Okay, good evening, everybody. Welcome to today's AOAM webinar, Methamphetamine Toxicity by Dr. Tamee Paison. My name is Julie Kmic and I'll be your moderator for this session. This is the third of our spring webinar series. Dr. Paison received his medical degree from the University of Toledo School of Medicine in 2001. He then completed his emergency medicine residency at the University of Pittsburgh Medical Center in 2004 and his medical toxicology fellowship at Banner Good Samaritan Medical Center in Phoenix, Arizona in 2006. Dr. Paison is currently a professor in the Department of Emergency Medicine, Division of Medical Toxicology at the University of Pittsburgh School of Medicine. He serves as the chief of the Division of Medical Toxicology and the director of the Medical Toxicology Fellowship at UPMC. He's also assistant medical director of both the Pittsburgh and West Virginia Poison Centers. Yet, most importantly, he's blessed with this amazing wife and four wonderful children. So I'd like to welcome Dr. Paison today to talk about methamphetamine toxicity. Thank you, Dr. Kmic. I always enjoy talking to this group and let me share my slides here. There we go. Yeah, and feel free to enter comments into the chat. Yeah, you can make this interactive. I'm happy to share any thoughts I have or any questions you have. Dr. Kmic will field those questions as we go. So my outline for today, there's so much to tell you about with psychostimulants. But basically, I want to go through a little bit of epidemiology of psychostimulants and how it is intricately woven into our opioid epidemic that we're dealing with at the moment too, because it's hard to untangle. It's it's not uncanny that the opioid response network is also interested in the psychostimulants. So I'll talk a lot about that. Also, I'm a toxicologist, we also also have to talk about the pharmacology. But I feel like the pharmacology really kind of helps you understand, you know, the issues associated with the psychostimulants. And then we'll talk about toxicity and treatment and so forth. Mostly acute toxicity. I mean, we could talk about chronic use, substance use disorders, and so forth associated with it. But I'm going to stick with the acute nature, because it ties in nicely with our opioid epidemic that we're dealing with at the moment as well. So let me get started here. So the funding is from a SAMHSA grant. And Dr. Kimmick and myself have no, no disclosures. Now heroin, I thought this was a talk about psychostimulants. So where does heroin play? Well, the big picture idea is, you know, back in the good old days, you know, our drugs of abuse were were cultivated in a field where the poppy plant opium is extracted. And lo and behold, you get heroin, right, extracted from the poppy plant and manufactured that way. But now, we're in a new era, that new era where I call our new normal of, you know, if it fits, it ships. And it's so much so that no longer are we cultivating drugs in a field in Columbia, but we're chemically synthesizing drugs and shipping it to wherever it may be desired. Largely, a lot of this chemical manufacturing is happening in China. But it's happening elsewhere as well. And so much so that these drugs are being cleverly chemically synthesized and in change and little nuances, and you can really get lost in all the little difficult chemical structures and how different they are individually. And that's why I'm a lumper. I'm going to lump things together in one big, nice basket, make it a little more simple. But so much so that it's hard to keep track of all these new psychoactive substances. So the United Nations has dubbed them NPSs, or novel psychoactive substances. And you can imagine hundreds of NPSs new over the last couple of years, and they're extremely hard to track, really hard to detect, and nearly impossible to police. So this is just a new normal that we're living in. And I'm going to go into more detail about this as we go through the lecture. So, you know, it's a good time to be a toxicologist. It's a good time to be an addiction psychiatrist. It's a good time to be involved with substance use disorder. Um, we have done a great job in curbing unintentional accidental deaths associated with motor vehicle accidents, drownings, falls, other unintentional issues. But poisonings, as you can see, are are rampant, you know, largely driven by the opioid epidemic. But stimulants are a big issue here, too. And this is not showing any signs of slowing down. So the opioid epidemic, and poisonings, psychostimulants, the whole cadre of new psychoactive substances are really driving our unintentional injury deaths across the country. And so this is something I don't know that we really kind of look at and discuss too frequently. But you know, the graph on the left looks at overdose deaths. And that green line on the left shows synthetic opioids, not methadone, but synthetic opioids, and how it has been escalating in terms of overdose deaths over the years from 2002 till present. And now we're over, you know, 20 deaths per 100,000 population. And heroin, for the most part, has been falling. But other natural and semi-synthetic opioids and methadone have been pretty flat over that time period. But I think we forget, you know, and this is this is the beginning of where I kind of intertwined psychostimulants with the opioid epidemic, but psychostimulants have been skyrocketing just as well. And you can see they're not nearly as prevalent as our opioids, but cocaine and other psychostimulants have really been on the rise and on the order of 10 deaths per 100,000. Now, the interesting thing about this data is it's maybe a little disingenuous. And I don't mean this to any fault of medical examiners and coroners, they have a tough job. But you can imagine when you have an autopsy, when you have a corpse, and you're looking for the cause of death, and it's clearly an overdose death, and you start drawing drug samples on them, you'll get a whole potpourri of different drugs in their in their body fluids, right? And you may find cocaine and methamphetamine and fentanyl, among other things. And how do you list one drug as the other in terms of its cause of death, it gets a little bit nuanced by based on the concentration and so forth and what's present. Certainly the history makes a difference. But, you know, I think a lot of these deaths are truly probably opioid deaths. But nonetheless, psychostimulants are clearly being intertwined and intermixed with these opioids. And that that's the important thing. Are they really the cause of death? I don't know. But they are definitely much intertwined in terms of our opioid deaths. And I'm going to go into that in more detail here next. I have to bring it home a little bit. Allegheny County, for those who you don't know, that's where Dr. Kimmick and I reside in wonderful Pittsburgh. And they have some great data on the Allegheny County website. I just want to show you a couple lines that that green line is showing you cocaine associated fatal overdose trends. And that's been steadily creeping up from 2009 to 2023. You can see that in that always busy lines crisscrossing. And the other line, that purple line are other amphetamines, just kind of generic amphetamines, the class of drugs has been steadily climbing as well. Certainly, it's not as high as those two top lines. The very top line are opioids. And that reddish line, the second line from the top is fentanyl. But those two are clearly driving the trend. But other stimulants such as cocaine, amphetamine are certainly a hotbed of issue here in Allegheny County. Cocaine is is definitely the predominant stimulant that we see in our area. Now, what's really interesting is, and a bit unfortunate is most, if not all of our data considering psychostimulant exposures and opioid exposures is related to dead people. You know, it's really based on what the medical examiners are finding, because they have such a great database of drug concentrations and drug levels in a corpse. So they have just a large amount of data that they can share and kind of base that on. So interestingly, you know, I'm the president of the American College of Medical Toxicology. And we have this great consortium of toxicologists across the country. And the FDA has supported some research called our Drug Overdose Toxic Surveillance Program, DOTS, cleverly acronym. And DOTS is looking at alive people, because you know, all of that comes from dead people. But basically, there's 17 emergency departments across the country, I'll show you those 17 sites. And not only do we get blood samples from them to do analysis, looking both qualitatively and quantitatively on over 1000 different psychoactive substances, we can get medical record data from their chart. And we can interview the patient too. So we can get a little more information, since they're alive, about what they were doing, what their intent was, and what was going around their drug, drug use, and so forth. So here are the sites, these are the 17 sites across the country. So it's a nice kind of snapshot of what's happening across the entire country. And Pittsburgh is, is there in the northeast, but we have a nice grouping of sites all across the country gathering data in this fashion. So interestingly, so these are the DOTS study has just started in the last I want to say, two years now, it's about two years of data. And this data is not published data. But this is just preliminary data, I was able to pull from the database, there's only an end of 285 cases. But these are the cases with, with blood samples that have drug concentrations, so forth. And what I find most intriguing is 72% of the cases have a stimulant in their system, right? That's only third behind fentanyl and adulterants. It's interesting that adulterants are number one, right? But in terms of everything else back to kind of the background of other drugs, cannabinoids, antipsychotics, antidepressants, analgesics, opioids, benzos, whatever, you know, stimulants are a huge proportion of the drugs that we're finding in people's system here. Now, what I think is most intriguing is how opioids and stimulants are intertwined. This is what's a real important thing. And this is goes back to my thoughts, how the opioid epidemic and stimulants are closely intertwined. 60%, about two thirds of the cases with analytical data have both opioids and stimulants, both in their system, which is amazing. Only 22% have opioids without stimulants and 14% have stimulants without opioids. So the vast majority of the cases are mixing stimulants and opioids. And this is important to what our treatments are. I'm not even going to go into details about this, but just in terms of the addictive nature of things and our addictive treatments and with substance use disorder and so forth, really changes, you know, how we may approach people in this regard. But certainly in the acute setting, you know, this is, I think, an important thing to recognize that both opioids and stimulants are mixed together. Now, this is the quantitative drug levels data that we're finding as well. And you can see on the left hand side of your screen are the traditional drugs, you know, we're finding methamphetamine, amphetamine, cocaine, benzoecanine. Benzoecanine, you know, is the metabolite of cocaine and vast majority of the quantitative drugs that we're measuring in the DOTS program are well known and seen by us. But on the right hand side, you know, we have a nice grouping of novel psychoactive substances. In particular, the three stimulants that we're finding are dimethyl pentelone, pentelone, and eutelone. And I'm going to come back and talk about these more a little bit later, but it's interesting that these are the other drugs, you know, the novel drugs that we're finding. A little commercial side note here is you'll see something called the nitazines, those bottom three in the novel psychoactive substances. I'm not sure if you can see my cursor, but they're below eutelone there. Those nitazines, as we call them, you're going to see more of these. These are another opioid. They're cheaper to make than fentanyl. They're more potent than fentanyl for the most part. And these are going to be, there's going to be a very common thing I think we're going to see here in the future. Just FYI, more to come on that. So this, you know, more data from our DOTS cases, it's interesting what we can see in terms of what's happening in this interlacing of opioids and stimulants does change how patients present, you know, with providing naloxone to lay people, to the police, to paramedics. You know, I mean, naloxone is being used a lot, appropriately and inappropriately, but it's out there to save lives. And it's a great thing that's happening with that. But interestingly, you know, with the naloxone out there, we're unmasking maybe stimulant toxicity at times and often offering precipitated withdrawal. It's certainly better than letting the patient die. But I don't know how to really give you a big overarching theme here. But what I found interesting is, you know, obviously with opioids only, 22% get benzos, 22% get an anti-medic, and 3% get an anti-psychotic. But if you're on a stimulant and you get naloxone, maybe you didn't need the naloxone, 40% are getting a benzo, 8% are getting anti-medic, and 8% are getting anti-psychotic. So you can see that, you know, the patients are more agitated, requiring other sedatives, sort of calm them down. I mean, I can, I can appreciate that you're precipitating withdrawal, and 22% or so getting anti-medics and benzos, but 40% are getting benzos with stimulants. But yeah, the trend is not holding completely true. It's interesting because, you know, opioids and the stimulants, you know, 15% are getting a benzo, 15% anti-medic, maybe 7% anti-psychotic. These are small numbers, as you can see. So I'm not really sure how to interpret these, but I think the lesson is knowing that opioids and stimulants are mixing and you're giving them naloxone, not only may be unmasking, the stimulant toxicity may be precipitating withdrawal, and sometimes it's hard to differentiate between the two. And since the biggest number of cases included methamphetamine, I pulled some methamphetamine data here for you. And I, again, don't know how to interpret this, but this is quite interesting, right? So in the methamphetamine positive cases, the Narcan or naloxone doses are higher than in methamphetamine negative cases. Interesting, right? So there's, the numbers are fairly similar. They're fairly evenly split, 94 meth positive, 117 meth negative, but the mean naloxone dose is 3.8 versus 2.6. I'm not sure what to make of this. I'm not sure if people are just giving naloxone when patients are altered or agitated in hopes that it makes them better, but we need to dive in this a little more detail. So it's interesting that those patients are getting bigger naloxone doses. Similarly, so I'll move, I'll change gears a little bit here, but with the same group, there's also prior to our DOTS study, Dr. Manini from Mount Sinai has a nice NIH funded grant looking at the same sites from our toxic consortium. I don't think there's quite, there's 10 sites across the country here and it's getting close to an end here. We have about a year left in the study and they've enrolled 1,800 cases to date. And the first aim is basic, was basically look at fentanyl analogs or fentalogs in patients with suspected opiate overdoses. Again, this idea was a look at a live patients that present the emergency department and not deceased cases from the coroner's offices. There was no survey, was purely just obtaining waste blood on patients who come in as an opiate overdose and get blood work drawn and go back to the lab and you can get the waste blood. Now we can analyze that waste blood for lots of different fentanyl analogs. Then we can evaluate medical chart, any medical consequences associated with the fentanyl overdoses. So we have a lot more data from several more years of information on these cases. And again, it kind of holds true to our DOTS, right? Nearly 50%, 48% had any opioid and any stimulant. So nearly half of the cases have an opioid and a stimulant. You know, 43% have fentanyl and any stimulant. So fentanyl or opioid and stimulants mixing together is really becoming more of the norm, which is interesting. And so as you see with the DOTS study that I showed you earlier, we had 60% stimulant and opioid, now here 50%. So maybe that trend is even climbing based on some of this data. It's an interesting trend that we're noticing. And I always find it interesting too that some of the beauties of both the DOTS and this fentanyl log study is you can see regional variations in what we're finding in these drugs. So in the fentanyl log, so we have a lot more data, you know, stimulant prevalence in New York and Pittsburgh is really not as common. We just don't see the level of stimulants here, as opposed to when I was in Phoenix, Arizona, everybody was on methamphetamine. I mean, methamphetamine was practically in the water it seemed, but this kind of holds true as you can see the stimulant prevalence, not as prevalent in New York and Pittsburgh, but definitely Atlanta, St. Louis, Denver, Los Angeles, Portland, very similar numbers across the South, you know, in the mountain region and in the West in terms of what stimulant use is among people with an opioid overdose. Specifically looking at methamphetamine, it's even lower in New York and Pittsburgh. See, we just do not see the methamphetamine use as I remember back in my fellowship days in Phoenix, Arizona, but you can see, you know, in the West mountain region, methamphetamine is just such a predominant stimulant that is used even in Atlanta and St. Louis, not nearly as much. So let's dive a little bit into the psychostimulant pharmacology. This is some of my favorite parts, just to kind of lump these drugs together. As I had mentioned before, there's so many new and varying drugs that are being chemically synthesized and released across the country that it's hard to keep track of all these, but I like lumped together, and this will hopefully make it a little more clear for you. So this, now, I guess the confusing part is amphetamines is a class of drugs, right? An amphetamine is a specific drug. This drug that I'm showing, this structure of this drug is amphetamine, right? And a chemical name of amphetamine is alpha-methyl-phenyl-ethylamine. So this little methyl group, that's the alpha on the alpha carbon. So this is an alpha-methyl group. That's a phenyl ring here. That's an ethyl group here, and there's an amine. So alpha-methyl-phenyl-ethylamine. And some clever person created a contraction. That means amphetamine. Very, very clever. So not only is that chemical structure amphetamine, that's a specific drug, but anything with that basic backbone is an amphetamine. So it's a specific drug, but if you start altering that drug on side chains and so forth, you just have a different amphetamine. And so this is how I like to lump things together with our psychostimulants, that largely they just fall into this amphetamine category. And here's a great example. So amphetamine there is top in the middle, and all of these drugs are amphetamines, right? So here's amphetamine, and then below it is methamphetamine. All you do with the difference between amphetamine and methamphetamine, you add another methyl group to the amine group. And that little one, this would always blows my mind, right? You add one little methyl group to amphetamine, and now you get much better CNS penetration, and you get a much better high, much more rapid stimulant toxicity from methamphetamine and amphetamine, by just making that subtle little change. And on the bottom there, you can see a fedrin, okay? Now that OH group is there on a beta carbon. It's a chiral center, which is interesting, right? So you just add an OH group to methamphetamine, and now you have a fedrin, which is a weight loss supplement now banned by the FDA. But if you change that OH group in three-dimensional space, you have pseudoephedra or pseudoephedrin, right? Pseudoephedrin, which is an over-the-counter medication you use for your sinuses, right? Mind-blowing. These little subtle changes go from a weight loss supplement to a nasal decongestant. Then over here on the top right, you have MDMA or ecstasy, right? And when you start, basically it's methamphetamine with some side chains on the phenyl group. And whenever you start doing that, you get a lot more hallucinogenic effects. So ecstasy, MDMA, and I'm gonna show you some of these more a little bit further on. You get much more hallucinogenic effects. So a lot of these NPSs and other psycho-stimulants that are out there are really hallucinogenic stimulants, right, or hallucinogenic amphetamines in this ballpark. Then I put dopamine up there, which is everybody's favorite drug. Just to kind of give you a comparison to the amphetamines and dopamine. Hey, Tony, I was just wondering, you know, back when they banned, or they put down pseudo-fed where you had to buy it behind the counter, basically, how much pseudo-fed would somebody have to buy to be able to manufacture methamphetamine? That's a good question. It depends how much you're gonna make, I guess, is the answer. You could, I mean, as you can see, it's just a subtle change, and it would be a milligram for milligram change. So if you have like a 30 milligram dose, you know, a 30 milligram dose of methamphetamine is a nice hit. So I guess it just depends how much you want to make. And not being in the drug manufacturing process, I'm not sure I can answer that correctly for you, Julie, or I'm gonna give away all my secrets, so. Okay, thanks. I was just wondering, a little curious about that, because I remember, you know, back when that change happened in the pharmacy. Yeah, and it certainly has curbed the manufacturing of methamphetamine in that way, but now they've found other clever ways to make methamphetamine, so. Good question there, Julie, as always. Okay. Crystal meth. So here's methamphetamine in its purest form. Yeah, this is my stash. I mean, no, this is just, you know, pictures from the internet, right? Okay. So psychostimulants in terms of the pharmacology of, right? You know, amphetamines, and it, obviously these, the mechanisms, granted, there's a lot of overlap, irrespective of the amphetamine involved, but, so I'm just, but I'm gonna just talk generically about psychostimulants and amphetamines in general. They inhibit monoamine transport, they inhibit monoamine metabolism, and they, I mean, most largely, the biggest hit, bang for the buck, is the stimulant neuronal release of all those good-feeling stimulants, serotonin, dopamine, norepinephrine, epinephrine. And on occasion, particularly when you have that side chain on the phenyl group, like ecstasy or MDMA, you get additional hallucinogenic effects. And a lot of these psychostimulants on the street that we are seeing now are a combination of stimulant and hallucinogenic. So yeah, this is my bathroom, and you can see how easy it's made, like Dr. Kimmick has mentioned, store-bought ephedrine or pseudophed, and you can make methamphetamine, and there's all sorts of clever ways of manufacturing it with or without buying pseudophed over the counter. Now, I wanna go back to bath salts for a little bit, which is kind of an oldie but goodie, again, because this is a lot of what we're seeing on the street. And, you know, it's funny when bath salts, quote bath salts, I'll get into the details here, first hit the street, people are like, wow, Paisan, I heard you can go to Bath and Body Work and snort bath salts. I'm like, no, you really can't do that. I mean, you can, but I'm not sure it's gonna get you the thing you anticipated, but, you know, bath salts was just a street term for this, right? So bath salts were just synthetic cathinones. So you can go to Bath and Body Works and start a bath salt, but not very good. Alternatively, you can buy synthetic cathinones and put it in your bath water, and you're gonna waste a lot of money. So it's just the street name for the stimulants that are currently circulating on our streets these days. And, you know, back in 2010, man, it's like 14 years ago, they were made as a legal high, right? They were marketed much like spice or much like the synthetic cannabinoids on the street, and they're marketed as a synthetic substitute for cocaine and meth. And as you saw, right, you know, the government is good at regulating drugs by a specific drug structure, right? It's hard to regulate drugs by a class. You know, it's easier with cannabinoids because you can say, we're gonna tease out cannabinoid receptor agonists. But if you start making amphetamines illegal or drugs that are stimulants illegal or hard to manufacture or hard to prescribe, you're gonna really cause a lot of problems, right? Because a lot of people are prescribing stimulants for ADHD and a multitude of other issues. So it's really hard to regulate stimulants. And so stimulants are regulated by the FDA by drug structure. And so you can see, I could take that amphetamine backbone and just make subtle tweaks to it, and it's a brand new drug. And if it hasn't been studied by the FDA, and it's not specifically banned by the FDA, it's technically legal. And if I sell something as a bath salt, not for human consumption, because it's just a bath salt, then I completely skirt the market in terms of the legality. Hey, I'm selling bath salts out of my van under the bridge. And if you want to snort this, that's up to you. But I'm just selling bath salts here, officer. So people would skirt the law, and this has been going on pretty regularly since 2010, and was following the same trend that we were seeing with aesthetic cannabinoids as well. And it was sold under a variety of different names, like Dub, Sky, Zoom, Bloom, Cloud Nine. This was one of my favorites, White Girl, super pure stain remover. I thought that was just hilarious in terms of drugs on the street, super pure stain remover. The interesting thing too, about this specific drug on this patient, is that patients at the time when we were really seeing a lot of the bath salts in Pittsburgh, they knew that MDPV, which I'll talk about a little bit later, MDPV was a specific bath salt that people were trying to avoid because it was really long acting and really causing patients to go crazy. And the bottom, I should have taken a picture at the bottom of this White Girl sample set does not contain MDPV, right? But lo and behold, what did we find in the sample, but MDPV, so not always quite sold as intended, which was interesting back in the day. So where do bath salts come from? Well, some genius realized there was untapped resource in this plant called cot. Cot, as many of you know, is a plant that is chewed and eaten socially acceptable, much like we drink our coffee, right? Can't go a day without my coffee. Largely in Somalia, Eastern Africa, the Middle East, people chew cot and eat cot, much like we drink coffee to kind of get through your day. And cot is the plant, right? But the active ingredient in cot is cathinone. And again, like the backbone, it's just another amphetamine as you can see, is that alpha methyl phenyl ethylamine backbone with a double bond O there in the beta carbon. This is cathinone, so you can see amphetamine on the bottom and cathinone on the top. And you can compare it to MDMA or ecstasy in the bottom right-hand corner to methylene on the top right-hand corner, right? Just that subtle little difference makes it a bath salt. Clinically, pharmacologically, probably doesn't make any significant difference, but completely different substance that people are tapping into. That's been right in front of our eyes for many years as people have been chewing this as a stimulant for a long time. And I wanna come back, right? I told you about our DOTS study, and I talked to you about the quantitative drug levels and analysis that we've been doing and the NPSs that we're seeing. And I talked to you specifically about the three psychostimulant NPSs that we're seeing, dimethylpentylone, pentylone, and eutelone. Well, what are those? But they are bath salts, right? So COT or cathinone there on the left, you can see dimethylpentylone is just another bath salt with all sorts of different side chains, as you can see, pentylone and eutelone. You can just see all the little tweaks and adding manipulation of that structure. You still get great stimulant effects from it, but you have new drugs. It's just interesting that these are the three. I think the most intriguing thing that I noticed about these structures, and that's why I think the pharmacology is so important to understand, is that all of them have that side chain on the phenyl group, much like ecstasy does. And so all of these would be considered in the category of a hallucinogenic stimulant. So hallucinations and stimulation. So various serotonergic, I just find it interesting that that's the predominant novel psychoactive substance that we're finding are various hallucinogenic stimulants out on the street. So, but that's our new normal and what we're dealing with at the moment. One thing I can't help but to mention when we talk about psycho stimulants, because we see this a lot in Pittsburgh, and I know you see it across the country, is welbutrin or bupropion or Zyban, whatever you want to call it, right, is another bath salt. It's a great label as an antidepressant, it's a great stimulant, it's a phenylethylamine, as you can see there, got that basic backbone, double bondo on the beta carbon, just like a cathinone. So it's a bath salt and it behaves like a bath salt. And we know, our college kids in Pittsburgh know that you can help you study for your test and stay up late. We know people who like to misuse stimulants can crush it and snort it. We know our prisoners in Pennsylvania, Pittsburgh specifically, call it prison meth, so that they can kind of like use it and share it among the prison inmates as prison meth. So it has an abuse potential, a great antidepressant, but I just want to bring your attention that it's also a bath salt, it's also a stimulant too. And overdose is a terrible psychostimulant overdose. So, in terms of our bath salts, I'll put that in quotes or psychostimulants, a lot is not really known, they're not really studied. A lot of our knowledge really is based on anecdotes and what our knowledge of amphetamine treatment, methamphetamine treatment is. Like I said, they're mostly stimulant, plus or minus hallucinogenic, depending on how that structure pans out. And they're used in all sorts of different ways, right? Normally people snort them or eat them. You know, I've learned over the years, you can crush and snort anything, you really can. So snorting and eating, rarely are they smoked, rarely are they injected. I'll show you some examples of injection while it's not preferred, but you can get an idea here from methylone, ephedrone, other bath salts. Onsets really quick, peak quickly, goes away quickly. MDPV was one we had seen a number of years ago, gosh, probably 10 plus years ago now. Onset was quick, peak was fairly quick, but duration was terrible. And with MDPV, sometimes we were intubating and sedating them, putting them on propofol because they were just so agitated, it was hard to keep them controlled. And it was a long duration, so we would just intubate them, sedate them and bring them in the ICU. So basically the pharmacology is the same, but the pharmacokinetics can be very variable depending on how many side structures and so forth are on there in terms of how they're metabolized. That's the nuance. So basically you don't really change what you do, it's just the duration of effects that you're gonna see in these patients. This was a fortunate patient who was at IV, and he unfortunately did not do well. But this kind of goes along the lines of why we try to avoid putting vasoconstrictive drugs through a peripheral IV, because you can get vasoconstriction. And I don't know exactly how this guy was intending to use it, but you can see it causes skin necrosis and so forth, particularly if you don't hit the vein correctly. So IV use has not been something that we've been seeing too often. And so, I mean, the psychosis, it's not a big mystery what they do, but tachycardia, hypertension, it could be the point of crisis, seizures, cardiac dysrhythmias, depending on the drugs, hallucinations, like I said, depending on the side structures, a lot of them say very psychotic generating in terms of hallucinations and so forth, self-injurious behavior associated with this, a lot of picking. So, I mean, you can see a lot of different effects from these drugs, depending upon exactly what you see, but this potpourri of different symptoms is very common with the psychostimulants. What do you do? I hate the fact that people dumbed down my specialty in a way that, you know, if they're agitated, slow them down. If they're hypotensive, give them a presser. You know, it's the aggressive supportive care model, but it definitely is in tox, right? So benzos for the psychostimulants tend to be our preferred treatment for them because benzos are pure. You know, they have one really great mechanism of action. GABA agonists, they're not going to prolong your QT interval. They're not going to make you more seizureogenic. They're not going to cause more dysrhythmias. We love in the tox land, we start with benzos always because it's just a great way in a pure fashion, not a lot of side effects that calm a patient down. So it's great first line treatment for the agitated hypertensive tachycardic patient. Now, once you start calming them down with a benzo, if you're not really making much headway and their blood pressures are really an issue and you're worried for a concern, then a short acting antihypertensive like fentolamine, nitroglycerin. We often use a lot of, a lot of ED docs are very comfortable with nicartapine and ephedipine because we use it for a lot of head bleeds. I think there's no issue with that, but fentolamine and nitro have been kind of the mainstay of treatment based on the literature. But certainly I would not begrudge anybody from using a calcium channel blocker. But in general too, I don't like using antipsychotics as a sedative in tox patients. Because you know, depending on the exact antipsychotic, a lot of antipsychotics are anti-cholinergic. Antipsychotics are pulling your QT interval. Antipsychotics can make you more seizureogenic. Antipsychotics can lower your blood pressure. I mean, there's lots of nuances, but in this circumstance, I think a dose of Haldol, a dose of your favorite antipsychotic is a good adjunct. You know, knowing the mechanism of action of what psychostimulants are doing to you in terms of causing a lot of agitation and release of catecholamines and so forth. And as an antipsychotic, you're blocking dopamine, which is probably a large portion of the cause of their agitation, of their psychosis, maybe of the hallucinations. So, you know, you give them like Ativan or Valium or whatever your benzo of choice is. You know, benzo, benzo, benzo. Would be my preferred way of treating these patients. And often when you give them that dose of Haldol, your favorite dose of antipsychotic, that's a nice adjunct to help calm them down. And you can't cool a patient down until you've calmed them down. It's interesting that the data shows hyperthermia is the best link to mortality in these patients. And you think about these patients, if they're hot, it's because they're running the equivalent of a marathon and are not the healthiest of sorts, right? So when they're hot, it's from all that psychomotor agitation, you have to cool them down. Is that if they're hot, that's the highest link to bad mortality, bad outcomes, but you can't cool them down until you settle them down. So chemically sedate them and then physically cool them with ice packs or cold saline or whatever you have. And you know, some, depending on the circumstances and depends how severe they are, you know, reducing stimulation, dimly lit room, head of bed elevated 30 degrees to prevent aspiration, physical restraints only until, you know, you can keep everybody safe and then you can chemically restrain them. You know, sometimes we're doing physical strains in the heat of the battle, preventing rhabdo and kidney injury by getting lots of fluids are often really dehydrated. We monitor the electrolytes, ferratinine and total CK, maintaining good chemical sedation to prevent the rhabdo and the kidney injury, then monitor the vital signs, right? Fever being critically important in monitoring. It's often the one vital sign that we don't get because it's hard to stick a thermometer in someone's mouth when they're agitated or up their butt. But certainly that's a critically important vital sign when we're looking at them and or short-acting antihypertensive, as I mentioned. And depending on what you're dealing with, the symptoms may last for days. So it has not been uncommon to intubate these patients, put them on propofol, shut it off, just shut them off for a few days until those drugs kind of go through their metabolic pathways. Again, chemical restraints, benzos, doping antagonists I talked about, Haldol. I use it usually in a limited fashion, as you know, because it has side effects. The one thing I do want to mention that we've had good success with is dexmedetomidine. Particularly for the really sick patients that maybe are intubated or in the ICU. Dexmedetomidine is an alpha-2 adrenergic agonist, right? It's a sympatholytic drug, and it's a great drug to bring down their blood pressure, bring down their heart rate, kind of sympatholysis. I don't give it without giving benzos, right? But to calm them down that way. But dexmedetomidine or Presidex is a really good drug that we found a lot of success with, particularly with our Welbutrin cases. Welbutrin and hydroxybupropion metabolite is very long-acting. When we see this patient in the ICU, we're often chemically sedating them for a couple of days. And so dexmedetomidine in our sick Welbutrin patients has been a good treatment for us. Now, this kind of comes full circle to our opioid psychostimulant. You know, we know somewhere between 50 and 60% of those patients are mixing their opioid with a psychostimulant. So what do you do? Obviously, it's hard for the layperson to do anything but give naloxone because that's all they have, and that's just sort of their knee-jerk response. But largely, my mojo is naloxone, for the healthcare provider, is not to awaken the patient, right? It's just to keep them breathing, keep them alive. Because precipitate withdrawal is terrible, unmasking whatever drug overdose or drug toxicity is intermixed with their opioid, I don't wanna unmask that. So the smaller the doses, the better, just to allow them to breathe and keep them alive is the key. The sleeping, breathing patient is, in my mind, in many ways, the best patient. Let them metabolize their freedom on their own. So really, the only indication for the healthcare provider should be apnea or hypoxia. Hypercarbohydrate would be another one. IV route is preferred because you can titrate it better. You know, we'll often give 0.4 milligrams at a time or 0.04 milligrams at a time, like really small doses every few minutes. Certainly, cardiac arrest may be pushing bigger doses. If you're in the field and you have nothing more than a four milligram intranasal spray, by all means, give it, but that's largely for the hypoxic or inadequately breathing patient. So not really intended to awaken the patient. And this, like I said, I think even knowing that opioids are mixed with stimulants in many ways, staying with small doses is critically important. And like I said, so, you know, our drugs, I can't speak for every drug screen, but our drug screen that we use here at UPMC is an antibody, half against amphetamine, half against methamphetamine. And so as you can see, the drug structures are very similar. They may trigger amphetamine screen positive, irrespective of which psychostimulant people are using. Certainly when you get down into the specific drug testing, you know, GCMS or LCMS, if you're doing more sophisticated drug testing for your substance use clinics, you may or may not find some of these psychostimulants because they may not be in the library because there's so many new ones out there. So don't be surprised if you see like a generic amphetamine screen positive, but you don't find a specific amphetamine because, you know, whatever drug testing laboratory, reference laboratory you're using may not have that drug in their library. So you may want to ask about, you know, how advanced their library is in terms of finding some of these new novel psychostimulants. So to close it out, oh, we're doing good on time too, perfect, is I just want to finish this talk and give you a few new emerging drugs, you know, that what's new, what's going to emerge. I don't know if these are going to be a big hit thing. You know, the nidazines that I told you earlier, I can almost bet my house that the nidazines are going to become very popular along with fentanyl as another opioid. These I'm not so sure about, but these are certainly ones that were, that are emerging and are out there and may or may not, but I just want you to be aware. It's interesting too, like I said before, you know, Chemical Frog is my favorite websites. I've never bought anything from there, honestly, but you can go on Chemical Frog. I think it's just chemicalfrog.com. If you Google search it, you can find all sorts of fun drugs that they sell there. And this is one of them. This is a tryptamine-based drug, you know, very similar to the magic mushroom and so forth. But if you just go on Chemical Frog, so a lot of these tryptamine-based drugs are becoming hip. I think it's largely in this, they're all natural, they're herbal. You know, I don't know, there's some appeal to that. So it's interesting they're sold as chemicals and the drug label, as you can see there, for research purposes only, not for human consumption. But I mean, obviously these are being sold for that exact purpose. So it's interesting what's out there. And man, you can buy anywhere from $50 to $780. I just got this offline a few days ago. So this is still there. So tryptamines are gonna be a top new commodity. And then 2C-X compounds, you know, we struggle to find these on our drug testing, which is the problem, so they're not easily detected, but they've been around for decades. They've been marketed as legal alternatives to ecstasy and other hallucinogenic stimulants. They often go ACID, B25, bromodragonfly are some of the common names out there. So when people say they're using ACID or people say they're using LSD, we really don't find LSD, we find 2C-X compounds. So it's interesting that I think what people think they're using is probably more in the line of a 2C-X compound. Not super common, but certainly out there enough. And you can see the backbone here. I got dopamine in the bottom and ecstasy in the bottom here on the left compared to, you know, bromodragonfly or 25B and BALM. You know, 2C-B, you can see, you know, some of these drugs and their similar characteristics, but very amphetamine-like-ish structures to those. Again, derived from 2C-B, marketed for decades, similar to ecstasy, first developed in early 2000s in Berlin, hallucinogenic effects, can last for a long time. And there has been, you know, news cases, you know, attributed to deaths and so forth with these drugs. So they're certainly out there, but to what extent, it's not completely clear. So, a lot, right? So that's my favorite drug down there, amphetamine. And the incidence is clearly on the rise, both mortality and non-mortality data. So this is an important drug class to discuss with your patients. And it's often mixed with opioids, you know, 50 to 60% of the time, certainly the majority of time, it's often mixed with opioids. Sedation for the acute overdose with GABA-Agnus is the key. Fever is critical to monitoring their temperature. A little bit of antipsychotic is always good. Naloxone dosing in our day and age. Smaller doses are preferential because the unmasking the psychostimulant toxicity or unmasking some other drug toxicity or unveiling precipitated withdrawal is not preferred. And as you can see that the novel psychoactive stimulants are constantly evolving, but that's why I'm a lumper in terms of looking at these kind of bigger picture. You can get a good idea of, they're all very similar. They have their little nuances in terms of duration of action and so on and so forth, lucinogenic effects, but they're all very, very similar. So with that little plug for the Pittsburgh Poison Center, Mr. Yuk, we love so much. Hopefully that was received well, Dr. Kimmick. Oh yes, we already got some people saying thank you and great presentation and wondering about your slides. Slides will be available on the website, on the AOAAM website under the hot topics. Under Dr. Poisson's presentation today. We do have one question here. Methamphetamine is not a metabolite of Adderall, but does Adderall result in positive point of care immunoassay for methamphetamine? Probably is the short answer there. What you should do is like check with your specific lab and they can give you more information because every hospital lab uses a slightly proprietary different product, specifically at UPMC where Julie and I work, Adderall would trigger our amphetamine screen positive and our screen specifically is amphetamine slash methamphetamine. Uses 50% amphetamine antibodies and 50% methamphetamine antibodies. So check with your lab and I would say probably does. So. We do have another question. How do you determine what is an adulterant and what may be a novel drug of abuse? Yeah, adulterant is typically not a drug that's giving you a clinical buzz, if you will. It's not the intended drug. So an adulterant would be something that is added, say like either is added to the loop down the drug. Like we see a lot of quinine, I would consider that more an adulterant than a drug of abuse. We see some quinine around, we see lopamisol in our cocaine around Pittsburgh a lot. So those I would consider more adulterants if rather than the true drug of abuse that is the intent of what they're trying to use. That's kind of the way we look at that. Okay. Do we know how much psychostimulant use is intentional? That's a good question. I don't know. From my experience, this is more anecdotes. I think it is intentional because what we're seeing at least in Pittsburgh is we see a lot of people who intend to use cocaine or methamphetamine and instead present as an opioid overdose. And they are opioid naive, but they were seeking out the stimulants. So from what I can tell anecdotally, I suspect a lot of them are intentionally looking for psychostimulants. And I think the psychostimulant use, it's never been a big thing in Pittsburgh as it was in Phoenix where I did fellowship. Opioids have always been the big drug of misuse along with alcohol, but I feel it's on the rise right now as well. On the slide of preliminary data, was fentanyl included in the opioids plus stimulant number of cases? Yeah. Opioids and stimulant number of cases. Was that, I can even go back here. Think on the dots. Yeah. Was it the dots one or the CDC one? Go back. Yeah. Still got to go back. Was it this one here, I think? Maybe. Yeah. Any opioid, any stimulant. Yeah. This includes all of them, but this is the one you're talking about. So usually when I'm using the word opioid, that will include fentanyl and any other opioid. You know, we see all sorts of different fentalogs. So that typically includes those opioids as well. Okay. So the line below where it has fentanyl plus any stimulant, and then there's going to be fentanyl plus any other opioids that weren't included in. Exactly. Okay. Thank you. We have a question about Selegiline. Which causes positive methamphetamine, which causes a positive methamphetamine drug screen? Does it have a similar amphetamine-like chemical structure? Yeah. You know, Selegiline is metabolized to methamphetamine. So, yeah. So Selegiline will be metabolized to methamphetamine. So in my mind, it's a true positive. It's a true positive in terms of meth. So that's the interesting thing about Selegiline is it's metabolized. For someone who is testing positive for amphetamine and claims to be using cough syrup, how can we determine if the amphetamine is false positive? Basically, you need to send that urine sample for comprehensive drug testing. So what you can do, you can ask your lab, if you are just doing point-of-care testing, you can call your lab or whatever your mechanism is and ask them to send it for confirmatory testing or conformational testing for what they found. And that will kind of tease out the specific drug. In most labs, we either use GCMS technology or LCMS technology to identify the specific drug that they found. Here's a question. Have the shortages of ADHD medication and or increased prescriptions contributed to increased street amphetamine use? You know what? I don't know, but that's a good question. That I don't specifically know. I'm not even sure if that's a known, if that is known, but that's a very good question. Yeah. What is your experience with testing positive for methamphetamine and they report using albuterol? Albuterol should not, should not typically trigger methamphetamine positive. I would, again, check with your lab just to be sure I'm not giving you bad information, but I can speak for what we use here in Pittsburgh. Albuterol should not trigger a positive methamphetamine drug screen. Okay. Another one about the toxicology testing. Is it possible to have a urine test positive for meth without amphetamine? Amphetamine should be a metabolite of methamphetamine, question mark? Yeah, yes and yes. But yeah, it is certainly positive. It was early enough. It's possible. So yeah, I mean, yeah, I think some purists may say otherwise, but I've seen every permutation of things. It's hard to say no to a lot of things. I think just about anything is possible these days. Do you think that psychostimulant test strips could be of social importance similar to how fentanyl test strips can be used? Maybe. I mean, I think the more knowledge that our patients have, the better in terms of what's available to them. I mean, I think it can only help them because clearly what people have access to on the street obviously is not always sold as billed. So I think these things would be very helpful to them for sure. I did have one question too. When you see people that are coming in, you get called to see them because it's psychostimulant toxicity. What is their initial presentation? Is it the altered mental status or is it cardiac in nature typically? Usually it's more of the psychostimulant agitation that's due to the big predominant thing. Depends on the exact psychostimulant, but typically they're just extremely agitated, coming in with police and they're being restrained and sedated and calmed down. That's probably the most common presentation. Okay. I'm not sure if this is something that you're comfortable answering. How do you address meds for opioid use disorder in a patient who's coming in with cocaine? Yeah, that's a tough one. That could be a whole lecture by itself, I suppose. Use that for the Dr. Kimmicks of the world to answer that. Yeah. I'm guessing that you probably, if you do see somebody that you have a low bar for starting them on buprenorphine, if they are using opioids and, but come in for the hospital for cocaine on your service. But yeah, that would probably be a question for another lecture in terms of managing that with your outpatients. There's another question here. Do you ever order racemic testing? You know what, Chris, I have not. And the reason is, the teaching is, if it's legal, it's the L-isomer. If it's not, you'll get more mixture, but we are seeing more and more illicit methamphetamine as the L-isomer. So I'm not sure how valuable the racemic testing really is anymore. And so I personally have not done racemic testing. I just haven't gone that far, but that is certainly something you can do if you're really trying to tease out illicit and medicinal use, but let it be known that a lot, because all these drugs are chemically synthesized, you know, and the chemical manufacturing process is not really well known, that a lot of illicit methamphetamine may be L-isomer. There is a long question that just came in, but I did notice too, it's 6.01. So I wanted to be respectful of everybody's time. I don't know if you have time for this last one. Sure. So it says, I work in corrections and some of my patients are dealers themselves. With regards to your statement that you see stimulants with opioid adulterants, no patients ever told me they intentionally add fentanyl to stimulants. Rather, it's the sedating effects of xylosine that lead to increased stimulant polysubstance use. And fentanyl is just so more potent that makes supply as an accident. Do you have any insight or opinion on if fentanyl is intentionally added to the stimulant supply? I don't, I honestly, I don't know, Chris. I just know anecdotally, and this is a little bit anecdote, right? Because the ones that I see come to me because they were trying to use Coke or meth or some stimulant, and instead they ended up in opioid overdose and have some kind of, you know, end organ dysfunction because they were passed out for a time. So I have a little bit of selection bias. I don't know the answer to your question though in terms of it's intentional or accidental or what have you. So it's a good question. Okay. Well, it's 6.02, so I just wanted to wrap up and thank Dr. Paison for the opportunity to learn from him today, from his clinical experience and his research experience with the Toxic Consortium. I wanted to remind everybody that we have another webinar next week, next Wednesday at 5 p.m. And we're going to have Dr. Joa De Aquino speaking on exploring the interface of cannabis, cannabinoids and opioid use disorder. So please join us again next week and thank you again, Dr. Paison. Thank you. Bye everyone. Take care.

AOAM webinar

Methamphetamine Toxicity

Dr. Tamee Paison

psychostimulants

opioid epidemic

epidemiology

pharmacology

toxicology

novel psychoactive substances

naloxone