Hello. My name is Steve Shoptow. I'm a professor here in the Department of Family Medicine at UCLA. I've been doing this work in developing medications for stimulant use disorder for almost 25 years. One of the very nice things to tell you this morning as we get started, is that we actually have something to talk about today. It's a red letter time in my life in terms of being able to use the understanding that I have of how to intervene for people with addiction to stimulant use, stimulants, and I'm very happy to be here today. These are my disclosures. The overarching goal of PCSS is to train healthcare professionals in evidence-based practices for the prevention and treatment of opioid use disorders, particularly in prescribing medications, as well for the prevention and treatment of substance use disorders. Our objectives are to demonstrate an understanding of the definition and epidemiology of stimulant use disorder globally and in endemic areas. I'm going to spend some time with key cultural factors in comorbidities. We're going to talk about the neurobiology and how that relates to people's behavior as they engage stimulant addiction and recovery from stimulant addiction. Focusing a little bit on withdrawal symptoms and their management, and then we're going to review the evidence for advancements in pharmacotherapies and behavioral therapies that can be brought into practice with a roadmap that may be more beneficial for folks who are working with stimulant use disorder. One of the things that's really important, and this is taken a little bit from the ASAM textbook, is that people who have stimulant use disorder experience it much differently than people who define stimulant use disorder like psychologists and psychiatrists. Generally, what we see is that the primary driver in life is toward health, and that when things start to cause problems, the drive toward health helps most people to just stop that. That's why we have this lens through which we can see where most people either don't use a substance or they use it in a way that does not cause problems, and how people experience that is it's fun. If people continue to use the drug or the substance, sometimes occasional use will cause problems occasionally to frequently, and so many people will stop, but people who continue will experience fun with problems. Then you can see where this is headed, whereas if you're continuing to the point where you meet criteria for addiction, mild to moderate or severe, what you end up with is fewer people at each of these points along the spectrum who are no longer experiencing the fun of substance use, but are experiencing mostly just problems. This is the way the DSM-5 defines stimulant use disorder. I'll leave this to you. It's in the slide deck, and many of you are familiar with it. But basically, the important part of these 11 items that you can total up to get a severity marker, is that these items are marked by a maladaptive pattern of use that costs clinically significant impairment or distress in the same 12-month period, meaning two or more of these. The important part there, of course, is the impairment or distress, and that actually is a key element of addiction. Some of the latest data that's out there, Michael Farrell's group in Australia showed that in estimating the prevalence of methamphetamines in the world shows that here in Australia has the highest prevalence of use, followed by North America, Southeast Asia, China, and Western Europe. You can see that it's a highly linked substance, that methamphetamines are highly linked to industrialized settings largely. When we look to find the methamphetamine prevalence across the US, what we see is from the National Survey on Drug Use and Health, that less than one percent over the past four or five years actually will report methamphetamine use in the past year. But what we also see is that people who are using other drugs like heroin or LSD have increasing rates of methamphetamine use going on. One of the things that we want to also understand is that there are problems in some of our estimators. The National Survey on Drug Use and Health, as well as other household surveys, are limited in their ability to measure adequately and reliably the number of people in the general population who have addiction problems. I have the citation down here for this paper, the Reuter paper. It's worth reading. It's something we use in our journal club to understand how biased our prevalence markers are in household surveys. Looking to UNODC to look at the prevalence of cocaine use globally, what we can see is that we see the Americas, North and South America, Australasia, over here and Western and Central Europe being the primary consumers of cocaine use in the most recent publication from UNODC. In terms of trying to understand just the numbers of cocaine users around the world and whether that's shifted much in the past 10 years or so, what we can see is that generally the use level is pretty much continuing to be stable or maybe increasing slightly with much of the use of cocaine being located in the Americas. Again, also in Africa and Europe somewhat. We looked to National Survey on Drug Use and Health and looked to see what's happening in cocaine use. Looking for the 12 and older group, these are the American adults, you can see it's pretty flat throughout the past 20 years with some minor shifting upwards and downwards fluctuation in the 18-25-year-old group as they've experimented with stimulants. One of the biggest problems with stimulants, whether we're talking about cocaine or methamphetamine, is the link in the United States to overdose and death. These are data that are just published in April this year from CDC showing that dramatic increase of deaths involving psychostimulants, particularly in 2017-2019. One of the things I have on here, the four waves of the opioid epidemic in US, starting with the opioid pills, moving to heroin in this era, moving in the introduction of fentanyl here. Here's where you start to see this increase of overdose deaths from stimulants and opioids. Now in the fully established era of fentanyl with stimulant use, you can see this high rate increasing here. One of the things that's important here is that this is the time where psychostimulants and no opioids deaths continue to rise, which is a real concern. As well, there are concerns out there, the chronic use of stimulants, cocaine and methamphetamine, but here we have methamphetamine data, are the primary driver of why young people die from heart attacks. You can see here in the US, just following that same epidemiology, the increase of stimulant-related hospitalizations from acute heart failure during the period that corresponds with the fourth wave here of the opioid epidemic, showing this very high interaction of stimulants involving acute heart failure. We've established that this is a prevalent problem. It has serious health consequences. There are also important ways that culture interacts. On the left here, we can see the reasons why people might engage methamphetamine use, the physical and psychological. Many of these factors are also corresponding with why people use cocaine. But around the rest of the clock, we can see here that if we start with up to the right at the top and move clockwise, methamphetamine has unique functions within gay male communities. It works to allow moving down people to be shift workers, to be able to work two jobs, and be able to keep going and pay the bills. It's popular among people who are bike, motorcycle enthusiasts. Continuing the clockwise movement, methamphetamine is one of the few drugs where women's involvement with methamphetamine use is about the same as men. It's just a little bit less than men. It involves women, often from religious groups, where women can use the drug to be able to stay thin, keep their house clean, and be ready to have sex when their husband comes home at the end of the day. Then finally, all the way over here to the left is the rural areas, where rural and youth are involved with methamphetamine, largely because there's nothing to do, and methamphetamine does help the time pass. One of the comorbidities of concurrent aspects of methamphetamine use is that among men who have sex with men, it is the single greatest predictor of HIV incidents, changing from actual HIV negative to HIV positive. These are data from two very different cohorts. One is Project Explore, which is HIV prevention trials network study that was conducted showing that the attributable fraction of HIV incidents in a sample of over 4,000 MSM here in the US was about 16 percent. Among the multi-site AIDS cohort study here, you can see that the attributable fraction of methamphetamine in predicting HIV incidents was 33 percent. The multi-site AIDS cohort study is a 35-year-old study of men who have sex with men who are living with HIV or at risk. You can see here that among this very long follow-up data that methamphetamine is established as a primary driver of HIV incidents. Cocaine use is similar but not quite as profound in terms of producing HIV infection among men who have sex with men. But there are other issues with cocaine use involving its linkage to psychiatric symptoms. You can see here in a sample of National Survey on Drug Use and Health, and this sample is 85,000 or more. You can see here that it's very common that cocaine use is linked with serious psychological distress, the involvement in mental health treatment, and peri-depression symptoms, including meeting criteria for depressive episodes, serious thoughts of suicide, suicidal plan and attempts. Clearly, there are all kinds of ways in which stimulants are involved with health risk behaviors. Let's shift gears here a little bit to talk about the neurobiology of a stimulant use and stimulant use disorder. There's main points before we get into the actual overview of this, and we're not going to drill down very deeply on this. There's 20 years of work on this that gets really specific in being able to show how the neurobiology actually drives behavior, either towards stimulant use in establishing addiction, or in terms of the difficulty in maintaining abstinence following addictions development and you start into treatment. One of the drivers that I want to think about here is the thesis that all behavior is brain expressed. That includes motivated, in quotations, behaviors like stimulant use. We're going to talk a little bit about how these substances have direct effects on neurons, and we're going to use this understanding to interpret what we know about behavioral and potential medication therapies and how they might work to sustain stimulant use and to enable abstinence. Cocaine and methamphetamine both work presynaptically to block the reuptake of dopamine. What happens is cocaine, methamphetamine happens in the neuron, dopamine gets released, and instead of it being able to be taken back up into the presynaptic side of the cell, both cocaine and amphetamine block that. Methamphetamine and amphetamine have an additional effect, and that is it actually increases reverse transport of dopamine into the cleft, meaning that it actually moves dopamine out into the cleft, and as well as inhibits the reuptake. This is important for a couple of reasons. What we see here is that in comparison to healthy controls, VMAT2, which is the dopamine transporter system in people who are stimulant using compared to controls, are more likely to have more VMAT2 with recent abstinence and less compared to controls with prolonged abstinence. That's important because people experience that with prolonged abstinence, they don't feel as sharp. It's a dull withdrawal symptom that can lead people back to stimulant use because administration of stimulants at that point takes away that symptom, and you've established a negative reinforcement model where by taking that substance instead of just taking it to get high, you actually take it to remove that uncomfortable withdrawal symptom. That's also in terms of cocaine and methamphetamine, what we also see compared to controls is that we see a reduction of dopamine synthesis, a reduction of dopamine transporter, a reduction of dopamine release, and a reduction of D2, D3 receptor density on the postsynaptic side. These are factors that work to actually lead to withdrawal symptoms of just feeling dull, a little dysphoric, like just a gray day sort of thing. That actually, as I said, leads to that negative reinforcement cycle. One of the questions I often hear is, well, why is it that people continue to use stimulants to treat, say, ADHD? Like methamphetamine or amphetamine can be used as a treatment for ADHD. The answer to that comes from Glenn Hansen's lab. He was a prior NIDA director for a brief period, but basically he was able to show that there's a distinct difference in terms of low-dose methamphetamine. That means that what happens here is that the low-dose methamphetamine use actually lets dopamine remain in the synaptic cliff longer by blocking reuptake, but it doesn't actually initiate the whole aspect, the cascade of the reverse transport mechanism, whereas with high doses, that's actually what happens, both the blocking of dopamine reuptake and also the activation of the reuptake reverse transporters. That's important for a lot of reasons, but it also kind of tells us that dose matters, that a lower dose is better for your neurons than a higher dose. We're going to start next with a case, and this is a place where you get to vote. There's no right answer, so please don't be shy. But James is a 42-year-old Black African-American gay man who is seeing you because his partner, John, is saying he needs help. John is complaining that James's weekend warrior use of methamphetamine is interfering with their life together. A weekend warrior is somebody who uses methamphetamine from, say, Friday to Sunday two to three times per month. He tells you that this is impossible, as he is in long-term recovery from addiction to crack cocaine from his early 20s, and he knows how to control his meth use. James became HIV positive a few months ago and has started HIV treatment and is currently virally suppressed, meaning a good response to HIV medications. James smokes cigarettes one and a half packs per day. In developing the treatment plan for James, which of the following best captures your thoughts about his primary behavioral role? A, stop or reduce methamphetamine use. B, stop or reduce cigarette smoking. C, consult with James' infectious disease physician. D, A and B, or E, all of the above. So, vote your conscience. Just give it a few seconds here. Give folks a chance to vote. Select their answer. All right. Okay, so you can see here there's a range of responses. Some people will... There's a good amount of people who say that we should focus on 16% say stopping or reducing methamphetamine use. The primary winner here was all of the above, talking with the infectious disease physician to understand the risks, to include cigarette smoking medications, and to work toward methamphetamine use. All right, so pharmacotherapies. We're going to talk about this. The data that I'm going to be talking about today is about how there is no FDA-approved treatment, but there's a limited set of pharmacotherapies that have some pretty remarkable evidence of efficacy, and it challenges us as clinicians to think about whether it's time for a treatment for stimulant use disorder as a foundation of the comprehensive integrated strategy. In fact, we published a commentary on this about if there were an effective pharmacotherapy use disorder, what would that pharmacotherapy do? That's one of the issues that we need to think about here is not just looking at what's available, but to begin thinking about what we would want a pharmacotherapy to do. Next slide. All right, so the first medication where there's evidence of efficacy is mirtazapine, 30 milligrams a day. Those of you in the audience may remember that mirtazapine is an antidepressant. It's called Remeron is its trade name. It actually has two studies that show remarkably similar effects, and one of the reasons why I get excited about mirtazapine is that the hardest thing we know to do in science is the same thing twice. Here we see on the left data from Grant Colfax from San Francisco among men who have sex with men and transgender women showing the black line showing a nice about 20% reduction in the in the percentage of people testing positive for methamphetamine use throughout the trial through 12 weeks. This was confirmed similarly by this was in 60 subjects. Phil Coffin in San Francisco, a few years later, replicated this finding and you can see here on the right, the purple bar shows the reduction of methamphetamine use over the past over the 12 week period of the trial again about 20% reduction, with most of that reduction happening in the first 12 weeks and it continues to hold throughout the up to 36 weeks, the number needed to treat for methamphetamine 30 milligrams a day to reduce methamphetamine use is eight, meaning that you need to go through eight people to get one person to show the desired effect here. Both trials were in San Francisco. And both were among men who have sex with men and trans women, but the reduction is the similar amount of 15 to 20% reduction of methamphetamine use. This is reduction that happens when people don't even have to think about what they're doing. They're just taking the medication going about their day. And among people who have severe methamphetamine use, a 20% reduction could be a clinically significant reduction. So in terms of these are data from Madhukar Trivedi and his group from NIDA's clinical trials group showing that in a sample of 403 people with severe methamphetamine use disorder, the largest randomized controlled trial of methamphetamine of the medication for methamphetamine use disorder in history showed about an 11% difference in the combination of extended release naltrexone Vivitrol plus high dose bupropion 450 milligrams a day in producing negative urine samples for people through peer through the period. It's a complex design, and I love to talk about it, but we need to move on because we're having problems. But basically, you can see here that in the first six weeks of the study, in looking at the weeks five and six, the reduction, the improvement in negative urine samples was significantly greater for people in the combination compared to placebo. That's the bottom there. And at the bottom on the right, you can see here that in the second six weeks, from week seven to 12, you see a similar significant improvement in terms of negative urine samples provided for the medication combination compared to placebo. So this is really exciting. So here we can see that the secondary outcomes in this trial were also significant. The blue bars are periods one and two in the trial design for the combination and the yellow bars are periods one and two for the placebo condition. And you can see here that in terms of percent negative methamphetamine urines provided was higher for the combination compared to placebo. The change in methamphetamine craving was reduced at a greater level for the combination compared to placebo, as was the reduction in depression ratings and improvements in treatment effectiveness overall. Next slide. I saw a question there about the dosing. There's only one dose for Vivitrol right now. So I don't know if that's true. It's 380 milligrams in the injectable. Here we have for cocaine use disorder, Francis Levin's team in Columbia did some very impressive work using mixed amphetamine salts extended release for people compared to placebo for people who have ADHD as adults and have cocaine use disorder. And what you can see here, the reason why I get excited about this slide is because it's a large study and you see a dose response reduction with the percent of participants with highest percentages of positive urines being produced for the placebo condition, a middle amount showing a significant reduction for the 60 milligrams per day extended release mixed amphetamine salts and a significant improvement over that by pushing dose up to 80 milligrams per day of the extended release mixed amphetamine salts in this condition over 12 weeks. Next slide. We also see that Francis and John Mariani and Kyle Campman at UPenn got together and talked about combining mixed amphetamine salts with topiramate. That was partly because Kyle has a long line of work studying topiramate for cocaine use disorder with some signals of efficacy. And so by combining mixed amphetamine salts with topiramate, mixed amphetamine salts here being 60 milligrams per day and the topiramate dose being 100 milligrams BID ramped up over time, John Mariani showed that you were twice as likely to provide three or more weeks of negative urine test results at the end of the trial if you were in the medication combination compared to placebo. That's on the left. And Francis Levin showed that similar sort of reduction we saw about a 20% reduction, 15% reduction in positive urine test results during the trial for a 12-week replication trial. Again, another example of my excitement being the dose response in the ADHD trial and in a broader group who don't have, then, you know, we see this strong reduction, the same thing twice sort of thing. Repeat doses on the two. It is 60 milligrams of mixed amphetamine salts extended release plus 100 milligrams BID of topiramate over the 12 weeks. Next slide. So the summary here is I really want to emphasize that we don't have an FDA-approved treatment for medication for methamphetamine or cocaine use disorders. What we see is that in both of these conditions for methamphetamine and cocaine use disorder, there are candidate medications. There are mirtazapine 30 milligrams a day, has effects that are replicable in men who have sex with men, and there are trials underway to see if it works more broadly. It's important to recognize that the effect of mirtazapine, actually the effect of all of these medications, is in reduction of use, not abstinence. For comparison, naltrexone for alcohol, the number needed to treat is 12. So for the combination of bupropion and extended release naltrexone, it was nine. For mirtazapine, it was eight. So we're talking about in the same sort of neighborhood in terms of the effect that you would expect to see if you were to use these medications with people who have methamphetamine use disorder. Similar size of effect here for the mixed amphetamine salts in the comorbid group of people living with cocaine use disorder and ADHD, showing those dose response effects, and the combination of the mixed amphetamine salts plus the tapiramate showing two replication studies. So next slide. While we don't have FDA-approved medications, that evidence is there for those medications, the primary driver of care in the country for stimulant use disorder are behavioral therapies. Next slide. In looking at the meta-analysis of all behavioral therapies to treat stimulant use disorder, we can see that contingency management has the greatest effect size. You can see that by looking at the size of the blue dot here, and that in comparison, in this meta-analysis that compared hundreds of studies that have been done, we can see that contingency management is the highest efficacy. I think it's kind of interesting to see the effect of treatment as usual, that in randomized control trials, treatment as usual is about the same size or maybe a little bit larger than cognitive behavioral therapy, which makes sense because most treatment as usual is based on cognitive behavioral therapy. Next slide. Contingency management, when thinking about it, it's an operant conditioning started by Skinner, the theory, back in 1938. The original concept was worked out with delinquent boys in group homes, and it was adapted to work in methadone maintenance clinics by Maxine Stitzer and was expanded to work with cocaine use disorder by Higgins Group. The original voucher contingency management program now has an alternative fishbowl method developed by Nancy Petrie. Next slide. This is Nancy Petrie here on the left with a fishbowl. Unfortunately, Nancy left us far too soon. Basically, the fishbowl method, you get, when you provide negative urine, you get increasing draws from the fishbowl. You get three and then you increase one or two draws with each negative consecutive sample to some cap that you have. Those samples slips in there, there's 100 of them in there, 50 of them say good job, 30 of them say a low prize, 17 say medium prize, and three say big prize. You develop a prize cabinet, and then if you pull one of those slips that say you can choose a prize for these low, medium, or big prizes, you get to go shop in the cabinet, and that actually is a way of keeping down the cost of contingency management strategies while also capitalizing on their efficacy. On the right side here is a spreadsheet that just sort of shows how an increasing voucher reward program can work using contingency management with urines on Monday, Tuesday, Thursday, Friday, the values as they go, as you go through time with consecutive negative urines increasing over time with a bonus for consecutives leading up to some amount of weekly total. In meta-analyses of contingency management, there are four of them now, and they all show that the effect size of contingency management is between 0.4 to 0.6, which is a medium to large effect size. Just for social comparison, the effect size of most antibiotics are in this same range, which leads me to say if contingency management were a medication, it would be the standard of care. Next slide. I include this slide. It's work by Deanna Martinez at Columbia, which I think is one of the most elegant studies ever done. She recruited about 35 or 40, sorry, 25 people with cocaine use disorder and brought them into the PET lab before they started a contingency management program for cocaine use disorder. If you look on the right side, we can see here that when they came in at baseline, they were challenged with methylphenidate, which is Ritalin. It's radio labeled. You can see here that there were two groups, responders and non-responders. At baseline, if you had percent change in the binding potential following the methylphenidate challenge, you were significantly more likely to respond to contingency management than if you didn't have that percent change in binding potential. That binding potential change goes back to D2, D3 availability, which goes back to those original thoughts about the neurobiology of stimulant use disorder. I think it's also very important that she confirmed here that there's no normal distribution of people responding to contingency management. You either respond or you don't. This is an important finding in the sense that we not only want to think about, well, contingency management works so well, but it also has a group of people for whom it doesn't work. This might be a group of people for whom a medication might have particular impact or import in their life. In terms of cognitive behavioral therapy, cognitive behavioral therapy is a workhorse within the treatment delivery system. It teaches skills to instill abstinence, teaches early recovery skills, especially use of structure. The importance of structure, the scaffolding of how you run a life without using drugs, is all about how to do that. It teaches skills to interrupt craving. It teaches skills to return to abstinence following lapse or relapse. It's been adapted now. Kathy Carroll here on the right also was taken last year far too soon from us. She did a lot of this early work in establishing cognitive behavioral therapy using therapy manuals for drug addiction that are available online. The reference is here. It's also available to be conducted using computer-delivered cognitive behavioral therapy. That's the CBT for CBT. Next slide. An alternative behavioral therapy with some evidence of efficacy, not a lot, but some, is motivational interviewing, which was developed by Miller and Rolnick and is oriented around a brief series of sessions, usually four. It can go up to 12, but it's usually some brief series of sessions that explore why people use a drug, what the costs are, their understandings of how the drug works in their life and around them. This motivational interviewing technique is based on the natural change process that can be elicited by using a set of techniques that emphasize people always using their own metrics to understand the positives and negatives of their substance use. It's all client-centered. We don't confront people in motivational interviewing. It actually does seem to work with people to stay in treatment longer, promote some specific behavior changes. One of the advantages is it's really especially useful for adolescent populations where taking a stand is usually never a good idea when working with an adolescent. Next slide. Finally, one of the things that we know about is that over all these years, and some of this data we saw here, was that treatment works for who it works for. Over the past 30 years in my career, I've chronicled this again and again. One of the things I like to think about is the cost of particular interventions and the chronicity of someone's sub-stimulant use disorder be taken into account when recommending treatments. It's usually not a good idea to start with an expensive rehab if a participant, if a patient hasn't actually tried a 12-step group. I kind of like to think about saving more intensive treatments for further down the road, recognizing that stimulant use disorder, whether it's in a young body or an older body, is chronic and relapsing, and multiple treatments are usually required before somebody actually meets their substance use goals. In thinking about treatments that are available for behavioral therapy, contingency management is increasingly available. Don Filippis has done a very nice job with extending Nancy Petrie's work in getting contingency management to be an available option for people in the VA medical system. People with cocaine use disorder can request contingency management and be provided, and the early returns show that it actually works as well in treatment in the VA system as it does in the research clinics. There's a lot of political things that need to be worked out. Some of the states, like California, where I live, is working to see if we can build contingency management within the Medicaid environment so that we have availability across the board, but that's continuing, and it continues to be something that requires some of our involvement as we scale up. Motivational interviewing, brief sessions, it requires skilled interventionists. Some people who believe they can do motivational interviewing actually can't, but it is something that is really wonderful to be able to use, and I certainly, in my career, I found it to be very helpful for people who are in the adolescent range of life, and they're having their first interactions with substance use problems, but it also works for some of us old dogs as well, so it's something that has a modest effect size. Cognitive behavioral therapy, also a modest effect size. It's teachy. If you talk with people who have been through CBT, it can be very difficult. Some people are just not good students, so you kind of have to find out whether it works, and it works well with people. Some people it does, and some others it doesn't. One of the things that's particularly important about CBT that has to be thought about is that, as we were talking about that neurobiology, that some of that cognitive dullness that's caused by the change in dopamine receptor availability in sustained withdrawal is something that actually can counter-select for CBT, that sometimes what you want is more action-oriented treatment, like even behavioral activation using a schedule as opposed to teaching a lot of educational aspects, and then, of course, I like to always end with recognizing twelve steps. It's a ubiquitous social fellowship that's really important, and for people who can use it, I really recommend it. One of the things that's really also important about people who cannot use twelve steps is that the fact that you don't like twelve steps doesn't absolve you from the responsibility for some sort of community social recovery, and what instead that means is you have to be better at finding naturally occurring things like book clubs or movie groups or cooking circles or bowling leagues as a way to be able to engage community in a meaningful way so that you don't just find yourself alone because the connection is really an important part of the recovery process. Next slide. The case of James continues. So, James returns to see you the week after the intake. He tells you he's not interested in working with you to do the things he already knows how to do in establishing some kind of recovery, so that's what I was talking about. People learn over the lifespan about how to manage their substance. In his early 20s, he was a member of Cocaine Anonymous for years and has no interest in returning to that program now. His medical insurance is comprehensive in coverage. He's not opposed to medications but would really like to be part of a contingency management program, though that's not currently available at your clinic. He doesn't want behavior change school, but he likes talking to you. So, what is your first recommendation for James' treatment plan? All right, let's vote your conscience. Okay, so the majority of folks are leading with motivational interviewing, four sessions. That's a nice choice. It allows some exploration of what James might be willing to do. Cognitive behavioral therapy and the potential for the combination extended-release naltrexone and high-dose bupropion are about the same level, at about 18%. Very nice. Some folks interested in HIV medication counseling, and one person wanted to talk about smoking cessation medications, which is always a favorite of mine. I do like to mention smoking cessation. It is an important piece of many people's lives in continued recovery. Next slide. Uh-oh, are we stuck again? Oh, here we go. No, no. Yeah. Okay. So in terms of translation of these concepts to practice, the prerequisites to translate these findings to clinical practice include the following. Perhaps the most important, an energetic champion to implement evidence-based treatments into practice. The system is not ready for us yet. We have to get involved to change the system. This includes emphasis on scientific evidence and translation of programs to clinic. We need someone who will advocate for investments in training staff and in changing workflows within the clinic to address the whole person, not just their substance use problem. Quality improvement processes, including clinical supervision, team huddles, staff training, need to be implemented in the practice setting as we bring these treatments online. Multiple disciplines within and also linked to the treatment team should be involved, including medical conditions, clinicians, behavioral specialists, recovery navigators, all working at the top of their licenses. And then finally, the infrastructure support to manage the concerns and the documentation required for reimbursement using insurance, Medicare and Medicaid. Next slide. That's a lot to do. But our closing points are that stimulant use, misuse and disorder are based in neural adaptations that correspond with development of addiction, targets for treatments, and I would argue response to those treatments. There's no broadly effective FDA-approved medication, but there's compelling evidence for medications for methamphetamine and for cocaine. It does raise the question of if it's time for stimulant addiction treatment to start with medication foundation. Contingency management is the most efficacious behavioral therapy, though MI and CBT are used more. And integrated treatments provide help to people that can include biology, behavior and culture. All elements are important to helping people reach and maintain their goals regarding their stimulant use. Next slide. These are my references. Next slide. Continued. Thank you very much. This is where you can contact me. Next slide. I would like to make you aware of two resources offered through PCSS that may be of interest to you. One, first, PCSS 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're happy to prepare you with one. To find out more information, please visit our website using the web link noted on this slide. Next slide. Second, PCSS offers a discussion forum, which is comprised of our PCSS 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 slide to access the registration page. Next slide. This slide simply notes the consortium of lead partner organizations that are part of the PCSS project. Finally, please reference this slide for our contact information website and Twitter, Facebook handles to find out more about our resources and educational offerings. Next slide. With that, I will close. Okay, so thank you, everyone. We've got some time for some Q&A from the audience. Dr. Schapta, we've got some hands raised. So I'm going to start with Laurie DeLong. My colleague will unmute you on our end, and you'll be able to ask your question. Oh, I'm sorry, I didn't realize I had my hand raised. I apologize. Oh, no worries. Thank you so much for attending. Okay, so let's go to Suzanne Fogger. My colleague will unmute you on our end, and then you can also unmute yourself and ask your question. Hi, I asked the question about the dose of naltrexone, and I heard that you said the long acting, but supposing the individual wasn't interested in the long acting, is there a dose that's available for the daily dosing? Sure. The daily dose is 50 milligrams. That's the marketed tablet. It's got a little bit of evidence for use for stimulant use disorder, but it's not as good as the injectable because it has some medication compliance issues. One of the advantages of the injectable product is it's on board, and it can help people not have to make that decision about taking those tablets every day. The bupropion 450 also has to be taken every day. So if you've got somebody who's really motivated, it's possible they could do the 50 milligrams of naltrexone oral plus the 450, but we don't have data that talks about either the safety or the efficacy on that. All of the data come from the injectable product. Great question. Thank you so much for your question, Suzanne. All right, so we've got a few more hands raised. I'm going to call next on Jan Campbell. Jan, we'll unmute you on our end. You'll be able to ask your question. Can you hear me? Yes. I have an opioid-dependent clinic with a lot of methamphetamine use, can't use naltrexone, so I'm wondering if there's any data for the bupropion 450 independent of the naltrexone. The short answer to that is no. There are some data. We've looked at 300 milligrams of bupropion in our clinic, and as well, there's a national study that was done. When people take the medication, it appears that it does help people reduce methamphetamine use. But the issue of the medication compliance is something that diminishes outcomes. If you don't take a medication, it won't work. So there is that. As well, just to remind you, you also have available to you 30 milligrams of mirtazapine daily as a potential to think about. The combination of those two? Oh, I couldn't address that issue. There's no data for me to say anything about that. All right, thank you. Thank you so much for your question. Next, I'm going to call on Dr. Mohammad Chaudhry. We're going to unmute you on our end, and you can ask your question. Thank you very much. Sorry, Dr. It was a really wonderful presentation I just heard about, as well as bupropion. Yes, can you listen to me? We're having a little difficulty. There's a bit of a delay. If you wanted to type your question into the Q&A, I can relay that to Dr. Chaudhry. Thank you very much. Thank you. I will do. Okay, so he's going to type his question. While he's doing that, we're going to call on Jan Poole. Jan will unmute you on our end, and you can ask your question. I'm sorry, I don't have a question either. No problem at all. Thank you for attending. I'm sorry, I don't have a question either. No problem at all. Thank you for attending. And let me just see if Dr. Chaudhry has typed his question. Not yet. So we will call on Susan Spies. We're going to unmute you on our end, and you can go ahead and ask your question. Hi. Yeah, my question is whether there's any data on the diversion or abuse of amphetamine salts when it's prescribed in patients with stimulant use disorder. That's a great question. No, there's not much. I know that in the randomized controlled trial setting, you're responsible for recovering what's dispensed that doesn't get taken. So I don't know that there's any sort of understanding of potential or there's no measured response in terms of diversion that's happened in the trials using the mixed amphetamine salts. One of the questions that follow from this is, is the field ready for using a stimulant to treat cocaine use disorder? And that is something I think we want to, I welcome engaging this discussion. And I take us back to that issue of medications having an effect independent of a person. So the idea of if somebody has a very heavy problem, a very severe addiction problem, they may be able to experience the change in stimulant use that a medication, a stimulant might bring around, whereas someone who has less of a severe cocaine use disorder may not. So just kind of something to keep in mind as we go through this and as if we actually move to that point of being able to do evidence-based care more broadly, I think some of these implementation questions will rise to the front. Thank you so much for your question. So we did get Dr. Chaudhry's question into the chat box. He is saying, I want to know more about mirtazapine and the treatment of stimulant use disorder. Yeah, so it's an interesting idea that 30 milligrams of mirtazapine might be helpful to people who have stimulant use disorder. Those two trials are impressive. 30 milligrams of methamphetamine is a fairly significant amount of mirtazapine. And so what happens is people get a little drowsy. You give this medication toward the end of the day before people go to bed, they go to sleep, and they wake up the next day. One of the comments, I've interviewed both Grant Colfax and Phil Coffin about this, and Phil and I are working on another trial with mirtazapine. One of the thoughts might be that the mechanism of action here could be the restoration of sleep foundation. That the idea here is that people actually have better slow-wave sleep and longer periods of sleep that actually helps them establish more non-drug-using activities during their day-to-day following. So it's an interesting idea. It's not just an antidepressant, but it also may be having some profound effect on sleep. Thank you so much. We've got maybe time for one more question. Edward Piller has his hand raised, so we're going to unmute you, Edward, on our end, and you can go ahead and ask your question. Edward, are you there? I had to unmute. Sorry. Can you hear me? Yep, we can hear you. Great presentation, Dr. Shaptar. I appreciate you. Question about NAC and its role, if any, comments on combo therapy or use alone. Yeah, the unfortunate thing about N-acetylcysteine is that it didn't show any effect in terms of changing stimulant use behavior. So Rebecca McKeaton has done a trial of NAC for methamphetamine use and actually was really stunned to see that nothing changed. So it's actually nice to your brain to take N-acetylcysteine, which is always nice, but it doesn't do anything in terms of changing stimulant use behavior. Thank you. Thank you so much. So we are at the top of the hour. Folks, if you still have questions and you weren't able to get them answered, we recommend heading over to the discussion forum. It's a great place to post your questions and get some answers to those clinical questions. Dr. Shaptar, thank you so much for presenting today. And thank you, everyone, for bearing with us through those technical difficulties. Those are always fun and exciting. We'll get them next time. And again, you'll be receiving an email to log into our new learner management system, and then you'll be able to access the CE activity stuff. So thank you, everyone, again, and have a wonderful, wonderful rest of your afternoon. Thank you, Dr. Shaptar. Thank you.

stimulant use disorder

treatment

Dr. Steve Shoptaw

mirtazapine

mixed amphetamine salts

bupropion and naltrexone

contingency management

cognitive behavioral therapy

integrated treatment approaches