CBD Safety Essentials: What Healthcare Providers Need to Know
Welcome, everyone. We’ve got some people coming in. We’re just going to wait a moment or two to give everyone some time to dial in, and then we’ll get started! Thanks so much for being here.
For anyone who cares to share, if you wanna put in the chat, let us know where you’re from, what your profession, what’s your interest level in this. We’d love to hear from you and see who’s joining us. Someone raised their hand. What does that mean? Sorry, we haven’t done the raised hand thing before. Cape Cod. Nutrition, awesome. With Sombra. Holistic health, RN, awesome! So you’ll have a good pharmacology background. Let’s see, licensed massage therapist. “Oh, I didn’t mean to raise the hand.” Physician, Qigong practitioner, lots of massage, MD. No, Baltimore, MD. Acupuncturist.
– Reiki, love it.
– Yeah. Physical therapy, very cool.
– Dental hygienist, love it.
– We’ve got a really broad range here.
– Naturopath, yeah, this is great.
– Ooh, naturopath, woohoo!
Ontario naturopaths have a heck of a time with their regulatory licensing boards. They really have a lot of challenges. So, we feel for you. They actually can’t even prescribe CBD.
Isn’t that odd? RN in Florida. Great, I’m in Florida too. So we have a lot of people who are non-prescribers, and that’s okay. We’re going to try to break it down and keep it simple today. I’m a naturopath, and I barely remember my pharmacology classes from 20 years ago, so we’re going to try to keep it real basic and start from the beginning. Somebody has, “A chiropractor, a physical therapist, “a massage therapist, and acupuncturist, and nutritionist.” There’s everything you need.
We have an oncology massage therapist, very interested in that. Oncology is my area, so very interested in the work that you do, Laurel. Interesting.
– Yeah, that sounds like a field.
Well, we’ve got a good quorum here, so I think we can go ahead and get started. But thank you everyone so much for attending this CBD CLINIC and Charlotte’s Web webinar. My name is Amanda McConnell. I’ll be here on the backend, just helping to facilitate and make sure everything is going smoothly on the technical side. Today I’m joined by Brian Grosso. He is one of our sales representatives for CBD CLINIC and Charlotte’s Web, so you have him to answer any and all questions in regards to sales. Then our presenters this afternoon are Dr. Jen Palmer and Dr. Jeff Lombardo. I’m very excited to welcome Dr. Jen and Dr. Jeff here with us today.
– [Jen] Thank you, Amanda.
– [Amanda] Oh, and I forgot to mention, so sorry, Jen, to interrupt. If you have any questions throughout the presentation, please feel free to drop them in the Q&A section on the bottom. We’ll be answering questions as we can throughout the presentation, as well as answering a bunch of your questions live at the end. So, don’t forget to drop questions there! Thanks so much!
– [Jen] Thank you, everybody. Just give me one second here to make all the buttons work properly. All right, Amanda, how does that look for you?
– [Amanda] Looks great.
– [Jen] Okay, and I have little cardinals visiting my window right now to say good job. Okay, so today we’re going to be talking about CBD essentials and what you as healthcare providers need to know, especially knowing that you’re not pharmacists, you may not be prescribing physicians, but you still are concerned about CBD interacting with potential medications that your patients or clients might be using. So I’m Dr. Jen Palmer. I’m a naturopathic doctor, and I am the Education Director for Charlotte’s Web. And today, we have our guest host is Jeff Lombardo, who is a pharmacist from the UB School of Pharmacy and Pharmaceutical Sciences. He also is with the UB Center for Integrated Global Biomedical Sciences, and he has a very extensive resume. I’m going to let him share a little bit more about himself before he gets started, which will be the second half of this presentation. So today, what we’re going to be talking about is, I’m going to give a little refresher over some basic pharmacology concepts, which we all could use, unless we’re doing this every day. My goal is to really give healthcare providers some basic tools that are required so you can effectively assess the potential for a drug interaction or know when to be concerned and know when you have to do more research and try to just give you a general understanding of common but some mild adverse effects that might happen with CBD. So I’m going to also share some published safety studies, and then Jeff is going to share with you some real-life data collected by our company on some adverse events over an 18-month period from our CBD consumers, and then he’s going to also share some insights on a liver toxicity study that we did with a company called Valid Care. So lots of good, practical real-life information here, not just theoretical. So again, as many of us are non-prescribers, it would be just good to do some basic refreshers on some terminology. So pharmacokinetics, that’s explaining how drug interactions can alter the serum levels of a particular drug, drug interactions meaning also drug-nutrient or drug-supplement interactions. Pharmacodynamics, that’s going to explain how the drug’s mechanism of action can be altered by another drug or compound, and in some cases, you’ll find it enhances the drug efficacy, and sometimes it suppresses. So that’s why you need to understand how to evaluate this. Now, you’re going to be more likely to see or be concerned about interactions when two substances are sharing the same pathways for absorption or distribution or mechanism or excretion, and because CBD is metabolized by the liver, there is potential that it could interact with medications based on whatever enzymes are involved with the two compounds. So these are just some basic factors to consider or think about. It’s not always, this drug does this, and you always have to quit one or the other. I mean, there’s a lot of complicating variables of how they might interact. So think about metabolic interactions. This is when one drug can affect the metabolism of the other drug, and it can affect that in different ways. It could actually prolong the activity of the drug. It may reduce the activity of the drug. It may change the intensity. It may even change the actual side effects of that drug. Then there’s drug distribution. That’s how a drug can change how a second drug or compound is absorbed or distributed throughout the body. Then this convergent pathways is when two drugs or two compounds are being metabolized through the same pathways, and that can cause antagonistic effects, where they cancel each other out, or it could cause a synergistic effect and make it feel like you have more of each. So in order to be able to predict any kind of convergent drug interactions, especially with CBD, you really need to have them both be well-researched and understand how they work. Fortunately, most pharmaceutical medications have that kind of information available, so you’re able to research that if you’re not familiar with them. There’s a great downloadable e-book that I found on projectcbd.org. That’s in the link there on the bottom, and we can share that link with you if you’re interested. It’s a really good overview of how to look at drug interactions and how CBD works. I just find it to be a really easy manual to have on hand to get some basic information, and it’s a freebie that you can download. So we can share that resource with you, if you’d like. So a little refresher, cytochrome P450 metabolizing enzymes. So these are the enzymes that are in our liver. They’re used for phase one detoxification. They’re not just in the liver. They’re in other organs as well. But there’s dozens of different kinds of CYP enzyme subfamilies. So that’s why this can be a very complex subject. So typically, these CYP enzymes are metabolizing toxins that you’re exposed to, medications, hormones, and of course nutrients, foods. Lots of herbs are metabolized via these CYP enzymes. So there’s always potential for any of those things to interact with each other when they’re taken together. So when you’re talking about inducers of the CYP enzymes, that means it’s speeding up the enzyme action, and then if you’re talking about an inhibitor, it’s slowing down the enzyme action. So what that’s going to do is really prolong the drug’s mechanism, and then you’re going to have an increased risk of toxicity. One good example that we are all familiar with is grapefruits. So grapefruit juice has flavonol in that, and that’s a compound which is known to inhibit CYP enzymes. So if it’s being taken with certain medications that are using the same CYP enzymes, it can actually prolong the drug’s metabolism, so it has a longer half life. If you’re interested in refreshing yourself further on CYP enzymes, there’s actually a sort of fun video out there on the YouTube, and somebody kind of goes through and explains the CYP enzymes in a more fun way, but there is a little bit of swearing at the end, so if you’re sensitive to that, you might wanna avoid it. But it is a great short of a refresher course, if you’d like to learn that one. So let’s talk about CBD pharmacokinetics. So, I just wanted to share just a few little tidbits about CBD that will help inform you whenever you’re trying to decide if CBD is right for your patient, especially if they’re using medication, and also kind of give you a little bit of understanding of how it works and how to use it. So, the CBD pharmacokinetics, they really are variable depending on a lot of different factors. That’s why, when we always make the recommendation about dosing, we say start low and go slow and increase it, because everybody has their own correct dosing. That’s because there’s all these different factors that can be part of that. So the CBD delivery form certainly impacts that, whether you’re doing it orally, inhaled, topically. It all affects the pharmacokinetics. Then also the person’s individual genetics, their metabolism, their body weight. All these things will impact how they deal with CBD. I know people that have very high tolerance to it and they take very high doses. I know people that are ultra-sensitive and five or seven milligrams of CBD is all they can handle, and that’s because there’s just all these different variables that affect it. The half life of CBD, that is also variable based on different factors. So the amount you take and how long you’ve been taking it can affect the half life. For example, a 20-milligram dose orally will have a half life of about two hours, but if you’ve been taking CBD for a long periods of time, that half life could be much longer. If you’re using CBD inhaled, it’s going to have a really quick initial onset, but it has a much shorter half life, so it doesn’t act for as long in the body. So both of those factors and helping determine how you would want to dose and what delivery system you’d wanna use for the CBD. Something that’s really important to know is that CBD is highly lipophilic. So it’s fat-loving, and therefore, it’s not on its own really bioavailable, but it’s very helpful to take fatty foods with that. In fact, one study showed that eating a fat-rich diet with the CBD can increase it by four to 10 times for the absorption. And so, because of that, in our opinion, the nanotechnology is really not required, because you’re going to get the same results just by taking fatty foods with it. We don’t know enough about the nanotechnology effects, the long-term effects. You know, those water-soluble or Liposphere products, we don’t know enough about the effects of those, so we haven’t really dug into those as far as Charlotte’s Web products are concerned. And it’s good to know CBD, it’s fat-loving, and it accumulates in our fat tissue if we’re taking it for long periods. So if a patient loses a lot of weight after taking a lot of CBD, they might experience that persistent activity as the fat cells are breaking down. The major metabolite of CBD is 7-hydroxy cannabidiol, but then it gets metabolized into as many as 100 different metabolites. So we have to think about how CBD itself is being broken down with the CYP enzymes, but then we have to factor in what’s happening with all these metabolites. And right now, we don’t have all that information. As you can tell, it’s pretty complex. So there’s still a lot we have to learn on that fact. It’s very important to know if you’re using CBD topically, that is not absorbed systemically. CBD on its own with just normal topical application doesn’t go past the subcutaneous layer, and it doesn’t get absorbed into the bloodstream. There are transdermal topicals, THC and CBD, and those are made so that they do drive in deeper and they do get into circulation, but normally, a regular topical is only working exactly where it was applied, and you’re not going to worry about drug interactions from that. So CBD, like I said, does have the potential to interact with prescription drugs that may or may not have clinical consequences. Sometimes, theoretically, there’s an interaction, but it doesn’t really show up in the patient. But drugs that have a very narrow therapeutic window are definitely going to be a risk factor. So thinking Warfarin and benzodiazepines, those are drugs that will interact with CBD and can have serious consequences. So those, you really want to do the math on. So much of the pharmacokinetic data that we have about CBD is based on the drug Epidiolex, which is an approved FDA drug for seizures, and it’s different, because it’s a CBD isolate, and it’s given in much higher doses than a full-spectrum hemp extract. In fact, it’s about 10x more than you would take in a full-spectrum version. So obviously, the pharmacodynamics are going to be very different. So we don’t have as much data on the full-spectrum hemp extract, especially at those lower levels, so we still have a lot to learn on that. But I do know that Jeff is somebody who is working on that kind of research. The drug interactions can be very variable. In some cases, the CBD increases the drug metabolism. In some cases, it decreases it, and then sometimes, vice versa. The drug affects the CBD mechanism. Just because you see that there’s going to be a drug interaction doesn’t mean that the patient can’t take both things. It simply means that you have to manage the dosing and put some more thought into it so that you can continue to use both drugs. Sometimes it means lowering the drug dosage or raising it, but there are ways to do both simultaneously, even though there’s some known interaction there. So that’s the good news. If you have some kind of liver disease, or the liver isn’t functioning properly, that of course can alter CBD metabolism, and then the CYP enzymes we know are primarily used for CBD mechanism are the CYP3A4, the 2C9, and the C19. So the goal here is to understand what enzymes are breaking down the pharmaceutical drug and then determine if there’s some overlap with the cannabinoids, and then figure out if you need to be concerned about that and how you can adjust each one. And so my last slide, there are several review studies that were published about CBD safety research, and those were published in 2011 and 2017, and they compiled everything that existed at that time, and both of them found that CBD was safe at doses up to 1500 milligrams per day, which, by the way, is the amount that is given in the drug format of the isolate. So that was well-tolerated in humans and did not cause serious side effects, was the conclusion of both of those reviews. Some of the minor adverse events that people may experience with CBD could be sedation, some drowsiness, especially of it’s combined with other sedative compounds like alcohol or medications. Also, it could cause irritability, and there’s some potential for fertility issues that have been kind of out there that are still being explored, so they’re doing more research on that as well. There was a study published by another CBD manufacturer on their adverse events reporting, and theirs covered a two-year period. In that period, they determined there was only two incidents that were categorized as serious adverse events, and then there’s just a lot of minor adverse events such as gastrointestinal discomfort, which is definitely what we found from our own data as well. Jeff is going to be talking a little bit more about our own adverse event reporting and our paper that we are going to be published later in the future, near future. So some compounding factors to consider, full-spectrum hemp extracts, these have a lot of other cannabinoids in there. They’re not just CBD. So we still have a lot to learn about the metabolism of all the other cannabinoids and at what levels do we have to be concerned about with that, and then cannabinoid metabolites, like I mentioned, those may have some kind of interactions. So obviously, it’s not a super-straightforward concept, but you just have to be really aware of how the mechanisms work, and also just be a little bit assured of the fact that we do have a lot of real-life data that’s shown that pretty much, these seem to be pretty safe. We know that a lot of people have been taking medications with these and not experiencing any serious adverse effects. So nothing to be really scared about based on just real-life data. So Jeff is going to jump in and share some more research information with you.
– Thank you, Jen. Good afternoon, everyone. As Jen had mentioned, I’m an oncology pharmacist by training, UB School of Pharmacy, and we have a drug development wing at the University where we’ve been doing a lot of work in the cannabinoid space for about five or six years. What I wanna share with you today, and I’m going to reinforce a lot of the good points that Jen has mentioned about potential interactions that could occur, theoretical drug interactions, and go over some of the data from our liver toxicity study that we just completed. So this was a study about a year to take that really answered some of the questions about the safety. So why was there so much noise or chatter about safety? A lot of it comes with kind of some of the FDA guidance and some of the positions. So this is an excerpt from the FDA website if you go on there, what do you need to know about cannabis products or CBD in particular, which we’re going to focus on today? There are some questions that are out there in the scientific community about safety and efficacy, number two, but they have a statement here at the bottom that the FDA really only has limited data on the safety of these products in the marketplace. As we know in the marketplace, it has expanded over the years, and easier for the consumers to get direct-to-consumer in some of the stores. So we worked with the FDA to design this study looking at 12 companies that use various products in the marketplace. But a little background information, Jen alluded to the point, this idea of liver toxicity curries some problems that can occur. So this is a landmark study that’s really from the Epidiolex Devinsky trial from the New England Journal of Medicine, which led to the approval of Epidiolex. The primary outcome, just to refresh everyone, you know, what they studied was seizure reductions, and they compared it versus placebo, and we notice that patients received Epidiolex, their monthly amount of seizures decreased from 14.1 to 5.7 in the treatment period. That was statistically significant, and led to the FDA approval of this product, of Epidiolex. Currently, there’s three approvals for it, with Lennox-Gastaut, Dravet syndrome, and TSC, and what it is, as Jen mentioned, is really a single isolate, high concentration of CBD-only product. It’s the only FDA approved product on the market right now to handle or to treat these three types of indications. Now, with any drug, when it goes into development, first thing we need to look at is safety, and we look at efficacy next. But if we look at the cell, and Jen had mentioned at higher doses, there is a little bit of concern about potential liver toxicity.
– Jeff, could you share slides?
– Oh, I’m so sorry, you cannot see my slides.
– We can’t see them, yeah, and you don’t know that. There we go.
– [Jeff] So you have not been able to see my slides.
– [Jen] There we go, perfect. I thought you were winging it.
– [Jeff] No, let’s go back, and I apologize to the group here. So lemme recap real quickly through these slides. So this was the FDA warning letter, or kinda that you go on their website that states that CBD is a problem, and we have limited safety data, and the need for more data of CBD in the marketplace. This was an example, the excerpt in the New England Journal of Medicine article, Devinsky, which led to this kinda primary method of primary endpoint that led to the FDA approval, and as you see, the reduction in seizures per month was clinically statistically significant. This is Epidiolex if you were going to a pharmacy and you picked it up, or a specialty pharmacy had it mailed to you. This is how it comes, single isolate and three indications. And I think this is where Jen appropriately let me know that I was not sharing my slides. But when you look at the drug in the marketplace, or in a clinical study, you wanna match up the efficacy, but also the toxicity profile. Okay, so some things that kind of stand out here, when I look at toxicity, I tend to focus in on percentages. Anything greater than 10, 15 percent above the placebo, I start to consider that this is somewhat significant and could be burdensome to the patient. A benefit analysis needs to be done, but you see that some diarrhea and fatigue and decreased appetite could occur at some of the higher doses that were seen in this clinical trial. This is, if you go to Epidiolex for Healthcare Practitioners on their website, there is this issue about hepatotoxicity or hepatocellular injury. There is a warning that Epidiolex or CBD products can cause this dose-related transaminase elevation. Now, what transaminases are are cells in the liver, and when you have acute injury, you will see an increase in the lab reading above baseline. So your normal range might be between 15 or 40, and if you take a drug or another type of compound, if you tend to insult or have injury to the liver, those hepatocytes or those cells will break open, and you’ll see an increase or an elevation in your blood. And that’s exactly what we did in the study. And this was the first time really showing this data. So this group is kinda the first to see a little bit of it. We submitted it to publication, and we’ve had one meeting with the FDA already to discuss our results, but it was an observatory trial. Here was the investigators: Dr. Kaufmann, Dr. Aqua, myself. Dr. Kaufmann was our medical director. Dr. Aqua was our lead PI in the study, and Dr. Lee was our statistician. And why did we do this? If these products were in the marketplace, and there was this perception that CBD products, whether they’re full-spectrum, broad-spectrum, or single isolate, can cause liver abnormalities or potential toxicity. So our objective was to determine, if patients were taking these products, if they had elevation. So this was real-world evidence, and in order to qualify for this study, they had to be on a product for at least 30 days and be on a product for an additional 30 days. At the end of time, we did some blood work to see what was going on. We picked a point of statistical significance, which was about two percent above what we thought would be normal, so we set that at 4.5. Once again, this was an observatory trial. We opened up to many distributors of manufacturers of these products that are in the marketplace. I mentioned at the end of 30 days, we looked at ALT, AST, alkaline phosphatase, which is kind of a non-specific indicator of liver injury, and bilirubin, which is another sign of liver toxicity evaluation. When that goes up, you can potentially have a problem long-term when you start seeing some type of obstruction from some potential injury. So in the study, who qualified? So patients had to be greater than 18 years of age. We mentioned that patients had to be taking for a minimum of 30 days. Then they had to take it for another 30 days and their journal that had that information. Then they were willing to have some blood work done. Now, initially, when we enrolled, we had some inclusion criteria/exclusion criteria here, which is very similar to some of the things that Jen talked about as potential problems when patients take CBD along with certain prescription medications that have drug interactions through the metabolic pathway. Now, I can tell you in this study, we screened about 20,000 individuals, and in that screening, we obtained a host of data, and we have a follow-up study that’s ongoing right now to answer some of the questions that came out of the findings I’m just going to show you. It also came out of a meeting that we had with the FDA as far as some follow-up. But in the results, the majority of individuals were taking products for six months, 12 months, or longer. So this was a little bit more the exception to the rule of patients, how long they were taking product. So, frequently asked questions. Once again, why did we do this study? The FDA needed data. These products are in the marketplace, and number one, when you’re taking a product, what we need to understand is, are they safe? So there’s real concern, and I know that the FDA and some regulatory bodies have concerns about certain patient populations and certain drug combinations. Just to remind everyone, Jen mentioned a comment about individuals who are talking Warfarin. Warfarin’s a medication that you take if you have a blood clot or atrial fibrillation, and you need to maintain that blood level between two and thee, which is, or 2.5, 3.5, which is therapeutic based on your indication. Now, there are some reports that patients, when they start CBD products, their INR elevation can go very high, and that’s susceptible to a bleed. So it’s not a contraindication at this point, but what it means is you really need to have a plan put in place to say, “Okay, “if you’re going to start a combination of certain drugs, “what type of monitoring plan do I need to do? “Do I need to increase that? “How vigilant do I need to be to see “if these theoretical drug interactions do occur?” And why is it important to the CBD industry? Well, the companies that I’ll show you in the next slide, I believe, that participated, they’re really buying in and going to find science and data to prove that these products are not only efficacious, but they’re safe. So I’m going to show you some of the data. These are the 12 studies, excuse me, these 12 companies that participated in this study. There was a range of products that we used within these companies, and I’ll show you a chart how they were broken down. Okay, so once again, this is the first time you’re seeing, we’re really showing you any of this data. We submitted it to publication. But out of the 1450 individuals that started the study, you know, once again, this is right during COVID. At the end of the study, once again, after 30 day, where patients had to be on a product for at least a minimum of 30 days, 839 of them were able to go get some blood work done. Some of the patients didn’t wanna leave their homes, and hence the kind of follow-up study that we’re doing now because of COVID. But if you look and see, we have a breakdown of products. 467 of the individuals had a full-spectrum hemp product, had a CBD isolate, or broad spectrum, a majority of isolate or full spectrum. And here we have some of the ranges of the average daily dose that you see below. Before we get to that, what are some of the products that they used? It was a combination of tinctures, it was a combination of capsules, edibles, some of the nanotechnologies that are out there. We have a breakdown. Then we have the average daily dose that they were taking, in a range. When I look at these doses, they’re varied. I mean, the literature, you can see that patients, where it’s reported that an average daily dose of a full-spectrum may be 60 to 120 milligrams a day. Some were taking higher; some were taking lower. But we gather a lot of information around dose. Now we get into what we call the money slides, which was basically, what did we find? Was there elevations of these early indicators of liver injury, once again, the hepatocytes, these transaminases that we look at? We look at AST and ALT. Okay, here we have a breakdown. ALT was more of a non-specific, excuse me, ALP is more of a, alkaline phosphatate is a non-specific marker, but we see in the incidents of approximately 10%, five percent, and those two were statistically significant. The other were not, an increase of only 14 individuals or bilirubin of 1.7. So when I see some type of elevation as a pharmacist or you as a clinician, you wanna look at severity, and that may statistically be significant, but is it clinically, right? Does it really matter? So I like to grade things as far as validated scale of how many percentages or how many times, which is called upper-level normal. So the upper level of your normal range, okay, is it one time greater? Is it two time greater? Is it three times greater? I start to get a little maybe nervous or cautious when these things start moving into the greater than three times upper level normal. So let’s look back at the data of the individuals. Once again, we have 800-plus individuals of the LLT elevation of the 76, a 9.4%, but as we increase the significance of two times greater upper-level normal, you see the number drops considerably, and if we see that greater than three times the upper level normal, we only had three individuals report it. In drug dosing, if a patient came into clinic and had their blood work done and they started either prescription medication, herbal supplement, or dietary supplement, three to five times upper level normal might be the time where we say, “Okay, let’s stop. “Let’s give things a rest, “and let’s see if the blood work goes back down to normal “when we discontinue the medication.” Once again, these individuals were taking it for at least 60 days minimum, some for over a year, and this is what we saw in the blood work. So kind of a breakdown once again, just another way of looking at the data, full-spectrum, broad spectrum, and isolate. Once again, greater than one, two, three percent, this is where I would focus in on, is this three percent upper level normal. We see the numbers of patients are very low, and the percentages is very low as well. Now here, in this study, we gave the companies their unblinded data, but we blinded them to the whole cohort. So once again, 13 brands, one additional at the end, but you’ll see the prevalence range from 13.3% to down to as low as six percent of the individuals that accrued in their arm for the study. Once again, kind of rule of thumb, when I start seeing toxicities in the double digits, 10, 15%, I tend to start to investigate things and be a little more concerned. So let’s go back to Epidiolex and their website of healthcare practitioners. Once again, the reason why we did most of these studies, and we’ll go through some of the findings before kind of drawing some of these concLusions to kinda reinforce some of the things that Jen had said, that there are certain drug combinations that can increase elevations in these transaminases. In the data that I showed you initially with some of those patients that were greater than 10%, that in fact was the case. We saw drug interactions where patients were not just taking CBD alone, but they were taking a combination of five or six or seven medications all together. So in a coming slide, is it CBD that’s causing the problem, or is it the combination of medications together that can be causing the effect? That actually might be the case. And when you discontinue the products, as stated in the package insert with Epidiolex, once again, that the only FDA approve, so that’s the only one that is really going to have kind of a medical document posted to give some type of guidance, resolution of, if you do have an elevation of transaminases, discontinuing the product should go back down to baseline. I can tell you that we’re actually doing that in cohort number two, the study that’s ongoing now, to see if that truly is the case. Once again, we had some issues with COVID, and now that luckily we have that under control, we’re following up with that study to confirm some of those findings. Jen had mentioned about considering dose reductions or discontinuations. A lot of these things are theoretical on paper, per theory. If they go through the same metabolic pathway, these drug interactions can occur. Have a plan in place. It’s not a contraindication, but consider it. But I can tell you in the case of clobazam with CBD, it’s a medication used for seizures, that definitely is the case. So if you have a patient, and we found it in another study that when these two medications were given together, you really had to do a 50% dose reduction up front of the medication. So, a little bit of conclusions about this study, the investigators, that data shows that the use of self-medication in these individuals are safe, and the rate of LFT elevation was similar in the patient population to having multiple medical conditions. We talked about, they’re on other medications as well, but we looked at comorbidities, whether it’s hypertension, had some type of mild liver dysfunction, renal impairment, we saw some of that as well. So the combination of those disease states possibly could be elevating. So once again, it was statistically significant in those two groups. Clinically, we felt that it was not clinically significant. There was an incidence of higher elevation; however, we did not feel that was significant, and liver failure was not present in any of the individuals. So that’s an important point, right, ’cause the acute early injury that you may see are these transaminases. They’re signs, but if that’s not attended or corrected, what can happen is you could have some obstruction in the liver, which causes your bilirubin to go up. That’s usually a problem, but we did not see any of that case, and it really kinda is that marker or clinical finding that was negative in this trial was good to see. So the last thing I’m going to show you, Jen had mentioned that CW had put together a safety paper that was submitted for publication. The company has, a part of their customer service, any adverse event or any call that’s reported in has a protocol and defers that to healthcare practitioners to assess that, see what type of category that falls into and give recommendations. But these are some of the numbers that were published over an 18-month period, looking at the number of units sold, the number of servings sold. Looking at all that were deemed significant, only 431. If you look at a percentage, 0.022, and broken also down by servings sold. So once again, you’re always going to have those outliers. There’s possibilities, but the side effect profile was very low, adverse event reporting was very small, and you’ll see more details in that publication. It breaks it down per organ system and goes through the whole policy on how they do that.