Taking Healthcare by Storm: Industry Insights with Dr. Michael Hambuchen and Dr. Todd Davies

In this episode of Taking Healthcare by Storm, Quality Insights Medical Director Dr. Jean Storm speaks with Michael Hambuchen, PharmD, PhD, Assistant Professor, Department of Pharmaceutical Science and Research, Marshall University School of Pharmacy, and Todd Davies, PhD, Associate Director of Research and Development, Division of Addiction Sciences in the Department of Family and Community Health, Marshall University’s Joan C. Edwards School of Medicine.

Dr. Hambuchen and Dr. Davies discuss their motivations for substance use and overdose research and explain why combined opioid-stimulant overdoses are unpredictable and dangerous, including naloxone-unmasked agitation and complications from fentanyl contamination. They describe preclinical studies combining naloxone with dexmedetomidine to manage post-reversal agitation and with an alpha-2 antagonist to address fentanyl-xylazine effects beyond respiratory depression, and highlight the need for multi-pathway treatments, better drug-supply monitoring, and improved testing and long-term, customized therapies.

If you have any topics or guests you'd like to see on future episodes, reach out to us on our website.

The views and opinions expressed by the host and guests are their own and do not necessarily reflect the views, positions, or policies of Quality Insights. Publication number QI-022026-GK

Transcript

 Welcome to "Taking Healthcare by Storm: Industry Insights," the podcast that delves into the captivating intersection of innovation, science, compassion, and care. 

In each episode, Quality Insights’ Medical Director Dr. Jean Storm will have the privilege of engaging with leading experts across diverse fields, including dieticians, pharmacists, and brave patients navigating their own healthcare journeys. 

Our mission is to bring you the best healthcare insights, drawing from the expertise of professionals across West Virginia, Pennsylvania and the nation.

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Hello everyone, and welcome to another episode of Taking Healthcare by Storm. I am Dr. Jean Storm, the medical director here at Quality Insights. And just a little warning, we are jumping into the deep end today, but I think everybody is ready for it, and I sure am as well. Today's guests are two leading researchers in substance use and overdose science.

Dr. Michael Hambuchen, a Pharm D and PhD, and Dr. Todd Davies, a PhD. Their work focuses on improving how we respond to today's most dangerous. Overdoses involving fentanyl, methamphetamine, and xylazine. Through innovative preclinical research, they're studying how combining naloxone with other targeted medications may better reverse the life-threatening effects of these increasingly complex drug exposures.

Their findings have important implications for emergency medicine, first responders, and harm reduction efforts nationwide. So I am so excited to get started with this conversation. Michael and Todd, thank you so much for joining me today. Thanks for having us. So this question is for both of you and then maybe as we go, you can kind of choose maybe who addresses or you both kind of weigh in.

You both have advanced scientific training. What originally drew each of you into substance use and overdose research, and what keeps you working in this field today?

All right. I guess I'll take that one first. So, you know, I've had, you know, I have some family with substance use disorder. I don't, I don't think that's a, that's an uncommon, particularly here in West Virginia where we, where we're working.  But really I came down you know, my background is in clinical research.

So, I was running our clinical research center here and we had a bunch of data around neonatal abstinence syndrome and something that I was just learning about, and the dean at the time says, Hey, I've got a, we've got a bunch of data to do something with it. And so  so I did and I started, you know, pulling in the data and calculating and, and starting to investigate this area and very, S you very quickly realize that, you have kids that are suffering and then you have moms that are suffering, and then you need support systems for the moms. And then it just grows and grows and grows and grows from there to where you're looking at, you know, science from a whole community aspect.

And as a scientist, it's really fascinating to look at all of the community aspects and with all of these confounders and being able to tease out what's going on. So it's a fascinating field  but there's also a lot of interest. It's really it's great 'cause everything we do has an enormous impact on somebody In a good way.  You get to see, you know, from the clinical research side, we get to see some real success stories of people coming into our programs or coming into our clinical trials and really having a profound uh, effect on their lives and, moving forward. The number of, you know, most of the participants we get in our clinical trials.

Come to us from previous participants in our trials because we had such a profound effect on their lives. Michael, how about you? I just honestly when I was in pharmacy school, I just found the topic just so fascinating. And during most of the program we didn't talk about substance use disorder and illicit drugs really that much.

And it was just something I just kind of, my roommate and I actually just kind of took to learning about on our own. And then we had an addiction course in pharmacy school that was, run by somebody who was actually in recovery, who was faculty. And that really just I don't know, it just helped me understand that it was more, it was a disease state, just like any other, like treating diabetes or something, you know, a chronic disease state.

 And, uh, when I finished pharmacy school, I decided that I would rather contribute to pharmacy by contributing to drug development.  Rather than practicing as a pharmacist. and I did a, a rotation during my last year of pharmacy school and a pharmacology lab. And I, I just had a blast. And the preceptor asked me if I wanted to go to grad school, and he um, asked me what, what, what did I wanna work with and what kind of came to me.

I just kind of, the answer to monoclonal antibodies. And he said, well, you don't have to go very far for graduate school to study this. There's a gentleman that was actually just directly downstairs from this preceptor who, uh, developed anti PCP or odine and anti methamphetamine monoclonal antibodies.

And I was sold immediately. I basically set up a meeting and told s Michael Owens that I wanted to join his laboratory and, and help him develop these therapeutics. Just, and after that  I was on a 32. We actually interact with clinicians. You know, actually treating patients rather than doing basic science research like us.

And it really just, it, I guess it just made me feel more compassion for individuals that are suffering from substance use disorder. Just seeing like, you know, talking to the people that actually treat these people. And  when I came here and set up my, my own um, independent laboratory, I, I was just very excited to meet Dr.

Davies because. Ultimately  I want my work in animals to contribute to human health and he's given me a way to do so as well as been a huge influence on my research by making it more translationally relevant to human health. Yeah, I think that's huge, right? Translationally relevant.

And that's what I'm gonna try to do today with your studies for all of the individuals who are listening. So. listeners who do not have a science background, what is happening in the body during a combined opioid and stimulant overdose that makes these cases so dangerous and difficult to treat?

So we're, you know, talking opioids like fentanyl and stimulants like methamphetamine? Correct. So what makes a combined overdose, so difficult and challenging. I would say overall it would be the unpredictability of it. You don't, you don't know exactly what they're on. You don't know, you know, what, ratio there is of the different substances, so they can behave really unpredictably.

And for example, with methamphetamine and opioids, you have two opposing effects on the cardiovascular system with the opioids causing, you know, more like bradycardia and hypotension while the amphetamines are causing the reverse. In addition to this, it makes it harder to detect opioid induced respiratory depression.

And in addition, the opioids can mask the methamphetamine induced agitation. So like methamphetamine, ag induced agitation is a major concern upon acute presentation and, and methamphetamine overdose. And, so I guess like with the opioid present, it can match that. And when Naloxone's administered, it would unleash this agitation.

 another, uh, factor that I find probably the most scary out of all of this is the adulteration of methamphetamine. So when individuals are taking or using methamphetamine or cocaine, and they don't know that fentanyl's there, they don't intend fentanyl to be there. And these patients will be less likely to have naloxone on hand as well as they're not gonna be as tolerant to the opioids as well.

And Todd could add in anything I'm missing here. No, I think got as usual.  you nailed it.  think, one of the issues is there seems to be  when you look across the data, there seems to be.  A higher incidence of overdoses when there's a speed ball effect where you have an amphetamine with a, with an opioid.

Prevailing theory is that's because the amphetamine is also causing vasoconstriction along with the respiratory depression. So you know, we know the combination is, more severe. We also know that in the patient population, the people that are, using a list of substances or, in a, in a more  severe state of active edition are more likely to use the combination products.

So there's a whole host of confounders there that are working, but there's clearly, as Michael very clearly addressed. There's, there's some physiologic things that we're, we're trying to avoid, and it, can be one can mask the other  but those symptoms can pop back unexpectedly sometimes.

Yeah. Scary. Scary. So the, the Fentanyl methamphetamine study looked at combining naloxone with DMed Toine. I hope I say that right. Uh, It takes practice for sure. Yeah. But in simple terms, what problems were you trying to solve for first responders and emergency clinicians?

Well, really, and, I'll throw this to Michael here in a second. to give you more meat on it, but you know it  the by, by giving Naloxone with Dexa meine  the idea is, you know, to suppress primarily that, amphetamine induced agitation, right? It can cause a lot of problems in the field for some of our first responders and our emergency room clinicians.

It's less of an issue in the emergency room 'cause they have a number of medications that they can provide.  But that agitation can, can be a real problem. The other issue is oftentimes you'll have individuals who are not enthusiastic about, interacting with the healthcare system or  if they're overdosing, they can get combative.

So, so the, the sedative nature of the DEXA melatonin can create a, a, a stronger safety profile for our first responders in our emergency room clinicians. and so like the beauty of Todd, were you done? I, I didn't mean to jump in. I'm excited about this, I suppose. Oh, man. Go all. All right.

So the, the beauty of using DIN for this, so actually, well, the idea came from I, we just kind of heard about. Actually, I heard it from Jan Rader about they were seeing this like with the unmasked agitation with opioids and the stimulants together, and I just kind of put in the back of my mind like, man, we could do that in rats like that, I can design this study, but I, I didn't really know what I wanted to use for the treatment because typically you would use like a benzodiazepine for like acute meth induced agitation.

And, and my concern there was that the benzodiazepine could have a, a drug interaction with the co-administered fentanyl or heroin or whichever other opioid, because the naloxone has a pretty short half-life and either fentanyl or heroin in its series of active metabolites that they last longer. And so there's a conservative interaction there.

And so the beauty of DME Atomidine. Is it doesn't produce major respiratory depression on its own. Like you have to push a dose aggressively to produce respiratory depression. And clinically I guess the rule of thumb is basically it does not produce respiratory depression. And even better, it doesn't exacerbate opioid induced respiratory depression like benzodiazepines do.

And then besides that the drug's also really easy to work with.  it's bioavailable, like it could be absorbed by several different routes of administration. It's even compatible in solution with Naloxone as well.

Yeah. And so Dexa Benadine is a  one of a class of drugs of, of what we call alpha two agonists. And so what these, what this activity does in the body is it suppresses the, some of the stress system, right? So you're, it, it suppresses the receptor that is affected by epinephrine, no epinephrine.

So. The sedate of effects. It, it, it counterbalances that the body's overall  reaction to, you know, severe stress. And so it can make certainly it makes it in the animals, but, in humans as well. It can create a, a more, not just compliant patient, but it, can calm down a lot of those systems that are problematic.

 In terms of, you know, like the agitation that cause a variety of issues in the clinic, but also for, for the patient in terms of a rapid recovery and like building on what he just said right now. That's one real, he, he mentioned like, you know. Patient cooperation. That's one of the beautiful things about Dine is it produces a type of sedation that has a lot of in common with like natural sleep.

And so individuals and rats as well as we've found, they can, you can interact with them and, and  you know, give them, well not, you don't give the rats simple commands. They never listen to me. But you could interact with the patient, you can give them simple commands, and then once you finish interacting with them, they should go right back to sleep.

So what did your findings show about managing severe agitation after Naloxone reversal? And, and maybe we should touch on why this is such a critical safety issue for both patients and healthcare providers.

Oh, absolutely. So, it's basically that this agitation  it's dangerous for the patients  especially if, if they are manually restrained.

It's associated with like rhabdomyolysis and additional toxicity. And this is also extremely dangerous for the, or potentially extremely dangerous for the individ, for the clinicians that are caring for these patients because the agitation, I mean, it could range from just excessive movement. Up to, you know, potentially violent movement that could be, you know, a danger for the clinicians caring for these patients.

Yeah, I don't know if people really truly understand this. So if you have somebody who comes into the emergency room and they've had a fentanyl, methamphetamine combination, overdose, if you give these individuals Narcan, this is what we were just saying in this study. They become, can potentially become severely agitated because you're reversing the fentanyl.

That's why this work with the Dine, which I'm, this is gonna be the last time I'm gonna say it on the podcast, so very important because it's, we're able to manage that agitation. So we keep healthcare providers safer, we keep the patients safer, so that's why this study is so important. I wanted to switch gears a little bit and talk about Xylazine, because xylazine is being found more frequently in the drug supply.

It is typically a veterinary anesthetic.  It will put animals, you know, to sleep. So how does Xylazine change the traditional opioid overdose picture, and why doesn't Naloxone alone fully address it? Okay, so Xylazine definitely complicates it. And, and with Xylazine, I think we need to talk about Meine, which is, which is now in the illicit supply as well.

And Medit Toine is directly related to Dexa Meine. So  this is all gonna be relevant as we, identify what's going on with this. So when you look at the suite of Alpha two agonists. Which is both xylazine and Meine and Dexa meine are all in this  in addition to  commonly used medications like clonidine or laine or guanine, they're all alpha two agonists.

So Dexa meine is the strongest alpha two aus that we know. So it, causes the most significant effect. On that, on the adrenergic in, in terms of suppression of the adrenergic receptor, which is where epinephrine and no epinephrine vines. Xylazine is actually a really weak alpha two agonists. So some of the effect is coming from that suppression, but it also has some agonist effect in, in terms of, it activates what we call the kappa opioid receptor.

So, so there is some issues with more respiratory depression with xylazine than there is with a pure F two agonist like dexa meine. And stop me if I'm, if I'm confusing here. So with Xylazine, you see a lot of these weird effects in terms of the, the sores you see, the sort of phantom, you know, the zombie movement as, has been in described in a, a number of publications.

How much of that activity is due to the alpha two agonists and how much of it has to do with the agonism of the kappa opioid receptor? I don't think we really know that. And because you have this sedation, right? So both xylazine meine are gonna have this sedate of effects. So when Naloxone is administered in somebody with, with Xylazine, you're gonna get back about 80% of the respiratory activity.

So there's still oftentimes our, first responders still have to provide supplemental. Respiration for these with meine, we have seen, we don't have that same effect. So Naloxone can return a hundred percent of the respiratory depression. So, you know, they, they're getting oxygen, but they, but they remain anesthetized so they're unconscious.

But their oxygen is, coming back up. And, you know, when you start dealing with this sort of variety of, different kinds of drugs in the system, we still don't know enough about how these various polysubstance effects happen. So, but just talking about.

these alpha two agonists with fentanyl and, usually there's fentanyl and amphetamines. As the, dealers sort of learn how to use these medications, we're seeing a variety of combinations. Cause when a, person is, you know, goes and they get a heroin and an amphetamine mix, if there's xylazine in it, a lot of times they didn't like it because they would pass out and they would miss their high.

Yeah. And so they, they didn't wanna buy those, those drugs anymore. And so now what we see is a lower. Amount of xylazine, we'll see fentanyl, a combination of fentanyl, methamphetamine, cocaine, to sort of balance out the euphoric effects that people are getting from xylazine without completely anesthetizing them.

Yeah. So it's so, it it gets very complicated. Yeah. And, and when we look at Dexa Meine, right, the idea is if you are , given it by a healthcare provider, right? All drugs, even fentanyl when used properly by the appropriate healthcare provider is a very useful, very successful medication.

Dexa Meone is going to be in that same area, right? So it can be used. The, our, you know, our, our concept, we're still in animal models here. The, concept is it can be used to provide some lighter sedation  without using benzodiazepines, without using some more severe medications. Unlike a lot of the other Alpha two agonists, DEXA Meine is sort of a pure alpha two agonist.

It doesn't have a lot of other side effects, so, yeah. Yeah. So, so by focusing on that, you, you know, you hone it down to just that suppression of this, of this stress management system and avoid some of these, these other effects. So we think and again, there's still a lot of work to be done, so we think this is the medication that might be able to be used to.

Assist 'cause we don't see the respiratory depression to assist with handling these more difficult patients in a way that allows us to get them the, more advanced care, more appropriate care  more quickly. So this study that looked at reversing the Xylazine fentanyl combination overdose, I know there's, you said there could be many different drugs in mm-hmm.

 Combination. So this study looked at naloxone in combination with Aamaz Aamaz. Yes. So you looked at multiple physiological effects, like heart rate, body temperature, blood sugar. You were talking about respiratory depression. Mm-hmm. So why is it so important to reverse more than just. Respiratory depression or you know, someone's not breathing.

Like why is it important to reverse, you know, the effects on heart rate, body temperature and blood sugar as well,

I guess considering all these other factors. I mean, it's just there are contributors to the overall, you know, toxicity of the drug, but yes the respiratory depression, I mean, that's absolutely, you know, vital to deal with because if we don't get enough oxygen, we, we die quickly.

But with the other factors like they, they can result in, in toxicity as well. And this is something that, like working with Dr. Davies has helped me with so much. Is like thinking about my rats and these studies as like little patients basically. And so yes, we have like, you know, primary outcomes, but what we've been doing lately, uh, last couple of studies is really.

Digging into the side effects that occur as well. So we're trying to um, not just treat, you know, a single system, you know, we're trying to do the best we can to treat the patient. And the same thing with the, the DME hominine, like the, the most common side effects of dme, hominine is really bradycardia.

And then it could cause hypotension or hypertension, depending on. Dosages, like with what we're looking at. Mostly it's gonna be hypertension. And so that, that's, for example, that's a side effect of ded atomidine. But we're looking at these agitated patients. You know, another concern with methamphetamine or cocaine would be, you know, tachycardia and hypertension.

And so this side effect of ded atomidine could actually be useful there as well. Yeah. like I said, I feel like these two studies are very exciting and, you know, I guess just kind of looking at them together. So how could your two studies realistically change the way mixed drug overdoses are treated in ambulances, emergency rooms, or  in the community in harm reduction settings?

Well, I mean, it's about finding, new effective combinations that directly address the polysubstance issue Right. At the end of the day.  and Michael has been absolutely brilliant in, putting these together and building the, you know, the wrap models that really are as close as we can get 'em translatable to what we're seeing in the, human population.

But the idea is, can we. Provide appropriate supplement. Can we get at the. Molecular systems in terms of stress management, in terms of respiratory depression in a way  that is more effective than we're using. So, you know, Naloxone directly affects the opioid receptor, right?

And so the fentanyl affects the opioid receptor. The amphetamines are going through a different pathway if we're, if, if there's xylazine in it, they're going through a different pathway. So if we are not addressing the multi pathway approach in the polysubstance, which is, which is the reality of most overdoses these days, then you know, we're really we're not serving the public as, as well as we should be.

And one key area, we, think is the, the first carrier to look at is really in the alpha two agonist area. So we can find a way that we can treat these patients without exasperating the, the respiratory depression or, and, and. Controlling the agitation so we can keep our, our healthcare providers safe.

So we really do think this area is going to  change the way overdoses are treated. not as soon as we'd like to, again, 'cause research takes a while, but uh, unfortunately, yeah. Yeah. So yeah, like exactly what Dr. Davies said there. Basically we're, we're trying to create more tools for the clinician's toolbox for, helping these patients here.

And something you, you said kind of sparked something from that Xylazine or from the Naloxone Aamaz. Study and what Dr. Davies just said about, you know, we're trying to, you know, so help treat these issues without making other issues worse. We actually  used our preclinical models to do some of that with Xylazine, fentanyl and, and methamphetamine.

So just based on how AAMAZ all works, what's blocking the alpha two receptors, an alpha two antagonist, it can produce some stimulant effects on its own. So I had a concern. With  AAMAZ being used in combination, you know, if methamphetamine is present. Mm. And so we, we simulated this in, in our rat model, and so we had rats that were administered  fentanyl, xylazine, and methamphetamine.

And what we found with the Aamaz was that if we dose the aamaz properly, if we use just enough to, arouse, the rats from the deep sedation. It was fine, but if we gave excessive aamaz, it actually enhanced and prolonged the model of meth induced agitation of these rats.

So it definitely is a balancing act, just like Todd said. Yeah, I think this is so interesting. You know, I think about this a lot just with drugs that are legal to give patients You never know what the combination, you know, you have the effects of one and then the effects of another.

And sometimes when you give them combined, you don't know what the effects are gonna be combined. So I think this research is so very exciting and interesting. So last question. Looking ahead, where do you see the future of overdose reversal and substance use disorder research going? Especially as you said throughout our whole conversation, the drug supply is becoming increasingly more unpredictable.

I don't know where. It is going. I think Todd will have more insight on that. I know where I'd like it to go. I would like it, I would like to have more consumer level testing strips for the drug supply so people actually have some sort of idea of what they're using.  As well as I feel like substance use disorder  therapeutic development, I feel like we're going, it, it's, it's got to get better soon because I, I feel like a big problem in the past.

When you're testing these drugs the regulators, I guess one of the drugs to work kind of like amoxicillin for an ear infection, you know, give a short course of therapy. Oh wow. They're now, they're cured. the more modern understanding of substance use disorder, where it's more of a, chronic disease that needs to be treated  long term like, like diabetes or something like that.

I feel that just that mindset. Is going to improve  therapy. Something I've seen interacting with, like Dr. Davies and the clinicians that he works with is like a lot of the things that they actually get to work and individual patients are really highly customized for these patients. So I, I feel that we'll have you know, greater customization of these therapies, or I hope we do because it, it seems like it's, working pretty well. And, and another factor is, I, feel like when we published the first paper with the DME Toine Naloxone, there wasn't a whole lot of labs that were really looking at polysubstance use disorder. I felt like a lot of what I was seeing in , the, the literature was a bunch of single agents, but I feel like, at least on the preclinical side it's really ramped up the last couple of years.

Hmm. Yeah, and I think one of the things that we're trying to do here is, put a system in place so that, we can identify these things more quickly. It takes a while for our, toxicology labs to be able to build, you know, testing systems for the changing drug supply.

But we can see some of these things coming, right. So we knew Xylazine was in the, drug supply in other parts of the country before it came here. We knew melatonin was in the drug supply before it came here.  And here's a story. So we were I got a call one night from one of my, colleagues that, is connected throughout the state and, and she's like, look, you know, we've got this weird drug happening.

We've got these weird symptoms of. And we don't know what it is. Well it just so happens that Michael had called me the other day and say, Hey, there's these weird symptoms that the rat's having with a combination of, melatonin and fentanyl that are, that are interesting.

And so I was able to translate that. Because Meine, which is closely related to Dexa, Meine had come in the area, was in the illicit supply, and I was able to provide guidance to some of our, our, our hospitals in the area that were seeing it because of the animal work that we were doing and, and I think where we need to be.

Is to have this translational piece as part of the monitoring system where we're continuing to look at these variety of illicit substances. We're continually trying to, to look at these various mechanisms.  I do think the alpha two is, certainly gonna be an important target in the drug supply.

But that sort of. Vigilance right system. Having it in place where we can look at things ahead of time in the animal models, and so we have information  it may not directly carry over  but in the case of, you know, the recent case that we, we had it, it did translate  yeah, pretty straightforward.

And, and I think that's where the future of overdose reversal. , And substance use research is, gotta be. Right. So, and then everything we do in the lab can be built off of that. So the variety of things that we do, the variety of mechanisms that we look at, we know aren't gonna have pretty immediate real world value.

Yeah, that was a clear example of that.  the beauty of, you know, readapting these drugs. Because if you can use a drug that's already been FDA approved, we've already got the safety data. We already know about a lot about the drugs  in humans.

 And also uh, building on something Dr. Davies was just talking about, Naloxone Aamaz trial was directly from Dr. Davies's clinical experience. He actually requested me to create a model of fentanyl xylazine co intoxication. And that's actually where that project came from.

He wanted to build a model and we built it and started testing some drugs in it. Yeah, it's, it's exciting and I'm ex really excited to see where it goes. Dr. Michael Hambuchen and Dr. Todd Davies. If people want to find out more about this research or about you, how can they do that? We're, we're both available.

I'm gonna recommend that you email Michael 'cause he's better at it and smarter than me. Um, oh, that, Michael, what is your email?  My last name  however it's pronounced bu he, I don't know how to say it either. So, at at marshall edu if you search for my. Goofy last name and the word methamphetamine. You'll probably find me pretty quickly. Okay. We will link that in the podcast and we will  maybe provide a link to the  papers we talked about today and, and we'll have another paper for you to look at soon.

We're actually finishing up edits on our most recent preclinical project here. Oh, very exciting. Well, thank you very much for joining me today. It was a very interesting conversation. Thank you. Thank you.

Thank you for tuning in to Taking Healthcare by Storm: Industry Insights with Quality Insights Medical Director Dr. Jean Storm. We hope that you enjoyed this episode. If you found value in what you heard, please consider subscribing to our podcast on your favorite platform.

If you have any topics or guests you'd like to see on future episodes, you can reach out to us on our website. We would love to hear from you.

So, until next time, stay curious, stay compassionate, and keep taking healthcare by storm.