The so people will be trickling in as people trickle in I mean, there are plenty of seats right up front here and In case you Need orientation to sort of what this top what this talk is. This is it. We're going to be talking about psychopharmacology you know around addiction psychopharmacology and and some of the ways to kind of think about incorporating that into general or general psychiatric or other practices and My name is Jeff DeVito, and I am the I see this space set up here for the other presenters I'm not gonna hold my breath for them to show up because it's just me So you're stuck with me for the next 90 minutes? and I've got a lot of ground to cover, but I want to start by just way of introduction What I'm aiming to do today is to provide Or try to provide that balance between You know the on one hand the clinical practice and sort of what you can try to do clinically and then also What the evidence base says and what the research does I'm going to try to navigate those two worlds and you'll see me You know struggle at points to kind of try to balance sort of like what the research says relative to sort of what might? Be useful in clinical practice. So who am I? What do I do? I'm not a researcher I Am based out in California. I work with a number of sort of Medicaid Related entities out there. I've got you know working in NTP. I work in County Community Mental Health Center, and I also work with a Medicaid managed care plan Why am I giving you all of that as way of background? because some of the cases that I'm going to be drawing from today are going to be drawn from my experiences in those settings and I'm going to be looking a little bit more at sort of individuals that are you know, perhaps a little bit more complex to draw out some of the themes that I'm going to be talking about today and So with that Got some disclosures. I have to disclose that I do have some equity shares in some companies that I shouldn't and I Always have to declare these it's from an inheritance but Be it be it known that that is what I'm disclosing financially a couple other things to talk about here, you know Primarily, I'm gonna be I am gonna be talking about off-label uses of some medications I'm gonna do my best to identify that as we go along because much of addiction psychopharmacology and treatment is Off-label because we use things that may not have FDA indications specifically for particular indications Also disclosing here that I'm the lead editor for the forthcoming APA publishing third edition of the clinical manual of addiction psychopharmacology This has been a long time in coming I'm actually meeting with the publishers right after this to talk about where we're at with that But that will be forthcoming. So a lot of the material that I'm going to be drawing from today Is actually a sneak preview of some of the stuff that's going to be in that textbook So just to alert folks to that piece of it. This is a the cover for the second edition I've been negotiating with them about a more exciting cover perhaps for the third edition, but As I mentioned before the cases that I'm going to be talking about are based on real cases But there are amalgams identities have been shifted significantly and the discussions are not intended to be sort of like very specific sort of treatment recommendations, but That's what it is so Objectives for today. I want to introduce at least my framework for thinking about Approaching pharmacotherapy for substance use disorders in complex patients this is just what I've arrived at through the years of working in different settings and Take what you will from that and I also want to review the state of the literature on pharmacotherapies For substance use disorders for a number of substance use disorders that you can you know that I have listed up here This obviously is not comprehensive I tried to cherry-pick some of the ones that I thought we would be most interesting and perhaps most Clinically relevant to a lot of your practices depending on where you're practicing and what you're seeing and I am going to frame it like I said around three separate cases You'll see I'm going to be using the cases as kind of a springboard to then talk about some of the pharmacotherapy research and then Try to tie that back into then thinking about like oh, this is how I would potentially approach You know this particular patient or some of the the strategies that I might employ in those situations There's going to be a lot to I'm going to be focusing primarily on you know psychopharmacology, but I always want to make the caveat here that that I'm not I'm not saying that Psychopharmacology is the only way and the only aspect of treatment that we should be considering lots of different psychotherapies behavioral interventions alongside Pharmacotherapies that that can be very effective just for 90 minutes I had to kind of condense it and kind of focus on the pharmacotherapies and that was the topic that I was asked to present on so with that I'm going to introduce here in the beginning sort of my Framework for thinking about like when I'm talking with folks I do a lot of talks sort of across Northern, California for example in a lot of rural health settings and There you know the idea of like having a psychiatrist actually come and talk with them about how we think about approaching complex behavioral patients is kind of a luxury and in a lot of instances and So I try to kind of Make it distill it down into something that is accessible for the most number of people who may not be total you know Behavioral health experts so to speak. So first thing I like to say is make the darn diagnosis some of you may have encountered this right where For a lot in a lot of instances. I'll go in the room to talk about a complex case Someone will present the case and they will say oh this person, you know, they've been using this they've been using that and I'll ask the question like has anyone ever made the diagnosis of opioid use disorder Has anyone ever made the diagnosis of the one that never gets done, especially in California cannabis use disorder Has anybody made that diagnosis yet in this patient? Let's let's name it I had a supervisor in training that used to you know used to like to say this too which was you know put your nickel down say what you think is is the diagnosis because if you if you identify the You know when you make a diagnosis the treatment has a tendency to work better So make the darn diagnosis second thing Know your enemy to some extent That doesn't mean that everybody needs to be a an expert Psychopharmacologist around how methamphetamine works, but just knowing some of the basics around how alcohol works in the brain how methamphetamine works how opioids work knowing some of those basics can be helpful because the pharmacotherapy is really stem from that and provide some anchoring to that and This is where you're knowing the basics about your options knowing the basics around what research is telling us Around what's effective for different substance use disorders? I also encourage people to think about when you're encountering a patient with a substance use issue Think about what phase of their use pattern they're in are they in the intoxication phase are they in withdrawal? Are they in post acute withdrawal or are we thinking about maintenance? where they've been off of substances for a while and you're looking to kind of enhance the Their recovery process, but thinking about these phases is helpful because the pharmacotherapy is Can be you know, it can be different in those different phases This is one I had a talk this morning where I mentioned this as well and this is often something for me that happens where Complex patients lots of things going on lots of psychosocial issues Lots of medical issues lots of psychiatric substance use issues and I say listen take a mess and pick a starting point Think about where you're gonna start and just start you have to enter into the fray at some point and There's not a script for where the best place to start is but be comfortable with thinking about pick a starting point For me. I often use the the the thing in the back of my mind that I'm thinking about is sort of what's the most Dangerous thing to them right now in terms of their substances or otherwise like what's the thing that could kill them today? What's the thing that could kill them tomorrow and work backwards from there? And again, not a perfect model, but you need to start somewhere So the other thing I like to encourage people to do is treat the symptoms in front of you and the example that I like To give around this is is think about the individual that's using methamphetamine I know that might be hard for a lot of people to imagine it might not be something people have seen before in, California Every day see this all the time very very common and one of the things I often hear when I'm talking with people about like managing folks with methamphetamine use is well They're psychotic, but the psychosis is due to the methamphetamine so I'm not gonna treat that that needs to be treated in substance use and What I try to reorient people to is that the psychosis is the psychosis They might have gotten there because of methamphetamine They might have gotten there because of schizophrenia. They might have gotten there from some other reason, but treat the symptom That's in front of you if the person's coming in and they have psychosis treat the psychosis Be mindful about trying to understand why they might be psychotic what might have led them to that, but at the same time Don't be afraid to treat the symptom that's in front of you As Always consider medical and psychiatric co-occurring conditions think about these be mindful of these in in some instances These can be can be relevant I think sometimes people get really caught up in the idea that like oh this person has this you know medical condition So I'm very nervous about treating them and oftentimes I have to kind of reorient them and say you know the classic thing as well I I don't know their LFTs are a little bit up because they've been drinking. I don't know if I can give them naltrexone It's like well, they're drinking You know like that's also gonna have an impact on there. Thank you. There was some laughter there That's also gonna have an impact on their LFTs so be mindful and be aware of these things, but don't necessarily make Let it scare you off from treating folks This is one I used to I used to say kill two birds with one stone And then somebody corrected me recently and said it might actually be a little less You know jarring to say feed two birds with one stone so by this I mean think about if people have co-occurring issues, and you'll hear me talk about this in some of the cases if there's a co-occurring You know alcohol and And opioids you could think about naltrexone, you know think about things that might have multiple purposes think about you know bupropion for smoking as well as for Stimulants like for example, and you'll hear me. These are specific examples from what we're going to talk about One thing that for me mentally that I think about when thinking about Medications and treating folks and this isn't just for addiction psychopharmacology But this is just a again you're hearing my framework for thinking about this I reframe in my own mind thinking about all medication conversations are in negotiation and To me that's helpful because it starts to get me in this mindset of like I'm working with this other person to find some Common ground and some common end point and that's a negotiation And I'm going to talk a little bit about what what I mean by that and we move forward so This is the last one don't be afraid to get creative and be pragmatic and think outside the box Example of this was asked to see a patient that was using a lot of alcohol but had very very significant cognitive impairment and Was living independently, which was surprising but very very very very limited short-term memory and every day would go out and would visit the local the local liquor store and Would get you know beer and bring it back to the apartment and people like well We can't you know, we this person needs residential substance use treatment and I said well What good is that going to do this person isn't going to be able to necessarily? Process and learn skills in the way that we would expect them to so With this person. I'm thinking more environmental modification What can we do to make it less likely that this person is going to go and get alcohol? So we talked to the store owner and we said is there a way that we could kind of steer this person if they do Come in to buy something else The family was involved in all of this as well and the other thing we did is we stocked his fridge in his apartment with non-alcoholic beer and That actually helped because he went to his fridge and he would take it and he he liked the taste of it I guess but that he wouldn't go out to the liquor store as much and obviously he wasn't getting as much alcohol that way So that's again. Are you gonna find that in a textbook in terms of an approach? No, but Don't be afraid to get creative and to think pragmatically and to think about other modifications that that might be necessary. So We're gonna cover a lot of ground. I Love Gary Larson My kids I've introduced to them and I'm glad that they're starting to appreciate the humor of this as well But if we pull this off, we're gonna eat like kings We've got a lot of ground to cover if I pull this off. We're gonna eat like kings. So for starters I want to talk about negotiations so This is a framework that I find to be useful in thinking about Approaching conversations with patients about medications Now this is from I've pulled here from you know, Chris Voss never split the difference folks heard of him or seen his TED talks They're they're very compelling. You can look at the the TED talks or read the book In this he was an FBI negotiator and he talks about sort of like how to do negotiation and There were a couple things in how he describes this that I thought were useful for the practice of medicine for the practice of psychiatry one was sort of he talks about this idea of tactical empathy Now that's not quite as as as gentle as sort of, you know Am I empathy, you know that we talked about motivational interviewing, but he talked about tactical empathy Which is that the it's more than emotional understanding it's trying to recognize the other person's worldview their fears their aspirations and That having trying to really understand that will give you an advantage when thinking about how to then communicate with that person and how to Understand sort of like where they're gonna be able to meet you and where they're not going to be able to meet you The active listening again. This is also very much sort of motivational interviewing and in some ways 101 He talks about doing this accusation audit where you list the worst Accusations that the patient could make against you and then address them up front So kind of address the power differential in the relationship right up front talk about that like, yeah, you know Why would you trust me? You know like what? What you know really opening that and creating a space for them to talk about that is helpful in framing the the conversations And then well-timed questions So he talks about this idea of like that that's right moment Where the person that you're talking with says that's right where you find some synergy between what they're expressing and what you are also listening to and trying to convey and Recognizing that like okay when I get a that's right moment. I need to I need to build off of that I need to I need to use that as my anchor point to then be thinking about pivoting into conversations about You know what we're doing with the medications because all of this is an attempt to build trust and connection with the patient so Again, I'm setting the framework here before we kind of talk about the nitty-gritty of this study said this this study said that because I want people to keep in mind that like this is what we're doing We're trying to build trust and connection because you could understand every study in the world on Bupropion you could understand the positive studies the negative studies in terms of methamphetamine use with bupropion But if you don't have trust and connection, it's not gonna matter So that's that so let's talk about start with a case here Schizophrenia methamphetamine and nicotine anybody seen this before I Got some laughter. I got some some motion there. I Try my best to make this as riveting as possible Try my best to make this as riveting as possible 35 year old man history of schizophrenia methamphetamine use disorder tobacco use disorder traumatic brain injury of unknown severity Chronic lower back pain and homelessness uses methamphetamine daily two packs per day tobacco cigarette smoker I threw some COPD for good threw in some COPD for good measure Myriad other things on top of that. So again Complex patient. This is a the kind of patient that a lot of providers are gonna run the opposite direction say Too much, right where to even start with this. So first thing again thinking about my framework make the diagnosis Spend some time figuring out like methamphetamine use disorder nicotine use disorder identify it. You know, I mean How often do you look at a chart where the person smoking two packs a day and they don't list? Their you know tobacco use disorder as part of the as one of the conditions that they have make the diagnosis put it down Know your enemy So very very specifically here again, I'm doing some very basic level methamphetamine What does it do it increases transmission of monoamine neurotransmitters dopamine norepinephrine and serotonin? It blocks reuptake and it also stimulates release of monoamine Neurotransmitters, I pause there for dramatic effect cocaine a lot of times people say well cocaine is just the same thing as methamphetamine or If a study worked for cocaine, it's gonna work for methamphetamine Can't really make that I think it's a good starting point if you're gonna research something and say oh There was a there was a signal in the literature with cocaine patients Maybe I want to study that in methamphetamine patients But remember cocaine does not stimulate the direct release of mono amines It blocks the reuptake, but it doesn't stimulate the the release the analogy that I've used with patients is I say You know what methamphetamine does is it takes those neurons and it and it squeegees them Every every bit of dopamine that it can get out it squeegees all that dopamine out Cocaine just kind of takes whatever was whatever came out and just keeps it from going back into the cell so it's it they're different beasts I Love putting this one up here because again, I do a lot of community presentations and I'm like, you know You can get methamphetamine over-the-counter You can you can go into You can go into CVS. And this is this is me. I went into CVS. That's my hand. I went into CVS and I got lev met amphetamine, okay, so they spell it differently and I don't know if that's like the European spelling but the So that's a levo methamphetamine, so there's you know the two isomers of methamphetamine levo methamphetamine is not felt to be a Psychoactive but it is a pretty good like bronchodilator And these are the inhalers like you can buy these over-the-counter. So methamphetamine a little side note just kind of keep things lively What does nicotine do? Nicotine or s nicotine which is found in tobacco Binds stereoselectively to nicotinic cholinergic receptors and specifically the alpha-4 beta-2 nicotinic cholinergic receptor nicotine causes the release of dopamine in the Mesolimbic area the corpus striatum in the frontal cortex. So some commonalities nicotine Also produces the the release of dopamine not as much dopamine as methamphetamine But there is a common final pathway there between the nicotine and the methamphetamine and you'll see this in all substances of misuse that one of the final common pathways is release of dopamine that triggers the initiates the process of the euphoria and getting people Getting people in the behavioral pattern of using so Back to the framework know the basics about the options know the clinical phase that you're in I want to draw people's attention when we're talking about stimulants broadly That recently the ASAM and triple AP published this the management of stimulant use disorder guideline Which is available if folks haven't seen this. This is really this is really pretty comprehensive It has a lot about behavioral interventions lab testing How you do assessments? You know different medical cautions around, you know considerations with people who are using stimulants Also talks about psychopharmacologic interventions now the next couple slides I'm going to draw Heavily from these stimulant use disorder guidelines in terms of pharmacotherapies for for methamphetamine use disorder Specifically so first of all we think about like phase of phase of Phase phase that the patient is in when they're coming to see you. So are they in the intoxication phase? Are they intoxicated on methamphetamine? If they're intoxicated on methamphetamine, what do we think about in terms of pharmacotherapies? So first thing is we basically think about benzos. Benzos are pretty much the primary thing that we think about for intoxication on methamphetamine. It's common for people to talk about using antipsychotics because people come in often on stimulants and methamphetamine in particular and are highly psychotic. When they're actively intoxicated, we tend to think about can we manage this first with benzodiazepines and maximize the benzodiazepines before introducing an antipsychotic? Why? Because of several things. One, stimulants lower the seizure threshold. Antipsychotics, lower the seizure threshold. You potentially increase the risk of seizure. The other thing is the poikilothermia. I had a boss that loved this term and I love it too. Sort of that reptilian thing where you are able to, your body temperature adjusts to the environment, to the ambient temperature that you're around. Antipsychotics and stimulants can, well stimulants can cause your body temperature to increase and the antipsychotics can actually decrease your ability to regulate that temperature. The possibility of having hyperthermia in particular if you're loading people who are intoxicated on methamphetamine with antipsychotics. In particular, we talk about avoiding clozapine and chlorpromazine owing to these seizure risks. Those are two in particular that we avoid with intoxication on methamphetamine. There are some notes here that like if you're in a hospital setting for example and you, they're still hyperadrenergic after maximizing benzodiazepines, then you can consider things like beta blockers, alpha one antagonism, calcium channel blockers, nitric oxide mediated vasodilators. Ultimately, obviously in a hospital setting you could be thinking about Presidex and anesthesia basically at that point. But suffice it to say in a hospital setting, start with benzos, work from there. If the vital signs are stable, if folks are looking pretty otherwise okay other than the fact that they've got some residual psychosis that's when I start to think about like okay, do we need to add in some sedating potentially antipsychotic or neuroleptic like olanzapine for example. So acute withdrawal, what do we do about acute methamphetamine withdrawal? What does the science say? What does the literature tell us on this? Well the literature tells us that basically what is acute withdrawal? Acute withdrawal from stimulants, 12 to 24 hours of somnolence and irritability. This has been reviewed. There have been some randomized clinical trials on this and a Cochrane review of this basically said that there were no pharmacotherapies that were found to be resoundingly effective in treating this acute withdrawal from stimulants and methamphetamine in particular. Then we have the post-acute withdrawal. So they're out of the sort of like 24 hours of somnolence and irritability but now we've got the depression, we've got the anxiety, residual insomnia. In these instances, what are the recommendations? Symptomatic, think about and this is obviously you can't read this that well. I can barely read it and I'm looking right at it. I put this up here because as a demonstration of sort of what's in the guidelines. These are all guidelines for looking or suggestions and commentary on sort of the strength of the data around using different sedatives or sleep aids in individuals in particular in the post-acute phase when trying to kind of get people back to sleep. So again, lots of different suggestions here about possibilities that you could use in that scenario. Moving forward and thinking about like stimulant use disorder, like methamphetamine use disorder in particular, what are our pharmacotherapies? So this is someone who has, you've made the darn diagnosis. They've got methamphetamine use disorder. What does the literature tell me about what I could consider using in these individuals? So bupropion, Welbutrin. This is, and I'll just be honest, there are studies. I say, you know, three studies here. There have been many different studies of bupropion, some that have been positive, some that have been negative. It's interesting because there's a narrative that has come out of a lot of the literature on stimulant use pharmacotherapy, stimulant use disorder pharmacotherapy. And that narrative is that oftentimes the studies have as their initial endpoint like abstinence. And the findings of the study will be that no, did not support, overall it did not support abstinence. However, it's in sub-analysis or secondary analysis of the data that we start to see signals emerge that maybe specific populations might respond better even though the overall effect was that it was a negative study. There might be sub-populations within that data that are being hidden by the overall results. So in a lot of these bupropion studies, what we've seen is that for people with really severe methamphetamine use disorder, that bupropion's not that effective. But if you take out the folks who are more low to, like mild to moderate methamphetamine use, that there starts to be some significance. So you start to think about like, okay, well, if this is someone who has low to moderate or mild to moderate methamphetamine use disorder, maybe that's someone that bupropion might be effective for. The dosing, generally in all the studies have been, you know, start at one, like bupropion XL, start at 150, go up to 300. 300, you know, being where most of the studies even out at. So guidelines also talk about consideration of like, again, feeding two birds with one stone or one stone. That was a pause for, that was not an intended joke there, but I still can't quite make that transition away from killing two birds with one stone to feeding with one seed. But this is the best image I could find was a coffee mug, I guess, that you could buy with this, but with this phrase on it. But thinking about also like bupropion, and we're gonna talk about nicotine and treatments. Bupropion's also a treatment for nicotine and for tobacco use disorder. Think about depression, it's also an antidepressant. Start to be thinking about like, how can I be parsimonious with my medications in a way that will minimize the polypharmacy? There was a study that came out looking at the combination of injectable naltrexone and bupropion. This is a Travati study that came out in 2021. And it was generally positive, it was not overwhelming. It wasn't like, oh my gosh, like this is the cure to methamphetamine use disorder. But it was positive. And the reason they did this study was because there were some studies that said maybe naltrexone has some effect on methamphetamine use. Other studies that said it didn't. Some studies that said bupropion. This is where a phase that we're in in addiction pharmacotherapy research now is thinking about like, okay, let's take some of these meds that don't have strong signals, but let's put them together and see if we can get a stronger signal. And that's what happened here. So again, bupropion and naltrexone combination, that's 450 milligrams of bupropion, so a little higher than a lot of the other studies have taken it. And then we're also thinking about like co-occurring alcohol use disorder because of the naltrexone component and co-occurring tobacco use disorder because of the bupropion. What about topiramate? There have been studies that have shown that topiramate up to 200 milligrams daily has been helpful for some people with methamphetamine use disorder. So again, this narrative, I desperately want to move around behind this, but like this thing won't move with me. We're back to this narrative. If you just did a PubMed search and looked at topiramate and methamphetamine use disorder, you're gonna see a bunch of negative studies. But again, secondary analysis, it turns out that for topiramate in particular, if the person is able to get to abstinence before initiating topiramate, then topiramate tends to be better, tends to have some effect in those individuals. So somebody who's actively using can't stop, topiramate might not, according to the literature again, might not be the best option. But if you've got somebody who has gotten into detox and has been through the withdrawal phase and is looking for something to kind of help them along, topiramate might be a good option. Big problem with topiramate, side effects. It's not, doesn't get the nickname Dopamax for no reason. I mean, cloudy thinking, word finding difficult, paresthesias, glaucoma, renal calculi, all lovely stuff. And it does happen, people do get these side effects on topiramate. Not everybody, obviously. So what about mirtazapine? I don't know about you all, I love mirtazapine. I use a lot of mirtazapine with a lot of my patients. It tends to play well with other medications, doesn't have a lot of med-med interactions. It's easy to dose and it helps people get to sleep. Of course, the problem is it does also help people gain a lot of weight, but oftentimes one of the most challenging things with people who are using stimulants is the fact that their sleep is so disrupted and it takes a long time for that sleep to get back. So I really am looking at things that like, can I also help them with their sleep issues? And mirtazapine is a great option for that. So there have been some systematic reviews, meta-analysis that have not shown benefit in methamphetamine use disorder with folks that are tried on mirtazapine. But there have been two smaller randomized clinical trials out of San Francisco, where I've been, that shows in particular, these two studies, it was an initial study back in 2011 and then a repeat study in 2018 that was looking in specific at people that were using methamphetamine, also men who have sex with men, population. And what they showed was that the mirtazapine led to decreased methamphetamine use as well as a decrease in risky sex behaviors. So this was encouraging. Again, big meta-analyses and systematic reviews might not necessarily lead you to believe that mirtazapine is gonna be the best medication, but there might be subpopulations and I'm not totally convinced that we're not gonna see more benefit from mirtazapine moving forward, in particular because of that help with the sleep component, that being really important. So one of the more controversial things that's in this new stimulant guideline is the use of psychostimulants to treat stimulant use disorder. Okay, I just saw, just me saying that, I saw three or four heads nodding, which means, all right, I'm not alone in kind of recognizing that what they are saying in these guidelines is very specifically, they're saying that clinicians who are properly trained, and we'll talk about that, but they're actually saying physicians that are properly trained could consider the use of psychostimulants to treat stimulant use disorder if they have the appropriate, again, training and if they have the appropriate resources for monitoring in place. This is based off of literature that is mixed and is not 100% convincing, but there's enough signal there that the writers and the group that put the guidelines together said that this is something that you could, as a clinician, consider doing. So what are the cautions that they add in relation to this, and what are they actually asking, or what are they saying you could use? So I'm focusing in, really, on methamphetamine. There's a whole section in the guidelines about cocaine that has a few more psychostimulants that have a little bit greater research base, but for methamphetamine, it's fairly limited. Psychostimulants, we avoid use, or they advise avoiding using the, avoid using these in individuals with a history of stimulant-induced mood disorders, in particular, stimulant-induced mania. So something that people get nervous about is the idea that, okay, the Harrison Narcotic Act of, what was it, 1911, 1914, I don't, stipulates that physicians can't prescribe narcotics to a known narcotic addict for the purposes of treating their narcotic addiction. That's why we had to have the X waiver for buprenorphine, because we were prescribing an opioid to a known individual who was addicted to opioids for the purposes of treating their opioid addiction. So methadone has a waiver from that Harrison Narcotic Act, and buprenorphine had to get one. That was the Data Act of 2000. So why are we not, like, why are we not concerned about that with stimulants? Well, because the law actually, the Harrison Narcotic Act, defines what a narcotic is, and narcotic is not cocaine, or methamphetamine. So, well, I'm sorry, it's cocaine analogs, and the Harrison Narcotic Act covers cocaine analogs as well as opioids, but it doesn't cover methamphetamine, and it doesn't cover the prescribing of the psychostimulants that we would be prescribing, because we don't prescribe cocaine, right? We prescribe, you know, methylphenidate, we prescribe Adderall, whatever it might be, or dexmethamphetamine. So they also recommend that this should only be considered by people who are board certified in addiction medicine, or addiction psychiatry, or commensurate training with ability for close monitoring. Again, I'm just repeating what they said. I was not part of this committee, by the way. Monitoring, they think, is very important. I would agree with that, if you're going to consider prescribing psychostimulants for the treatment of stimulant use disorder. Pill counts, drug testing, urine drug testing, more frequent clinical contact, more frequent PDMP checking, things like that. You want to have pretty tight reins on this, pretty close eyes on folks. For methamphetamine specifically, what are they saying? That if you were to consider this, which med would you consider using? Long-acting methylphenidate. The studies show sort of ranges between 18 and 70, starting at 18 and titrating up to 72 milligrams. There are some studies that look at lower doses, around 54 milligrams, but the long-acting methylphenidate is the formulation in the guidelines that has the most research base in relation to methamphetamine. Again, for the cocaine populations, there are additional psychostimulants that they talk about. What's my experience with this? I have no experience. In my populations, the idea of being able to prescribe a psychostimulant to an individual who's homeless with all of these different other issues and being able to control the variables around concurrent use of methamphetamine plus the stimulant that I'm prescribing. I've had the same problem with benzodiazepines, by the way. It just, it is hard to imagine a scenario in which I could control the variables. Now, would I consider it in an individual who is homeless who's now in a residential setting where I can eliminate some of the variables? I would. I have not done that yet, so that's my full disclosure on that piece. Not many people have. I checked with one of the authors of the guidelines last night, and he also told me that in their process of putting this together, they were not aware of any community clinics that were doing this. This was mainly, the research on this has been primarily in research settings as opposed to in real world sort of clinical settings, but we're moving in that direction. These guidelines kind of are sending us that way. So, tobacco use disorder pharmacotherapy. Start with nicotine replacement therapy. And again, a lot of material on these slides, but I wanna hone in for folks on some things that are worth remembering about NRT. If you're not in this world a lot, you might not know this or you might have forgotten this, that NRT, it comes in a number of different forms. There's gums, there's lozenges, there's nasal sprays, there's inhalers, there's patches. Lots of different ways to get the nicotine into folks. And the research is different, actually, between the different forms. So, for example, did you know that the gum is believed to be best used when on a fixed schedule, not PRN? Chewing one piece every one to two hours regularly as opposed to, and we'll go into this in the lozenge, which is better potentially in a PRN fashion. Again, for folks that haven't been in this space for a while remember for the gum, it's about buckle absorption. So, chew, park, chew, park, like leaving it, chewing it to kind of open it up and then parking it in between your gum and your cheek is for optimal absorption. It's not how much you swallow, which again, patients may get underdosed if they're not instructed that like, this is how you're supposed to do this. Some of the recommendations about duration, six to 14 weeks has been what's studied, but there's indication that lengths, keeping people on it for longer may be better. Here's the lozenge. The lozenge, you know, again, kind of thinking about like one to two hours for the first two to four weeks and then you can decrease it. There's some data here that I've presented on abstinence with the two milligram versus the four milligram, you know, versus placebo, pretty, you know, pretty similar. But again, and these are in research settings around this. My experience is I have not had a lot of success with trying to do smoking cessation with people with two milligrams of a lozenge alone. And we'll talk a little bit more about that. The lozenge does release more nicotine than the gum does. So you're getting a slightly higher exposure with that. Has phenylalanine in it, the lozenges do, so you have to be careful with the phenylketonurics. Transdermal, number of different formulations, number of different strengths. Typically it's applied in the morning, then people can take it off at night or they can keep it on through the night and put it on again in the morning. What I've found most patients tell me is that if they're gonna have a problem with any of the NRTs, one of the biggest problems that they describe to me is, and this is a weird one, and people can raise their hands if they've also heard this from patients. Bad nightmares. People have heard this, I'm seeing some hands. Bad nightmares. So this may be a reason why for some people you might want to advise them like, hey, try not to use your nicotine as best you can. I mean, it's better to not smoke, but try not to use your nicotine replacement right before you go to bed. And if you're gonna be using a patch, think about taking it off before you go to bed to minimize the risk of the nightmares because the nightmares can be pretty distressing, as they are, I mean, this is a room of psychiatry folks. We know about nightmares, although maybe it becomes therapeutically rich to have that experience and be able to process those. But there's little evidence for a withdrawal syndrome from nicotine replacement. Remember that with the patches, there's a lag. The peak concentration's about two to six hours after application, and you don't actually reach a steady state until two to three days. So you wanna get people on it and keep them on it at least for a week or so to kind of understand what their steady state is gonna look like. Now, by prescription, you can also do nasal spray and inhaler. The fastest way to get nicotine into an individual is through the nasal spray. It's faster than the inhaler. So nasal spray gets the nicotine in faster. I've had a terrible time getting nasal sprays and inhalers dispensed from pharmacies and available and or covered. So that can be a challenge for folks. But again, aware of the fact that these these may be more effective for some people that need to have the feeling of something other than like a lozenge in their mouth, like a cough drop, the feeling of having something either inhaled or sprayed in their nose. Again, for the inhaler, it's just a mechanism of getting it into the buccal mucosa. It's not actually being absorbed through the lungs. So sometimes kind of reorienting patients to the fact that like they don't have to, you know, get this giant inhale in and get it all into their lungs. Kind of similar to what we think about with Narcan, right? Narcan's not working when it gets into your lungs necessarily, it's just working when you get it into your nasal mucosa. So what about combo nicotine replacement therapy? this is the most common approach that I take, which is patch plus lozenge or gum. The most common issue that patients report to me with is that they were underdosed. Now they don't know that. They don't tell me I was underdosed with my NRT. They come in and they say, oh, I did the patch for a while and it didn't work. I'm like, well, how much were you smoking? They say, well, two and a half packs a day. And their PCP put them on, you know, a seven milligram patch. It's like, okay, let's dial this up. And let's just throw a lot, as much as we can on this to try to mimic the amount of nicotine as best we can that you'd otherwise be getting from your cigarettes. So there's evidence to suggest that the combination of patch plus, you know, some oral lozenge or gum is more effective than the patch alone. So you're in a space where there is research on this and that does back up the idea of combination nicotine replacement. So what about the other treatments for tobacco use disorder? Bupropion, as we already talked about with stimulants, blocks dopamine and norepinephrine reuptake and it actually antagonizes high affinity nicotinic acetylcholine receptors. So studies have looked at this and have demonstrated. That's why it's FDA approved. You know, the Zyban, the trade name, is FDA approved for the treatment of tobacco use disorder. What we typically say is that you want to identify, it's easy to do. It's not rocket science. Identify a quit date, about a week out. Start it because it takes about a week to get to a steady state of the bupropion. Start it. We start it at 150 milligrams once a day for three days and then we go up to 150 milligrams BID thereafter. Treat at least 12 weeks, may need to be on longer. Again, not rocket science. Many of you are already prescribing buprenorphine, bupropion, I'll probably make that mistake a few times, in your practices already. What about varenicline, Chantix, trade name? Alpha-4, beta-2, nicotinic, acetylcholine receptor, partial agonist. There were a lot of concerns about neuropsychiatric side effects, suicidality, depression, psychosis, worry about this in different individuals. All those have been assuaged. And they've actually been studied now. Varenicline's been studied specifically in folks with schizophrenia, for example, and found to be safe in those individuals as well as folks who are depressed. There were concerns about cardiovascular problems that people might remember a lot of the black box warnings. Those have also been largely discredited or are no longer supported by the literature and a lot of those black box warnings have disappeared. We think about the dosing here in the course. We also think about folks identifying a quit date one week after starting or longer, again, to allow the varenicline a chance to get to steady state. Okay, so let's go back to long, circuitous route, back down to this individual that I introduced in the beginning. So what would I be thinking? How am I approaching this person? So for starters, I'm trying to think about, like, hey, what's the thing that's most likely to kill this person, you know, right now? And right now, to tell you the truth, what I'm most concerned about killing them, and this is me practicing in San Francisco, has nothing to do with a drug that they identify taking, which is I'm worried about fentanyl. So I'm going to want to have, and you're going to see this a theme with each of my cases, talk about naloxone, talk about naloxone, talk about naloxone, get it out there. So I am going to be concerned about the possibility of methamphetamine contaminated with fentanyl or high-potency synthetic opioids, and I'm going to be talking with them about naloxone. Then I'm going to be looking at the, you know, what would I be thinking about next? I'm going to be looking at, like, okay, is the guy intoxicated in front of me? Did I watch him inject or smoke methamphetamine before I had the encounter with him? In which case, then I might be thinking about, like, okay, we might need a higher level of care. We might need to be thinking about, like, the goal of our session is really about getting you into a safer place, get you evaluated, then we can kind of think about what pharmacotherapies we might want to initiate at that point. Now, in terms of pharmacotherapies, once I get to that point, what might I be thinking? Well, bupropion might be a decent option and also the combo product of the bupropion plus the injectable naltrexone. This is where I'm also starting to get a little bit pragmatic about this, where I know the person's using methamphetamine, I know there's a high likelihood that there's fentanyl contaminating the methamphetamine where I practice. So if I can get this person onto injectable naltrexone, I'm providing some good coverage for the possibility of overdose with fentanyl with that medication plus, again, combining it with the bupropion, I might be able to get some traction. Now, this guy is using a lot more methamphetamine than what the studies had indicated. Studies showed that bupropion might be better for folks with mild to moderate methamphetamine use as opposed to severe. This guy's got pretty severe methamphetamine use. Nonetheless, I think this might be a negotiation that I'd be willing to have with this patient because I'm trying to, again, establish the trust, establish the rapport. If I start out with topiramate, if I start out with something like that, I might not get much traction because of the side effect profile. If sleep is something that we really align on, like, okay, that's a real problem, sleep, then I might be thinking, okay, let's do mirtazapine. Would I consider bupropion in the morning, mirtazapine in the evening? Yes, although I'm starting to get into the non-parsimonious area where I start to get a little bit leery about that plus I'm looking at an individual who may not be able to be that compliant with multiple medications. So I'm trying to be pragmatic with what they're coming in with, but also trying to see if I can address some of the issues. Eventually, if they're psychotic, again, treat the symptom that's in front of me. They're psychotic, I'm going to try to treat their psychosis. I'm going to try to get an antipsychotic on board. I'm going to prefer to try to target things like sedating antipsychotics, again, because of this emphasis on sleep, thinking about olanzapine, thinking about Seroquel. For the nicotine, again, we can think about optimizing NRT if he's willing to do that. And if I've done the bupropion for the methamphetamine, ostensibly, maybe I might get some traction with the bupropion for the tobacco use disorder as well. I'm probably, like I mentioned before, I'm probably not going to do a psychostimulant treatment in this individual just because there's too many variables, unless they're in a controlled environment, and unless I've got the proper infrastructure to ensure safety with that. Okay. Case two. 50-year-old man with a history of major depressive disorder, generalized anxiety disorder, sedative hypnotic disorder, alprazolam, clonazepam, who knows how much, maybe 12 milligrams a day of Xanax, of alprazolam, who knows? opioid use disorder, fentanyl, primarily, also homeless, in and out of jail. Okay. Another looking for head nods here. This seem familiar to folks, or is this just my world? All right. I'm seeing some head nods. Good. So let's think, I want to take a moment to think about fentanyl and what's different about fentanyl, and I apologize, I see at least one person in the audience that was at the talk this morning where we talked about fentanyl, a little bit of repeat in this from But when we talk about fentanyl, one of the things that we, you know, that we're concerned about is the, for starters, as we think about sort of, fentanyl has a somewhat anomalous pharmacology relative to other full agonist opioids. It does not operate exactly the same way as other opioids. We used to think, and we were taught in clinical settings, it was true that fentanyl was generally considered to be a short-acting opioid. Well, things are different, apparently, if you take a lot of fentanyl, and you take a lot of it chronically for a long time, something happens, something changes with the fentanyl, it becomes much more long-acting in appearance. Why is that? Because it's highly lipophilic, essentially it gets, you know, sequestered into the third space and then slowly elutes back out. And as opposed to cannabis, cannabis does the same thing, THC can kind of sequester in the third space and elute out. The difference is that when THC elutes out of your fat cells, into your bloodstream, that low level of THC is not clinically significant at that point, not significantly, like it's not like people are continually intoxicated feeling on their, when they're off of cannabis and it's eluting out of their fat cells. Fentanyl's different, because it's so efficacious at the receptor, it can really efficiently activate the mu opioid receptor, then it is clinically significant at a low level eluting out of fat cells and into the bloodstream. So we have to be considerate of that. It causes respiratory depression. That's how people die in overdoses, is they stop breathing. And that's a major consideration, a major concern. So respiratory depression, and it happens much quicker. It can happen in the order of 15 minutes as opposed to a couple hours with heroin. One of the things that's interesting that the anesthesiologists knew about fentanyl for a long time, but now the rest of the world is being introduced to, sadly, is that one of the other things it can do is cause what we call wooden chest syndrome and acute vocal cord closure, meaning that, and this is, this is non-NARCAN responsive, where the fentanyl will cause the muscles, the chest wall muscles to tighten up to the extent that you can't actually move them, you can't breathe. And the vocal cords may tighten up and close to the point that you can't get air through. So in anesthesia circles, they get around this. Like in the operating room, they intubate people and they mechanically ventilate people, right? So, but now, unfortunately, in the real world, outside of the operating room, not that the operating room's not the real world, it's the real, it's a different world, is that what we see is that this may be accounting for some of the perceptions that we have that NARCAN isn't effective in fentanyl overdoses, is that what we're actually up against is that if fentanyl is causing this wooden chest syndrome and the vocal cord closure, and you're pumping NARCAN into that individual, that's not reversing the vocal cord closure or the chest wall tightness, and as a result, causing a perception that the NARCAN isn't effective, when in fact, the studies have shown that NARCAN is effective against fentanyl, it might be more an issue of timing. It might be, if you can get the NARCAN in faster, it may prevent the wooden chest syndrome, it may prevent the acute vocal cord closure, and may reverse the overdose more effectively. So I'm cheating a little, I'm telling you a little bit more about what's in the next couple of slides as well, but again, these are some of the things that are different about fentanyl. As I mentioned, we've looked at this, there's a push, there's pharma companies that are very interested in kind of thinking about this idea that like, well listen, if people are requiring many, many doses of NARCAN to reverse their opioid overdose, then we should be giving higher doses of NARCAN to people. The data actually doesn't support that, the data says that four milligrams is just as effective as eight milligrams in reversing opioid overdoses, including with fentanyl, it's just a matter of timing that is more significant. So again, there might be some risks with higher doses of NARCAN, I've seen this in my harm reduction circles, where patients are like, you know, I don't want a bigger, like, I'm not going to take your NARCAN if it's like the eight milligram one, I only want the four milligram one, because it's going to make me more sick, and I could have the conversation with them and the argument with them about sort of the efficacy, you know, and the science behind that and whatnot, it doesn't matter, if the patient's already decided they're freaked out about the idea of getting sicker on a med, they're not going to take it. So I'm not going to, you know, I'm not going to push that. So again, you know, there are some risks associated with the higher doses of naloxone. So the key, again, for naloxone is the timing when we're thinking about this world with fentanyl in it. There are other people that are working on different things, I just learned this morning that there's someone working on a transdermal phrenic nerve stimulator that's shown to be very effective in pigs, but not yet in humans. I just learned that this morning. But there are other sort of implantable naloxone devices that didn't actually pan out. But people are thinking about different options for how to reverse opioid overdoses in the age of fentanyl. Okay, opioid use disorder, aside from NARCAN and rescue folks with NARCAN, we think about methadone, buprenorphine, and naltrexone. Here are some basics about all three. These are our three FDA-approved treatments for opioid use disorder. They, in their own ways, are uniquely effective. Buprenorphine and methadone, in particular, lots of research, lots of studies supporting their use in opioid use disorder. Naltrexone, a little bit more in the long-acting injectable form is shown to be a little bit more effective. But in certain populations, naltrexone, we'll talk about that, may be more effective. So methadone, only delivered in an opioid treatment program, with some exceptions for some hospitals, emergency rooms that can do initiations. There's legislation that's talking about kind of liberalizing methadone treatment. Methadone programs are highly, highly regulated. If you've never worked at one or been to one, I always suggest people take a field trip, go see what is involved in methadone treatment. It's very, very rigid, very, very highly regulated. It works. Started here in New York, worked and has continued to work since the 70s. You can see some of the side effects, some of the pharmacologic principle or pharmacological components of methadone and how it works. Bottom line with methadone is it's intended to be sort of a once-a-day dosing, has a long half-life, so it takes a wake, ostensibly craving, and withdrawal for 24 hours before the next dose is given. People in the beginning of treatment have to go every day to get dosed, and in time they earn take-homes, depending on how well they're adhering to the program and if there are other stresses or issues that are coming up. Methadone program is incredibly useful for me with people who need a lot of structure. It can be, you know, people say, well, what if somebody's really, really disorganized, they're schizophrenic, they can't pull things together. I've seen it work fabulously for folks that are incredibly disorganized because it is so structured. I've seen other people that are incredibly disorganized that it doesn't do well with because it's so structured and they can't get there and things like that. So methadone, the pros, it's administered in a clinic, so there's a lot of oversight, there's a lot of therapeutic structure, there's daily monitoring, it does decrease illicit opioid use, it's easy to make a referral to other treatment because, again, you're in a clinic with a lot of support, and the earning home doses is actually a really compelling sort of contingency management approach to changing behavior. The cons, you have to attend daily, there's strict rules, there's the stigma of going to a clinic, many people have heard all of these things before. One of the pharmacologic things I think that's really important for people to understand about methadone is that methadone has a weird process to get to steady state. It can take about five days to get to a new steady state when you've changed the dose. So the problem that people run into, especially in hospitals where people aren't familiar with methadone, is they increase the dose up and they say, oh, I'm just going to take you up to 100, I'm going to put you at 100, and day one, they're fine, day two, they're fine, day three, they're fine, day four, they're fine, and day five, they're out. They're unconscious and they're overdosed. And they're like, wait a minute, but it can't be the methadone. We started that five days ago and they've had it at 100 milligrams for five days. It's like, well, no, because their blood level was slowly rising each day and then it wasn't until day five that it passed the toxic threshold. So that's one of the challenging things with methadone, especially in hospitals, and that's usually the most common thing when I was a CL psychiatrist that I'd be called to see was somebody who was, you know, there were suspicions that they were bringing in illicit opioids and things when their methadone had actually been increased too quickly. Buprenorphine. Now, of course, I'd expect everyone to just know this was buprenorphine based on the chemical structure up there, which, anyway, that's a joke. The difference with buprenorphine relative to methadone is that it can be done in an outpatient office-based setting. It's a partial mu receptor agonist and a kappa opioid receptor antagonist, and I'm going to come back to that piece. It's a little side pearl that I'm going to sneak in for you all. But the partial mu agonist effect is interesting because that's what gives buprenorphine what I think is its magical property, which is that it has a sealing effect. That if you increase and you keep increasing the dose of buprenorphine, eventually you get to a point beyond which more buprenorphine will not increase the likelihood of respiratory depression and will not increase the risk of overdose. So buprenorphine has this cool ability to be relatively less worrisome in relation to overdose. It's also less euphoria generating than full agonist opioids. It is a sublingual, and it comes also in a long-acting injectable form. This is a photo of the injection. It's an abdominal injection, relatively painless as I guess any injection is. But the side effects of buprenorphine are pretty consistent with the side effects of other opioids, constipation, sweating. I always encourage people to talk with their patients about the constipation issue. I once had a kid that I was treating who we were in a group setting, and he came in one day, and his eyes were all bloodshot, and everybody was concerned about him. And he's like, finally, she officially admitted, he's like, listen, I haven't had a bowel movement in like a week, and I've been pushing really hard, and that's actually what caused that. This toxicology has all backed that up as well, but the constipation can be a real thing. Then again, people that are using fentanyl, people that are using heroin, they're also getting constipation. The constipation is less with buprenorphine, but it doesn't go to zero. Plays pretty well with other meds. Methadone does not play well with a lot of meds. The whole book chapter is written on the drug interactions with methadone that are noteworthy. Buprenorphine, that chapter is much smaller. With both buprenorphine and methadone, this is something I want to emphasize, both buprenorphine and methadone, you can treat people's pain. A common conversation that I have is somebody's in the hospital, and they broke their leg, and the hospital's saying, they shouldn't be in pain. They're taking 200 milligrams of methadone a day, and I'm like, no, no, no, the 200 milligrams of methadone is just getting them to the point where they're like everybody else. Now you have to treat their pain on top of that. What do you do? How do you treat pain? Well, one way is that you can divide the dose of methadone up more so that it's given more frequently, because the analgesic effect is only about four hours, or you can give more opioids on top of that, and paradoxically, you could do the same thing with buprenorphine. You could give it more frequently, and you can actually add phylogenist opioids on top of it in an acute pain setting. I'm not talking about chronic pain. For some people, dividing the dose is helpful with chronic pain, but in other folks, there may be other things that you need to be thinking about for chronic pain that are non-opioid related. So just a note here about buprenorphine and naloxone. This is the suboxone, the combination. Why do we combine them? Well, we combine them because we're taking advantage of a very specific difference in the bioavailability of the naloxone relative to the buprenorphine. Buprenorphine is bioavailable sublingually. Naloxone is not, okay? So if you take a buprenorphine naloxone film or tablet as prescribed, dissolves in your mouth, the buprenorphine will be absorbed, the naloxone will stay in your spit. You swallow it, the naloxone will come out in your poop. Like, that's the pharmacologic difference. So why do we do this? We did this, the manufacturer did this in the beginning to discourage the possibility of diversion and misuse. So specifically to discourage the idea that somebody would crush up their suboxone and inject it, because injection naloxone is highly bioavailable. Like, you can get a lot of naloxone if you inject it. So that was why we did it, it was for fear. We're gonna talk about fear with another medication in a minute. So common misperceptions, patients will use their buprenorphine or their methadone to get high, and once you have tolerance to the buprenorphine and the methadone, that high feeling isn't there. Is this just substituting one drug, one addiction for another? And what I tell people is like, no, addiction is a constellation of behavioral factors as well as neurobiologic factors. However, when we're treating people with buprenorphine and methadone, our goal is to keep them stable enough so that we can work on the behavioral things, the behavioral components of the addiction. Tapering off the, get them off the medication, you know, common misperception, get them off the medication as soon as possible. Bottom line, the longer people stay on these meds, the better they do. Sometimes that means for the rest of their life, just like we think about insulin and medications for diabetes, hypertension, asthma, similarly. Again, this idea that the medication's gonna cure everything. Medications rarely cure everything, so it's not a panacea. You still have to be thinking about underlying psychiatric and other issues. There are some implications for buprenorphine in the age of fentanyl. I'm not gonna go into this in great detail right here, but suffice it to say, one of the concerns is that when we start people on buprenorphine, that it could precipitate withdrawal if they've been using fentanyl. And the other notion is that people have this, there's this misconception that like, oh, buprenorphine won't work with people who are using fentanyl. And both of these turn out to be manageable, but we might be needing to kind of change some of our thinking about how we approach the treatment of opioid use disorder, in particular with people that are using fentanyl in relation to buprenorphine. So the first thing about the precipitated withdrawal is that we can mitigate the risks of the possibility that they'll get precipitated opioid withdrawal by waiting longer until we start the buprenorphine. So we can wait, instead of 12 hours, we can wait 24 hours. In order to facilitate that, we're really encouraging people to think about using adjunctive medications, clonidine 0.1 milligram, bentol, Zofran, use adjunctive medications to help extend the amount of time that they get off of the fentanyl before you start the buprenorphine. So that being sort of like one of the approaches to thinking about how do we start, how do we minimize the risk of the precipitated opioid withdrawal. Second thing is thinking about how do we potentially address this issue that people feel like, oh, after I've been using fentanyl, I don't feel like the buprenorphine is holding me. We used to say that the top dose of buprenorphine was 16 milligrams. We're now starting to think that we may need to, for many people that have been using fentanyl, that we may need to increase that threshold. We might need people on 24, 32 milligrams. Got several patients right now that are on higher doses. It just took more to get them to feel held in other words, like less craving, less withdrawal symptoms. So that's some of the implications of buprenorphine. So along those lines, I wanted to encourage people to take a look at this. This was a guideline production that I was involved in forming. Came out about a year ago, a little over a year ago. Practice-based guidelines, buprenorphine in the age of fentanyl. We really were working to try to make this as practical as possible and try to kind of dispel people's concerns that like, because of fentanyl I can't treat people with buprenorphine when in reality you very much can still treat people with buprenorphine. This is a slide you're not gonna be able to see anything on, but it is pulled from those guidelines looking at, and people will have my slides afterwards too if you wanna look at it. This is just a listing of various adjunctive medications. Loperamide, clonidine, bentol for abdominal cramping, lofexidine. These are meds that are very effective in helping people get through the feelings of withdrawal that they might be having. Finally here, let's talk about naltrexone. Naltrexone is a full antagonist. Whoops. A full antagonist and a full opioid antagonist, and it's the least studied of the three opioid use disorder medications. A lot of the studies that looked at naltrexone and the treatment of opioid use disorder looked at it in relation to, or these studies were done in Russia where there's no methadone, there's no buprenorphine, and sort of naltrexone is kind of your only option. Over here what we've found is that by and large, naltrexone, the oral doesn't seem to be that effective for treating opioid use disorder because people stop taking it. The injectable seems to be much more effective because people continue to take it. So the long-acting injectable can help with cravings, but it can be somewhat more complicated to initiate because you do want to wait seven to 10 days off of all opioids before you start it. That's when we lose most people is that they can't make it the seven to 10 days before you start the naltrexone. Very specific populations that might be more amenable to this treatment, physicians, pilots, people that can't be on, by virtue of their professions, they can't be on agonist opioid treatment, but they can be on naltrexone. It's a pure antagonist, no agonist effect in relation to that. So, moving forward here. I apologize, just give me one second. Okay. Wanted to make sure that, since the slides were loaded separately, I wanted to make sure that we had the right one. So remember this guy was using, this case that we were talking about, he was using opioids and he's using sedative hypnotics. We don't know how much. So when we think about sedative hypnotics, let's run through what the literature tells us about the treatment of sedative hypnotic use disorder. So, for intoxication, people love to talk about flumazenil. Flumazenil's really not advised for the treatment of, like the acute treatment of benzo intoxication. In part because in some, there might be some folks that work in emergency rooms and have had good effect with this. The real concern that we have is that if you have somebody who's highly dependent on sedative hypnotics and you hit them with flumazenil, they're gonna go right into pretty significant withdrawal from that and you might precipitate a seizure in doing so. So we generally encourage people not to do that in the intoxication setting. Most of the intoxication management is gonna be observation, you know, emergency room, you know, mechanical ventilation if necessary, if it gets that bad. So what about withdrawal for sedative hypnotics? Withdrawal for sedative hypnotics can be pretty nasty and it doesn't follow all the rules that we would assume that it would follow for like alcohol, even though sedative hypnotics and alcohol are very similar. So mild symptoms, you can see here depression, you know, feeling kind of bad. Severe symptoms can be, you know, can be worse than that. And then you can have a post-acute withdrawal that can last weeks to months. What are the, for sedative hypnotic use disorder, what are the pharmacotherapies? Well, I can tell you that the pharmacotherapies, the literature on this is pretty slim. There's not a lot of great robust studies of this, but there are some things that kind of shake out. So one is thinking about tapers. So one effective way of getting people off of benzos is to taper them off. Tapers, there's two strategies. One strategy is that you can switch them to a longer acting if they're taking Xanax or alprazolam and switch them to clonazepam and get them onto a longer acting and then taper from there. Or as has been my experience, sometimes you can't cross taper and you have to taper them with what they're taking. So Xanax, taper with Xanax, that kind of thing. And I've had some instances where we've had to do that, where clonazepam just didn't work and we had to go to Xanax. The being flexible with the dosing, the general recommendation is 10 to 25% of the total daily dose reduction every one to two weeks. Again, so we're talking like a high dose alprazolam, it's gonna take a long time on that protocol to get them to zero. I've tried many times to do daily observed dosing in the community and I've failed every time because people tend to take their Xanax on top of what I give them. So, but I have had more success when I get somebody in a residential setting and I have an arrangement with that program to do a slow taper of the benzodiazepine from there. Inpatient setting, phenobarbital, there's an emerging literature on this that is revisiting protocols that were developed many, many years ago. Phenobarbital, long acting barbiturate that can be useful because it's also something that is not particularly abuse, you know, readily abused. It's not something that people seek out. I've never heard a patient say, gee, my drug of choice is phenobarb. It doesn't make you feel that good, but it can be pretty effective in preventing withdrawal. A lot of this is, again, kind of confined to, and you can see the dosing regimens that the different studies have used here if you're interested. And, you know, again, it's more in an inpatient setting because of the risks of phenobarb in the outpatient setting. It can be, have a high risk of respiratory depression. So, adjunctive meds, carbamazepine, start 200 milligrams up to 600 to 800. A few studies have looked at that and have shown some mixed results. Valproate, 500 to 2,500 milligrams. I've used that several times as an adjunctive medication. It's been helpful for folks. Gabapentin, again, limited research. All these, obviously, off-label. There is no FDA-approved medication for this, but gabapentin and pregabalin, kind of similar, you know, medications. You can see the regimens here. The gabapentin regimens are similar to the alcohol regimens, which we'll talk about in a second, but the idea here being that you could combine a taper with some adjunctive medications. The last one that a good friend of mine in Oregon likes a lot and has been talking a lot about has been using oxcarbazepine as an alternative to carbamazepine for the treatment of sedative hypnotic use disorder, simply because the side effect profile is a little bit more favorable. You can see the dosing regimen that folks have been toying with here, starting at 150 and titrating up to about 1,200. Clonidine is another one that is effective at reducing the adrenergic surge that can come with benzo withdrawal, similar to what happens when people are coming off of opioids. They get this adrenergic surge. They don't feel good because of that. Clonidine takes that edge off. So what would I be thinking about with this guy? I'm thinking about, this is the easy, I love it when I am consulted on a case where there's an opioid use disorder in the mix, because I say, okay, it's easy to know where to start. Let's talk about medications for opioid use disorder. That's potentially the thing that's gonna save this individual today. So let's get that conversation going. Let's see if we can get that moving. Naloxone, again, I'm gonna be talking about that. Be thinking about the level of care. I might be thinking about buprenorphine injectable. This is a homeless individual. He's kind of been in and out of jail. I don't know about where you all work, but we're starting to get a little bit more traction in our carceral settings where I am, where they might be willing to do injectable as opposed to sublingual buprenorphine, because it's ostensibly less divertible if you inject it than sublingual. But I will point out this, though. So I get him started on Suboxone, the combination naloxone-buprenorphine. Three weeks later, he's just nauseous all the time. And this is actually drawn from an actual case of mine. And we're trying to figure this out. We're doing the labs. We're trying to figure out why is he nauseous? Why is he vomiting? And it's just getting worse. And we start to realize it's temporally tied to when he's taking his Suboxone. Like within 45 minutes of his Suboxone, he's nauseous. I'm like, all right, well, let's try something. Let it dissolve in your mouth. Leave the spit in your mouth for five minutes. And then when you're done, spit it out. Don't swallow it. Did that, nausea went away. There are some people that the, even though the naloxone component is not bioavailable orally, when it gets into their stomach, it can irritate their stomach and make them feel nauseous. So, and I've talked with colleagues, this is a real thing. So anyway, I put that out there again as a little pearl. Now, I mentioned before also that this guy's depressed. And buprenorphine also has this kappa opioid receptor antagonism. Kappa opioid receptor antagonism can have an antidepressant effect. Now, I'm not here to tell you that buprenorphine is an antidepressant. Please don't get that message. But I am saying that clinically, it has been my experience that people that are very anxious and depressed, while using opioids, I get them onto buprenorphine and the depression and the anxiety get a lot better. There have been studies of using buprenorphine in the treatment of depression. Those are in the literature. I'm not advocating that. But I am saying that there is something to be said that you might, again, kind of feed two birds with one seed. Get back to that. I got it right this time. So with the sedative hypnotics, with this individual, I started him on a clonazepam taper. I said, oh, I've got this. I'll convert him over to clonazepam equivalents and then I'll taper that down. I did so. Didn't do well. Actually did really bad. So then I said, all right, let's convert him. Let's just do the taper with alprazolam. Let's get him into a residential setting where we can monitor the administration of the medication and taper him down and he did well. For maintenance, I might consider gabapentin. Six, 900 milligrams TID. Again, thinking about what are the things I might, the phases of treatment and once I get this person into a maintenance phase, this person may need some additional pharmacotherapies to support them. I know there's risks around the combination of gabapentin and opioids, that the gabapentin may actually increase the likelihood of overdose. I also know that in the setting of relapse, that the risk of overdose is incredibly high independently of that as well. So I'm thinking sort of what's potentially the safest strategy that I might be able to propose with this person. So on to the last case here and I promise we'll be wrapping up. This one I'm excited about because there's a part of this one I've never presented before. So I'm waiting to see how it goes. All right, so we've got an individual here who has interpersonal issues, alcohol use disorder and cannabis use disorder. So this is a 25 year old woman with a history of alcohol use disorder, cannabis use disorder, fear of abandonment, unstable chaotic relationship, shifting self-image, impulsivity, self-destructive behaviors, extreme emotional swings, explosive anger. Does that sound like anything? Anybody ringing a bell? Okay, other providers hate her, quote. She's in and out of the emergency department frequently, often with vomiting that providers identify with her, quote, needing attention. She is married and has a very supportive spouse. Okay, so here's the first thing I wanna highlight with this case and then we'll circle back to this. I see this all the time. Nobody gives the diagnosis of borderline personality disorder. Nobody does. You do. All right, we got one. I heard some nods in here. Other people I'm sure do as well. But it's amazing. I'll go into a case conference with an individual who has been really, really problematic and really been severe for a long time and no one has given the diagnosis of borderline personality disorder. Nobody's tied the BPD to trauma. And everybody's like, no, no, no, no, no, no. We don't go there. We don't do that. All right. Right, but in this case, I'm not putting the trauma in there, but there is, doesn't have to be trauma, but oftentimes there is and it goes undiagnosed. So let's think about cannabis and cannabis use disorder. In the interest of time, I'm not gonna go through this. This is just kind of some of the basics around cannabis and THC, how it works in the body, what receptors it hits. How do we manage intoxication of cannabis or intoxication on cannabis? We manage it by keeping people safe. That's essentially it. If it gets more severe, we can think about sedative hypnotics. Really, really severe, we could think about some sedating neuroleptics. What about cannabis hyperemesis? So I threw that part in there that this individual continually in the emergency room vomiting, it's attributed to her needing attention, but could it be that it's also related to the fact that she's using a ton of cannabis and she has developed cannabis hyperemesis? So what is cannabis hyperemesis? It is seen in chronic cannabis use, episodic vomiting, abdominal pain and nausea, temporarily relieved by hot showers. The hot showers thing, again, many of you have probably heard this. That's a key to this. There's different phases. There are different treatments. One of the primary treatments is discontinue the cannabis use, right? Duh. It can be really hard though because people are really committed to the idea that you use cannabis to treat nausea, but yet there's this paradoxical situation where the cannabis is causing the nausea. And how do you kind of work with a patient and convince a patient? Typical anti-emetics don't really work for these folks. So your typical things, your Zofrans don't really work. Hot bathing does. Topical capsaicin is really effective for a lot of these folks. There is a literature also for using very low dose of benzodiazepines and very low doses of Haldol or Druparadol if you're in the hospital that supports the idea that those might be effective in handling some of the emesis. But the main thing is thinking about discontinuing, excuse me, discontinuing the cannabis. So what do we know about the medications for the treatment of cannabis use disorder? What kind of options do we have? There are, there's no FDA approved treatment for it. There's a wide variability in the studies in terms of effectiveness. Some little hints here and there. But antidepressants, again, there may be some role to play whether you're treating a co-occurring depressive disorder or if it's actually treating the cannabis use disorder itself. Difficult to say. There was paradoxically one study that did show that venlafaxine may actually increase the severity of cannabis use disorder. Antipsychotics like quetiapine, some evidence in some studies, again, mixed. You can see the dosing here that John Mariani and his crew did here at Columbia. 25 to 300 milligrams titrated over four weeks did show some reduction in use. There's interest in the anticonvulsants like gabapentin and topiramate. Again, mixed results from all of these studies. But again, if I'm looking at an individual and I'm looking at the fact like, oh, there is some mixed results in studies around mirtazapine, but this person's really got an insomnia problem, that might tip me over to saying like, this is, I'm thinking mirtazapine in this individual might be a good option, because again, I'm trying to feed two birds. Using cannabinoids to treat cannabis use disorder, not something that is routinely gonna be done in an outpatient practice. People may be trying to do this on their own through dispensaries and other places, but again, not convincing evidence that using cannabinoid agonists are gonna be helpful. There was a very interesting study that looked at NAC, and it's N-acetylcysteine, in the treatment of cannabis use disorder, with the interesting thing about the study, though, was that it found to be very effective in 15 to 21-year-olds, but in repeat study, looking at older folks, it washed out. Maybe something magical is happening with people between 15 and 21 with N-acetylcysteine, and you can see the dosing here, and I tried, by the way, I did try to include dosing on here for folks that the studies had used for your convenience if you're looking at the slides later. Some evidence for naltrexone and varenicline as well, but again, mixed studies, so nothing definitive. What's a summary of the cannabis use disorder? No FDA-approved meds, some benefit potentially for gabapentin and NAC for younger folks. What about alcohol use? We've got some slides here on the basics, like how do we define alcohol use disorder? I'm gonna skip over these in the interest of time, although I'm gonna wait, I see one person about to photograph the slide, and got it, all right, cool. So this, again, in the interest of time, this is just how alcohol works in the body, what neurotransmitter systems it impacts. The main reason I put this up here is not that everybody could kind of read and memorize all the different systems, but compare this to a lot of the other drugs that we've talked about already, alcohol does a lot. It hits a lot of different receptor systems. As a result, there have been a ton of different medications that have been trialed in trying to use them as a way of treating alcohol use disorder. What about alcohol withdrawal? What do we use to treat alcohol withdrawal? We primarily use benzos. There's fixed dosing or tapers of benzos. There are studies here that I've referenced that talk about how in folks that may be very severe, putting them in the hospital on a fixed dose as opposed to doing a CEWA may be more effective. In my experience, CEWA is great, and CEWA being the scale that you use, obviously, to monitor the severity of alcohol withdrawal. CEWA is great. The problem with CEWA is that you have to really know how to do it. And most nurses, most hospital staff are not trained in how to do the CEWA appropriately. And so as a result, you get scores that vary wildly, and people end up getting over-benzoed for their alcohol withdrawal as a result of that. One way to avoid that is to put people on fixed dosing of benzodiazepines, or, as we'll talk about in a second, you could also think about fixed dosing of phenobarbital in the hospital. Generally, we tend to prefer, for the benzo tapers, we tend to prefer longer-acting benzodiazepines, like your diazepams, your chlorodiazepoxides. Lorazepam and oxazepam tend to be used a lot in hospitals. My concern with lorazepam in particular is that it works for about four to six hours. So if you're not really on top of things, you can miss people and get behind very easily. The longer-acting benzos give you a little bit more cushion for that. This is a slide looking at the differences between the big studies that have looked at the differences between fixed dosing versus symptom-triggered, and then recent studies. These are meta-analyses from 2022, and then also benzos versus anticonvulsant therapies, monotherapies. Right now, monotherapy with anticonvulsants is not advised as the primary course of action in alcohol withdrawal. If you're not familiar, another great guideline to look at around alcohol withdrawal, very comprehensive. How about medications for alcohol use disorder? The FDA-approved meds, we've got naltrexone, both long-acting and oral. We've got camperol or acamprosate, and we've got Anabuse. Some other meds with some data that support it. Disulfiram, I wanna take a second to talk about this. I love Anabuse. I think it's a very effective medication in the right patient. And this patient that I'm presenting here may actually be the right patient. For me, Anabuse, the principle is simple. You take the med, if you drink on top of it, you get sick. So how does it work? Fear, back to that issue, it's fear. You're afraid of getting sick. So the first question I ask people is like, I paint this picture of how sick you could get. And if they say, and then I ask them, I'm like, with everything that I just told you, do you think that there's a possibility that you might try to drink on top of this? If they waver for half a second, I'm done. Like, I'm not gonna try it. But if they're like, oh my God, no, I don't want, I'm like, yes, we're in. This might be a good option. Second thing is observe dosing. I've had a lot of success with patients who are in stable relationships with supportive loved ones where we can enter into an Anabuse contract. You can't read this, this is poorly photocopied. Anabuse contract, which articulates very specific terms and conditions by which the individual receives their Anabuse on a daily basis from a loved one. And this is an example of a contract. I use this contract with patients. I might, I think I've tried to clean it up so it's more legible, but like, you know, this, and I've had partners come in. We have a session where we just talk about the Anabuse. We enter into a contract and it can be very effective. Because the number one reason Anabuse doesn't work is that people stop taking it. I've also had success with Anabuse for people that like drink when they're traveling and know that they're at risk for drinking when they're traveling, but when they're home, they don't have a problem. So we talk about, you know, why don't you consider taking Anabuse on an as-needed basis before you go away. Naltrexone, we've already talked about a lot of the principles around Naltrexone. It's a mu-opioid blocker. A lot of people say, well, why would we use that in alcohol? I have this conversation with patients all the time where I say, the first couple drinks that you take, you get buzzed. Part of that buzz is being mediated by the release of endorphins and endogenous opioids. If you take Naltrexone, you might not notice much, but what you might experience is that you just don't feel like drinking as much. So Naltrexone's subtle. Anabuse is not subtle. Naltrexone is subtle. Oral and intramuscular options are available. Camperol gets a bad rap. It is designed to stabilize people in that post-acute withdrawal phase. It is helpful for people in that phase. European studies were all very, very positive on Camperol. American studies have not supported Camperol as much as the European studies. What's going on in Europe versus here, I don't know. Nobody's been able to really reconcile those two, aside to say that there may be a role for some patients that feel particularly compelled to take a medication three times a day, because Camperol is dosed three times a day, and why it's 333 milligrams or 666 milligrams, the number of the beast, I don't know. But that was just a reference for biblical people out there. But the idea that it's an odd dosing, but you have to take it three times a day. Topiramate may be one of the more effective medications that we have for alcohol use disorder. Meta-analysis of seven randomized controlled trials showed that topiramate had good effect on abstinence, as well as craving and urine toxicology screening. As we talked about earlier with topiramate, the issue with topiramate is typically side effects. That's why most people don't end up thinking about topiramate as first line, even though we probably should, because its effect size is comparable, if not a little bit even better than naltrexone. It's just naltrexone tends to be better tolerated. Again, the dosaging of topiramate for alcohol use disorder, starting low, starting at 50, increasing up to 150 milligrams twice a day, being the typical dosing. Gabapentin, I promise I'm coming down the stretch here. I'm gonna stop, I'll go through gabapentin, and then we're gonna move on to the last final part of this. But gabapentin, several studies have supported the use of gabapentin in the treatment of alcohol use disorder, others have not. Dosing has ranged from 600 TID to 900 TID, different dosing regimens, but generally speaking, in that range of TID dosing, six to 900 milligrams a day. I've successfully also, just as a side note, I've successfully detoxed several people off of alcohol using just gabapentin. People who are mild, milder alcohol use disorder, sometimes if somebody's had a relapse and just needs something to kind of ease them out of the relapse, it's been pretty effective with that similar dosing. I'm gonna skip over these. Finally, this part about what about the borderline personality disorder? Okay, this is the part I was excited about, and I'm sure I'm over time. But the, doesn't get diagnosed often, much to the harm of patients, I think, to not get the diagnosis. We've shown, studies have looked at this to show that if you give the diagnosis, people do not get destabilized by being given the diagnosis. Alcohol use disorder, by the way, is also similar in sort of its stigma. So now you've got somebody who potentially has two stigmatizing illnesses, and how are you gonna manage that? So fast forward here to talking about, put a plug in here for good psychiatric management for borderline personality disorder. And just a show of hands, has anybody seen this book? In this room, okay. This was written by John Gunderson and developed by John Gunderson up at McLean, who was a supervisor of mine and had a wonderful approach to kind of thinking about patients with significant personality disorders. And it was a very pragmatic approach. And he really set out to provide guidance. He was a borderline personality disorder expert. He sought to provide guidance to clinicians that are not experts in borderline personality disorder about like how, some basic things of how can you, how can you manage people and think about people with borderline personality disorder and manage them effectively in non-specialty, non-borderline specific specialty settings. And this is the book that came out of that. The reason I'm putting this up there is that this introduced several principles around treating borderline personality disorder. And we actually are now imminently, it will be published, releasing a book on good psychiatric management for borderline personality disorder for individuals that also have alcohol use disorder. So that will be coming out. I wrote a chapter in that, by the way. I don't get any money for it. I'm not like, I don't get money for any of this. But the, I just think it provides a very, you can't read this, but it provides a very good overview of principles for thinking about how to work with people with borderline. And in that book, we're gonna be looking specifically at alcohol use disorder as a co-occurring illness. This is just looking at kind of comparisons between BPD and AUD. And again, people have the slides available to them. And I could not break this down and make it fit in a way that was legible. But I felt like it was a really good thing to at least introduce people to. Principles of good psychiatric management are included here, but I'm gonna skip forward in the interest of time to talk about eight principles of the pragmatic approach to thinking about pharmacotherapy for alcohol use disorder in people with borderline personality disorder. Don't ask me to say that again. Number one, co-treat. Treat them both. Treat the borderline personality disorder and treat the alcohol use disorder together. That's the most effective way to get it moving. The framework for thinking about this, you can borrow from the medical model as well as from the 12-step model. Medical model, you have an illness that is out of your control, but it is your responsibility to address. A big part about good psychiatric management for BPD is talking about supporting patient's autonomy and agency. You want them to feel like they're not, that this is not, they're not completely broken and unfixable. There's a problem, but it's fixable. And it's in your ability to fix it. Borrowing from 12-step model, joining in fellowship. You're not alone in this. In 12-step model, we talk about taking a moral and emotional inventory in good psychiatric management. We also talk about this idea of taking an inventory and really getting to understand yourself that way. In prescribing, we talk about safety is the top priority. We are prescribing medications to decrease drinking. That is what we're, that is our top priority is to increase safety by doing the prescribing. It is vital to keep patients in treatment. This is somewhat new in the alcohol use disorder, GPM world, relative to others, the previous edition, where we're really trying to keep people in treatment and sometimes the medications are being used in order to help facilitate keeping people in treatment. Encourage patient autonomy. I already alluded to this. Treatment is always voluntary and it is collaborative. You have to navigate that fine line between the use of medications to treat a medical illness and emphasizing self-care while not falling into the trap of reinforcing an overly medicalized view in which the patients see their AUD as something that controls them and that they can't fix. So you have to navigate that line. If I'm gonna be prescribing naltrexone, I'm not gonna be framing it in a way that says that you're taking this med because you're broken and this is gonna fix you. It's this is to help you be able to do the things that you're capable of doing anyway. Prescribing medication's only based on value. Treaters should negotiate for behavioral change at every opportunity with every medication, thinking about, okay, we wanna change a med. We wanna change a dose of a med. Let's tie this to some behavior change that we are interested in achieving as well. Let's put these two together. Let's pair these two. Tie the medications to specific behavioral change targets. Avoid polypharmacy as much as possible. Best way to do this is to have conversations right at the start about deprescribing. Like, I'm gonna prescribe this and this is how we're gonna come off of this. Have that conversation up in the beginning and that'll help down the road. Final slide I have is very wordy, but it's meant to be sort of an example and it is from the forthcoming book of a way that one could talk about this with a patient who has BPD. We both want you to take medication that works and not waste your time with medication that doesn't work. It's important to define what working means in advance, what medication should do for you. Once we decide that, we'll need to measure the value of the medication as we go. If we find that one of your medications isn't helping, we'll stop it, gradually if we need to. When we stop medication, if we're right that it doesn't help, you won't notice a thing. It's like if you subtract zero from 10, you still have 10. Even so, people can have a psychological reaction to knowing that we are changing medication, a placebo effect. Because of that psychological reaction, emotional ups and downs are common as we reduce the dose. Sometimes people worry that the emotional ups and downs are a sign that we made a bad decision, that reducing the medication makes them worse. But most often, that's not the case. We'll want to pay attention to the overall pattern of your primary symptom with and without medication, not just the fluctuations at one moment. And if we discover that the medication is more valuable than we thought, it's always possible to go back on it. So again, wordy, but kind of offers a very specific framework for kind of supporting autonomy, setting some boundaries, setting some expectations, making it clear what we're gonna do, how we're gonna evaluate the medication moving forward. Incredibly helpful with people with BPD for being able to consolidate and organize the thinking. So what did I end up doing with this amalgam person here? Pick the medication that was most likely to kill them. In this case, it was alcohol. In this case, I talked about disulfiram contract, like let's get an anti-abuse contract, let's get you onto anti-abuse. Partner was supportive on board with it, went a long way to reestablishing trust between the two of them. And then I also initiated gabapentin, 600 milligrams TID, to on top of the anti-abuse to prevent some of the cravings that might have come up. Around the cannabis, it was psychoeducation. I tied the cannabis use to the vomiting, to the hyperemesis, and that was enough to inspire the individual to say, okay, I get it. I showed them the literature. They were like, okay, this is a real thing. Let's give it a try. Sure enough, the hyperemesis got better, and the cannabis use went away. At the same time, obviously, we were working on co-occurring issues and stabilizing the alcohol use disorder. So that, I know I've probably gone way over. I never know the timing. But there are a ridiculous, absurd number of references that I've put in here for everybody in case you want to look at that. But otherwise, I can't believe this many people stayed this long, and my voice is held out. So, thank you. Thank you. I'm happy to take questions. At the same time, I know people might need to go to bed. I have a question. They're not. Okay, I can check with the folks. I did upload them, so they should be there, but I don't know what happens after I upload them, but I can let them know that they're not, that people aren't seeing them in the app. Yes, we haven't seen them. Sorry about that. So, these days, I'm from St. Louis. People are using whatever the drug they are using. Everything shows up in it. They're smoking marijuana, acknowledging marijuana, or acknowledging methamphetamines, but the fentanyl is in that, too, and everything is in there. End up in a hospital with the fentanyl overdose, blah, blah, blah. What's the role of, that's what I did, actually. What's the role of giving them Vivitrol, just a safety net so that they don't die? For? Schizophrenic, cortex, PTSD, whatever it is. What's the rationale for using Vivitrol on somebody who's just overdosed on fentanyl, or? Oh, right, yep. Well, some of it depends on is there something else that the naltrexone might help with? For example, if they're co-occurring with alcohol and they're using meth, but if that's not the case. So, there have been some studies that have shown some positive effect of naltrexone with stimulant-using individuals, more with cocaine than methamphetamine. Those are not consistent. There have been other studies that have shown no effect. The premise behind combining the naltrexone and the bupropion was because there were some studies that said that naltrexone might be helpful for some people with methamphetamine use disorder. So, part of the thinking is, and then part of it is then thinking like, well, if they are gonna continue to use methamphetamine and there's increasingly fentanyl present in that methamphetamine, then are we potentially feeding two birds with one seed by providing some protection against the fentanyl by having them on naltrexone? Again, not 100%. The binding affinity of buprenorphine is better than the binding affinity of naltrexone in terms of blocking fentanyl, but it may provide some coverage for them.

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