Hello, everyone. Thank you for coming to this session on the NIDA clinical trial network, where we'll be talking about the research updates and future directions in the treatment of methamphetamine use disorder. This is the session was organized by Dr. Subramaniam, who is not able to come to the session today, so Dr. Volkow is going to step in as the co-chair. Chair, please come in. Good afternoon, everyone, and welcome, and we're very happy to see you all in person. First time I'm here in two years, and today we selected for you a fantastic session that relates to one of the most challenging issues that we're facing right now in the substance use disorder world, which is the treatment of methamphetamine addiction. Methamphetamine use has increased dramatically in the United States, and so has the number of people that have ended up with a methamphetamine use disorder. But even beyond that, there has been an even larger increase in people that are dying from a methamphetamine overdose. There are many unknowns in terms of how do you actually address the big challenges that we face, and you will be hearing some of the details about why is it that we're seeing such a high rate of mortality with methamphetamine that we have not seen in the past, that can not only be accounted by the fact that more people are taking it, there is an increase, but the increase in overdose deaths is much greater, indicating that the exposure of methamphetamine that people are getting in the streets is much more dangerous than it was in the past, highlighting the challenge that we have as clinicians, on the one hand, to screen for methamphetamine misuse, and importantly, to screen for methamphetamine use disorder. And thereupon, the importance of this particular track today, where we're going to give you an update of what is it that we are planning on doing in the clinical trial network for developing interventions for methamphetamine use disorder, and what is it in the future. And with that, I give you back the microphone. Thank you. Thank you so much. So before we get deeper into talking about methamphetamine use disorder, I do want to present this slide. So I'll just walk you briefly through what this slide is showing. And this is just the context of talking about mental illness, developing treatments for mental illness, and I compare it to the mortality rate associated with heart disease and cancer. So if you look at over the past two decades, the mortality, age-adjusted mortality rate has gone down by over a third for heart disease. And it isn't that we have come up with better treatments for heart disease during that time. It's because of things like screening, making sure that, like, the chains of care are well-maintained, making sure that we are intervening appropriately, and using the current treatments in an evidence-based fashion. Cancer, the first time in human history, the deaths due to cancer, mortality due to cancer, has been going down and has gone down about 20 percent. But in contrast, during the same period, deaths due to suicide in the United States have been going up. So the burden of mental illness is continuing to go up, and we can make changes by developing new treatments, but also by implementing better evidence-based care right now. And I just wanted to then move on to the data regarding the methamphetamine overdose deaths, and this is, again, the data referred to just now. If we see that between the year 2014-15 to 2018, there has been a dramatic exponential increase in deaths due to methamphetamine overdose. And this has been true in men, and similarly, it's also true in women, that there has been, like, a sharp increase in overdose deaths due to methamphetamine overdose. This is also data, again, has been published, is that during the same period, between 20 So these are data from the National's NSDUS, National Survey on Drug Use and Health. And over there, again, between 2015-2017 to 2018-2019, there has been a sharp increase in the prevalence of methamphetamine use disorder across the age group. So it's not any particular age group that we see this increase in, but it's even, like, in younger age group, as well as middle age groups, that we are seeing these increase in methamphetamine use disorder. And it has also, there has been an increase even by sex and sexual orientation. So the increase in, across the heterosexual or homosexual orientation, sexual orientation, men and women, we are seeing this increase. And we are also seeing this increase across race and ethnicity. So if we see that the prevalence of methamphetamine use disorder has increased over tenfold in black Americans, as compared to what that was even, like, a few years ago. So we are seeing these increase in methamphetamine use disorder across the range. And that's why I'm really excited to be a part of this presentation today, where we'll talk about some of what is currently available, what some of the recent research studies have been, what we are doing right now as part of the Clinical Trials Network of NIDA, and then what are some of the studies that we have planned. Now before we get started, how many people in this room have heard of the Clinical Trials Network of NIDA? So I'll say about 40, 50 percent people. So most of my research training has been in depression. So I was not aware of the Clinical Trials Network of NIDA until about a decade ago when I started working with Dr. Trivedi. And it really has been a phenomenal resource to the scientific community to really do cutting-edge clinical trials within the NIH framework. So I'm really glad to be part of this initiative. So I'm going to, two of our presenters are not here in person, so I'm going to toggle back a bit, back and forth. So just to introduce Dr. Trivedi, Dr. Trivedi is my mentor at UT Southwestern in Dallas, Texas. He is the founding director of Center for Depression Research and Clinical Care. But his work has extended beyond just doing research with depression, as well as doing he has been the PI of the node at UT Southwestern, which was initially the Texas node for Clinical Trials Network, and is now the big Southwest node where it encompasses UT Southwestern, UT San Antonio, as well as our lead co-PI at UCLA, Dr. Steve Shopta. And he has been published widely. He's going to talk about his work related to the development of pharmacological treatment for methamphetamine use disorder. So without further ado, I'll start the video that was recorded. Hi, I'm Trivedi at UT Southwestern, and I'm going to present on research updates and future directions in the treatment of methamphetamine use disorder. These are my disclosures. I have consulting relationships with pharmaceutical manufacturers. Research report in this presentation was supported by National Institute of Drug Use Award for Clinical Trials Network, and however, the content of the presentation is solely the responsibility of myself and my team, and does not necessarily represent the official views of the National Institute of Health. For the study I'm going to present on, just for disclosure, alkalines provided injectable extended release naltrexone and matched injectable placebo for that trial, and I'll describe that when I describe the results. The objectives today are to assess processes used in identifying putative medication candidates and list promising pharmacotherapies for stimulant use disorders. I'll describe the rationale for targeting symptoms associated with stimulant use disorders and provide evidence supporting recommendations of future trials of medications that address symptoms during the growth from stimulant use. Stimulant use disorder is a serious illness associated with medical and mental health morbidities. It leads to marked functional impairment and has a deteriorating course. Since 2014, the number of deaths involving psychostimulants have risen significantly each year, with about 24,000 deaths in 2020. Those numbers have increased in the last few years. Compared to opioid use disorder, while there has been a lot of attention on opioid epidemic, there are indeed several treatments available for opioid use disorder, including reversing acute toxicity and overdoses in emergency room settings with naloxone and treating opioid dependence through medication management. Unfortunately, opiates are not the only problem. Fifty percent of treatment-seeking opioid use disorder users also use stimulants. Over 50% of opioid-related fatalities also have stimulants in their system at the time of death, and there are a number of primary, there's a large number of primary stimulant use disorder patients also. Unfortunately, there is no FDA-approved medication for the treatment of methamphetamine use disorder and Lycopene use disorder. And effective treatments has been identified as an essential public health goal, both for the public health as well as from NIDA initiatives. The goals, I would say, are to improve quality of life, medically manage the course of illness with evidence-based care, create objective measurements for recovery status, standardize treatment in ways that behavioral therapies cannot, reduce stigma and reduce costs associated with drug use, death, and secondary consequences. A large agenda, but I think that for now, for my presentation, I'm going to focus a little bit on the results from one of our large trials that was funded by NIDA. Before we jump into the results of the trial, I'd like to talk a little bit about where we are going with stimulant use disorder trials and pharmacotherapies. At least three decades of effort and resources have been invested to explore pharmacotherapies. There has been development of pharmacotherapies for stimulant use disorder, has been a priority for the scientific field in NIDA. There have been hundreds of RCTs conducted to evaluate over 60 different drugs for stimulant use disorder. No treatments, unfortunately, have been developed for drug use in clinical populations. Bottom line, we don't have a treatment, not for lack of trying, but unfortunately, none of these have really panned out. The CTN, the Clinical Trials Network, constituted a stimulant task force report that I chaired with my colleague Jennifer Potter from UT San Antonio. We actually developed a consensus around research priorities using medication repurposing options. The consensus was that we should consider things that are medication combinations. We may want to also address associated targets like sleep, circadian rhythms, anhedonia, dysphoria, et cetera, depression, and also really actively look for rapid-acting novel treatments because currently the treatments we have tried have not significantly improved our outcomes. Just a little primer on dopamine dysfunction in stimulant use disorder. All of you probably already know, but cocaine primarily blocks the dopamine transporters. Amphetamines and methamphetamine inhibit uptake and increase reverse transport of dopamine into the cleft. Amphetamine and methamphetamine affect dose dependence. Low doses block the transport. High doses reverse the transport. Both of these affect serotonin and neurotransporters. I think one area that we would suggest we should be thinking about in this cycle for stimulant use disorder which includes binge and intoxication, withdrawal and negative effect, and we've seen this with stimulant use disorders often, stress and reward circuits, the preoccupation and anticipation. In general, the right side of the box with looking at withdrawal and negative effect and stress and reward parts of this have not been as well explored, so that is one area to really consider as a target for us to develop treatments for stimulant use disorder. The pre-focused candidates that the task force really thought through include naltrexone plus bupropion. There has been early evidence for efficacy for a number of stimulants but not really strong and we'll see from the results. We saw we did find the results. The other is ketamine which would really go in the direction of rapid acting molecule. There are obviously still strong interests in replacement treatments with amphetamine and ketamine salts. Vertazepine potentially related to its effect on sleep, but there is data that are limited for stimulant use disorders. The other options are buprenorphine, suborexant, especially with sleep and there is now increasing interest in the field in academia but also in the industry on psilocybin and there is some really emerging data that seems to be promising. So ketamine and psilocybin fall into that category of rapid acting molecules that may have an immediate effect and can be sustained over time. Given this background, the absence of really effective treatments, the potential for repurposing, I think the one place where we started and that was thankfully funded by this clinical network was the ADAPT trial which was really deemed as accelerated development of additive pharmacotherapies. In general what it means is combination treatment. Again no FDA approved medications, but there were some promising results from naltrexone and bupropion, very minimal data but still seemed like there was some suggestion. The pharmacotherapies did not lead to the benefits but maybe a combination could be seen as a potentially complementary effects. Again going back to that box in terms of the mechanism I suggested may be worth considering. So bupropion and naltrexone were thought of as something we should try. We proposed a small open label pilot trial in order to really test the feasibility and get some idea of the efficacy. In that study we defined responders as six out of eight urine drug screens as negative in final four weeks of treatment phase. What we found in that study in that eight week trial was that nine out of 49 participants met. We had argued that we should at least have nine out of 49 patients that were in the trial meet criteria for response. We were successful in getting 11 of the 49 in that study to reach responder status which led us to the larger multi-centered definitive trial. So the two medications are naltrexone which appears to obviously reduce reinforcing effects of amphetamine, potentially reduce likelihood of relapse and decrease claiming, but in addition when we added bupropion the idea was that it may reduce cue craving and decrease amphetamine use and affect the negative effect of the synophin after the first day of use. So we and then one of the things we reviewed was the entire existing literature and found several challenges to the identification of efficacy for pharmacotherapies from previous trials. One of the main issues that we ran into were the sample sizes were too small often, that the placebo response rates were very high, the dropout rates were very high, and one of the other things was that the heterogeneity of the patient population going in was significant so that some were only using on weekends, some were using longer, et cetera. So what we tried to do in this design was several things. One is we used SPCD design which is sequential parallel comparison design. I'll describe that in a second. We also did make all the efforts possible to reduce placebo response and increase treatment of their accepted exposure in the study and reduce with dropouts. As you'll see I'll show you that we were able to accomplish all that in this. That is basically a sequential parallel comparison design as you can see on the right side. It's a two-stage study which is basically an adaptive study design where the first step is a combination of medication versus placebo with a disproportionately higher number of people randomized to placebo. Those on the placebo are, so that is a six-week trial. At the end of six weeks the placebo responders stay on the treatment. The placebo non-responders then get re-randomized to placebo versus combination. Those on the active medication combination in the first stage continue irrespective of whether they're responders or non-responders. The timing of this re-randomization in six weeks, the criteria needed to randomize them at the end of the six weeks were both kept blinded, so the investigators were kept blinded to these two characteristics and you'll see that that helped us accomplish the lower placebo response in the process. The study itself therefore had two stages of six-week each which is a 12-week medication phase. Visits were twice weekly. Oral medications were dispensed weekly. Injections for naltrexone were given every three weeks which was another change from the PDR or the product insert where naltrexone was recommended every four weeks. We got dispensation from the FDA to be able to give it every three weeks. So those were the elements of this randomized control trial. As you can see the first stage people are randomized to the medication combination 109 of the 403 and 294 in placebo. Of the placebo those who got were non-responders and response was defined as four urine drug screens week five and six and at least three out of four urine drug screens had to be negative for them to be defined as a responder. If they did not meet that criterion they were defined as non-responders and they could then be re-randomized at the end of stage two to placebo versus medication combination for an additional six weeks where again the response was defined as week five and six which is virtually 11 and 12 weeks, four urine drug screens, three out of four had to be negative. This was a sample we ended up with. Not surprisingly about two-thirds male. They were mean age of 41. About half of them were never married. Interestingly about 38.7 percent of the population was employed and 64.7 percent had more than a high school education. You can see the race and ethnic distribution. African Americans were 11.9 percent and Hispanic Latino 13.6 percent. Days of methamphetamine use prior to the consent by study site you can see that each overall basically what we found was that the mean days of use for methamphetamine, the study and the total as you can see on the right side is 26.7 days. It's clearly indicating that the patients that went into the study had been using methamphetamine almost every day. About a third of them were using IV methamphetamine and the others were using oral methamphetamine. Treatment exposure by state of treatment arm. As I mentioned earlier, we took real trouble, made all the efforts necessary in the conduct of the trial to ensure that we had decent, very good treatment exposure and these are the numbers overall in stage 1, 75 to 83 percent and if you look at compared to previous trials this is much better treatment exposure than stage 2, 77 to 83 percent. Therefore we were able to accomplish a significant retention as well as treatment exposure in both stages. These are the ultimate results where stage 1, stage 2, remember this is a sequence of parallel comparison designs so that there is weighted average for responders in stage 1 plus responders in stage 2 and that weighted average response rate is 13.6 percent of the medication combination versus 2.5 percent on placebo. Several things to think about. One is the placebo response rate both in stage 1 and 2 and in the weighted average is distinctly very low. Not surprising if you look at clinically your patients with methamphetamine they don't automatically on placebo get better. Same thing we were able to, so this was a truly reasonably well-defined phenotype that we ended up with. The second thing is obviously that the combination effect is five times, about five times better than the placebo leading to about a number needed to treat of nine. I'll share with you a little bit in the next few slides, but that effect size is clearly definitive and compared to any other treatments in substance use disorder it is in the range that normally would lead to clinical change in treatment options in the real world. These are the raw data for negative urine drug screens by stage and by treatment arm and as you can see in the red or pink and green in the first stage the significant difference between drug combination versus, medication combination versus placebo. Same in stage 2, the medication combination was producing many more negative urine drug screens. So how does it relate to other studies and you can see this was a large enough study that 403 participants in the study in the other trials, modafinil, multazapine, ondansetron, topiramate and methylphenidate. Some of them are single site studies which makes it hard for really generalizability. There are some effects in a number of them like the Coffin study. It was a single site study and more importantly that included primarily MSM population and did not have the generalizable sample we had in DAP2. In general the number needed to treat if you look at other studies for other things like preventing relapse to heavy drinking and alcohol use disorder with naltrexone, naltrexone in abstinence for opioid use disorder or bupropion for smoking cessation, the number needed to treat are in the range of what we found with this study clearly suggesting that this should be taken very positively by the clinical world. These are the participating sites. One plug for the clinical trials network of NIDA in my view. This network is really a very highly functioning, very active participants across all the nodes as you can see on the right side that participate in the conduct of these clinical trials. For our study the eight sites were the Greater New York Node, North Star Node, Southern Consortium Node. At that time we were just the Texas Node. We are now the big Southwest Node and the Western States Node. All these sites really deserve a lot of credit. They put in all the hard work and we were able to recruit three participants for this study. Obviously a lot of people put in a lot of effort towards this. My colleagues at UT Southwestern and the big Southwest Node, Walter Ling really served as a very senior and important advisor for us during the study. MSN, the Clinical Coordinating Center and the Data Statistics Center clearly provided significant input and help. From the NIDA CCTN, Dr. Udi Kitsa and Steve Sparenberg served as wonderful, important scientific liaisons for us. I'm going to stop here. Thank you very much. We'll go with Dr. Brady's presentation. Dr. Brady is a distinguished professor at Medical University of South Carolina where she is also the principal investigator of their CTSA and has been doing research in substance use disorder and psychiatric disorders and their comorbidity for over three decades now. Let's listen to Dr. Brady's presentation. I'm Colleen Brady and I'm here to talk today about transcranial magnetic stimulation in the treatment of methamphetamine use disorder. As you all know, methamphetamine use disorder is on the rise. We know that from all sorts of reports of search and seizure and emergency room visits and unfortunately often laced with fentanyl. So methamphetamine has led to a number of drug overdose deaths increasing over the past couple of years. So finding a treatment for methamphetamine use disorder has really become a priority. As you also probably know, there have been hundreds, if not thousands, of medication trials in the treatment of methamphetamine use disorder and really some have shown some marginal efficacy. One that you'll hear about in this symposium which has shown efficacy, but there's clearly room for improvement in the treatment of methamphetamine use disorder. So today we're going to talk about a new approach. Just to let you know, my disclosures, I am a consultant for Indivior Pharmaceuticals, Invera Pharmaceuticals, Alkermes and Sage Pharmaceuticals, but I'm not going to be talking about products of any of these companies today. What is transcranial magnetic stimulation? I'm sure you've seen a lot about it in the lay press and in science magazines and most of you probably know, but basically it's a non-invasive form of brain stimulation where you really change the magnetic field to cause electric currents in specific brain regions through electromagnetic induction. In this picture right here, what you see is the head is positioned and then a wire coil is placed over the head and that is what's used for the brain stimulation and the placement of the coil and the depth that the coil can reach is what determines which brain region is being targeted. Now the brain and behavior effects are actually frequency dependent. With a high frequency stimulation such as 10 hertz, and that's what we're going to be talking about for most of the studies we're going to be talking about today, what you get is higher cortical excitability or an amplified neural response. With a low frequency stimulation such as 1 hertz, what you do is decrease the cortical excitability and attenuate the neural response. Depending on what your target is and what your aim is, you might want to either increase, let's just say you're looking at executive function and you're looking at the more frontal cortical or dorsolateral prefrontal cortical areas, you might want to amplify that response to amplify executive control. If what you're aiming at is limbic areas, nucleus accumbens, those sorts of areas, you might want to use a lower frequency to attenuate the neural response. Basically the theoretical construct that most of the studies using TMS in the treatment of substance use disorders, basically we are using higher frequency, 10 to 20 hertz, and targeting the dorsolateral prefrontal cortex with the idea in mind that you can improve executive control over those subcortical areas, that limbic arousal circuit. Another approach, of course, would be to use a lower stimulation and target the limbic arousal circuit. This is a fairly recent review, although 2016, it's a few years ago, but I think the main thing I wanted to show with this is that there have been a number of studies done. Most of them have very small sample sizes. That's the second line. In the second row, you can see sample size, the highest, and this is 115. Most of them are in the 10 to 30 range. Various areas have been stimulated, but I'd have to say that the vast majority are focused on the dorsolateral prefrontal cortex. As you know, TMS was really first used in the treatment of and approved in the treatment of depression. In the treatment of depression, they used this 10 hertz focused on the dorsolateral prefrontal cortex. Because the treatment of substance use disorders generally came after that, they started use with these same parameters. So the conclusions from this particular review were that an acute effect on craving for drugs and alcohol is shown quite frequently. Almost all of these studies, you can see, show a decrease in craving. But there are very, very few studies who have actually investigated either relapse or use of the substance. Usually, these are very short term, one to five session studies where all they look at is craving. Various regions have been stimulated. The mechanisms are really not very well understood, but these investigators concluded that there was great potential and further investigation is needed. One of the other things I want you to notice from this slide is that most of these studies are done in nicotine dependence. That is actually where the first regulatory studies that were done that were used to get FDA clearance for TMS in nicotine use disorder. That's this study right here. This is a study, I'm sorry, I moved ahead too quickly, published in 2021, again using repetitive TMS for smoking cessation. This was a multi-centered, double-blind, randomized trial done really in sites throughout the world. 262 subjects, so this is a very decent sample size. It is sham controlled, three weeks of daily treatment and three weeks of follow-up. The primary outcome is a four-week continuous quit rate, which is really pretty standard in the FDA for smoking cessation. Based on this study, the FDA cleared TMS for short-term smoking cessation. You can look at the data right here. The sham is in the clear bar. The active is the black filled-in bar. We're looking at continuous quit rate at week six and week 18 in both by the intent to treat and the complete sample and also CO monitoring. But we're more interested in stimulant use disorder. To be honest, there are not many studies done at all in methamphetamine. The vast majority that have been done so far have focused on cocaine. The vast majority of these have looked at the dorsolateral prefrontal cortex or the medial prefrontal cortex, mostly using this high frequency, a variety of sessions, and again, almost all of these are looking at craving immediately after treatment. So they're really not looking at use or recovery or relapse. One study here that's very interesting, this was done at our site, looking at methamphetamine, very small sample size, but what they did was use the lower frequency and actually just in a proof of concept found that this lower frequency, as you might expect, targeting the dorsolateral prefrontal cortex actually increased craving in these individuals. So basically they decreased the executive control over those limbic systems in methamphetamine users. So there have been three studies now done, all done in universities in China, looking at methamphetamine use disorder. In this study, what they found was either left or right, both high and low frequencies, so they used either the 10 or the 1 hertz of treatment to the DLPFC decreased Q-induced craving for methamphetamine. So they had 50 males with methamphetamine use disorder, daily treatment for only five days, however, and craving was measured immediately before and 30 minutes after treatment. And this graph right here on the lower right side is probably the one that's of most interest. We're looking here at left or right-sided stimulation versus the sham group, and you can see decrease in post-stimulation craving in both of those groups. And surprisingly decreased in the low frequency group as well. The next study is targeting withdrawal symptoms in methamphetamine use disorder, so going beyond craving but not quite going to continued use and relapse. Again, 50 men, sham controlled. This is 10, so it's a higher frequency targeting the dorsolateral prefrontal cortex, 10 treatments over 12 days, and what we're looking at here are withdrawal symptoms by a scale that basically looks at appetite and sleep and mostly those somatic features of withdrawal. And you can see this is the treatment group, that's the sham group, so significant differences in withdrawal symptoms, significant differences in Q-induced craving and depression, a little bit of a change in depression, not much change at all in anxiety. The next study, as you probably noticed, both of those other studies have been looked at male. So in this study, they looked at 90 women with methamphetamine use disorder. All were receiving treatment as usual. It was a psychosocial treatment, and I think this for the most part is daily intensive treatment, 10 hertz over the dorsolateral prefrontal cortex, 20 treatments over five weeks, so basically five days and then weekends off. Again, primary outcome was craving measured pre-end of treatment and 60 days post, and you can see, again, this is the treatment group, this is the control group, so craving is definitely decreased, but we really don't know much about use and particularly use in the days after people end their intensive treatment. So as usual, all good science leads to more questions. So there are currently approximately 200 TMS studies in substance use disorders that have been published since 2000, and a number of questions remain. One is the dose. 20 or more sessions are used in depression, and so I think that has definitely been the thinking in substance use disorders, and as you saw in the treatment for smoking cessation, I think they used 30 sessions. Frequency, 10 hertz is the most common use. That's the frequency of the simulation itself, but how about how frequently you actually give the treatments? Recent studies have shown that multiple treatments per day sort of jump-starting the treatment in depression can be very useful. That's something that really hasn't been explored much in the treatment of substance use disorders, so that's another question. Target, again, dorsolateral prefrontal cortex is the one most commonly used, and what's the durability of effect? Are maintenance treatments going to be something that we're going to need to use and what sort of adjunctive therapies are best along with the TMS? Again, one of the things I have to say is I think we're going to learn a lot. We have definitely been following in the very capable footsteps of the depression researchers in this area, and I think they are now looking at those questions of durability and maintenance treatments, but these things are definitely not explored yet in the substance use literature. I wanted to just talk about a study that is ongoing. We've probably recruited about 30 participants at this point. I'm a co-PI along with Madhupar Trivedi, who you all know well and has certainly been a leader in TMS in the treatment of depression. We are recruiting 160 methamphetamine or cocaine use disorder people with methamphetamine or cocaine use disorder. We're using the dorsolateral prefrontal cortex focused higher frequency, the 10 hertz, and we do have a sham control. We're going to use 30 sessions over an eight-week period with a very flexible delivery schedule, so people can get two sessions a day. We're not going to go higher than that, but they can get two sessions a day, and we are actually encouraging that early in treatment, trying to sort of front load or jump start the treatment. Cue reactivity before each session, so we're going to show people cues that will activate those circuits that are associated with their substance use because that does seem to be one way to increase the effectiveness of TMS in the treatment of substance use disorders. We're also exploring EEG measures as biomarkers. We're using daily digital monitoring of craving, substance use, mood, stress, and sleep, and we do have CBT. Cognitive behavioral therapy is available to people, but they are not in other treatments, and they're not required to do the cognitive behavioral therapy. Primary outcome really is feasibility. Can we get these people in for 30 sessions of TMS over this eight-week period? And then certainly we're interested in efficacy as well. What is the efficacy of up to 30 sessions? We're going to look at the percent negative of last urine drug screen per week for the seven-day period. And with that, I hope that I'll be able to come back next year and give you all some results. We're very hopeful. And these are my references. Thank you very much. So we talked about the findings from adaptive study. We talked about an ongoing study of TMS for stimulant use disorder, and now I'm going to talk about a study that is being developed as part of the clinical trials network, which would be looking at the treatment using ketamine for methamphetamine use disorder. These are my conflicts of interest. Most of these have to do with my work in depression research. I was part of the phase three studies of esketamine. Esketamine is FDA-approved for treatment-assisted depression, as well as depression with suicidal ideation or behavior. But we will not be talking about esketamine, but we will be talking about racemic ketamine today. So just a quick primer on the new mechanisms of glutamate neurotransmission. So one key aspect to remember about glutamate, which is the major excitatory neurotransmitter, is that it has a tripartite synapse. So glutamate, when it is released from the presynaptic neuron, goes into the synaptic cleft, but is then taken up by the glial cells. And then from glial cells, it's converted to glutamine, which is cycled back into the presynaptic neuron. There is a critical role of glial cells. So we have to still understand basically what the mechanisms are, and the impact of glutamate, how soon that impact is, depends on the type of receptor that it's binding to. So broadly, glutamate receptors are of two types, the inotropic receptors, which are basically ligand-gated ion channels, so when they open up, the channel opens up, it allows the flow of ions through the membrane, and changing the membrane potential. And then there are metabotropic receptors, so these are receptors, when glutamate binds to them, there are downstream metabolic signaling changes that happens, and again, based on the type of the receptor it is, it can either stimulate it, or it can inhibit it, or it can have more of a homeostatic role. So these are the broad, very broad overview of glutamate receptors, and several different drugs are being targeted, or being developed that target these. I will talk about ketamine today, so ketamine has been around for over half a century now, it is primarily used as an anesthetic agent, and I grew up in India, my dad was a physician in India, so I saw ketamine being used there in pediatric setting, or in settings where we don't have very good monitoring systems available, because unlike other anesthetic drugs, ketamine doesn't drop heart rate and blood pressure, so it can be used in emergency settings very easily, however, its use as an anesthetic is limited because of psychosis, so when we use ketamine for anesthesia, more than a quarter of adults will complain of really problematic, like dissociative symptoms when they're coming out of anesthesia, and it has also been used for chronic pain, it is definitely something that is a drug of misuse, so there is misuse potential related to ketamine, and chronic misuse of ketamine is associated with cognitive impairment, so that does lead us to think about how much we are dosing, how we are going to use ketamine, and what doses and how frequent are we going to use it. So just a quick review of use of ketamine in treatment of depression, so one important aspect of ketamine is, and we'll look at those data, that it is pretty rapid onset, so just a quick reminder that most conventional currently available antidepressants can take four to six weeks to attain maximal efficacy, ketamine has a more rapid onset of action, most studies of ketamine have been by intravenous route, where the bioavailability is much better, using oral ketamine does lead to a lot of like first pass metabolism, so if we take ketamine orally, most of it is broken down by the liver, and then ketamine is metabolized to hydroxynorketamine, and there is a lot of exciting research about how these ketamine metabolites may have their own effects on our brain, and ketamine has a really short half-life, so that is why it becomes such a good anesthetic drug, that we can dose it, and then when we stop dosing it, the effects go away, and that also has implications on how we do the infusions and how we treat them. So this is just two initial studies, so this is the first study of ketamine, which was a crossover study, so it was ketamine versus saline, just a single infusion, what I want to point out about these studies is the time frame, so the follow-up period was in a matter of hours, instead of a typical antidepressant study, where we would follow up people over weeks to months to see what the effect is, and even in this study, we saw that the dissociative symptoms were peaked pretty rapidly, consistent with the effect of ketamine, but then gradually depression improved, and these findings were then replicated by Zerate and colleagues at National Institute of Mental Health, and then followed up by a lot of work at Mount Sinai, where a repeated dose of ketamine were used, and what was shown was that by repeatedly dosing ketamine, the improvement was maintained over a period of time. So with a single infusion of ketamine, most people experience a return of depressive symptoms, so most people are back to their pre-depressed, so pre-ketamine depression level by a week, some people may go on for several weeks to months, but by repeatedly dosing ketamine, that improvement in depression could be sustained, and then that led to the studies of intranasal ascetamine, and these are findings from treatment-resistant depression, again, acute phase trials, which were fixed dose, or flexible dosing, and of the acute phase trial, only one of three was significant, so statistical, reached the statistical significance, but the second positive study that was used for the approval of ascetamine for TRD was actually the longer-term study, so individuals who had improved on ascetamine, or were limited on ascetamine, were then switched to either placebo, or were continued on ascetamine, and by switching to placebo, by removing the ascetamine, the relapse rate in treatment-resistant depression were twice as high, so again, suggesting that long-term continued use of ascetamine may improve, or may sustain improvement associated with ascetamine. So we talked about the burden of stimulant misuse, and I'm going to skip over that slide, and just talk about two particular studies for ketamine for substance use disorder, and these are the two studies over here, a study of cocaine dependence, and then a more recent study of ketamine infusion for alcohol use disorder. So first, the study of ketamine for cocaine dependence, this was, the study design is notable that everyone was on an inpatient unit, so as people who wanted to be enrolled in the study, they were admitted to an inpatient unit, so there was a five-day inpatient stay, and ketamine was, or midazolam, so it was a double-blind study, was administered in a single infusion over 40 minutes, so this is very consistent with what is typically used in depression literature, so going back to Dr. Brady's presentation, a lot of these doses and paradigm were based on what has been done in depression, and along with the ketamine infusion, mindfulness-based relapse prevention was initiated, relapse prevention was done more frequently during the inpatient stay, and then less frequently, so once a week afterwards over the five-week period. So with the five-week inpatient stay, the starting point for everyone was that they had attained the negative urine drug screen, and then the study outcomes were how frequently, which was the time to first use or drop out, and as you see that there was, everyone was in negative urine drug screen, but then the likelihood of either drop out or first use was markedly higher, so far fewer people in the midazolam arm were able to maintain that negative or non-use as compared to those in the ketamine arm, so just a single infusion was suggestive over a four-week period, when paired along with the mindfulness-based relapse prevention was able to maintain the improvement in the single infusion study. The other study that I mentioned was ketamine for a treatment of alcohol use disorder, so the interesting aspect in this study was, unlike other studies in substance use disorder, this was a repeated infusion study, so most studies in substance use disorder of ketamine have been single use, and here the dose was a bit higher, so if you notice, it's .8 milligram per kilogram, whereas in most depression studies, the dose has been .5 milligram per kilogram, and it was three infusions over three weeks. The other interesting aspect of this study is that it was really a four-arm study, so it was therapy plus ketamine, just education, ketamine alone, so that was the second arm, a third arm was therapy plus saline, so saline was the control condition here, and then education plus saline, so education plus saline would be considered like an active control condition in this study, and the sessions where there was mindfulness during infusion experiences, so it was encouraged people during the infusion to practice mindfulness. So these are the findings of this study, which were just recently published, so if you see the yellow are ketamine plus psychotherapy, so the two active arms, they had, there was a much higher percentage of days abstinent in that, but ketamine plus psychoeducation followed along with, but not as much, so numerically, statistically they are not different, but numerically it does seem that ketamine plus psychoeducation was not as good as ketamine plus psychotherapy, psychotherapy alone, which is the red, placebo plus psychotherapy was in between, and then the inactive condition, which is placebo plus psychoeducation was definitely lower, so the two conditions that included ketamine were both superior to the control condition that was inactive, so suggesting this raises the issue of how we go about doing studies with ketamine, and then raises questions with psychedelics, what role psychotherapy has, and that's something to keep in mind. So the study that we, the concept has been approved by the Clinical Trials Network Committee, and is being under development right now, is a double-blind randomized control trial of ketamine versus midazolam, here, again, following in the footsteps of ADAPT2, we would be looking at individuals who have moderate or severe methamphetamine use disorder, the dose of ketamine used in the study is higher than that is used for depression studies, so we will be targeting .7 milligram per kilogram of over a 52-minute long infusion, and midazolam is .02 milligram per kilogram, which is similar to what was used in the duck wars study in cocaine. We are planning for a much more intensive treatment series, so this is three infusions a week over six weeks, so a total of 18 infusions, and that again goes to the idea that maybe we need more prolonged treatment to get that improved abstinence that we are targeting in individuals with methamphetamine use disorder, so there is six weeks of treatment followed by six weeks of follow-up phase, so we want to, again, see that, do people get better, and those who get better, do they stay better or not, so that's why we have the six-week of follow-up phase, the planned enrollment is 120 people across four sites, which is fairly big when it comes to ketamine study, but probably may be underpowered in terms of generalizability of that, and the definition of response is the same as ADAPT2, which is during two-week evaluation period, are three out of four urine samples negative, that is how we will define the response for this study. So just quickly, so targeting glutamate neurotransmission may offer new treatment, we are definitely learning that from our experience with depression studies, depression studies have shown that ketamine and its S enantiomer may have rapid and robust improvement, but what is really important is that there has not been any study of ketamine for individuals with methamphetamine use disorder, and in the context of stimulant use disorder, repeated infusions of ketamine haven't been studied, so this really, we are excited about being able to do this study, because this would allow us to answer several of these questions in a comprehensive fashion. These are the references, and I'm going to stop and have Dr. Volkow do the discussion, and then we'll take questions. Thanks very much for that wonderful presentation, and I'm going to right now aim to do a summary of what is going on in my brain in terms of the presentations. For you that do not know about the clinical trial network, what it works, how it works, it basically is an infrastructure that we have built at NIDA to be able to do trials rapidly where there is already some evidence of efficacy for treatment interventions to determine the extent to which these ones can be replicated in larger samples. And what's notable from the clinical trial network has been how well it has worked and how it has enmeshed itself very much into the involvement of the healthcare center, the healthcare treatment centers in the management of substance use disorders. In methamphetamine use, as I said at the beginning, as is the case for cocaine use disorders, the challenges have been quite large. And as I'm listening to the presentations, there are common tips that are emerging. First of all, we heard three presentations. One of them is, can we identify medications that are already approved by FDA for which the combination can significantly improve outcomes? And this offers a tremendous advantage for us in the field, because once you have a medication that's already out there, it becomes much easier to then bring it into the market. There are challenges when you are actually trying to get the FDA to approve two combinations that you don't see with one. But clinically, it gives us a great opportunity. What's interesting of the study that was proposed, actually, that was on the ADAPT, that actually showed that the combination of bupropion and naltrexone significantly improved the outcomes of individuals with moderate to severe methamphetamine use disorder, is that the outcome, actually, is a very difficult one to reach, which is to have three negative urines out of four, which in other words, basically, is demanding that the individual stop from taking any drug. And it's not considering alternative, intermediate outcomes that may be beneficial for the patients. For example, if an individual is able to significantly reduce the doses of methamphetamine that they are using, that could be beneficial for that particular individual. If the treatment intervention, for example, could reduce not just the craving, but the depression, and improve their sleep patterns, or improve their executive function, even though it's not resulting in three out of four negative urines, it could be beneficial. So despite this big challenge, and it's something that we've been actually discussing with the FDA, why is it that the only approved outcome right now for the FDA is negative urines, which is, again, almost demanding, if you're looking for an antidepressant treatment, that there's no symptoms of depression. So we're working to try to get alternative outcomes that can be beneficial. And I would be very interested on identifying the extent to which of those individuals, because again, the number of individuals needed to treat to get a response is an N of 9, which is better from what we had in the past, but it's still a large number in order to see a positive effect. I suspect that if in turn we were looking at other intermediate parameters, there would be benefit. And of them, one of the areas, I mean, everybody has been focusing on craving, because of course it's very relevant, but there's another one that the patients themselves endorse as one that will be very valuable for them to control their drug taking. There's actually two of them. One of them is depression, and that's one of the factors that lead people to keep on taking drugs, because they want to actually feel better. And the other one is they cannot fall asleep. So they take drugs actually in combination, so if they are taking methamphetamine, they may combine it with opioids to help them sleep, or alcohol to help them sleep. And that initiate a more severe process of drug taking. So if we look at the three presentations today, the one of the combination of bupropion, which is an antidepressant with dopaminergic enhancing effects, the second one, which is ketamine, which is approved, is a treatment approved for the management of severe depression. And then ultimately, transcranial magnetic stimulation, which is in the dorsolateral prefrontal cortex, which again has been approved by the FDA for the management of depression. So the three interventions that you heard today already have been shown to be beneficial for depression, to the extent that dysphoria and depression is frequently prevalent in individuals with methamphetamine use disorder, we can start to understand that this could be one of the mechanisms by which it's therapeutically beneficial. The other common theme that I think is important for us to look into, both as we manage patients suffering from methamphetamine use disorder, or other substance use disorders, or when we're actually doing research, is what we've already learned from many other medical conditions. That when you combine medications, you tend to have much better outcomes than when you study them in isolation. So for example, we saw a presentation today of the potential of TMS for the treatment of methamphetamine use disorders, cocaine use disorders, alcohol use disorders. But except for the last trial, where they were looking at an educational intervention, we do not see the application of the transcranial magnetic stimulation in parallel with another therapeutic intervention. So if one thinks about it, for example, we know that naltrexone may have potential beneficial effects by itself, or methamphetamine, or we just saw a presentation, bupropion, too. So if we combine these modalities, could we improve the impact of those interventions? And I think that that's another important consideration, both for the management and for research. And then the third element that I think emerges, as I was listening to this presentation, and most notable in terms of presented in the diagrams by the transcranial magnetic stimulation session, is the notion of understanding what are the neurocircuits that are disrupted in the process of addiction. So we tend to think of a dorsal prefrontal circuitry that enables us to exert executive function, self-regulation, and a ventral prefrontal below it that basically assigns saliency value, and it's a limbic cortical region that is implicated in craving. To the extent that those two prefrontal circuits are engaged in addiction, understanding their relative preeminence in a particular patient is an important one that I would like us to start to think forward in terms of identifying and not dealing with each individual with a substance use disorder as identical to another. But by identifying the unique disruptions in the brain circuitry of an individual, we may first start to think about the notion of personalizing the treatment interventions. And I think that that's the way we have to think into the future as more and more we are getting information about what is the neurocircuitry dysfunction in mental illness, in substance use disorders, and in their comorbidity, and as we understand how to use these neuromodulation technologies to either stimulate them or to inhibit them. So with that, I want to end up my formal discussion to bring it up for any questions that any of you may have. This is a naive question. The difference between methamphetamine abuse and amphetamine abuse. What is the difference? Well, methamphetamine and amphetamine are both stimulant drugs that exert similar effects overall by actually blocking the dopamine transporter, as was said earlier, at small doses, but reverting it and releasing dopamine at high doses. In preclinical studies, we know, though, that methamphetamine is a more potent stimulant drug than amphetamine. Nonetheless, both of them produce severe addiction, both of them have high rate of neurotoxicity, because not only they produce addiction, but they also produce significant damage to the vascular system. And that is not something that we've discussed, but because of that, it is not infrequent to have severe cognitive impairments in the individuals, whether it is with methamphetamine or with amphetamine use disorder. Thank you very much, Nora, for that excellent presentation on a very important topic. I'm very concerned about the growing prescribed amphetamine-like medications. We're seeing that in clinical practice, that many individuals are coming in, they try it in college, it's wonderful, they have ADD, they almost demand these drugs like Adderall or Vyvanse. Is there any research in this particular area of the growing prescribed amphetamines and whether that's leading to addictive disorders that it appears to be from clinical practice? Yeah, no, and thanks for bringing up this question, and it in a way relates to the prior one about the notion, recognizing that amphetamine, which is a medication we use for the treatment of ADHD. Also, when misused, can be very addictive. And the concern that while we've gone through the epidemic that was triggered by the over-prescription of opioid medications, we don't want to emulate that with the over-prescription of amphetamines. We've already been there in this country in the 60s where there was over-prescription of amphetamine and a massive problem of addiction with amphetamines. There have been reports of increases in prescription for amphetamines. And actually, we are very interested on trying to determine if in fact, they have been significantly increased, specifically right now, during the two years of the COVID pandemic. Because one of the issues is that we have seen a rise in misuse of many substances. But also, as we're starting to see that one of the long-lasting consequences from COVID infection is fatigue, the concern that physicians may rely on amphetamines to actually try to energize their patients. And so, we are in the process of trying to get our hands on prescription data to be able to monitor. But I've raised the alarm, and I've basically been sort of asking the same question that you have asking. We need to understand what's happening with the prescription of stimulants that seem to be going up. So, thanks for bringing it up. Yeah. Thank you for this wonderful program. It was very, very useful and well presented. So, I appreciate all the presenters. The second presenter did make a comment about the contamination of the methamphetamine supply with fentanyl. I don't know if that's an issue in other parts of the country, but in Arizona where I practice, it's very rare for us to see a urine drug screen that's just positive for methamphetamine. They're almost always positive for methamphetamine plus fentanyl. So, in the first study, looking at naltrexone plus bupropion, is there any information about whether their urine drug screens were also showing fentanyl in their study population? Because I would think that that would be a little bit of a confounding factor, or at least something to be thinking about. Yeah, no, and thanks very much for asking that question, because we've looked at the latest numbers from the CDC of overdoses, and more than 60% of overdoses from methamphetamine contain fentanyl. And this is data all over the country. Oh, it is, okay. And it has been increasing. So, it used to be one year ago it was 50%, now it's 60%. And we're seeing that fentanyl is used to contaminate many drugs. I thought that you were going to comment on something that actually jumped in my brain when I was listening to Madakar's presentation, which was, if we do treat people that have methamphetamine use disorder with naltrexone in combination with bupropion, we are going to be protecting them from overdosing if they buy a drug that contains fentanyl. And that just jumped into my brain. And I said, overall, we know that, because naltrexone has a very high affinity for the opioid receptor. So, if you are blocking it, fentanyl is not going to be able to result in an overdose. But for that specific question, do we know if they had, I do not know, I do not know if they had. So, yeah, I wouldn't speak for Dr. Trivedi, but having a negative urine drug screen for opioid during the screening was one of the requirements, and I think fentanyl was negative. So, no, eligibility requirements. So, there were eligibility criteria around negative urine drug screen for opioid. So, those users were screened out. I don't know how many, but it could be that the contamination was not that major an issue going back several years that the study was actually being done. So, the study was done about three or four years ago, the recruitment of the study was done, so. Yeah, no, and I suspect that, as we have been seeing, the contamination is increasing. But the other possibility, too, is you screen someone whether they fit the criteria or not. Then they get into the trial, and many of them are continuing taking methamphetamine. So, the issue is in those urines that are there, are we keeping the urines? Can we test for fentanyl? So, we definitely are testing for fentanyl. So, they were negative. Those urines, all of the urines that were collected during the period of the clinical trial were negative for fentanyl? I know all the studies we have going on right now as part of CTN, we definitely test for fentanyl in addition to other drugs. So, we do a panel of 11 things, and one of those is fentanyl. So, we do get that on every one. But that's now, but I mean, I think that it would be. I'll have to go back and look at the data. No, it would be interesting, because we could have a record, historical record of what has happened to the urines with methamphetamine and fentanyl. So, and I, but I do not know if they are kept or not. Bottom line is it is a major issue, and it's not going to go away, because the dealers are making much more profits by combining them. Yeah, absolutely. Thank you. Thanks. I do not know how the order goes, so I'm going to go left, right, right, left. Yeah, that'll work. Hi, so Lisa Fortuna from San Francisco General Hospital, where I'm the Chief of Psychiatry there, and my question was a little bit triggered with your comment about intermediary outcomes. So, the population we serve are primarily unhoused and homeless and with serious mental illness and multiple substances. And so, I'm just wondering what you think the opportunities are for combinations of sort of psychosocial interventions, you know, studying that, right? I mean, you looked at mindfulness. We're trying to use contingency management, risk, you know, harm reduction sort of strategies. Are there any opportunities or studies coming up where we're looking at how do we do that in a pragmatic way, right? We're very hard to serve populations of trying to use a combination of psychopharm and psychosocial interventions. Indeed, and you are probably putting your finger in one of the most challenging populations to treat those that are homeless that have both comorbid mental illness and substance use disorders. We are targeting specific requests for proposals to investigate these very difficult-to-get populations and to address, for example, importantly, the extent to which providing housing or providing secure food or support for, if they are women, for the rearing of children significantly improve outcomes. So, I mean, in this population, if we do not address the huge gaps that they have for lack of social support systems, I find it will be very, very difficult to engage someone in treatment. And so, yeah. And by the way, the highest rate of mortality with all of these increases that we're seeing with overdoses during the COVID pandemic, the highest rates are among the homeless. Hi, good afternoon. Stephanie Jolin from North Dakota, where meth has been an issue for a very, very long time. So, I have kids as young as 13, because I am child and adolescent, starting their methamphetamine use. And so, part of the trouble here is that I can't get them on naltrexone, because it's not FDA-approved. But also, I noticed in the study, you guys use Wellbutrin up to 300 milligrams, and I find a lot of my kids, especially if I start at that dose, end up getting psychomotor agitation. So, was there any data as far as starting on a lower dose, titrating up, things like that, or did you just start at the 300-milligram dose? You were involved with that trial. So, it was started at low dose, but rapidly, I think it was within four days that it went up to the dose of 300. Again, the idea was, in this study, which was only in adults, was to get to a good enough dose for a long enough period of time, because again, the SPCD design truncated the treatment duration to just six weeks. That was the study design. But you're right, none of these data really apply to child and adolescent population, because we don't have, yeah, we cannot extrapolate these data. Yeah, and I think, I mean, I'm going to take advantage of you bringing this question, because that's probably the largest gap area that we have. We have very, very little work as it relates to the treatment of substance use disorder in adolescent populations. And the issue that is particularly serious and urgent right now is that adolescents now, for the first time, are being exposed to fentanyl, because fentanyl, whether it's through methamphetamine or more commonly, illicitly bought prescription drugs, that could be amphetamines, the likelihood of them being contaminated with fentanyl is much higher. So we've seen more than a doubling in overdose deaths from fentanyl over a period of two years. So it is key and crucial that we start to develop therapeutic interventions for adolescents. And unfortunately, not necessarily things that have been shown to work in adults. Apply into adolescents. Thank you. Hi, my name's Graham Scanlon. I'm a psychiatrist at a psychiatric hospital in San Diego. And as everyone else is saying, thank you so much. It's truly amazing, I really appreciate it. One of the thoughts I had is a question that always comes up about dual diagnosis versus a pure substance-induced. And it reminded me of a fellow, when I was still a resident, a friend who was a fellow, he said that treating patients with substance use like they're bipolar, even if they're not, even if he didn't maybe make that diagnosis, their substance use went down or went away. It's just a story that made me think of that. No, I think that it is a very valid story. And to me, the message that I'm getting is the one that I was also trying to say. I mean, we cannot just equate one patient with the other. I mean, individuals with substance use disorders end up there by different trajectories. And one of the trajectories may be an underlying depression that led them to be vulnerable. Another one may be anxiety. Another one may be basically just experimentation and very enhanced neuroplasticity and ending up in addiction. So the extent to which you, you need to consider what a unique presentation is for an individual in order to be able to maximize and to tailor the intervention that you're going to be giving. It is, as has been highlighted all along, one of the characteristics in the severe addiction is the frequency with which you have depression and enhanced stress reactivity and anxiety. And the patients, there's a very interesting series of very small series of studies done with deep brain stimulation of the nucleus accumbens. It's being done by researchers at West Virginia and funded by NIDA. And I went to visit and interview the patients because I was interested to know, to get a sense of whether there could be in that small sample any evidence of benefit. So I was able to interview two of the three patients that at that time had the surgical procedure. And what was very interesting is both of them said the moment that they turned on the stimulation like a switch, the anxiety was gone. And they said that made a complete difference. And basically one of them was saying, if you don't realize how severe my anxiety was, I couldn't even look at the eyes of my parents. I was so, so anxious. So to the extent that we understand how these symptoms that are part also of other mental disorders are contributing to drug taking, we actually can be more effective in helping our patients. Thank you so much. Thank you so much for the wonderful talk. So I'm from Canada and it can be very challenging to access injection naltrexone in Canada because outside of special access or research purposes. I was curious if there's any literature evidence to support oral naltrexone instead of injection naltrexone for this condition, although there would be some adherence issues. Yes, and I know that there's no trial that has been done with oral naltrexone and bupropion. But a lot of trials have been done with oral naltrexone for opioid use disorder. And it's actually a therapeutic intervention that is used in many places in the world like actually Vietnam or China. It is very difficult for patients to be compliant. And Chuck O'Brien, who was the lead person pushing the use of naltrexone for the treatment of both alcohol and opioid use disorder brought it up all along. The problem is we cannot get patients to take it on a daily or every other day because it can allow us for 48 hours. So it's very difficult for patients to comply with the oral naltrexone. You have to have extremely motivated patients. Thank you. But I mean, I'm surprised. Have you contacted the pharmaceutical to see if you can get it from alchemies? I'd spoken to a pharmacist within the Center for Addiction and Mental Health in Toronto and we had some challenges getting the injection medication, so. I didn't realize that. Yeah. Thank you. Thanks. Hi, David Crockford. I'm also a Canadian. I'm out in Calgary. The Health Canada won't actually approve the vitriol, the injectable. So it's, and then with it coming off patent, nobody wants to actually do the trials. That's part of it. But anyways, one of the things which keeps getting pushed by people who are in the harm reduction kind of focus is, oh, should we be prescribing stimulants to people? And I'm struck by it because, you know, I see it as the issue that you give people stimulants, you actually increase the use. I see people relapse with it. I was struck by your trials before looking at methamphetamine users where you would give people methamphetamide or methylphenidate to actually induce cravings. That, what do you think of this idea? Because it's not on the list of drugs. And I've seen like at least four meta-analyses which are all negative for the use of stimulants. Is this something even on the radar of people wanting to use? And what do you think about this whole harm reduction idea of like using stimulants? The meta-analysis actually, there was a large meta-analysis done for evaluating the effect sizes of the use of amphetamine as a substitution therapy for cocaine use disorders and methamphetamine use disorder. And overall, they basically, the conclusion is that there is some evidence of efficacy. So it cannot just be disregarded. They look at amphetamine, they did not look at methylphenidate. Methylphenidate has been shown to be effective only in individuals who have a stimulant use disorder with ADHD. But otherwise, you can see that it can actually trigger craving. From the perspective of the research that we have funded at NIDA, we've spent millions of dollars on clinical trials to evaluate different amphetamines like drugs for the treatment of cocaine use disorder predominantly. Where the signals are weak and where there is the possibility that there may be a signal, not only drugs that block or revert the dopamine transporter but also target the vesicular monoamine transporter, the VMAT transporter. And the problem there, because the data in the preclinical models is very solid with these VMAT transporter blockers, the problem that we have to bring it into the clinic has to do with side effects. But it is, an amphetamine has some effects at the VMAT. So some of the data actually do show that there is some efficacy for amphetamines. But it's a weak one, there's tremendous variability which in my brain probably suggests the fact that we have heterogeneous populations. I also would like to be able to look at that data, which of course we don't have, and assess its potential benefit with other outcomes. So like I was saying, one thing is that you have a positive urine, but these positive urines are not quantitative. You either have or do not have. But what about if that urine was able to show that you have a much lower content? That could actually have a protective effect because you are less likely to, for example, have a toxic effect. We don't have, and again, there's no, because they didn't look at these alternative outcomes, we really do not know if there was, where there are other positive effects, like improvement of cognitive function, which is likely to have been beneficial. Thank you. Ricardo Rios, I practice psychiatry in Virginia and in Maryland. Thank you for the presentation and thank you for the interventions of people here and that have educated us about this topic here and all the possibilities that we will have perhaps in addressing this problem. I was interested in asking you about in looking in upstream situations, prevention, will alleviate our work here as a strong aspect of it. What would you think that it would be appropriate to that? Yes, we didn't speak about prevention because we don't do much work on prevention in the clinical trial network, but it is clear that as a nation, we need to address prevention as a priority because we go from the opioid overdose crisis to now to the psychostimulant overdose crisis to that of drug combination crisis. And in terms of prevention interventions, certainly there's a lot of work that has been done on research showing evidence-based prevention intervention that significantly improve outcomes. And that goes from universal interventions to actually provide education to children, teenagers, families about drug use to personalized and targeted prevention interventions. And I always, as a psychiatry, I've always spoken up and say, you need to actually evaluate in every single patient that you have, that goes to you, whether it is a child, adolescent, or an adult, history of a substance use disorder. Because in an adolescent or even in a child, the early use of substances may be actually an early indication of an emerging mental illness. And if you do not treat it, that individual will continue taking drugs to auto-medicate. So it's a key component that we, in psychiatry, have the responsibility to actually screen. And if it is positive to do an intervention, commensurate where that individual is. If they are not experimenting but they are at high risk, then that's going to be, of course, very different from someone that's already regular user that's starting to have adverse consequences for their drug use. But we need to do it as part of our practice. Thank you. And as a curiosity, from the funds that NIDA has, what percentage is devoted to the upstream interventions? For prevention, I would say that probably our prevention research is like 25 to 30%. All right, thank you. Thank you. Nora? Yeah. Hello. My name's Patrick O'Neill. I'm here at Tulane. Dr. O'Brien was one of our graduates, actually. He was our Alumni of the Year about five years ago. Had the pleasure of meeting him. Wonderful guy. Do you guys have ever get approached by other parts of government? Because you and I both know that every opiate epidemic has been followed by a stimulant epidemic going back to the early, early 1900s. It's happened multiple times. And every time there's a, and murder rates go down during opiates. Murder rates go up during stimulants. And this is going to be a big crest. And it's already happening. But do you get approached by other parts of government to discuss this stuff? We basically work closely with different agencies in the government because we have to. Without it, we are not going to solve the problems that we're facing. And so one of our closest partners, of course, is SAMHSA because they provide with treatment and prevention. So it is crucial that we engage on providing with evidence-based intervention and we help them on implementation of those models. We work also very, very closely with HRSA because actually, if we develop treatment, we want to ensure that these treatments are basically reimbursed for those practitioners because otherwise they are not going to be used. We work with the DEA because they basically have the regulations of how can we or not do research, what are the requirements to do research with schedule one substances. We work with the FDA because we can do all of the research showing that an intervention has positive efficacy. If it's not approved by the FDA, then it will not be reimbursed. So we work with multiple, multiple agencies and it's coordinated through the HHS. We are the science agency. All right, thank you. Thank you everyone for hanging in there and such a very stimulating conversation. So we are at the end of the session. Thank you again for participating. Thank you. Thank you.

methamphetamine use disorder

research updates

interventions

methamphetamine use

overdose deaths

naltrexone

bupropion

transcranial magnetic stimulation

ketamine

depression

substance use disorders

glutamate neurotransmission