Okay, so good evening everybody it's five o'clock and want to start the webinar on time so welcome to today's webinar on the fourth wave addressing the intertwined fentanyl and stimulant overdose crisis by Dr. Stephen Shopta and Dr. Daniel Ciccarone. My name is Julie Kimmick and I'll be your moderator for this session. This is the last of our webinar series of hot topics on the treatment of opioid use disorder and stimulant use disorders. Dr. Shopta is a licensed psychologist and director of the Center for Behavioral and Addiction Medicine. He is professor in family medicine and psychiatry and biobehavioral sciences and vice chair for research in family medicine at UCLA. From these contexts he conducts a portfolio of research that focuses on the medical treatment of addiction and of HIV prevention in the context of addiction. His research collaborations are with basic scientists and clinicians to study the ways that drugs of abuse, especially methamphetamine, affects biological processes relevant to HIV transmission. Dr. Shopta energetically maintains the research and clinical policy efforts to bring novel and high-impact solutions to delivering culturally competent care for persons affected by addictions and HIV. In addition to his extensive research portfolio he maintains a limited clinical psychology practice at UCLA treating patients with severe substance use and mental health disorders. Dr. Ciccarone is professor of family community medicine at UCSF. His research is centered on the contextual issues of treatment and prevention of HIV, AIDS, and related diseases in socially marginalized populations. His recent research is in exploring the different medical consequences of use of various sources and forms of heroin. His team is exploring the economic, anthropological, historical, clinical, and public health dimensions of this crisis. His work has been published in JAMA, New England Journal, PLOS Medicine, and other peer-reviewed journals. Dr. Ciccarone is also a medical educator and has largely worked towards improving the social, behavioral, and prevention science content within the undergraduate medical school curriculum. He's responsible for designing extensive curricula, editing syllabi, and recruiting faculty, hosting sessions, and direct teaching, as well as designing and leading assessment activities. So I'd like to welcome you both to this webinar and thank you so much for presenting. Thanks, Julie. Thanks, Dan, for joining and for those of you who weren't here last week to hear Dan's talk. I know these are videotaped and it's worth listening to. It was a tour de force. He set the bar high. I hope to keep up the quality. So the charge is on. Let's see how we do today. Let's see. I should be able to see my screen okay. So we'll get started. So this is the funding slide for the ORN. These are my disclosures. I do receive clinical supplies. I have several clinical trials that I run and I receive a drug and matching placebo from Alkermes, Gilead, and from Indivior. These are Julie's disclosures. Let's see here. But today we're going to do a discussion. This is meant to be an interactive talk. We're going to demonstrate an understanding of epidemiology of substance use, of stimulant use disorders that focus on cultural factors and comorbidities that correspond with both methamphetamine and cocaine use disorders. Dan gave you an overview of the general epidemiology. Today I'm going to drill down into culture groups and we're going to talk about how this understanding helps develop culturally competent treatment plans for treating stimulant use disorders. We're going to identify key neurobiology factors in the development and maintenance of stimulant use disorder and how these relate to treatment options and treatment outcomes. You may be thinking that a case-based approach wouldn't really focus on neurobiology, but it's our contention that all behavior is brain expressed and understanding how brain works in the setup, the development, and the maintenance of stimulant use disorder is important in thinking about treatment. Then we're going to talk about understanding the quality of and the extent of evidence supporting advancements of pharmacotherapies for the first time in 30 years. I can stand in front of a group of scientists and clinicians and say we have some evidence that shows that we have some medications to consider and we'll talk of course about the behavioral therapies, but you all know that anyway, but we'll go over it as it's important. We're really going to focus on the patient's perspective today and I think it's important to always start with the idea that how patients see things is different than how physicians and clinicians see things. Patients see their substance use, their stimulant use, as a spectrum. It runs from the regular stimulant use to stimulant use disorder and it's on a spectrum of severity. Basically, most people across the population either don't use stimulants or use them in ways that don't cause problems and that's just fun, but with continued use what happens is that people will start to have occasional problems that can be frequent, can go to frequent, and sometimes are mild or a little more severe. In life, the course, the force in life is toward health and people will usually stop when the problems begin. That's the course of normal development and that's why most people don't go on to develop substance use or addiction because the problems actually help people to decide to put down the pipe or whatever it might be. You can see that as this sort of spectrum works across from left to right, you have more people at the left who are not using or using without problems to few people on the right with people with serious addiction problems. This is important and it's also important to understand that people move across this spectrum imperceptibly. Substance use, stimulant use is an almost automatic behavior that people don't understand how they move into something that's fun to something that's just problems. This is how clinicians understand the DSM-5 and you can see the 11 criteria and how we add them up. This is really important and I'm not going to go over this because this is a clinical group but what I bring these about is to show you that this is really black and white and articulated in numbers and with definitions whereas the other slide, how patients see their substance use is more of an analog sort of thing that's full of color and lots of different things that are going on. It's an important place to start and I said we're going to be doing case-based learning so let's start with the first case. Today we'll be voting, there will be polls, we're going to start the first poll and this is the intake with James. James is a 42-year-old black African-American gay man who is seeing you because his partner John said he must. John is complaining that James's weekend warrior, I will go over that in a bit, use of methamphetamine is interfering with their life together. James tells you this is impossible as he's in long-term recovery from addiction to crack cocaine that happened 20 years ago. James says meth isn't crack and his experience in recovery helps him to control meth use. James became HIV positive three months ago and has started HIV treatment and currently is virally suppressed, meaning a good response to his HIV drugs. James smokes cigarettes about a pack or a pack and a half a day and he smokes Newports. Now this case is packed with information so there's no right answer here but I want to tap the crowd here and get a sense of where we are. What is your primary treatment goal for James? Choose one. To stop methamphetamine use, to reduce methamphetamine use, to stop smoking cigarettes, or to coordinate addiction care with his infectious disease physician. So vote your conscience. Okay how are we doing with the poll? We have about 60 well 70 percent in right now. Okay let's go ahead and call it and let's let's go over the responses. Let's see what people are. Okay excellent, excellent. So all of these options are good. I kind of like the one at the bottom to coordinate addiction care with the infectious disease physician. And then the goals about stopping or reducing methamphetamine use, those also came in strong and you know those are good goals and we'll go over those and unpack those as we move forward. And then a few people mentioned stopping smoking cigarettes and I'll provide some data about why that's a reasonable choice. Okay now I can't get my slide to advance. Why is that? Okay. All right let me stop share and come back. Okay. Sometimes things just get stuck. Here we go. So this is a pretty graph and I just wanted to share it because it's new and Dan was going over the general epidemiology of stimulant use. But you can see here that the, whoops back up, that this area over here is the people who are using cocaine only. This is 3.3 million who are using prescription stimulant only and 1.5 who use both cocaine and stimulant. I'm sorry this is methamphetamine use down here. And then these intersections are the people who combine drugs. And as we you can see here that there's a lot of allegiance to the stimulant that you're using. There's not a lot of co-stimulant using which I think is an interesting point. And then I have here the data on just how many people are using by age and you can see that the highest rate of use is among adults 18 to 25 and then the next highest is among adults 26 and older and the youngest is in the adolescent group. So that's good news. But one of the things we don't want to, I'm bringing up this slide here to show you that Joey Palomar published a couple years ago showing that stimulant use, methamphetamine use across the population in the National Household Survey is low, less than 1%. And it stays pretty stable. But what we see is that among people who report heroin use or LSD, you see this slope that's increasing over time. That sort of fits, right? We know that people who are, there is, as Dan was presenting last week, this whole thing about fentanyl, heroin, and methamphetamine is on the rise across the country. And we can see that that's indeed the case here among people who are using methamphetamine. And I include this paper here. This is a real dandy of a paper. Heroin use cannot be measured adequately with a general population survey by some really smart people, epidemiologists from University of Maryland. And it's really worth reading to talk about the biases that are in National Household Surveys. So I know we all drag and drop those pictures out of the National Survey on Drug Use and Health. But it's also good to remember that when we begin to disaggregate what's going on in the sample, the assumptions may not hold. And it's just worth reading and upping your game. Dan presented this last week. I also like to mark it up by showing you where the waves of the opioid crisis are. And you can see here across time where they are. And I think it's always good to see that it is this issue of psychostimulants and opioids almost equal to the psychostimulants alone in terms of overdose death that is going on in this country. And just before you all joined, Dan and I were talking about the new data that are out about overdose deaths. And it appears, again, we have another round of overdose deaths that are going to be over 100,000 in the last year. So sad stories are continuing. And the stimulants are contributing to this greatly, not only by themselves, but also in their combination. What I want to talk about, you know, Julie, if you can watch the Q&A and just make sure that if there's questions that need to be asked as we go along, that'd be great. So, you know, I bring up this slide to show a few things. That methamphetamine has effects and functions that shape treatment goals. And the reason is because methamphetamine in particular, but cocaine to a lesser extent, has particular function within different groups. On the left here, I'm not going to spend time with what methamphetamine does. You're familiar with that. But it's always good to see these sorts of things. But let's talk about gay men. And among gay men, methamphetamine allows a type of sex to occur that is not possible when you're not using methamphetamine. It's called chem sex or sex at the extremes. And it actually builds a community of gay men who value that behavior and engaging that together. So as the ethnographers have written about this quite extensively, and the point I raise about this is that for each of these groups like gay men, when you pull methamphetamine out of the picture, it leaves a hole in the behavior repertoire that has to be addressed. Medication can't address that vacancy. It's something that has to be addressed by a therapy or actually getting people out into life and doing things like exercise or rock climbing or doing something or whatever. Another group that has cultural affinity with methamphetamine are the shift workers, the people who are working two jobs a day in Los Angeles. If you're on a regular sort of blue collar salary, it's going to require another part-time job to be able to pay the rent and to keep the energy going. People will often look to stimulants like methamphetamine because this allows them to be able to meet their goals. That actual need to provide the rent and the energy to support that paying of the rent is a major treatment problem. Again, that's not going to be addressed by a treatment necessarily, but a medication that might have a mild stimulant profile could actually fit very nicely for this particular culture group that finds it helpful to use methamphetamine to be able to live their lives. Among bikers, methamphetamine is important. It helps them stay out on the highways longer. Of course, that's a long story in California where crank methamphetamine was moved up and down the Interstate 5 between Los Angeles and San Francisco for many years with these biker groups. It was major piece of culture here in Los Angeles or in California. Among women, this is one of the greatest mysteries in my life that in Utah, one of the real estate functions that you have when you buy a house is you have to assert that methamphetamine was not made or sold in the house because it's such a general problem across the population in Utah. For women, using methamphetamine, it allows them to stay fit, thin, able to get their homework done, and be interested in sex when their husband comes home. Again, looking at how a drug works is important in putting together that treatment plan. Then finally, among people who are in rural areas or in youth, the idea of having time pass is something that methamphetamine actually accomplishes very easily. You can take methamphetamine, it's got a long half-life, and you can just kind of coast and get by on particularly boring situations where you might be. That's the culture issue. Now, I want to talk about dose and frequency of use and how that affects brain. This has to do with how people use the drug. Weekend warriors is something we like to call here in town when people will start using methamphetamine, say, on Thursday night, Friday morning, again, Friday night. If it's among gay men, they might use an erectile dysfunction drug like Viagra or Cialis to prevent something happening like inability to sustain an erection. Saturday and Sunday, again, uses. Then on Sunday morning, smoking out with weed and a benzo Sunday evening, sliding into work Monday or Tuesday. This is a behavior pattern that would happen maybe once or twice a month. It usually costs about $100 to $250 for the weekend with regional cost differences across the nation. This is what use patterns look like for shift workers. And you can see that twice a day dosing to be able to get your jobs done and occasional dosing on the weekend to manage withdrawal symptoms looks like this. And the blue moon, the people who are able to just get away with using methamphetamine every few months, this is what that looks like. If you combine all this in terms of what happens, you can see that there's some substantial differences between the exposure of meth per month and the behavior that gets set up. So like for weekend warriors, let's assume that on average, a person is using a quarter gram a day for their meth use. So that's a substantial, serious, moderate to severe level habit. Some people use a lot more, but that's a serious sized habit. If you just look at the weekend warrior, that in a month, you're gonna be exposed about, you're exposing your brain to four to five grams of methamphetamine. Whereas shift workers, it's twice, sometimes more than twice that amount that they're exposing their brain to. And the blue moon folks, it's like a gram every three to six months, which is really much less. So you can see that in terms of like dose and frequency of dose to the neurons, there's significant differences in the way people use this drug. There are also important differences in naturally occurring abstinence that happen with these patterns. For weekend warriors, people may be able to put together two weeks or even longer of naturally occurring abstinence where they're not trying to not use the drug, but it just happens naturally. Whereas shift workers, the longest they may pull together would be four days and maybe even a week. But generally speaking, they're always using the drug. So the idea about being able to stop is something that the shift worker may not be thinking about. Whereas the weekend warrior, it's like, it's not a big deal, they can stop. And they just don't understand that in a couple of weeks, they're gonna have that urge to use again. They're just gonna go out and they're gonna act on it in a sort of unknowing way for the most part. And the blue moon folks, they can stop and stay stock for a long period of time, which helps them to define that not as a problem. One of the things our group just published on is, is there any link between social adversity outcomes and this sort of pattern of use among people? And so what we did is we have data from a cohort of men who have sex with men that we've been following for eight years here in Los Angeles, and every six month panels where we get people to come in, provide urine samples, blood samples, hair samples, all kinds of biomarkers. And then we also ask them a lot of questions every six months. And in terms of reported methamphetamine use, you can see down here that you could respond none, monthly or less or weekly or more. And what we see is a reliable pattern that happens with these breakouts, where if you look at the social adversities and health adverse outcomes, you can see that people who are using none have fewer probabilities of having this condition, each of the conditions, whereas people who are using monthly or less are middle more likely and weekly or more the most. And you can see that happens here for unemployment, for housing instability, for intimate partner violence, having new anal partners, concurrent sexual partners, exchange sex, look at that, very beautiful, positive STI tests, detectable viral load among those who are living with HIV, and then renal condition, neurological conditions, psychological conditions also tending to look in the same way. So the bottom line is there does appear to be significant benefit to not increasing frequency or reducing frequency of meth use. That speaks to the issue of, do you have to have somebody who wants to have abstinence or is reducing their methamphetamine or cocaine use a reasonable goal? These data would tend to support the second part of that. I'm not gonna spend a lot of time with this, but our group is also looking at some of the ways in which these health outcomes correspond with genetic and social genomics, which is the expression of pro-inflammatory cytokines that correspond with different experiences in life. What we've seen is that methamphetamine use, HIV, and intimate partner violence, all three independently will promote the release of pro-inflammatory cytokines among people who we've been following in the end study. It's an important finding because it also talks about how that not everything that we experience is about our bad decision to use a drug. It's also about the way that methamphetamine, an important drug that's pharmaceutically grade on the street, interacts with our body to promote health outcomes that have independent negative effects. This isn't all just about bad judgment or a disease. It's also about the way in which this drug interacts with our body and other pathogens that our body may have to promote the particularly bad outcomes. What we also know among men who have sex with men, as we talked about, and also among heterosexual women, that speed and cocaine both have a very strong sexual overlay. It promote, these drugs promote sexual activity. And among men who have sex with men in cohorts, two cohorts, these data are somewhat old, but there's new cohorts that are coming along showing the same sort of thing. And in fact, in our cohort, it's also the case where if you start living without HIV, either in Project Explore here in the U.S. in 2006, or the Max Cohort Study, which is still in place after 35, 40 years now, the primary reason why men get HIV incidence is attributable to methamphetamine, with 16% attributable fraction in Project Explore and 33% in Max. So the primary driver, one of the primary drivers of HIV incidence among men who have sex with men in this country is methamphetamine use. Now, one of the things that happened here, because I'm a researcher, one of the things that we find here is we have these fellows that come along, and Colby Passaro is one of the smartest ones I've had coming to work with me here in town. In early 2000s, Kathy Reback and I did a behavioral, a controlled behavioral study of cognitive behavioral therapy, contingency management combination and a control condition to look and see what happens to people who are methamphetamine dependent if we could see outcome differences by these treatments. That's a long story, and I'm not going into that, but Colby came along and said a couple of years ago, can we follow up these guys who were part of this study in the early 2000s and see whether they're still alive or not, and look along whether they were cigarette smokers or not, and also look and see whether they had HIV or not, because 60% of the sample were living with HIV. What we see here in 20 years, realistically, what we see is that HIV status really had very little to do with survival rates. Here, the best survival rate were people living with HIV who were non-smokers, and the men who were dying more frequently were the people living with HIV who did smoke, and in fact, if we look over here at the pre-mortality rate of folks who were using tobacco on top of being a gay man who uses meth, with meth dependence and had HIV 20 years ago, and has been living with HIV for 20 years, that if you just adding tobacco use to the picture, basically quadrupled almost five times the pre-mortality rate, which is fascinating. So one of the things I like to tell my patients when I see them is one of the best things you can do, even more important than stopping using your methamphetamine use, is to quit smoking, because the cigarettes will kill you. I do have a question that came in. I just wanted to know, the participant said that the data presented on men who have sex with men and HIV was done pre-prep, and wondering if these stats would be different today. That's an awesome question. It is better, it is better. The attributable risk will not be as high, but it's still, the signal will still be there. We, in our cohort of 500 HIV positive, half of them are HIV positive, half are negative, half are drug users, and half are non-drug users. We've had 12 HIV incident cases over the past four or five years, and among those 12 cases, all but one was methamphetamine involved. And the one that was not methamphetamine involved was somebody who used alcohol, who got really blotto, and had the same sort of blackout sex that led to him becoming HIV infected. So by and large, the answer is yes, prep helps, but among men who have sex with men who are using methamphetamine, it is still a top attributable risk for becoming HIV infected. And parts of the reasons are not only just behavioral, that people don't take their Truvada. It also, as we have some data, I'm not talking about today, but we have data from an infectious disease doc who works with us who has been taking gut samples from gay men when they come into visits, swabs and sponges to collect fluid in the lower gut, and has been able to see that when methamphetamine use is recent, like in the past two days, she sees a release of pro-inflammatory cytokines in gut that is not matched in circulating blood. We know that the establishment of HIV happens in gut. So if you increase the amount of pro-inflammatory cytokine with methamphetamine at the time when HIV may be coming into the compartment, you actually increase the risk that the immune system gets activated and can help establish an infection. What we don't know is if you have prep Truvada on board, if you have the TDF on board, would that actually work counter to the pro-inflammatory cytokine release from methamphetamine would that work counter to the Truvada? It's not, I don't know. It's a great question. And the other part of that is among people living with HIV, if you take methamphetamine, what we see is independent of behavioral medication taking, a higher rate of uncontrolled viremia in people who are living with HIV that corresponds with recent methamphetamine use. The paper is out there. It's Jen Fulcher, F-U-L-C-H-E-R is the main author. And it talks about how this effect is seroneutral. This effect affects inflammatory cytokines in gut, particularly for both men who are living with and without HIV. So it's an interesting question. And if I had another career to run, if I had that much more time, it's something I'd spend time with because it's an important one. But my gut tells me that it's not just about whether you take the pill or not. I think there is something going on biologically between methamphetamine and how our immune system acts and both to promote viremia and also to promote infection in the people who are not living with HIV, but a great question. Thank you. So relevant neurobiology, all behaviors brain express, including motivated or automatic behaviors like stimulant use disorder. Cocaine and methamphetamine have direct effects on neurons and stimulating and sustaining dopamine release. And behavioral and potential medication effects therapies have mechanisms that affect neurotransmission, which in turn correspond with behavior change. So this is absolutely my favorite picture ever. This is from George Koob's lab. It's Asha is the first author. And it really does show you what happens with the transmission pathways for methamphetamine and cocaine. And what you can see here is that cocaine primarily blocks the dopamine transporters in the cleft. That's the part that's in the, there we go, in here. Methamphetamine both inhibits dopamine reuptake here into the presynaptic side by blocking dopamine transporters, but it also increases reverse transport of dopamine into the cleft. It actually will move methamphetamine from here back over here to block the transport of dopamine back into vessels. And in fact, that free floating dopamine that's in the presynaptic side is the reason why the presynaptic damage happens from high dose methamphetamine use. There are also things that go on here in terms of like VMAX, the vesicular monoimmune transporter too, showing that in comparison to controls that VMAT2 in recent abstinence goes up, which explains why it is that people actually have that sort of honeymoon feeling when they stop using methamphetamine or cocaine. And the reason for that is the receptor supersensitivity that is about the VMAT2 increase compared to controls. But that wanes with prolonged abstinence, which corresponds with complaints of people saying, I feel like I'm 85%, it's a May gray day, or it's a June gloom day sort of thing, that that's sort of how people go around. And some people believe, and there's data to show that that corresponds with this reduced VMAT2 compared to controls. And we also see reductions in dopamine synthesis, dopamine transporter reduction, dopamine release being lowered, and dopamine D2, D3 receptor density going down over time. At high doses, what we see is that this is an important point here, and patients will ask you about it. In methamphetamine and amphetamine, there's a question about how do you get along with ADHD being prescribed to people who have, I'm sorry, you have stimulants being prescribed to people with children with ADHD, and sometimes for adults with ADHD. And the answer to that is because the drugs actually help focus attention and actually help with behavior problems. And at low doses, Glenn Hansen's lab was able to show, that's the Albergue's one, that high doses actually are the part of the equation. When you're using methamphetamine or these prescribed amphetamines at very high doses, this secondary pathway opens up where this reverse of dopamine transport allows more dopamine to be within the cytoplasm of the presynaptic neuron, which leads to blubbing and other sorts of damage to those receptors. So, and of course, both cocaine and methamphetamine have 5-HT and serotonin and norepinephrine transport effects. So at low levels, amphetamines actually have a therapeutic effect, and they block primarily dopamine transport. And it's not until you get into the higher doses, something up and around 150 or 200 milligrams, that you start to see this high dose damage pathway. That's important. So let's do another case. Marissa is a 43-year-old Caucasian mother of two boys, ages 13 and seven. I'm sure you know where this is going. Both of the boys have symptoms of ADHD and teachers from middle and elementary school classes for the boys have mandated that to continue in class, the boys must be evaluated by a physician with clear recommendations for managing impulsive behavior. She breaks down and cries as she tells you her husband had ADHD as a kid and still has adult ADHD symptoms. She says that he uses methamphetamine as a central coping skill to help focus for big work projects. He never received psychostimulants as a child, but believes if he had, he'd be completely addicted to it. What do you recommend for the boys? Do you prescribe psychostimulants to both boys to manage ADHD symptoms? Do you prescribe psychostimulants for the older boy, but not the younger boy? Do you prescribe psychostimulants for the younger boy, but not the older boy, as there's evidence that a window of efficacy for using stimulants for ADHD may have passed for the older boy? Or do you prescribe benzos for Marissa and provide a letter to schools, noting that there will be no stimulants for fear of encouraging adult stimulant use disorder? Please vote your options. Okay, Julie, where are we? Oh, we're at about 34% right now. Okay, let's give people a minute more. Okay, let's see where we are. It looks like it stopped. Okay, so first three choices, of course the fourth one was just for fun, but the first three are interesting. So there is evidence for both. Prescribing psychostimulants to both boys to manage ADHD is a reasonable way to move forward. Steve Henshaw has done some work showing, and there's some meta-analyses that show that psychostimulants used medically for boys or for children will not statistically lead to stimulant use disorder later in life. So the idea of using stimulants for what they're prescribed for makes a lot of sense. There is some question that you might want to use more for the younger boy, but not the older boy. There is some data that suggests that when starting psychostimulants for behavior problems is more effective in younger than older patients with ADHD. But always just understanding that these medications could work is a good place to start. So let's move to the next slide. Oh, pharmacotherapies, how apt. So for the first time in 25 years, I can talk to you about a medication that works. I was one of the people who did this study. It's called ADAPT2. It was published in the New England Journal last year. And it was basically a very complex trial design where we used Vivitrol every three weeks and Bupropion 450 milligrams a day. What we did was we assigned people at baseline in one to three ratio active to placebo, and then had a observation period in the last two weeks. They came in twice weekly. And during this period, if you provided three of four urines that were negative for methamphetamine, we called you a responder. And if you didn't, you were a non-responder. And we have this enriched placebo group with basically 300 patients in the placebo group in here to see what would happen. And what we see here very nicely is in this, in the medication group, you see this nice percentage increase of negative urine samples that moves to here. For the placebo group, at this point, these guys end their contribution to the analysis. And here, these guys in the placebo group who were non-responders were re-randomized in one-to-one fashion, active to placebo. And you can see here again that starting with seven, the same sort of slope increase in terms of response and producing negative urine samples for the medication combination with no corresponding increase for placebo, with again, this period here, the last two weeks, showing a significant difference between the two groups. And the weighted difference between placebo and active and placebo conditions in the first and the second part of the study was about 11 percentage points, which corresponds to a number needed to treat at 12 weeks of nine, meaning you need nine people to treat to get somebody with a positive response. We saw similar outcomes for the percent of samples that were methamphetamine-negative urine over the trial, the change in methamphetamine craving, the change in depression ratings, and the change in the overall outcomes of the trial. So that combination has strong evidence of efficacy in terms of reducing methamphetamine use in a broad population. Among men who have sex with men, there are two trials from San Francisco that were done by Grant Colfax originally here in 2011, showing the decline of methamphetamine regression line here over 12 weeks. And then Phil Coffin redid the same thing basically to 12 weeks here, same slope, generally speaking, with continuation of effect out to week 36. You can see here, the important part of this is there's no increase of outcomes over the period of time, and all of the change occurred in the first 12 weeks. So at 12 weeks, the number needed to treat here is eight. And just to give you a sense of where that fits with alcohol use disorder, a number needed to treat for Vivitrol for reducing heavy drinking days is about 10, and maybe it's 12. So this is the neighborhood of where medication effect we accept for bringing on, you know, in terms of risk to benefit for patients. So clearly, these two studies seem to work. There is some take-homes that are not great for this trial in that it was done with men who have sex with men in San Francisco. Needs to be redone in a broad population, and I know Phil is working on that now. For cocaine, Frances Levin has been working on a stimulant with mixed amphetamine salts extended release, and she started with cocaine use and ADHD, and has great data showing a dose response in terms of cocaine-positive urine samples on the y-axis here over time. And you can see here again, the placebo is doing the worst with the low-dose mixed amphetamine salts doing the middle and the high-dose doing the best. This was replicated in a general group of cocaine users, not with ADHD, by John Mariani, and again by Frances Levin. Again, seeing the same sort of thing, whether you look at the first trial of the people who presented three or more weeks of negative urine, then the trial was basically twice as high for the medication versus the placebo group. The similar group repeated using a different marker in terms of positive urine toxicology, and you can see that the medication group also seen this nice, slow response. This is very exciting. The dose of Diparamate here is 200 milligrams, and this dose here was 60 milligrams. So let's talk about Mark. Mark is a 45-year-old Caucasian man who is Marissa's husband. She says, given your prior excellent advice for the boys that he needs to consult with you. In your interview, Mark says he's never been honest with Marissa, and that he's using methamphetamine daily in order to keep up with his daily demands. He has severe withdrawal when he misses a day. He sleeps most of the day and has severe fatigue and medicates that using cannabis, which leads to binge eating sessions. Marissa thinks his colds happen and that he shouldn't smoke weed so much. He cannot blow his cover and enter a treatment program, but he would be interested in starting a medication to reduce his methamphetamine use. What choice has best evidence for you to proceed? So what's the best choice here? I would recommend that Mark accept abstinence as a goal before using medications. B, to prescribe extended release naltrexone every three weeks plus bupropion for 50 a day. Do you prescribe mirtazapine, 30 milligrams at bedtime, or do you prescribe mixed amphetamine salts extended release? So your best choice here with the best data. A couple more seconds. Okay. It looks like we can close the poll. All right. What do we get? Awesome. The prescription of the extended release naltrexone in three weeks plus bupropion is the winner here, and I think that has the best evidence to move forward. I will say I'm not going to do any sort of like promotion of this approach, but I do think the evidence there with the 400 patient trial is strong enough to be able to leave it to you if you want to go off label in this respect. So let's see. I'm frozen again, so I'm going to go back to here. So after 30 years, we finally have some things to talk about here, that there are some signals for medication treatment, a large trial for the extended release of bupropion, naltrexone and bupropion over placebo for reducing lymphamphetamine use. The metazapine effects in MSM are impressive, particularly the replication, because we know in science the hardest thing to do is the same thing twice, and seeing that is really impressive. Metastemphetamine salt ER shows consistent signal for cocaine addiction. Again, the same thing, the hardest thing to do in science is the same thing twice, with dose effects observed for people with ADHD, and the combination of the extended release of amphetamine plus tapiramate shows two replications, which is very strong. And that is the essence of my recommendation, that there is evidence to consider medication as a foundation of treatment for stimulant use disorder. This is not a treatment for stimulant use disorder, but the foundation, which is why the picture here is about a foundation. It's not a house. It's not a building. It's not something. It's just a foundation, and it's a place to start, which is an exciting place to be, because up until this time, we haven't been able to do this. And the important thing about these medications is they have an effect on behavior that people don't have to actually invest time, energy, or thought about. In what's going to come up soon is in the trial of the combination of extended release naltrexone plus bupropion, what we see in the medication group is a significant reduction of ad libitum cigarette smoking, which is exactly what you would expect to see. We didn't address smoking in the trial, but bupropion is an approved treatment for smoking cessation, and in fact, we see that effect. So the fact that people are there in the trial taking the medication, not necessarily trying to quit smoking, are actually responding to the medication by reducing their cigarette smoking. That's how I think these medications work in stimulant treatment. For the people for whom they work, it actually just helps reduce the amount of methamphetamine they're using without them thinking about it, which is a lever that if it works, I want patients to have that lever. I have a couple of questions. One question about the extended release naltrexone and bupropion. How long do you need to do that treatment for sustained effects? No one knows. So we do know for 12 weeks is what is a good place to start. That's where the data leave off. And I really don't know. I mean, maybe it could be that, you know, within 12 weeks, people get it and they're able to move on. Or maybe what you do is you kind of work with people and use it clinically beyond the 12-week point in the same sort of way of just monitoring urine samples and talking with people as they're going along to make sure they're still getting benefit from the medication. But right now there's zero data to address that issue. I agree with the zero data, but I would strongly suspect that a longer period of treatment is going to be necessary to act as this foundation that you talk about. Yep. And then what was the follow-up for the trial? Follow-up for the trial was four-week safety visit. That's all it was. It was just, are people still walking and talking? And that was it. So it was 12 weeks of active medication and then four weeks just to make sure they're okay. So we really don't have anything about this longer-term treatment, but I agree with you, Dan, that this is an important piece. Yeah. And the person had just asked that there was no long-term follow-up, which I think... Yeah. Okay. All right. All right. We've got 10 minutes left. I'm going to just breeze through some slides here. Just basically one of the reasons why I have this slide here is this is Rebecca McKeaton's work. It's an only but goodie with large numbers of people in Australia who self-selected with methamphetamine use disorder into no treatment, detox, and residential rehab. And I love this slide because it shows that at the end of three years, there's really no significant difference between whether you went to no treatment, detox, or residential rehab, but the benefits of treatment that occur here are in the three months to one year range in terms of spending a lot of money and resource on behavioral treatment for methamphetamine use disorder. And in fact, that's what we see here. If we look at the meta-analysis behavioral therapies, the contingency management is a really significant treatment effect compared to other kinds of treatments like CBT or even treatment as usual. The slide deck you can kind of go through. I don't want to spend time with this. This is how contingency management works. You provide urine samples for either vouchers or cash. That's the right side of the slide. Or you get draws out of a fishbowl that correspond with prizes. And you can see they're laid out here. This is Nancy Petrie, who is a colleague of mine who was taken from us far too soon. And I just want to recognize her work. There's a lot of data around the biology of how contingency management works. And in fact, what we know from Deanna Martinez at University of Columbia is that if you have dopamine D2, D3 receptor availability, it actually predicts that you'll respond to contingency management. These are the people who have the response to contingency management. And they're the same people who have D2, D3 receptor availability. And you can see that those who are non-responders don't have this D2, D3 receptor availability. So here we have a biomarker. It takes a PET study. We're not going to do this to tell you whether you're going to be able to respond to contingency management. But it starts a whole list of questions that we think of clinically about how to best use this treatment with our populations. The box is important. The effect size of contingency management is strong and been replicated in multiple meta-analyses. And if it were a medication, it would be the standard of care for stimulant use disorder. Here's another one that was taken from us far too soon, another colleague of mine, which means I'm getting to the end of the table. And I assume we'll have my picture up here. But this is Kathy Carroll, who is one of the main promoters of cognitive behavioral therapy for cocaine addiction. Here's her treatment model. You can download that if you don't have it. And she actually took this approach and made it to be able to be delivered on the computer with cognitive behavioral computer based therapy for cognitive behavioral, computer-based training for cognitive behavioral therapy, which is a website that's still open. And you can actually use at home to do your treatment. Motivational interviewing, the data suck, but people use it a lot. And because it's very cool and it's fun, and it helps talk with, it helps patients to understand their behavior better, which is great. But the outcome data are not as strong as safer contingency management. Let's do one last case. Lorenzo is a 33-year-old gay Latino man who was brought to the emergency department after he took off all his clothes and ran up and down the block where he lives, shouting to the men in the trees, who were powerful men, who he had sex with, were here to get him and send him back to Colombia, where he would be killed. Lorenzo had periods of panic that resulted in his being assaulted by staff and eventually required restraints in the emergency department. You're being consulted as the treating physician, and you've read the research on mirtazapine for methamphetamine and MSM, but the mirtazapine did nothing. What do you recommend for Lorenzo? To continue the mirtazapine, there's a therapeutic window that must be reached. Use the standard protocol for psychotic patients in the ED, antipsychotics and dentists. Do you start cognitive behavioral therapy for methamphetamine use disorder plus mirtazapine, or do you do nothing until the picture resolves? So, devote your conscience here. This is actually a real case. Okay, let's see where people are. Okay, good. You start the standard protocol for psychotic patients in the ED. That's the winner. And the reason for that is because none of these medications or talk therapies are gonna work while people are psychotic. So you do want to bring people down. With these medications coming on board, it's important to have some context that we're thinking about using them. In the emergency department, when somebody shows up and is combative and psychotic, the idea is to bring down that level of agitation and be able to get persons to the point where they can engage a medication. So you really have to start with being able to get people down to the rest of us. So I'm going to stop here, I think, for questions. Okay, thank you. If there are any questions, please enter them in the Q&A box. I don't see any ones right now. Okay. Well, I will follow up with one that was brought up last week, which is my thoughts about whether you can use, instead of using the extended release naltrexone plus the high-dose bupropion, what about using oral daily naltrexone plus the 50 milligram naltrexone tablet versus the injectable form to go with the high-dose bupropion? And the answer to that question is it's not optimal. One of the problems that we have for people who have methamphetamine use disorder is terrible medication adherence. Even in the best of cases, people will not do regular taking of medication. Now, on the other hand, Glenn Milo Santos has been using oral daily naltrexone as a harm reduction approach for people who are heavy drinking, men who have sex with men, and also for men who have sex with men who are using methamphetamine and is reporting significant reductions of both heavy drinking days and in terms of reducing methamphetamine in this population. I think these are boutique sorts of studies. The strength of Madhukar Trivedi's work is it's 403 patients. It's a controlled dose. He makes sure that people are at an optimal dose to produce the outcomes. So while it's technically possible, it's just not behaviorally likely that people are gonna get that exposure dose that you need to be able to respond to the methamphetamine. For that reason, I would say, forget it. Steve, in one minute, what do you think about buprenorphine for stimulant use disorder? Oh, thanks, Dan. I'm actually starting a trial on this. In about three months, we're gonna start a trial for buprenorphine, for a suffocate, for severe methamphetamine use and opioid co-use. So it's like seven or eight days of opioids in addition to heavy methamphetamine use. So we're gonna do that, and we're gonna do the repetition of the buprenorphine plus Vivitrols, looking at that kappa antagonist approach for buprenorphine disorder. So we're gonna be doing that as well. So I'm all over buprenorphine. I think it's an awesome, we may be seeing more of that in, oh, really, great. We may be seeing more buprenorphine with some evidence behind moving forward. Buprenorphine is one of my favorite medications. I always like to say it's safer than Tylenol. The kappa antagonism is impressive. I mean, the ability to get people off of other mood drugs is extraordinary. And at least an additional rationale is your 108,000 people who died last year. If we can see an effect for buprenorphine in reducing stimulant use, we have all the more reason to bring that drug on board and actually benefit from the protective value against fentanyl in case our patients show up with that. The only problem is kicking the can down the road, and that is at some point, you need to get people off the buprenorphine, and that's a singular challenge. So we're going to have data on that because we're going to be using sublucate by itself with these methamphetamine users who are using opioids, co-using. So we'll be able to chart what happens because we do know that the detox from sublucate is easier than oral buprenorphine. So it may be that it may not be as big an issue as we're worried about. So we'll see. Okay, we're at six, but I just wanted to get these last two questions. I think they'll be real quick. Any support for the use of Baclofen? Nope. Okay. I did that trial, don't do it. Okay. And is there any carryover from these findings for treatment of crack cocaine addiction? You know, that's another talk. I mean, the whole issue about using, you know, mixed amphetamine salts, extended release with a cocaine patient, I think for crack patient, I think is worth thinking about. The data are strong and I would absolutely think about it, but it does require rethinking how you want to land on the issue of using, you know, a stimulant for stimulant treatment. And personally, I'm for it because if it helps stop that crack cocaine smoking, it's a great thing. Okay. And any complaints in patients about CNS effects when they're taking Naltrexone? Sure, there's some. You get people who get a little nauseous and they have a little mood stuff, but by and large, Vivitrol is easier to tolerate than the oral Naltrexone. And I think that's one of the advantages of having the bupropion on top of it. It helps with some of the mood destabilizing effects of Naltrexone XR. Exactly. Okay, well, thank you so much to both Dr. Shavta and Dr. Ciccarone for these great presentations for the last two weeks. And it was a pleasure to have you both here each of these last two weeks. So this is the end of this webinar series. We are going to have one planned for August, September. Dates are yet to be determined, so watch your emails for that. And then I hope that you guys all sign up to attend those webinars again. And thank you so much for attending. Great. Bye-bye. Bye.

webinar

fentanyl overdose crisis

stimulant overdose crisis

medical treatment

therapy options

Dr. Stephen Shopta

Dr. Daniel Ciccarone

addiction

HIV prevention

stimulant use disorders