to talk with you today. Thanks for joining us this morning or afternoon. I am a physician, addiction medicine, internal medicine and infectious disease. And I spend most of my time doing research, largely testing medications for various substance use disorders, doing some behavioral interventions, doing a lot of work around overdose and acute drug toxicity and some HIV and hepatitis C work as well. Today, I'm gonna be talking about methamphetamine and a really novel strategy that I'm quite excited to share with you. The disclosures have all been reviewed. There are no relevant financial relationships or ineligible companies to disclose. I will be discussing some off-label use of medications for helping to treat methamphetamine use disorder or prevent toxicities. So hopefully by the end of this talk, you'll have some sense of the trends in morbidity and mortality related to methamphetamine use in the US. And you'll be able to explain the primary causes and mechanisms behind methamphetamine toxicity, particularly deaths and distinguishing acute from chronic effects. And you will be able to evaluate some evidence-based interventions for treating methamphetamine use disorder, both pharmacologic and behavioral strategies. So in terms of the epidemiology of methamphetamine use, we have seen it expand in recent years. Traditionally, there was more methamphetamine use in the Western states compared to the Eastern states. That's landed a little bit, but there's still a little bit of a division there. About 200, about, excuse me, 2 million people reported past year use in 2019. That was a pretty substantial increase since 2015, and it may have increased a bit since then. In general, a little over half of people who report past year methamphetamine use will have a use disorder. And among those who inject, about 75% will have a use disorder. This is in a little bit of contrast to, for example, cocaine, where about 20% of people who report past year use have a use disorder. So in terms of the complaints that people present to emergency rooms with relation to methamphetamine, they're really divided into three groups. About half of the complaints are psychiatric, something previously referred to as agitated delirium. About a quarter are cardiovascular in nature, chest pain, palpitations, things like that. And about a quarter are trauma, so injury-related presentations that are also associated with methamphetamine. And when we look at deaths, the distribution of deaths, these are data from a few years ago, but they hold pretty well today in terms of the combination of opioids and stimulants, which is both methamphetamine and cocaine, but in about equal proportions. The, as you can see, the majority of deaths that involve opioids also involve stimulants. And then as you look at methamphetamine deaths specifically through the years, those are in black here with the methamphetamine plus opioid deaths in gray. You can see that methamphetamine without opioid deaths have increased. They increased until around 2019, and they've been pretty stable since then. They may have increased slightly, but the vast majority of the increase that we've seen is in deaths that involve both methamphetamine and an opioid, almost entirely fentanyl. And this is important because these two types of deaths are actually very different. And there is a problem with reporting methamphetamine or more broadly stimulant deaths that don't include an opioid with those that do include an opioid, because these are qualitatively different deaths. And I'm going to argue that we should consider the methamphetamine opioid deaths akin to opioid-only deaths or opioid overdose deaths, whereas the methamphetamine deaths that don't involve an opioid have a different mechanism, a different process, and should be thought of as a distinct group of deaths that requires different interventions. One of the ways of looking at this is to look at the additional causes of death included on the death certificate. So a death certificate doesn't just have one cause of death. Oftentimes it has multiple and also has contributing conditions to the death. So if you look at those additional conditions for stimulant, stimulant opioid, and opioid deaths, so it's stimulants without opioids, opioids and stimulants, or opioids without stimulants, you can see that the stimulant without opioid deaths have a lot more cardiovascular, cerebrovascular, that's strokes and brain bleeds, and also any other additional causes of death contributing to the death. In contrast, the opioid stimulant deaths and the opioids without stimulant deaths look very similar with almost no cerebrovascular events, way less cardiovascular conditions, and way less other causes of death contributing to their death. So here, I really wanna impress that we need to think about opioid stimulant deaths in the same breath we think about opioid deaths. But when we think about stimulant deaths, we need to separate it out from the opioid stimulant deaths. Also, when we look at these on, if you're doing, let's say, an overdose fatality review program, or what we did here, a psychological autopsy study, what we find really is that the opioid stimulant deaths, they look like opioid overdose events. They involve cases where somebody used an opioid and almost immediately got quiet, non-responsive, started to get blue fingers, had reduced respiratory rate, and then required assistance to be revived if they were able to be revived. In contrast, the stimulant no opioid deaths, these generally involve something like a person standing in line at a grocery store, grabbing their chest and collapsing with no evidence of them having used drugs in the last hour. They've used drugs that day, but not in the last hour. So it's really not what we think of as an overdose event, and frankly, not even an acute toxicity event. The stimulants seem to contribute to the underlying disease that results in an event that leads to their death, but it's vastly different mechanism than what we see with opioid overdose deaths. These are more data from San Francisco. Here, we try to divide the deaths by acuity. So you might have a death certificate that says acute opioid toxicity, meaning an opioid overdose, and you might have a death certificate that says the person died from sepsis with chronic heroin use. And so that would be a non-acute opioid-related death. And so what we see here is that almost all of the opioid deaths are considered acute. In fact, 98% of the opioid and stimulant deaths were considered acute toxicity deaths, 85% of the opioid deaths without stimulants, and 70% of the stimulant deaths without opioids, and 6% of the alcohol deaths without opioids. I would like to propose that that 70% of the stimulant deaths without opioids is actually an overestimate. It's probably much less than that. In fact, it's probably closer to the alcohol data. If we divide these by where the deaths occur, for the deaths, the stimulant deaths that occurred in the hospital, it's about 40 or 50% are determined to be acute toxicity. Whereas those that occur in the community, it's closer to 80% that are determined to be acute toxicity. The difference there is when something happens in the hospital, we can actually see what's going on. And we can see that they died from, let's say, a cardiac arrhythmia. Whereas the medical examiner can't determine that an arrhythmia killed a person by autopsy, that there's no evidence of this on autopsy. Unfortunately, the truth is that autopsies are far less valuable than television would have you think. And we aren't able to learn as much as we'd like from those studies. They are able to document, let's say, the chronic cardiovascular disease that may have put someone at risk of a cardiac event leading to their death. But most of the time we can't actually document that cardiac event because there's no physical evidence of it after the death. So a brief summary here. We know that methamphetamine use is prevalent and it's rising. Most of the emergency care related to methamphetamine is for psychiatric followed by cardiovascular and then injury related events. About half of stimulant use or events or deaths are methamphetamine and they present mostly in the context of fentanyl. And deaths that are attributed to acute methamphetamine toxicity that also involve opioids really seem to be similar to an opioid overdose death. And we can probably consider them the same for the purposes of developing prevention programming. Deaths that are attributed to methamphetamine without the involvement of opioids are commonly due to cardiovascular or cerebrovascular events. And they appear to be more consequences of chronic disease rather than true acute events. So let's talk a little bit about that chronic disease. There are two really main pathways of toxicity for methamphetamine. The first is the heart and blood vessels. So we definitely see a methamphetamine related cardiomyopathy, which I once thought was related to tachycardia and hypertension from methamphetamine, but it actually seems to be more immunologically inflammatory mediated. The second thing that we see is electrical conduction disorders, arrhythmias. And we also see a prolongation of the QT interval with methamphetamine use that we know puts people at risk of potentially fatal ventricular arrhythmias. We do see damage to the intima, the layers of the large blood vessels, and we can see aortic dissections and other large vessel dissections. We do see a higher rate of myocardial infarctions or what's commonly referred to as a heart attack. I will say cocaine is more associated with heart attacks because cocaine is directly pro-arthro sclerotic. So cocaine generates plaque buildup in coronary arteries quite directly. Methamphetamine is not as well documented to do that. We definitely see ischemic strokes, meaning clots thrown to the brain causing strokes. And we see with methamphetamine quite commonly hemorrhagic strokes or bleeds in the brain due to, presumably due to chronic cerebral hypertension. We also see gut ischemia. So we can see clots to clots or hypertension, frankly, within gut vasculature leading to low blood flow to the intestine or other intra-abdominal organs. And we see kidney injury, rhabdomyolysis, when we tend to see that more in Southern States where temperatures are really hot. And that's where you have, somebody gets really frankly too overheated and they have muscle breakdown and the muscle metabolites damage the kidneys. And that's a disorder called rhabdomyolysis. We don't see that with stimulants too often in more temperate climates, but in warmer climates, it does pop up in emergency rooms with some frequency. The other side of toxicity is a little bit North. So the brain, as we discussed already, we see hemorrhagic strokes and ischemic strokes. We do see a higher rate of development of Parkinson's disease. This is presumably due to basically burning out the dopaminergic system and about a two-fold higher rate of Parkinson's. We see seizures, tend to see that a little bit more with cocaine than methamphetamine. And we definitely see a reduction in executive function, in concentration and in memory with long-term use. We also see the development of psychosis. About a quarter of people who use methamphetamine regularly will develop a psychotic disorder. And we definitely see a lot of impulsivity and risky behaviors. In fact, methamphetamine use is so strongly associated with HIV transmission that it, by old epidemiologic criteria, it would have been considered causal, but of course it is not causal. So why do we see so much of this with methamphetamine? I'm not gonna talk too much about the mechanisms of action of methamphetamine, except to say that it's highly active in dopaminergic and norepinephrine systems, as well as serotonergic systems. So taking a little bit of a step back, when I think about toxicities, and this is where I spend a lot of my time is thinking about this. When I think about opioid toxicity, we have a really clear mechanism. We know that opioids reduce the drive to breathe. They allow us to tolerate a higher level of carbon dioxide in our bloodstream. And when we take too much, that carbon dioxide gets too high, and eventually that oxygen level starts to come down. And if we don't get help, eventually our heart will stop and we'll pass away. So the emergency presentation of opioid toxicity is this overdose construct that we all know well, and that is the cause of most of the deaths. In contrast for stimulants, it's really unclear to most people what this stimulant, quote, overdose is. And that's the only time I'll say that phrase, because I think that phrase is hugely problematic. As I discussed, the two main categories of toxicity we see are vascular and psychiatric. For emergency presentations, those vascular presentations are usually cardiac complaints or a stroke, and that's usually the cause of death, of the deaths that we're able to measure. For psychiatric events, we see the cognitive decline, psychosis. The presentations are these agitated delirium type presentations. And I would argue also some of these injury-related presentations, and we don't count them as methamphetamine-related, but people who use methamphetamine have a much higher rate of injury-related death and suicides and homicides than people who don't use amphetamines. So I would argue that some of the injury and trauma-related deaths among people using stimulants are probably related to the psychiatric toxicity of those drugs. And I will broaden psychiatric to neuropsychiatric. So the brief summary here, methamphetamine use results in cardiovascular and neuropsychiatric toxicities. They likely result from cumulative exposure and binge pattern use, much like we see with alcohol use. This is a really important point. When we talk about alcohol use, we wanna know how many drinks do you have in a week? How long have you been drinking? How much do you, how often do you have more than X number of drinks in one evening? Similarly with stimulants, with methamphetamine, what we really wanna know is how much do you use a day? How long have you used? And do you go on runs? Do you go multiple days without sleeping? Those are the sort of parallel to alcohol toxicities. And what I'm concerned about working with patients is the free, is the length of time somebody has been using. And if they are using in a binge pattern where they go days without sleeping, that's what I see as associated with the toxicities that we see. In general, most people, just like most people who die from alcohol consumption aren't dying from acute alcohol toxicity, but instead the sequelae of chronic alcohol use and chronic toxicity from alcohol use, most of the deaths from stimulants that don't involve opioids are likely related to chronic toxicity. So addressing these toxicities and trying to reduce the mortality means addressing methamphetamine use and use disorder as chronic conditions. It's very different from trying to prevent this acute opioid overdose presentation. So when we move on into clinical care, the rest of the talk is going to be about this four-tier strategy for addressing methamphetamine use in clinical practice. When I work with patients under this rubric, I do it very explicitly. I tell patients that I have a four-tier strategy to addressing methamphetamine use. And to be clear, I'm addressing methamphetamine use whether or not there is a use disorder present because there are toxicities to methamphetamine that should be addressed regardless of the presence of a use disorder. The first is assessment, and we'll go into this in some more detail. But basically, fundamentally, it's the DSM-5 diagnostic process, but it is also a bit of exploring why people use stimulants. Second is routine prevention. I do my outpatient work in an HIV clinic, so we do almost all of this automatically for all of our patients. But really, people who use drugs need aggressive infectious disease screening and vaccinations and access to preventive interventions. And frankly, everyone should have Naloxone. The third is use reduction. We have some good strategies for use reduction that many people are gonna be interested in. And the fourth is toxicity prevention. This is the novel part of this schema. And when I talk about this with patients, I will tell them that I have a four-tier approach. I'll list off the four tiers, and then I will dive into each of the tiers. The first tier is assessment. Obviously, you're gonna use your motivational interviewing techniques. They work better than anything else, whether you're working with a patient or you're working with a spouse or your children. Super valuable approach to life. And I always start by exploring the benefits that people get from stimulants in contrast to alcohol or opioids or a lot of other substances. Stimulants have a very clear functional role for many individuals, whether it is staying up so that you can drive a truck at night or so that you are safe on the streets if you're unhoused. There are some real functional roles that stimulants play for people. It's not just about experiencing pleasure or coping with boredom. It is also about work and staying safe, and it's also about managing pain. There is a clear mechanism of pain relief from cocaine and amphetamines that has been under-recognized since the 90s. And it's important for us to recognize that people might be using these substances in part to manage these issues on their own. Once you've gone through the benefits, you start going through the risks that people perceive. And as you go through the risks and the use pattern concerns, you end up with a DSM-5 diagnosis. But you want to continue the process regardless of whether or not you have a DSM-5 methamphetamine use disorder diagnosis. As you all know, there are a few categories of effects that we think about for a use disorder diagnosis, tolerance and withdrawal from the drug, use patterns, using for a longer period than you intend, being unable to cut down or quit, spending a lot of time trying to find or recover from the drug, having a strong craving to use, and then the group of harms to social work or fun activities, continuing to use despite knowing about the negative consequences, failing to fulfill major obligations, using in physically hazardous situations like walking out in front of traffic or driving a car, and continuing to use despite these problems. So those are really what you're looking for for the use disorder diagnosis. And then you're going to move on to routine prevention. So there's a lot of screenings that need to be done. And one of the issues with these screenings is sometimes we forget to do them again. I myself am guilty sometimes of looking at a patient and seeing that their last hepatitis C screen was in 2017. I'm a little bit late since I argue that we should do it every day, sorry, every year, not every day. The second is your vaccinations. And I would argue to be very aggressive with these vaccinations. The hepatitis, the tetanus, the influenza, the COVID, the pneumococcal vaccinations are all really important. And I can't emphasize enough how important the HPV vaccination is. We have a vaccination with the human papillomavirus vaccine that is available to people through age 45, and it prevents cancer, oral and neck and penile and anal and vaginal and cervical cancer. These are terrible diseases, and I've seen too many people lost or severely disabled from these diseases. And the underuse of the HPV vaccine is heartbreaking. Naloxone should be given to people regardless of their opioid use, because we know that fentanyl is often accidentally accessed when people mean to access another drug. A little bit of background on that. In general, fentanyl is not put into stimulants. Stimulants are definitely put into fentanyl to cut the sedating edge. In general, people who are intending to use another drug who access fentanyl, it happens because they either get the wrong drug from the person that they're obtaining drugs from, or they find a white powder substance that they assume is cocaine or methamphetamine, or they pick up the wrong implement. Maybe their friend smokes fentanyl and they smoke methamphetamine and they pick up the wrong pipe. So those are the mechanisms by which unintentional fentanyl use occurs and results. Unfortunately, if you don't have an opioid habit, even a small amount of unintentional fentanyl use could result in overdose and death. So we strongly recommend that anyone who accesses non-prescribed or street drugs carry naloxone in the event of unintentional fentanyl use. Fentanyl test strips are useful, but they're complicated. You have to water down the methamphetamine sample, or it's always gonna be positive because there's cross-reactivity with the strips and methamphetamine. Pre-exposure HIV prophylaxis. We know that a lot of our HIV is driven, transmission that remains in the U.S. is driven by methamphetamine use. And if we don't address methamphetamine use, we certainly would never get to zero. And post-exposure prophylaxis for sexually transmitted infections, gonorrhea, chlamydia, syphilis, with doxycycline. DoxyPEP is a highly effective intervention. And then smoking cessation, because we know that smoking is really bad for your heart and certainly magnifies the badness of methamphetamine use on your cardiovascular conditions. And then of course, treating associated psychiatric disorders and ancillary support housing for housing insurance and food and making sure people have an ID so that they can access things. All this stuff is incredibly important. All right. So I'm gonna jump to use reduction in a moment, but I'm gonna start with the toxicity prevention piece. So when I think about toxicity, we have cardiovascular, neuropsychiatric, and then we're thinking about prevention and treatment. So I'm gonna start with the cardiovascular. Actually, I'm gonna start with the treatment side of things. That's easier. For treating cardiovascular disease and somebody who uses methamphetamine, you should pretend that they are just like every other patient, because basically they are. There's one slight difference if they need a cardiac, if they need a defibrillator because their heart disease is so advanced, it might have to be a slightly higher, it might have to be a slightly stronger setting on the defibrillator. But besides that, they're essentially the same as somebody who doesn't use methamphetamine. They should be treated with goal-directed medical therapy, which means treating them aggressively with everything that we do to treat heart disease. Oftentimes, people who use drugs are not treated for their hypertension or their congestive heart failure because assumptions are made about them and they are not given effective therapies. Beta blockers are often not given to people who use stimulants based on a myth of unopposed alpha activation propagated from a letter to the editor in the 1970s that has been disproven with numerous studies. So please don't avoid using beta blockers. If you somehow can't get over the 1970s mythology, then use Carvedilol because it's a beta blocker that also blocks alpha and protects you from the mythology of the 1970s that is still being propagated even in the best medical show on air, HBO Max's The Pit, which is outstanding, but they're still propagating that myth. The acute treatment of methamphetamine toxicity, frankly, beta blockers are really good for managing the cardiovascular events. And then benzodiazepines are also really good at helping with both the cardiovascular and the psychiatric components of acute methamphetamine toxicity presentations. The other element of treating acute presentations is the psychiatric piece, which is both benzodiazepines are useful as is troparadol and ketamine. Atypical antipsychotics are where we usually rely. And we've gone to using in San Francisco some self-administered as-needed olanzapine. We call them chill packs. And we've shown that when people get a chill pack, they show up in the emergency room a little bit less for methamphetamine-related psychotic events. And chronically for treating methamphetamine-related psychosis, we use the atypical antipsychotics. Olanzapine is a good choice because there's not a lot of drug interactions. Some people use risperidol or aripiprazole. I think there's some back and forth. I found olanzapine to probably be the most reliable. So in terms of prevention, we're outside of the data world here. So I have to admit that and say, what I'm saying here is these are really hypothetical. Obviously, smoking cessation is gonna help cardiovascularly because we know smoking is really bad for the heart and your blood vessels. We also know that methamphetamine is really bad, bad for your heart and your blood vessels, but it's not listed as a cardiovascular risk factor. So if you have somebody who uses methamphetamine, you plug their data into a cardiovascular 10-year risk factor scoring system, you might show that they have a 2% risk of an event, but they use methamphetamine every day. There's no way they're down to the 2% risk. Their risk is definitely higher. It's just not factored into the model. So the question is, what is the role of statins, atorvastatin and other statins for people who use methamphetamine? And I have adopted an approach of discussing the potential benefits of statins with patients and allowing them to opt into statin treatment regardless of their score on a cardiac risk profile. In particular, I use atorvastatin because it has blood brain penetration and statins have been associated with a reduction in the cognitive deficits associated with stimulants and a reduction in progression to Parkinson's disease. So neuropsychiatrically, I have some evidence that statins should prevent some of the harms of methamphetamine. For cardiovascularly, all I have is a little bit of animal data. I don't have much data. What I have is a likely mechanism. So statins modulate the same inflammatory pathways that result in methamphetamine associated cardiomyopathy. So statins in theory should help. I don't know that they do. And in addiction, we never have the kind of money to run that 20,000 person cardiovascular study that my cardiology colleagues get to do. So the other thing that is really important for cardiovascular health is dental health. And we know that our patients who use methamphetamine because of the dry mouth, because of poor diets and potentially grinding of teeth, because of a lot of dental decay. And that translates to cardiovascular disease, likely through the chronic bacterial burden that people are carrying in their mouth. So making sure people get dental care is very important. The final piece is sleep hygiene. And this goes for both categories of cardiovascular and neuropsychiatric. Sleep hygiene is so important. If you've worked with people who use methamphetamine, you've probably noticed that people who go on runs, who stay up for two, three, four, five days in a row using methamphetamine tend to be way worse off than those who get sleep every night. So that binge pattern use is an issue. And I think we need to be more aggressive in promoting sleep in people who use methamphetamine. So moving on to use reduction. This is our basic rubric for use reduction. We use this when we're working with primary care providers and their teams. In California, we have the benefit of Medi-Cal provided reimbursed contingency management. And in San Francisco, we also have some city supported contingency management programs. We'll talk more about contingency management, but it is our most evidence-based intervention for any stimulant use disorder. The two medication options that I go to first line that have the best data behind them are bupropion or mirtazapine with or without naltrexone and the naltrexone could be oral or injected and we'll talk about some of the specific studies but this is a general overview and rubric that I would recommend thinking about in order to simplify the approach to treating methamphetamine use disorder or helping anyone to reduce their use. Bupropion is also highly effective as a smoking cessation agent so if they smoke also I lean towards bupropion. Bupropion also is quite a stimulating drug so if somebody is using it to get their work done and to focus then bupropion and they're using in the morning bupropion might be a good replacement for that. Mirtazapine in contrast is a little bit sedating so for somebody who uses at night and goes out and parties mirtazapine might be a good option to take at 9 pm and they might end up getting some sleep that night instead of partying. Mirtazapine is also associated with a little bit of weight gain so if their BMI is 18 I lean towards mirtazapine and mirtazapine doesn't have any contraindications in cardiovascular disease. Bupropion does although cardiologists will often use bupropion because it's even though it's not great for the heart it's much better than methamphetamine so it's not it's not that you can't use it with cardiovascular disease but if you're a little bit timid mirtazapine is is a good option in that circumstance. And then when to add naltrexone. I add it whenever I can. We'll talk about the study of bupropion plus IM naltrexone that's probably our best data for treating methamphetamine use disorder. I often will add oral naltrexone particularly for somebody who gets some benefit from bupropion or mirtazapine but they still end up using on the weekend when they go out drinking with friends and then one o'clock or two o'clock rolls around and they're still out with friends and so they start doing speed. And so I in those circumstances I've added on oral naltrexone as needed just take it on Friday when you take it Friday morning with your bupropion or whatever and we know that as needed oral naltrexone helps people reduce binge alcohol use so in that case I'm trying to treat a trigger to prevent the trigger of alcohol use that leads to methamphetamine use. If you can get injectable long-term intramuscular naltrexone that is probably more effective. And if you don't respond to those in general we say think about an addiction medicine consult. There are psychostimulants that have been shown and that are included in the American Society of Addiction Medicine guidelines to treat methamphetamine use disorder. Federally this is acceptable. State laws vary in terms of if you can use controlled substances to treat a substance use disorder long term. And so you have to know your state laws to know if you can do this. In most cases if you are trying to treat attention deficit disorder you might get the ancillary benefits with reduced stimulant use. There are data behind that and some people clearly definitively do benefit from that and it would be permissible in most states. A little bit more on contingency management. This is just to say there's a ton of studies that show it works and it works in different populations and different settings. And what we see is reduced methamphetamine use. We also see reduced sexual risk behaviors. So really effective intervention. The Medi-Cal program in California has shown about an over 90 percent abstinence from methamphetamine use with their with the contingency management program implemented. So really impressive results. In terms of medications we've discussed most of these. The Riluzole is not available in the U.S. and there are some agents that have been studied that didn't show any benefits. The SSRIs, TCAs, GABA agents, benzodiazepine antagonist, verenicline, the nicotine agonist didn't show any benefits. I do want to throw out there though there are limitations to all these studies. Our benefits in these trials are based on a qualitative urine assay. So you either used methamphetamine or you didn't. We are unable in all of our trials to date to determine if somebody went from using two grams a day to a half a gram a day. And if they did drop from two grams a day to a half a gram a day they likely had real measurable benefits to their health. Many of my patients have said that they dropped from two grams to a half a gram a day. So what I've started to do is I send a C-reactive protein, a high sensitive C-reactive protein prior to initiating treatment. And usually it's elevated in my patients who use methamphetamine. It'll come back at 10 or 15 or 20. And then when they tell me that they've cut back from two grams a day to a half a gram a day, I send another C-reactive protein. And so far to date, I have an N of five now. I'm slowly adding to the numbers. What I find is that the C-reactive protein is substantially lower. It's gone from 15 to 10 to five to two to normal range. And then I'm able to give that feedback to the patient and say, hey, the level of inflammation associated with methamphetamine use is lower now. So whatever you're doing, let's keep up the good work. The other issue with the trials to date is medication adherence is generally very poor. It's usually around 30% in a lot of these trials, which makes it hard to determine effectiveness. In the ADAPT2 trial of bupropion plus injectable naltrexone, there was, people were paid $5 a day to take the bupropion and they had about 70% adherence. So if you can incentivize medication adherence, it can be really effective. So potential future agents, I think the one, the most exciting one- Dr. Coffin, it looks like your mic went out. Uh-oh. Can you hear me now? I can hear you. Okay. Can you hear, Shirley? I can. Okay. Yeah, we- I'm going to keep going. Assuming it's still working, I got a thumbs up. So some future agents, the GLP-1 agonists are the kind of most exciting realm of future therapies for methamphetamine use disorder. They have clinically shown some really extraordinary benefits. Many of us in clinical practice have seen people reduce or even cease use of multiple substances, particularly I'd say cocaine, methamphetamine, and alcohol. I've seen in my clinical practice, we don't have data on this yet, but the mechanism makes sense, this sort of reduction in craving. I do wonder if there are different phenotypes of use disorders and a phenotype of use disorder that's really driven by craving for the substance might be more responsive to a GLP-1 agent. There are also, there's been some research with NAC or N-acetylcysteine. That's been really mixed. Not really sure. It's available at vitamin stores. I kind of think of it like chondroitin and glucosamine for knee pain. Probably doesn't do much, but if you can afford it, maybe it's neuroprotective. Maybe it will help reduce relapse. So it's something that's an option for people that have the resources to buy it at a vitamin store. Monoclonal antibodies and vaccines are under development. While I sometimes struggle to see their roles, I also think this is such a horrible disease. I enthusiastically support any of the pharmacotherapies that are being developed to treat it. So a couple words on mirtazapine. In full disclosure, this is, some of this is my work. We did two trials of mirtazapine. These were among sexual gender minorities and they showed reduction in methamphetamine use around the 30% range in the first trial, a little bit less in the second trial. This line here shows where we stopped treatment. So we got about maybe a 20% reduction in use. And then it persisted for six months of treatment, and then it persisted for three months off treatment. So we did see a little bit of an extended benefit. We also saw a reduction in sexual risk behaviors in both studies, more prominently in the first study. By the time we did the second study, everyone was on pre-exposure prophylaxis. So there wasn't too much motivation to reduce sexual risk behaviors. And then in terms of the ADAPT2 trial, the bupropion plus extended-release naltrexone, we definitely saw a reduction in use. With the placebo group, only about 5% to 10% achieving negative urines. And the treatment group, we saw 20% to 30%, depending on the phase, or 15% to 30%, depending on the phase, achieving negative urines. So a definite improvement relative to placebo. Importantly, this was a somewhat unique regimen. The bupropion was 450 milligrams, which is a very high dose. A lot of patients cannot tolerate that high of a dose. The other issue is people were paid $5 a day to take the bupropion, which is clinically challenging to implement. And it's still unclear to me if most of the benefit may have been from the high-dose incentivized bupropion. The studies of naltrexone alone haven't shown a benefit for stimulant use disorders. So I'm mixed on the role of naltrexone in this case. I think the bupropion, my suspicion is that bupropion is the real workhorse, and naltrexone might be adding some benefits. It definitely intensifies the treatment and brings the person into clinic every month, which can offer opportunities for interactions that may also help to support recovery. So a summary, and then I'm happy to take some questions. Please use a systematic approach when you're addressing methamphetamine use with patients. Tell them you're using a systematic approach. Start by exploring the benefits that people perceive that they receive from methamphetamine use. Sometimes you're going to find somebody who only sees benefits and they don't see any harms, and that's important to know because then you know they're pre-contemplative in your stage of change. If you diagnose a use disorder, if it's there, but don't just walk away if there's no use disorder. You can still do a lot to help the patient. Ensure they have all the screenings, the vaccinations, the naloxone, any wraparound care that you can provide. Talk about the cardiovascular and neuropsychiatric toxicities of methamphetamine use. Ask them how much they use, how long they've used. Most people can tell you I use a gram a day, or if you know the local cost of the drug, methamphetamine in San Francisco is 10 bucks a gram. So if they say I spend 20 bucks a day on meth, then they use two grams a day. And how long have they used? And I calculate a gram year history. So if they've used a gram a day for 20 years, they have a 20 gram year history. I don't yet know what that means exactly, but it helps me kind of place it in that chronic cumulative exposure category and start to get an idea. You know, if they've used a gram a day for two years, they have a two gram year history. That's not a lot. I might not be pushing a statin on them just yet. So it can really kind of guide the rest of your care. And offer, but offer the strategies that can help. Think about, think about a statin. One thing I forgot to mention with the statin is I do send a CK, creatinine kinase, before I start a statin in somebody who uses methamphetamine. The reason is because the statin can increase CK. It's a toxicity that can occur. Also met people use methamphetamine sometimes have a chronic low, low level elevation in their CK. I, what I don't want to do is start a statin on somebody, send a CK, it comes back low level elevated, and then I have to stop the statin and the statin gets put in their allergy box. And then they can't benefit from it when they really, really need it later in life and have heart disease that really needs a statin because it's in their allergy box in their medical record. So I do send a CK beforehand. So I know their CK level before I start the statin. If they have chronic toxicities from methamphetamine use, really treat it aggressively, just like you would for anyone else with heart disease. And then offer the use reduction strategies, contingency management, if you can find it and try out the medications. The other thing is, you know, honestly, it's okay to try any medication for methamphetamine use disorder. Don't just, you know, don't feel like you're hamstrung by the small number of options I provided. Try anything. This is a terrible disease. Finally, just to run through briefly the conclusions, heavy text page, methamphetamine use is prevalent. Our ER presentations are psychiatric, cardiovascular, and injury. The deaths attributed to fentanyl and methamphetamine are almost certainly due to fentanyl. And those from methamphetamine alone are largely cardiovascular in nature, probably sequelae of chronic disease and more similar to alcohol related deaths than to opioid deaths. There are acute toxicity deaths from stimulants, just like there are from alcohol. But most of the deaths that we see in surveillance data appear to be from chronic disease or acute events that are sequelae of chronic cardiovascular disease. Use a systematic approach to address methamphetamine use, including an assessment, routine prevention, toxicity prevention and management, and use reduction. I have references that you can look through as you wish. And I believe Shirley and Jen have some comments on the mentoring program. Yes. So I would like to make you all aware of two resources offered through PCSS MOUD that may be of interest to you. First, the PCSS MOUD mentor program is designed to offer mentoring assistance to those in need of more one-on-one interactions with one of our colleagues to address clinical questions. You have the option of requesting a mentor from our mentor directory, or we are happy to pair you with one if you'd like. To find out more information, please visit our website using the web link in the mentoring program slide. Thank you, Dr. Coffin. And second, we have the PCSS MOUD offers a discussion forum that is comprised of mentors and other experts in the field who help provide prompt responses to clinical cases and questions. We also have a mentor on call each month. This person is available to address any submitted questions through the discussion forum. You can create a new login account by clicking the image on the discussion forum slide to access the registration page. And then the next two after that are the partnership slides, which simply note the consortium of organizations that are a part of PCSS MOUD's project. And then finally, please reference the contact info slide for our contact info website and social media handles to find out more about our resources and educational offerings. And then also as a friendly reminder, before we close out, PCSS MOUD will be recording this and archiving it on our website within two weeks of today's event. And within 24 hours of today's concluded session, you will receive an email from us with an evaluation and certificate claiming information. That concludes today's session. Thanks everyone for joining us today.

substance use screening

primary care

Dr. Jennifer McNeely

American Psychiatric Association

TAPS tool

screening tools

implementation guidance

US Preventive Services Task Force

electronic health records

methamphetamine use

addiction treatment

internal medicine

infectious diseases

opioid overdose

cardiovascular events

contingency management

motivational interviewing

pharmacological interventions