Good afternoon, everyone. Welcome to today's AOIM webinar on Kratom Consumers in the United States, What Clinicians Need to Know. My name is Julie Kimmick, and I'm going to be your moderator for this session. Today we have Dr. Kirsten Smith speaking on Kratom. We're very grateful to have her here today, fresh off her trip to Malaysia and Indonesia. She just got back Monday and is still a little bit jet-lagged, so I'm glad that she was able to make it. Dr. Smith is an assistant professor in behavioral pharmacology and research unit within the Department of Psychiatry and Behavioral Sciences in the Johns Hopkins University School of Medicine. After earning her master's in social work from the University of Kentucky and PhD from the University of Louisville, Dr. Smith completed a four-year postdoctoral fellowship at NIDA, an intramural research program working on translational addiction medicine branch. Dr. Smith completed her NIDA K99-funded project that involved a national ecological momentary assessment of daily Kratom use and a controlled drug administration sub-study that investigated the acute effects of commercial Kratom products. Her NIDA ROO-funded study at Hopkins will further examine the pharmacokinetics and pharmacodynamics of Kratom and will assess Kratom withdrawal. Dr. Smith plans to continue her Kratom research next by investigating the safety, tolerability, and human abuse potential of Kratom in healthy adults using both standardized and whole-leaf formulations and isolated alkaloids. So thank you so much for being here today, and I'm going to turn it over to Dr. Smith. Sorry, so happy to be here. So can we see the, we can see this all right. Um, yeah, so I am a little jot lagged, but I'm gonna, I'm gonna put on a good show for you, I promise. So we are going to talk about all things Kratom, and in particular what clinicians need to know. I believe that's already been discussed. I am NIDA funded, I do some consulting for the International Plan for Herbal Alliance, and then I serve as an expert witness in legal cases involving Kratom. So what is Kratom? So I really want to emphasize, and while I have you fresh in the audience, that when we talk about Kratom, we're really talking about many different things. And so I'm going to kind of unpack what, what is Kratom, because we say it, and I think we assume it's more homogenous than it actually is. So this is what the native leaf looks like. It's indigenous to Malaysia and Thailand, and now being grown as a cash crop in Indonesia, and exported from Indonesia quite increasingly. And just a little bit of chemistry, like I am not a chemist, but I do think it's important to cover this because it really is a complex botanical and the products that are derived from it, which I'll talk about in a minute, are also very complex. And so if you Google Kratom, the first thing that kind of pops up is opioid, right? And that is kind of true, but not completely. And it's, I think, very important for clinicians to understand at least some of the basics of Kratom pharmacology, because although there is opioid activity, it is not at all an opioid full stop. There is, in its major alkaloid, mitragynine, which accounts for the majority of the chemical content of Kratom leaves, which is, I should say, a very small part of the overall leaf. It's about 2% of the total leaf weight. And that's going to be important when we talk about effects. So it's the major alkaloid, mitragynine. It is a partial agonist that mute opioid receptors, but it also has alpha endergic and serotonergic activity, some adenosinergic activity in vitro, which is what caffeine involves, like caffeine, basically. And I should note, Kratom is in the coffee family. So 7-hydroxymitragynine, this is the other best studied chemical constituent of Kratom. We used to think that it was an alkaloid that was found in the leaf material, but what we really have come to learn now is that it's actually more of a byproduct that comes about after the leaves have been harvested, and it's below the level of quantification in most leaves. It really should be considered as an active metabolite of mitragynine. So after someone takes Kratom with mitragynine in it, it is converted by the body into 7-hydroxymitragynine. And this is important because it is a more selective agonist. It mutes opioid receptors, 14 to 22 times more potent than morphine. That doesn't mean it's comparable to morphine exactly. Again, that's from just in vitro binding studies. So we don't have any clinical trials that have compared the abuse potential of this to anything else. But again, in preclinical work, we do see that there is more rewarding effects from 7-hydroxymitragynine compared to its parent, alkaloid mitragynine. So the takeaway from that is mitragynine, the major alkaloid of Kratom, is very promiscuous and it acts on many different systems in the human body. This one metabolite is a more selective mute opioid receptor. It's a partial agonist, I should note as well. A few minor alkaloids I'm going to talk about, again, because I think it's helpful to understand the product. So we have speciocialatine, which is another selective mute opioid receptor agonist. Speciogynine, which actually has serotonin activity, a little bit of mute opioid receptor activity. Penanthine, which really has a lot of alpha-endronergic activity. And then coronanthinine, which has some mute opioid receptor antagonism, and then also some alpha-endronergic activity. And so again, these are just a few of the minor alkaloids. I'm not going to go further, but I want to really underscore that when we talk about Kratom as the botanical, it really is what my colleague at the University of Florida, Chris McCurdy, he likes to call this kind of complex symphony orchestra. And that really is the case. It is a very odd botanical and it's really hard to put it in a box. And that is important when we get to diagnosing disorders or pathologies related to it. Then we have not just the leaf, but we have all of these products that have been put into commerce in the United States. We have Kratom bars that have opened up in, I think, 28 states now that are serving kind of these like juice preparations. But then really we have a variety of products that are much different than the leaf material, and so a minute ago I said the leaf material contains about 2% of the total weight comprised of alkaloids. So that means that the whole plant material, you would have to eat a lot of it in order to keep escalating your attempt to get more and more of an effect. And what we know is that there's kind of a ceiling to how much plant material people can ingest. And so these products can bypass that natural barrier to ingesting more and more and more of the alkaloids. So these products include concentrated extracts or even just the plant material in dried form, which by and large really does have a similar ratio to the fresh leaves. It's just in a dried format. I say all this to, I think, underscore the fact that as clinicians, it's increasingly important if someone is appearing and reporting Kratom use that we ask what kind of Kratom, because clearly these are very different and they're very different than just the raw leaf material, which again can't be grown in the United States due to the tropical climate that's needed. So a very important point and takeaway is just what type of Kratom is someone using. This is even more important now. So in the past year, this is kind of like late breaking. We have now seen products that are essentially what I would not and what my colleagues would not consider to even be Kratom anymore. There's kind of this like big umbrella. Again, when we talk about Kratom, kind of like cannabis, right? So you could say with cannabis, you have hemp, you have CBD, you have cannabis with different levels of THC, and then you have something like synthetic cannabinoids, right? Those synthetic cannabinoids are very, very, very different than CBD or even cannabis. So what we have seen this past year are the production of these 7-hydroxymitragynine products. And going back to what I described earlier in terms of the pharmacology, these are, first of all, not naturally occurring in the Kratom leaf material. So clearly, they're a semi-synthetic version of this metabolite. And because it has mu-opiate receptor activity, and really that's it. I think it's now we have crossed this kind of line from, okay, this was Kratom. Now these particular products, I would consider personally to be more just an opioid, right? Maybe not a classical opioid, but nonetheless, a de facto opioid. And again, like if you know to ask about the distinction, then you might even say this is like opioid use disorder, whereas before we might say this is Kratom use disorder. When we start getting into diagnostic and assessment methods for this, which I'll talk about in a little bit. So is Kratom legal in the United States? Basically, yes. It's not scheduled by the Drug Enforcement Administration and the Food and Drug Administration considers it to be an unregulated and unapproved new dietary ingredient or illicitly marketed new dietary ingredient and does not consider it to be determined as safe for food or as a drug or as a dietary supplement. So it really is sold, Kratom is sold as a dietary supplement in this kind of gray market space that's not really regulated. What regulation has occurred has really been industry driven. So industry lobbyists, but also advocates and some kind of combination of attempting to put in state level regulations typically in the form of the Kratom Consumer Protection Act. They vary from state to state, but if you see here, all of the states in blue have passed some form of the Kratom Consumer Protection Act. And then we have some states where it's not illegal, but there are some local bans. And this is very dynamic. This is changing and will continue to change. Likely over the next few years, there is a federal version of this, which I'm going to be at a congressional briefing later this month to discuss. So the policy on Kratom is very dynamic and very confusing. So to illustrate part of the confusion, even going to like trusted places, like going to the FDA website to their page on Kratom or going to the National Institute on Drug Abuse webpage on Kratom, they're very different looking. And I come having been at NIDA for four years. I was around when the webpage was being developed. And I have to say it's pretty comprehensive. I would encourage anyone who is looking for information about Kratom to really go to the NIDA webpage because it has a lot more content and it has like citations that are updated regularly. The FDA page is much shorter and it has a different tenor. So I think the one thing I'll note too is that the FDA has recently completed a single ascending dose safety tolerability study for Kratom whole leaf. They got up to 12 grams of whole leaf material that was administered to healthy volunteers and did not have adverse events. So those data are not published. They've been publicly presented and they hopefully will be published. I would not guess before early next year, but they are moving forward with a human abuse potential study. So FDA has established some safety, at least up to 12 grams. But again, their orientation to this is very different than the NIDA's and for good reasons, because they kind of are tasked with the dietary supplement world, so to speak. So Kratom in the United States really began to be noticed around 2007. And it was among people who were using opioids or who had chronic pain or a combination of both. And since that time, we've seen many other people use for a variety of reasons, which I'll talk about, but it really did start with this kind of self-treatment for either an opioid dependence or an opioid addiction, oftentimes in conjunction with chronic pain. So who is using and why? That's what we're going to focus on a lot today. And as a prelude to getting into the weeds with that, I want to just briefly mention prevalence estimates. So the National Survey on Drug Use and Health have pretty low estimates for past year Kratom use, about 2.6 million at the highest. We have a couple of other survey-based estimates that put lifetime anywhere from 3 to 9 million. And then we have what I like to call back-of-the-envelope calculations, which we do have a citation for. It's based on kind of old import data at this point. And hopefully we will get some more prevalence estimates in the next year. But my exposure to the Kratom industry really does lead me to believe that the National Survey on Drug Use and Health estimates are really low and an underestimate. I would confidently say that there are at least 10 million people who have used Kratom ever, and probably at least over 5 million who have used in the past month. The sales data are pretty robust. And so again, while we don't have great prevalence estimates, it's safe to say it's anywhere between 1.7 million and probably 15 million. So again, very wide range there, but it's something that's growing. And if you are driving around your local town, if you look for Kratom signs in smoke shops or vape shops, you really will start to see it more often. So the most up-to-date published data that we have, I have data that we're collecting now at Hopkins, but the most up-to-date published data is actually from when I was at NIDA. So it's the way I think to best present who is using Kratom in the United States and how to best think about it. And so the study I'm going to present data from had three parts, a survey, 15 days of ecological momentary assessment, where participants enter data at random and scheduled intervals on their smartphone, and then they also shipped in a sample of their Kratom products. We also had a sub-study that I will talk about as well. So again, these have been published, the main study, and this sample is very similar to many of our other survey samples. So again, pretty representative group in terms of the other Kratom samples that we have data for. So the vast majority of our participants have been using over a year, some as long as 13 years, and the Kratom use population really is split pretty equally between men and women. It always skews non-Hispanic white, that's been pretty consistent, but with respect to socioeconomic status, it's pretty diverse. So we have some fairly educated people, we have many employed people, and then we have a very wide range of economic background. So with respect to those variables, it's actually pretty diverse. It's only race and ethnicity that is pretty not diverse. These are just a few screenshots of the study smartphone app. I'm not going to go into the methods too much because it will take all day, but essentially what we did is we had people complete beginning and end of day diaries, and then we had random and scheduled prompts during the day, and people would report their Kratom use anytime they used. We also analyzed 330 samples for the alkaloid content, and I'll just note here, because I'm not going to go in depth on that, that a lot of our samples were really, there was a lot of consistency across products. Of great importance is that most people who self-selected to this study were whole-leaf Kratom consumers. So we had some extract product consumers, which are the more potent kinds of product formulations, but we did not have nearly as many. So a lot of what this generalizes to is really the whole-leaf consumers, and to some extent the extract consumers, but just not as much. So this is showing you all these little dots here. They represent unique Kratom use events over that 15-day period. We had over 13,000 use events during the 15 days, and what we did was a cluster analysis based on the use event data. And so essentially what this is showing is five different groups, A through E, and how much, essentially who fit into which group based on the dosing frequency. So dosing cluster A, they were using more often, and these intermittent groups all the way down to dosing cluster E, which was using the least often. This is not based on the amount per dose, but just the frequency of dosing, which is actually an important factor we'll talk about later with respect to withdraw. So again, dosing frequency, but something to highlight here, which is that regardless of what cluster or group that participants fit into, you can see that they're all using in the earlier half of the day. They're using more in their first half of their waking hours. We know when they're going to bed, when they're getting up, all of the schedule of their study participation is based on their actual real schedule. So if they work the graveyard shift, we know all this, and we take that into account. So whatever their waking hours are, people are tending to use Kratom much more in the waking or first part of the day, as opposed to the latter part of the day. We did not see any binge use on the weekends or any other patterns that were indicative of a binge-like use. We asked people on the survey how often they use Kratom or how much, and people actually tended to overestimate how much they took compared to when they were reporting it in real time, which just goes to emphasize the importance of capturing data in real time as opposed to retrospectively whenever possible. And then the variability of use. So dosing cluster A, that group that was using most often, they were a lot more regimented in their use than these other groups. And in fact, those who were using less frequently had a lot more variability in their use. And that might be indicative of a couple of different things, including even tolerance and avoiding withdrawal, and also use for very specific motivations that we'll talk about. And in fact, some of the broad motivations for using Kratom that we assessed on the survey prior to the ecological momentary assessment phase have been established in other surveys. And there are dozens here, and there are actually more that I can't even put on the screen. The main thing to know is that there were not differences between our clusters or our groups. But what we see here is that a lot of the broad reasons for use include managing psychiatric symptoms or drug withdrawal, maintaining just quality of life for energy, pain relief, recreation, perceived safety compared to other substances, and as a long-term drug substitution. So again, these are just generally broad reasons why people engage with Kratom. One in particular that did stand out, again, not a lot of differences between our groups, but we do see that the group cluster A that's taking Kratom more often, they were more likely to be using as a long-term opioid substitute compared to the other groups. This group was also interestingly more likely to perceive Kratom as both life-saving, but also more likely to perceive it as habit-forming. So it's kind of a mixed bag there. And this group also is more likely to have ever received medication for OUD in their lifetime. So when we look at not these broad motivations that I just talked about, which could be things that maybe initiated use, but does not reflect why people continue to use. These motivations here are what we assessed in real time. And so what you see here are the top 10 of drivers of use. And again, these are thousands and thousands of time points. And so most people really are using for pain relief. That's a big one. And then also the stimulatory effects of kratom, which I don't think get enough attention. People, again, Google kratom, they see opioid, which we know opioids at low doses can produce stimulatory effects or, you know, increase talkativeness, things like that. But here we see that a lot of people are using for increased mood, energy, productivity, focus, a lot of people wanting to feel good, but not necessarily wanting to feel high. We also assess for that and it did not make our top 10. We do see people, some negative reinforcement here with some, it wasn't the top one, but it's in the top 10, using to prevent kratom withdraw. And so again, that's slightly higher among our dosing cluster A that's using more often, and then lower among this cluster E, which is using least often. And so the acute effects are pretty consonant with those motivations, right? So you're feeling energized, focused, alert, sociable, talkative, some not experiencing effects, which I actually attribute to the fact that we had a pretty big followup window when we were like, you know, dinging people after they told us they use kratom. I would probably shorten that to, you know, maybe 90 minutes. So it could be that we had gotten them on the tail end of their acute effects. And this is the time course of acute effects that we've also seen in our lab-based work as well. So really peaking about one hour after self-administration. And again, these are mostly whole leaf products. If this were like a liquid extract, you'd see that pushed over to the left of it. And so this is just a few, I mean, these are two of several items that we asked about sleep and other daily effects. And most people said it didn't really affect their sleep quality or quantity one way or the other. And to the extent that they did, most people say that it, you know, either improved the quality or increased the quantity, but again, not a lot of clear patterns here and certainly not a lot of group differences that really stood out. Okay. So this is probably my favorite slide. This is within kratom world. I'm also one of the few people that really has a background in addiction science and is clinically trained. And so I do think that, you know, assessing substance use disorder for kratom is really, really needed. We don't have a ton of case studies, which we'll talk about in a second. And I think there've been maybe at this point, five surveys including this that have assessed for substance use disorder for kratom, which we essentially now refer to as kratom use disorder. And there's actually a couple of publications that have just come out about this. So I do encourage you to look this up and read more about it because it's really it's because it's a unique substance to try to assess for. So in this sample, what we did see is that most people on average had across different clusters, less than four symptoms on average. Of course, you only need two symptoms to qualify for a mild substance use disorder based on DSM-5 diagnostic criteria. You do see here, obviously, you know, if you look up at the 12 mark, you see some people who are meeting criteria for severe substance use disorder, but here and in other studies, what we typically see is mild and, you know, followed by some moderate, very few severe. But when we look at the symptoms, which I think is actually really important because not all of these symptoms are equal to me. I think some are a little bit more concerning than others, but we do see, and this is, I don't think up for debate anymore, indicators of physical dependence. So using creative to avoid withdraw or experiencing withdraw, and then also tolerance. So those symptoms are by far the most common across all of our samples, but then some using more than intended, some craving, and then some could not control use, you know, which again are concerning. What we don't see here and what we've not seen in other samples are people endorsing symptoms related to psychosocial impairment or, you know, risky use, physically hazardous use, giving up important obligations, things like that, excessive time recovering from use. So again, a lot of what I think is clear at this point is that regular creative use does cause physical dependence, but it does not necessarily cause addiction. And I say addiction defined more like severe substance use disorder in large numbers. We indeed have very few case reports on this, and I'll actually, again, I'll touch on that in a minute. So with respect to creative withdraw, this is based on survey data. Just to be clear, this is not part of the ecological momentary assessment we did. So it is retrospective, but we do have people reporting that after one missed dose of their kratom, many people aren't experiencing symptoms, but craving is definitely the biggest one, followed by lethargy, difficulty sleeping, fatigue, irritability. And what's interesting is when we control for demographics and standardize the dose amounts across different product types, we see that the dose amount is actually less important than the frequency of dosing. So more withdrawal symptoms are evidenced after, or I should say, based on frequency of dosing rather than amount. Same here. So this is after stopping kratom use for one day or more. Again, same symptoms that are the top ones. You just see them more pronounced, obviously, because it's been a longer period of time since they last used. Again, irritability, anxiety, fatigue. A lot of these are nonspecific to any drug class. I should say that restless legs is something that we added on here because that's something we have anecdotally and qualitatively collected some information on that is unique to kratom, it seems, and it could be reflective of the serotonin activity involved with kratom. So I do think the withdrawal symptoms here and elsewhere have been documented as mostly mild to moderate. I am currently doing a three-day, two-night laboratory study at Hopkins that after a pharmacokinetic and pharmacodynamic 36-hour period, we shift over into a supervised withdrawal period and systematically assess what does kratom withdrawal look like? Do we see tachycardia? What do we actually see objectively? Because to date, we have no empirical data on kratom withdrawal. We just have some self-report. So these are two systematic reviews that I did with my colleagues when I was still at NIDA. And I have no life, unfortunately. All I do is study kratom. And so I have read every single case report ever written in English on kratom. So even from the time that these were published a year and a half ago, we have not had a huge uptick in kratom-related case reports, both for morbidities or for forensic tox case reports, or for case reports very specific to dependence, withdrawal, addiction, abuse. The terms are all over the place. And so I know this because I'm talking to a bunch of clinicians, and I deeply, deeply urge you that if you have kratom-related cases that are of any substance and have good data, I would really, really urge you to publish them because we don't have many. And clearly, there's a gap between reality and what gets published. So there are likely many more adverse events and or addictions related to kratom that are not getting published. But even when we look at things like adverse event reporting systems and poison control and tox databases, we really don't have a huge signal here. And so it's not just in the published case report literature, but it's even in larger monitoring and reporting systems like ToxIC and all of these different things. We don't have a lot of cases. And so there is this question of how dangerous is kratom? People ask me all the time, is kratom safe? Is it dangerous? And you can't say either are true because we don't have the proper studies yet. So I'm going to switch over to some acute effects that we observed in the sub-study that I did when I was at NIDA. This had six males, four females. They've been using for over six years. They were in their 40s on average. And they used 5.2 grams on average. I think the dosing range was 1.1 to 10.9 grams of kratom. And so we evaluated many different things, but essentially physiological parameters, subjective, psychomotor and cognitive, things like that. This was not a PK study. We did pulse and blood to verify the kratom alkaloids and quantify those in blood and urine, but this is not a proper PK study. And what we did is have people abstain from their kratom from essentially midnight the day before until they came into our clinic at NIDA. And we did not see, and these represent the individual, because there's only 10 participants, we're showing all the individuals and these thicker blue lines are the average for each outcome. And so we did not see any statistically significant or even clinically significant changes from baseline with in-person changes. So essentially everything stayed within normal healthy parameters. The one thing we did detect, and this is the first study to measure this, which was pupil diameter. So we did see pupils constrict after kratom product self-administration indicating the ovidirceptor activity. We did assess using Sal's kratom withdrawal prior to their taking their kratom, because we had them in a state of abstinence where it had been over 12 hours since their last kratom dose. And so we did detect a very mild Sal's score that of course went down after kratom self-administration. The drug effects questionnaire, again, we see the effects peaking around the one hour mark, and they really was between 40 and 80 minutes. So this is not a substance that is going to last all day, but it's certainly going to last a good two hours. You're going to be feeling the effects. Do they like the effects? And keep in mind, these are people who use chronically, right? So they do have some tolerance. People still reported enjoying the effects. They obviously didn't want more, but that, of course, increased as time from self-administration passed. And so of course, at the 160 minutes post-dosing, this wanting more score had significantly increased. So do you feel high? Again, very low. Out of 100, it was 15.2. We have this one outlier here, and I still am not entirely sure what's up with this one participant. I wish I could go back and ask this person what was going on with them, but this one participant did have an increase, whereas the others did not. Feeling intoxicated was very low across all participants. And then the Addiction Research Center Inventory Morphine Benzedrine Group subscale, we had other subscales, but we didn't get any indicators from them. But this one is an indicator of euphoria. And so what we did see is a very mild increase in this score. This was driven by 3 out of the 10 participants. And so again, this mild euphoria, it's kind of comparable to caffeine when this same assessment has been used to evaluate euphoria. Caffeine is the closest that it maps onto. And then this is reflecting psychomotor data. I'm not going to get into depth here, other than to say we did not see any changes. So again, no impairing effects were observed, both before and after the Kratom self-administration. There were really high rates of both accuracy and response. And so one thing I do want to note, when I talked to our participants, I did a qualitative interview with all of them. They mentioned something that I had not heard of before by this name. And it sounds like a 1950s pop band, The Wobbles. But this is what Kratom consumers, not all of them, but at least some of them, refer to as an experience when they take too much Kratom and they don't feel good. They don't necessarily feel bad enough to go to the hospital or seek help. In fact, none of them did seek medical help. But they did experience this when they were essentially in their early dose-finding phase, trying to figure out what is the right serving size for me. And so without fail, all of them at one point took an amount that was just too much for them. And what it sounds like is serotonergic excess, maybe some alpha-angioenergic excess as well. But the one thing that we know this doesn't look like is opioid toxicity. And even now, we have yet to link Kratom to any respiratory depression. We did not see respiratory depression in our study. I'm not seeing it in the current study. And we have people taking extract products in my current study. So I'm not saying that there is not a formulation of a Kratom alkaloid. Going back for a minute to what I spoke about earlier, those semi-synthetic 7-hydroxyimitragynine tablets, I'd be willing to bet that if someone took enough of those, that we could get respiratory depression. I think it's possible. I don't know for sure, but I do think it's possible. But with the vast majority of Kratom products in the United States, we really aren't seeing that. I do think serotonin is the undersung or under-told story here. We're assessing for clonus in my current study. We have seen signs of serotonergic excess. So nothing at the level of clonus, but there's some hyperreflexia and very mild ocular clonus. So penanthine and then specioguanine in particular are high affinity 5-HT1A receptor ligands. So I urge you to spread the word to other clinicians that the opioid activity of Kratom alkaloids is important, and certainly it's never going to hurt to give anyone Narcan, but I really would encourage other assessments for other pathologies to be looked at as well. So the driving simulation performance, this was another thing that we did with our participants. There are many, many, many outcomes for the four tasks that were programmed. And I'm only going to just kind of fly through this. But essentially, well, we had accidents, rule following, speed, and lateral movement. So those were our outcomes. And what we see, and this is just one of dozens of outcomes, and this paper is already published in case you're interested, you can go look it up. But essentially, we did not see any significant changes across main outcomes. There was one participant who showed a modest increase in the standard deviation of lateral position, and a decrease in their coherence score, which are essentially indicators of some impaired driving on that task, on this particular task, I should say. Everyone else had stable performance pre and post Kratom self-administration. I actually thought we might see people improve their performance, because again, at baseline, we had them in a state of kind of mild withdrawal. And if I were, you know, asked to do this task before drinking my morning, you know, coffee, I would definitely do better afterwards. But we really didn't see an improvement, and we didn't see a decline. Again, here, some other tasks, just all a lot within group heterogeneity. So, I want to say, again, this was with people who take Kratom regularly. I also think it is possible that if we were to enroll healthy volunteers who had never taken Kratom, and give them certain Kratom formulations, I do think we would see impairment. I don't necessarily think we'd see it with the whole leaf product formulations, but I do think that a Kratom naive consumer, or a Kratom naive participant, given an extract product, I really would expect impairment to be occurring with that. So, this is not generalizable to all Kratom consumers and all Kratom product types, but it is a snapshot of what we did find. I want to just talk briefly about what NIDE is doing, because I think a lot of us think of Kratom understandably and rightfully so as this kind of gray market product that's being sold in smoke shops, online, in this very gray market, murky, unregulated space. That is absolutely the case, but also NIDE has invested quite a bit of money and is continuing to investigate this, and essentially developing a semi-synthetic mitragynine formulation so that it could be used for clinical trials, because there is a reason why people are taking Kratom. We talked about going back to 2007, why did we first see Kratom use emerge in the United States, and why are we seeing people continuing to use it to this day, even people who've been using it for many, many years, analgesia, and then as a long-term opioid substitution, but with these, you know, stimulatory effects. So, from a drug development standpoint, there is some interest in moving this forward, at least maybe not Kratom as a whole botanical, but as, you know, a pharmaceutical in some other form, with perhaps one or several alkaloids synthesized. So, it is, you know, both a natural, marketed as a dietary supplement product, but it's also something that is being taken pretty seriously by people who think it could be a good pharmacotherapy for opioid use disorder. I'll just conclude and leave time for questions, although I can continue talking as long as needed, because I really do love to talk about Kratom. So we currently have a study, if for any reason you have patients that are taking Kratom daily, we are enrolling people right now. And like I said, we're looking at really trying to understand what does withdrawal look like, but also what are the pharmacokinetics? And essentially we're modeling real-world Kratom use in a controlled setting, but hopefully NIDA will be funding me to do safety studies and human abuse potential studies with healthy volunteers, because those are desperately needed. And we really can't do any of the more fun work, like looking at clinical endpoints until we get these safety studies done first. And so anything that I showed here that involves data collection, I had a lot of people involved with it. And so I just wanna recognize all of my wonderful colleagues as well. So I will stop sharing and then take some questions. Great, thank you so much. Well, we have one comment first. Somebody had mentioned that they had a patient who used Kratom, an adolescent who used Kratom to treat fentanyl withdrawal and had terrible constipation. Is that something that you commonly hear from individuals using Kratom about constipation? Yeah, so, I mean, first of all, I would beg you to write that up as a case report because we actually don't have a lot of reports of, we have a lot of reports of Kratom being used to attenuate heroin withdrawal and prescription opioid withdrawal. We have fewer documented cases of Kratom being used for fentanyl withdrawal. So that would be deeply of interest. I know you have no time, but yes, constipation is something that is reported by some consumers, again, who are using daily and multiple times per day. When this has been studied, to the extent that it's been studied, it's been very qualitative, and people say they manage it by drinking a lot of water and taking fiber pills and things like that. In fact, one, interestingly, we have had several people report using Kratom for IBS and it helping, I mean, because if you have irritable bowel syndrome, you kind of have the opposite problem of constipation. And so people have used it to kind of balance their GI tract out. I'm not saying that that actually works, but that's what they've reported. So yeah, we do see, we have had some reports of that. And I think it's interesting too, going back to the opioid properties for a minute, because what Kratom has been called like a biased agonist of opioid receptors, which means that it doesn't recruit the second beta-arrestin pathway. And so long story short, it's weird. We haven't seen respiratory depression, which would be expected if it is indeed this biased agonist, which is kind of too much to get into right now, but yet we do see the constipation. So it's kind of odd that we see one, but not the other. Speaking of withdrawal, are there any treatments that people typically use for withdrawal? So honestly, like I think any, as far as people, like when they do it themselves, they'll talk about taking vitamins or supplements or tea or things like that. I do not, I do know that within the case report literature, there's been an increasing use of naloxone and buprenorphine. And I'm, it's kind of curious because that's not necessarily like, in terms of induction, there's a timing issue here. So to answer the question, I think there's the comfort med aspect of it, and then there's the longer term treatment. And I think sometimes these get conflated because the case report literature is not super well-written right now. So there has not been one go-to. I do think that given that kratom withdrawal is typically mild to moderate, that some kind of comfort med that would also be given during opioid or even alcohol withdrawal could be warranted, but it all depends on the patient, right? So if they have a history of, you know, benzodiazepine addiction or something, like maybe you don't want to give them a benzodiazepine, right? So I think that most people can probably get through withdrawal without having a pharmacotherapy put on them. That's just my opinion. I have heard of severe cases of withdrawal, but they're not common. So if it is mild to moderate and someone can kind of get through it in a detox setting without having to put them on something else, I think it's ideal, but yeah, I mean, it's not, let me, I'll just say this, it's not well-studied yet. So I kind of need clinicians to tell us what they're doing. Yeah. Yeah, definitely, you know, I've seen people and they typically have an opioid use disorder in the past and maybe they stopped using opioids and then they found kratom and now it's problematic for them and they want to stop. And we have used buprenorphine and I've seen other people, I think somebody else had mentioned already in the Q&A about using buprenorphine, but I've also tried clonidine, like you said, and other conjunctive meds. Oh, and, oh, sorry, I'll just briefly put in a plug here. I do very much, I like how this was said, like I would very much, you know, go to buprenorphine for a patient that has a history of diagnosed opioid use disorder. And then as you said, found kratom, became dependent on that. I do think it's a very appropriate path. I am concerned having read some case reports in which there's a patient that has no history of opioid use disorder, and then they're just kind of, again, put on buprenorphine without, I think without necessarily thinking about the implications of putting someone on a pharmacotherapy when, if they've not ever been on a, you know, dependent on an opioid. Obviously buprenorphine is lifesaving, but because kratom, and we didn't really touch on this, so if anyone has questions related to like overdose or toxicology or fatalities, because we don't really have high fatalities associated with kratom, I think that putting someone on buprenorphine is maybe not the first path or choice I would make if they don't have an OUD history, and it's only kratom. I would very much try to just get them through withdrawal and then into any sort of behavioral intervention and not necessarily put on buprenorphine. Sorry, I have to, that's like my little soapbox. Somebody did ask about if there's any long-term impact on opioid receptors based on any kind of research in the brain after stopping lotus kratom use, like you might see with traditional opioids. So, I mean, in humans, no. I can, and actually, even in preclinical models, I don't think so either, because the chronic, I can say that any toxicity, dose-dependent toxicity is usually reversed, but as for the opioid receptor, I actually don't know that that's the case. I think, and I am not a preclinical researcher, so I'm not the best person to ask on this, but as far as I'm aware, I don't know that there are studies looking at that in particular. If there are, nothing has jumped out at me that is sticking in my brain at this moment. I can talk more about abuse potentials than I can about neurobiology or changes on that level, but I don't think that that's been the case, and again, I should reemphasize the fact that these are partial agonists, and they do seem to have a ceiling effect, and also, it goes back to, what do we mean by kratom, right? So a very isolated, if you were to take speciocialatine and isolate that and put that into a product and give that to a human every day, that is a very different animal. That is essentially an opioid, right? Same thing with 7-hydroxybuterginine, but that is not reflective of, again, most kratom formulations, and also, something else we didn't talk about is bioavailability. So when we have the whole-leaf kratom products that people take, whether it's the powder or capsules, the bioavailability is not great. So whatever they're taking, they're absorbing like 25% of it, and it's just really, again, it's a reason that we don't see impairment or intoxication. We see some effects, but we don't see this impairing effect or people getting high. If you wanna get high, you can get high a lot easier by taking other things, but again, with some of these extract products or isolated extracts, we're talking about different things. So I think it goes back to like the initial thing I brought up in terms of, we have to define what we're talking about when we talk about kratom. We have some interest in here, a little bit about the stimulatory effect, and has there been any kind of research or looking at it for ADD or ADHD? So at this point, we can't do any clinical trials for any clinical endpoints until we get through our safety studies. However, we know from several surveys and including the survey study I showed here that there are a subgroup of people who use kratom specifically for ADHD and ADD. It's not everybody, but it is absolutely one of the, like I showed a list of like several dozen motivations for use that is very much represented on that. We do have somebody who had mentioned that they had a patient who was a regular user of kratom and then felt dependence and cravings once he quit. He wanted to take oral naltrexone as a medication for recovery, which they prescribed to him and he felt it helped with cravings and avoidance of use. Do you know of any studies, case studies about pharmacotherapy for people who want to be treated for dependence? Yes. So if you look at those, you're going to see buprenorphine used more often. We've seen methadone used overseas for like four people, which I definitely would not go to first, but we did see naloxone or sorry. We saw one Vivitrol, I think it was one Vivitrol study. And then we've seen naloxone used in four studies, but it's not like, so in short, no, we have, in fact, publish your case report. Like these are the things that we really need to hear. So in short, buprenorphine has been the most commonly used intervention. Have you, another question was, have you heard of patients who use kratom while on buprenorphine and related to that, does kratom have a higher receptor affinity than buprenorphine? So with respect to higher affinity, so I would say it again depends on what you're taking. And that's a very unsatisfying answer, but it depends on in the real world. I actually don't know, and this is embarrassing. I know the 7-hydroxy 14 to 22 times more potent than morphine but I actually don't know off the top of my head, the binding affinity compared to buprenorphine, which is really embarrassing and I should know that. And I'm very sad that this is being recorded to be put on the internet for three years because I should know the answer to that. We can put something at the end. Yeah, yeah. But then, sorry, what was the first part of the question? People using kratom on top of buprenorphine. Yeah, so I actually have not come across that. I have come across more often people who have been on buprenorphine transitioning off of buprenorphine and onto kratom. That's something that I've come across several times but not both of the same. It doesn't mean it's not happening. I can say that in the ecological momentary assessment study we did, we evaluated all the other drugs being co-used with a contemporaneous to kratom. And what we found, and I'm sorry I didn't show it, was actually the most commonly co-used substances were fairly boring. Not to say they're not concerning, but so nicotine and caffeine were the most common. And then we had some cannabis over-the-counter analgesics like Advil, acetaminophen, and then vitamins, antidepressants, and I think that's it. Those are the most common. And then we didn't see a lot of illicit narcotics, things like that, or buprenorphine. So, I mean, I don't want to claim that it was zero, but it was probably, it was very low because it didn't, I know it didn't, it wouldn't have been in like the top 20. Just a couple of practical questions here. Are there any UDS testing for kratom? So I know there are some tests that, so most places have to send out for it, but, and mitragynine is typically the alkaloid that will be tested for as a marker for kratom. That is, that probably was good and sufficient for a while, but now I think given the introduction of these seven-hydroxymitragynine products, that seven-hydroxymitragynine should also be tested for separately. But, so no, I mean, most places can't do it in-house, they have to send out for it, but you can do it. I mean, I've reviewed intensive outpatient charts that have screened for kratom. So I think it just depends on what is available to you in your particular practice area, but you can test for it. Yeah, I mean, call your local lab that's doing testing if you're not doing like point of care testing. Somebody wants to know about the maturity or stage of harvest, and if that changes the alkaloid composition and the physiological effects. Yes, so it does. So what we know is that essentially the age of the tree does not matter as much, we used to think it did, but really the age of the leaf. So typically a tree will be at least two years old and then it'll be harvested like every 50 to 60 days. But the more mature the leaf is, the more mitragynine levels it has. So like higher mitragynine content. And then conversely, if it's a younger leaf, it'll have, mitragynine will always be the major alkaloid, that will never change, right? It's always the major alkaloid. But the level will go down when it's like younger. So as it gets older, it's a higher level. But when the leaf is younger, it will have higher levels of speciocialatine, which is important because again, that's a minor alkaloid, but it is a selective mu opioid receptor agonist. So yeah, so the alkaloid content will change based on not only the age of the leaf, but also conditions after it's harvested. So how much sunlight exposure does it get, the temperature, so environmental conditions will have an impact as well. And then typically it's fairly stable after that. It's not completely stable, but it's mostly stable after it's dried at that point. But yeah, it really will change based on the age of the leaf. So even people using leaf product could have very different products that they would get based on like, if somebody got young leaves versus older leaves. So this is like speculation, like as of right now, the 330 products that we tested were pretty similar. And I think that based on, in fact, like the trip to Indonesia just took almost guarantees that we'll probably see like a subtle shift, not just from Indonesia, but from a lot of other places that are now cultivating this. There's, you know, economically, there's a reason to harvest them faster. So I do think we'll see like a subtle shift from what the content, what the alkaloid content was a couple of years ago and what it'll be in a couple of years. As for the effect profile, the subjective effects, I think it will be subtly different, but I don't think it'll be radically different. And the reason I say that is because all of these minor alkaloids are indeed minor alkaloids. Like they're not these like heavy hitting things and they're all in this kind of combination. I don't want to say like an entourage effect, but it kind of is like that. And again, the bioavailability of the whole leaf products is not great. So there may be like subtle differences, but it's almost like, I don't think it, I don't know that we would be able to objectively, if we were to do like some triple blind thing and like have people take this leaf material versus this. I think if it's blinded, it would be almost not detectable. I think a lot of what we know is that there are outcome expectancies based on the marketing of Cranium products, because different leaf products will have different names. And I do think there's some outcome expectancies based on that. Again, the big, big difference are really whole leaf products versus extract products. That's, we're talking like apples and oranges. It's all a Cranium, but the extract products are really just a different animal. And within the whole leaf category, I think the variation is going to be minor in terms of its impact on people. So. Surprisingly, it's already after six. And we just had a ton of comments and questions and people who've had some cases in our Q&A. So I'm sorry that we couldn't get to all of them, even though we had about 15 minutes. So I wanted to thank you so much. This is very interesting. It's the first time we've ever had anybody talk on Cranium with the ORN. So I was really happy to hear your research and learn more from you. So thank you so much for doing this webinar. Yeah, next week we do have another webinar and it's going to be Dr. Catherine Chappell, who's going to be speaking on hepatitis C virus in pregnancy and opportunity to screen and treat. So we hope that we see everybody there or here next week at five. And again, Dr. Smith, thank you so much for your time. And thanks for doing this after your long trip and your jet lag. Thank you for having me.

Kratom

Mitragynine

7-hydroxymitragynine

Opioid receptors

FDA regulation

DEA scheduling

Withdrawal symptoms

Pain relief

Mood enhancement

Johns Hopkins University