw was potentially a difference in signaling pathways that can lead to liver injury. So you start talking about molecular signaling pathways and there's one in particular. It's called this protein called the C-Jun N-terminal kinases or junk J&K.
Trevor: And what we that's a great name for an enzyme.
Dr. McGill: So what we saw was a little bit more what appeared to be a little bit more activation of Junk with at least the one of the doses of CBD combined with acetaminophen. So that kind of gets to a whole other point is that when you first talk about drug drug interactions or herb drug interactions, you start with metabolism. But then we forget to say, oh, it could also have an effect on these downstream signaling pathways that can also lead to two different drug drug interactions.
Trevor: So I guess that is fascinating. I was sure you were going to start talking about glutathione as well, because the way back from pharmacology, that's the part I remember in acetaminophen overdose. But I guess the question for somebody who's out there right now using acetaminophen and CBD is, should they stop? Should they space it? And we might not have an answer yet, but any sort of clinical Pearls we can give to somebody who might be using CBD and acetaminophen together right now because, again, maybe they have an arthritic knee.
Dr. McGill: Yeah. I mean, I guess my response to that would be all things in moderation. Right. So, the first principle of toxicology is dose makes the poison. So I'm sure you're very familiar with that as a pharmacist. So, my advice would be just use things wisely. Don't overdo it. And that pretty much goes for all drugs, not just acetaminophen or CBD, but pretty much everything.
Trevor: Thank you. I think that's that sound advice. So, if you guys were going to write a headline about your study that the public should take away sort of a summary, a headline, what would what would it be about what you found?
Dr. Gurley: Oh, well, what we found is that we're certainly deserves a lot more research and a lot more investigation. Granted, the original doses we started with were certainly up on the high end. And so now we're waiting to see whether or not going towards the lower end, particularly in combination with drugs like acetaminophen. You know, just where does that concern start to ebb? When does it start to diminish? Which is really what's really surprised me as a pharmacist is that there's been this explosion of CBD use products, whatever and to be quite honest with you, we know very little about the pharmacology of CBD in humans. So there's a lot of more research to be done. And we're hoping we're hoping that we can at least fill in some of those gaps.
Trevor: Thank you.
Dr. Koturbash: I would like to second on what Dr. Gurley said I think this would be also a message to at least responsible parts of the industry as they probably need to do some further research into the product that they are selling on the market.
Dr. McGill: And I would again I would third that, we need more research. But in addition to that, maybe it's probably time to start looking a little more into regulation of these products just because, as Dr. Gurley said, the amount in the product can be so variable. And, you know, another question being, is it appropriate for special populations like pregnant women, for example, things like that? We don't know anything about it.
Trevor: So you're about to hear a separate voice. This is Kirk Nyquist, my co-host and nurse. He had a couple of quick add on questions.
Kirk: I guess the question I have in your study. Was there anything about the entourage effect and the effect of THC working with CBD? I'm also curious about where you study took place and were there any roadblocks, federal, federal roadblocks or anything restrictions on you studying on cannabis product?
Dr. Gurley: Those are certainly good questions. We did have to get a Schedule One license from the DEA in order to work with CBD. We were also the product that we utilize is a well characterized cannabidiol containing cannabis extract that was fully characterized by the National Center for Natural Product Research at the University of Mississippi. And of course, you're probably familiar with the University of Mississippi is probably the preeminent marijuana research institution in the world, for that matter. So, the product was well characterized. It knew exactly what was in it, not only CBD, but there was a you know, there was some minor components of THC, fairly, fairly low. There were some other minor cannabinoids and other minor terpenes. But this is a product is very similar to a lot of CBD, cannabis, CBD containing cannabis extracts that are that are on the market.
Trevor: That is great. So, I think we are done picking your very smart brains. We appreciate you talking about the study. I think this solved a lot of things. And, yeah, keep up the good research. We need more information about this.
Dr. Gurley: One final thing, the purpose of the study was not to alarm everyone and cause everybody to go into a panic, but our approach was to take a very scientific approach to this and started, you know, and just kind of try to put some foundations to a lot of the hype that's out there associated with CBD. I think a lot of it is. I think CBD in many instances has been mischaracterized with regards to its potential efficacy and there's very little information out there about its safety. And that's where we come in.
Trevor: That there are a lot of words there.
Kirk: That was very dense. I think I'm going to have to listen to this episode twice.
Trevor: Yeah, no, me too. And I read the paper, but yeah. No, they. But what I really want people to get out of that is and I think it was Dr. Gurley said at the end, they're not anti CBD. No, they don't hate the stuff. They don't think it's going to blow up everyone's liver. They don't want it, you know, thrown off the market. But they just want people to use caution, which seems reasonable.
Kirk: It's a medicine. It's a medicine. Treat it as a medicine. If you are taking CBD products, treat it like a medicine. I love the fact that they discussed the quality of the product that they're getting. If you're buying your CBD from a gas station, you might be suspect on what you're buying.
Trevor: Well, I thought another you know, they might not realize it, but another plug for Canada is we got a whole lot of regulations. If you go through our legal system, you know, it's not perfect yet. But if you go through our legal system and get legal CBD, you've got a much better chance of having exactly what's labeled on the bottle with what you took home.
Kirk: I agree. I mean, I was thinking two years ago there in our small town, there is somebody who was out there selling CBD products. And I mean, you and I were going, where did they get the license to do that? And what how is that happening? And I guess with the regulations, Prohibition 2.0, at least we do know or if you're buying it from a licensed producer, you do know what you're getting.
Trevor: Yeah, and I think that at that sorry is a huge advantage to buying legal cannabis products in Canada.
Kirk: That was a that was a cool scientific episode. I like that one.
Trevor: Yeah. Dense have another. Listen, because I know I need to listen to one more time.
Kirk: We should talk about our sponsor.
Trevor: Strainprint. They're everywhere and are fantastic. Even when we are in Saskatoon. Are two on stage guests where Strainprint users and promoters.
Kirk: As we are.
Trevor: As we are. So yeah. Strainprint. If you haven't heard us say this before, think about it like a diabetic log for your cannabis. Especially early in your disease is what came up a lot at Hempfest is when you're still trying to figure out how cannabis is working with your condition; having a log is fantastic.
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Trevor: Kirk do to have any music today.
Kirk: I really am enjoying the fact that Rene, our producer, is bringing music to us and bringing in another voice. Maybe we'll just challenge Rene, bring some music.
Trevor: Rene we got lazy.
Rene: Well it's OK to be lazy sometimes. That was another good one. Yeah. I enjoy coming up with some of the music for the end of the podcast and we try to keep it local of course, and we are out of Dauphin. And today I've got a cut by a guy named Jimmy Z. He's from Gilbert Plains, Manitoba. That's just down the road down highway number five from Dauphin. The song is Drinking All Night Long, Jimmy Z. Keeping It Local on Reefer Medness.