Welcome to the last event of the day in the paper session. We will be showing five 10 minute paper presentations. And then we'll have 10 minutes at the end for a general q amp a, please submit your questions to the q amp a box. And please indicate which presenter, you'd like your question to go to. So, with that, we will begin with, I believe Kevin shoe presenting Association of be appropriate on now track zone and opioid agonist treatment and stimulant related events in opiate opioid use disorder, a case crossover analysis. Thank you. I'm a fourth year research track resident, and incoming instructor in psychiatry here at Wash U, working with Laura by route, and today I'm going to be talking with you all about pharmacotherapy for stimulant use in people with opioid use disorder. I have no relevant disclosures. My research objectives are to one, discuss promising medications for treatment of problematic stimulant use in OED, and to show the power of big data to examine important questions efficiently that are hard to study via clinical trials in addictions. So, you know, as we know, a stimulant uses really search and reason years, and there's no FDA approved pharmacotherapies for this, but there's been some really hopeful and exciting development right, you know, with Dr. trial, you know, we found that the be pro P on and now track zone extended release combination corresponded with significant reductions met methamphetamine use, compared to placebo, and this is really hopeful news because, you know, we really haven't had a lot of promising pharmacologic agents for stimulant use disorders in randomized control trials, but a limitation of this study is that it really focused on folks with just amphetamine use disorder, and people with OED were not included. And, you know, despite these really promising findings that were found, you know, there's still some limitations and generalizability as a substantial proportion of patients with stimulant use also misuse opioids, and you can't just give them now track zone, as that would precipitate withdrawal people are actively using. So, as you can see in this paper in addiction, people with stimulants, and are also using opioids, they do worse mortality wise than stimulants alone. And we were curious about you know how the now track zone and be pro P on combination would fare in people who are using opioids and stimulants. These folks that weren't in the New England Journal of Medicine paper. So, ultimately, you know, this leads us to our research question right. You know, does this be pro P on and now tracks on extended release finding generalized to people with opioid and stimulant co use, and it's, you know, pretty hard to recruit folks with OED and just clinical trials looking at treatments for stimulant use. So we're curious right, could we use real world observational data to study this. So I'm going to explain our study design right now, just to rehash, you know, with the New England Journal of Medicine paper, Dr. looking at people with amphetamine use, and whether the pro P on and now tracks on extended release corresponded to negative urine drug tests. On the other hand, with our paper, we use observational design with insurance claims, big data to look at patients with stimulant use and opioid use disorder. So we were pulling from ICD codes pharmacy claims insurance billing, and our aim ultimately was to assess the relationship between days when people were taking be pro P on and now track zone, and their risk of developing hospitalizations or emergency room admissions for stimulant related acute events. And instead of just looking at the pro P on and now track zone. We also included opioid agonists right we were looking at, you know, buprenorphine and methadone as well. And my rationale for doing this was twofold. One of them is that you know preclinical and small cohort studies have shown reductions in stimulant use associated with opioid agonists, possibly owing to decrease cravings, but number two, it's also because you know antagonists like now track zone can precipitate withdrawal and people actively using opioids, and we also include SSRIs as an active comparator, and we sought to compare these treatments to the incidence of stimulant related acute events spanning hospitalizations for overdose accidents and psychosis. And our analysis ultimately span 51,000 people over 10 years of data and IBM market scan all of these folks had one at least one stimulant related acute events. So we're talking about a pretty high risk population here. And I want to emphasize, you know, that administrative claims can be really helpful for studying this type of question for two reasons. Number one is efficiency clinical trials can take quite a bit of time. And, you know, with the escalation and folks who are struggling with stimulant use these days. We wanted to quickly see if the results of the DAP-2 trial hold true in the real world. And number two, though, is also real world findings generalizability, right, we're talking about a broader sample of folks outside of a controlled clinical environment people with polysubstance use disorders who might not make it into the clinical trial. So the name of our study design, it's called a case crossover design, which I know might not be familiar to everyone here so I'm going to try to explain it in simple terms. So to mitigate selection bias and confounding case crossover design uses within person comparisons so you know this graphic here showing you know period of time, all within one person so you know you see a day when someone took bupropion, we tried to see if you know people experienced hospitalizations for stimulant use, while they were on bupropion, but within the same individual, right, we were looking at days when they were off bupropion, and we tried to see if they also had hospitalizations during this period. And you know, keep in mind, all of this is within the same person so you're controlling for the same, you know, it's all within the same person so it's the same race, the same age, the same comorbidities. And ultimately, right, we can use this to look at the relationship between hospitalizations for stimulant use, and the use of other medications right like buprenorphine, or whether people are using naltrexone right, are there hospitalizations associated with days when people are on and off naltrexone extended release, and the same goes for methadone, you really get the point. So, to turn this into an example and make our study design even clearer. Let's look at this graphic here. So ultimately, you know, all this is a period of time within one individual on the arrows here represent days of hospitalization for a stimulant related event. The shaded boxes are days when a person is taking medication, and there's no admission after associated with the medication use, whereas the shaded boxes are days when someone is taking medication, and it's associated with a hospitalization. This is all within one individual from period of time 2006 to 2016, this person had five admissions for stimulant use in this hypothetical example, I'm making up two in 2011, two in 2013 and one in 2014. So to select our observation period in this study, we ultimately picked a period of time of one year before and after the first admission, during which we counted the number of admissions people have, and we saw whether these admissions were associated with people taking buprenorphine, whether they were associated with people taking naltrexone, bupropion, etc. And we ultimately were able to make comparisons about the risk of each medication being associated with stimulant related hospitalization risk within the same individual. All right, so onto the data. So if we look at our sample, we ultimately had 51,000 folks with OUD, all of whom had problematic stimulant use with at least one stimulant related admission during the first year before and after the first admission. And, you know, during this period of time, we see that around 13% got bupropion, a third got SSRIs, a third got buprenorphine, we see quite a bit less methadone and naltrexone in comparison. In terms of demographics, we're seeing, you know, about half of folks were on Medicaid, half were female, the ages were pretty young around the 30s, and most folks are white. All right, so this is the money figure. Let's dive into the data. So this is ultimately a forest plot that is showing the odds of hospitalization for stimulant related events associated with days of medication treatments. So let me show you how to read the plot over here. So an odds ratio of one would be suggestive of no effect on the risk of stimulant related events. So an odds ratio of 0.8 would suggest, you know, a 20% decrease in the risk of hospitalization for stimulant related events. An odds ratio of 0.4, right, that's like a 60% reduction in the odds of, you know, stimulant related events. And as we can see here, right, a day when an individual receives buprenorphine is associated with an almost 30% decrease in the risk of stimulant related events compared to a day when the same individual is not on medication. For methadone, we're talking about a 40% reduction in risk. For naltrexone, we're talking about a 35% reduction in risk. And if you're looking at bupropion and SSRIs, the reduction in risk of hospitalization for stimulant related events is a bit more modest, about 20% and 10%. And you can see that these effects are sustained in secondary analyses stratifying by stimulant type, whether they're cocaine related events or amphetamine related events. So, you know, despite these results, right, I still want to really jump into some of the limitations we have to consider. You know, one of them is case crossover design can be helpful in mitigating selection bias, but it does not eliminate selection bias. And it also does not eliminate confounding by indication, although it plays a role mitigating it. The second point is generalizability, right? Half of these folks are on commercial insurance, they're young, they're mostly white, they're few people of color, and that does not generalize to the, you know, the real world population necessarily of people who struggle with OUD and are also struggling with stimulant use. And finally, you know, insurance claims are messy. There's always a risk of misclassification just because you're filling your medication does not ultimately mean you're taking it. So I want to just, you know, conclude, in summary, I think we have some pretty promising data overall, but there's some take home points, whereas Dr. Trivedi's trial was really awesome news showing that naltrexone and bupropion can be helpful for stimulant use. We extend the literature base further by showing that for people with opioid use disorder, actively using opioids who might not tolerate naltrexone induction, buprenorphine and opioid agonists may be promising treatments in terms of reducing a stimulant related adverse events. But last but not least, our results ultimately support the Trivedi RCT, illustrating the power of big data to examine important questions that are difficult to study in clinical trials. And with that being said, thank my team for this really complicated analysis, and I thank you for your time. Happy to take questions in the end. Thank you so much, Dr. Hsu. You really did make something complicated very comprehensible. Our next paper is by Tai Wu Park, Trends in Adult ADHD Diagnosis and Treatment in Patients with Opioid Use Disorder in the United States. Thank you. This is a somewhat related study, though not exactly. This is about trends in adult ADHD diagnosis and treatment in people with opioid use disorder, actually using the same data set as Dr. Hsu just spoke about, the market scan database. I have no relevant disclosures to present. The objectives of this talk are to describe the prevalence and trends in ADHD diagnosis and treatment among people with opioid use disorder, as well as to describe the prevalence and trends of ADHD treatment among people who are receiving medications for opioid use disorder. And then we also looked at relationships between patient characteristics and receipt of ADHD treatment among people who receive medications for opioid use disorder. Just very quickly, some background. ADHD is very common in people with substance use disorders. One meta-analysis put it at about a quarter of people with substance use disorders. And having ADHD in substance use disorders is associated with earlier onset of SVD, greater impairment, a longer course, and lower treatment retention. And treatment of ADHD among people with addiction may reduce ADHD symptoms and improve SVD outcomes at higher prescription stimulant doses and is associated with improved short and long-term SVD treatment retention. This is just from a recent CDC data that show that, you know, there's a lot of co-involvement in recent opioid overdoses in terms of other drugs like stimulants. And two of the second from the top line, the last line are cocaine and psychostimulants with abuse potential. So there is this potential risk of combining these medications. So the research questions we set about asking with this study are, among patients with OUD, what are the prevalence and trends of ADHD diagnosis and ADHD treatment? And then among people receiving medications for OUD, what are the prevalence and trends of ADHD medication treatment? And what, if any, patient characteristics are associated with the receipt of prescription stimulants among people receiving methadone, buprenorphine, or naltrexone? So just the studies designed in population, we actually did two analyses. One was a serial cross-sectional study. This is the prevalence and trends parts of this, looking at years 2017 to 2017, 2007 to 2017, ages 13 to 64. And to be included, you had to be continuously enrolled for at least six months in a calendar year. All of these patients had opioid use disorder. And similarly, with the retrospective cohort study, same study period, slightly older. And then, again, enrolled for six months in a calendar year and having opioid use disorder. And in the retrospective cohort study, we're only looking at people who are receiving medications for opioid use disorder. Again, we were looking, we were using the market scan database for this study. And this, this is a, as Dr. Xu was talking about, this is a people with private employer-sponsored insurance independence includes encounter level data, which includes diagnosis and procedures. And these encounters are inpatient, outpatient, as well as pharmacy data. So the outcomes we were looking at for the cross-sectional study, we were looking at ADHD diagnosis, which we defined as at least two ADHD inpatient or outpatient diagnoses during the study period. And then ADHD medication receipt, we looked at all of the prescription stimulants, as well as adamoxetine. And then for the cohort study, our outcome was concurrence prescription stimulant receipt, which we defined as having a stimulant prescribed less than or equal to 30 days of receipt of medication for opioid use disorder. And for that cohort study, we looked at the independent variables, age, sex, region, as well as psychiatric diagnosis. For analysis for the cross-sectional study, we were calculating proportions of people with an ADHD diagnosis and receipt of ADHD medication treatment in people with OED in each calendar year. And then we calculate, we also calculated the portion with receipt of ADHD medication treatment in those people. And then for the cohort study, we did a bivariate analysis where we compared patient characteristics between those who received stimulants and those who did not. And then we ran a logistic regression model, testing association between those characteristics and receipt of ADHD medication treatment. And so what we found was, and this is the prevalence of ADHD among people with OED. We found that between 2007 and 2017, that proportion or that prevalence went up more than three times, from a little over 4% to more than 14% of people with OED. And then this is the prevalence of ADHD medication treatment among people with OED. And that top line is the total, the triangle, the next line is stimulant prescription. And then the last, the lowest line is non-stimulant or ademositine, essentially. And we found that the numbers, the prevalence of treatment, proportion of people with OED who are getting ADHD medication is going up slightly over time. But it is, I think, interesting that, you know, a fair, about half of the people who with ADHD are getting treatment, and that is mostly stimulant medications. And then this is the prevalence of concurrent stimulant prescription in MOUD treatment, and this number is also going up. Not surprisingly, these are people who are receiving MOUD, and the proportion of people who are getting concurrent stimulants is going up about four times over the 10-year period. This is just showing, we looked at people with stimulant receipt and people who didn't receive stimulants among people who are getting medications for opioid use disorder. And we found that generally speaking, the proportions of people who are getting stimulants are younger, female. And then the regions, there is some differences in terms of regions. If you have a psychiatric diagnosis, not surprisingly, you're more likely to get treatment with a stimulant. And in terms of associations, this is our odds ratios here. We found that the older you get, the less likely you are to get a stimulant. Females are more likely to get a stimulant than males. Areas such as the South are more likely. The West is less likely. And then not surprisingly, having ADHD, it increases your odds of getting a stimulant. But also other psychiatric disorders are more likely to get stimulants. Although if you have a substance use disorder or stimulant, you're less likely to get a stimulant. So limitations, this is the privately insured and their dependence only. Very few patients in the database receive methadone. It's not very easy to track people who were receiving methadone maintenance treatment. And there were a few patient characteristics available. And it only records, this database only records care when insurance claims are submitted. So in conclusion, ADHD diagnosis and treatment in patients with OED has grown considerably between 2007 and 2017. About half of patients are getting a prescription stimulant of those who are also receiving MOUD. Prescription stimulant treatment is similarly grown in patients who are receiving MOUD. And we believe that further work on the risks and benefits of stimulant treatment of co-occurring ADHD and OED is needed. Thank you to my collaborators and thank you very much for listening. Thank you very much. Our next presenter is not here. So I think that's, I'm going to be, I'm sorry for the first two presenters. I'm going to be a little less strict. You don't have to stress quite as much to stay within 10 minutes. If you do 11 minutes, that'll be okay. And that'll also give us more time for questions. So our fourth presenter is Shakivia Johnson and she's going to speak on the impact of contingency management on adherence to extended release naltrexone. So again, I'm Shakivia and today we'll be talking about the impact of contingency management on adherence to extended release naltrexone. And this is a project that I did in addiction psychiatry fellowship at UCSF and the San Francisco VA with institutional mentor, Dr. Michael Hofer. And currently I'm an addiction psychiatrist at Boston Medical Center where I'm director of maternal child mental health. And so the only disclosure that we have is that this project was supported in part by the research and addiction medicine scholars program, the RAMS program through Boston University. And so our educational objectives are to identify limitations of naltrexone for the treatments of alcohol use disorder and opiate use disorder, understand the concept of prior space contingency management, describe how to use contingency management, how the use of contingency management impacts adherence to extended release naltrexone. And we'll just go through a little bit about the background on what we did and what we learned. And so when I first started the fellowship, I noticed that we had a very high no-show rate for the naltrexone clinics, anywhere from 10 to 30% of people per naltrexone injection clinic would show that was to me was just outstanding. And so I wanted to learn more about extended release naltrexone, its use and administration. A lot of patients complained about getting the injection or having injection site reactions or just having discomfort. I wanted to learn more about the efficacy of naltrexone to which it's pretty efficacious as long as people take it. And even in my clinical experience, people seem to do very well on the injections and a lot of times it would relapse when they discontinued them. And I also wanted to know more about why patients didn't choose naltrexone or what the barriers to treatment were and what modalities we can use to engage and retain patients in our naltrexone injection clinic. And so here's just a nice depiction of the adherence rates to the extended release naltrexone in general. Most people drop out by the third month. And here we can see on here, they started month zero, but by month three, more than 50% of participants are no longer receiving the injections. And so I've learned a little bit about contingency management through the fellowship. And we also had a program for using contingency management for amphetamine use disorder. And so I just wanted to do some investigation and learning about what we could do about improving adherence to the extended release naltrexone. And so in my review of the literature, I found studies that used voucher-based and hourly rate wage incentives for people using oral naltrexone. And that was shown to improve overall adherence rates and also improve the total number of doses of naltrexone that the participants took and also ultimately reduced their overall alcohol and opiate use. I did not see anything about using contingency management for improving extended release naltrexone adherence. And so for our study, we just wanted to do a small pilot study to see if we could increase adherence and improve retention and treatment of our patients with opiate use disorder and alcohol use disorder with extended release naltrexone. And I wanted to determine the impact of voucher-based incentives on clinic retention and adherence. And so our primary outcome was adherence to extended release naltrexone. And my thought was that incentives via contingency management would increase adherence to monthly naltrexone injections and also increase group participation and increase negative hearing toxicology. And so for our study, we had 25 veterans that we included with either opiate use disorder and or alcohol use disorder with the vast majority being alcohol use disorder, but I wanted to offer this program and incentives to anyone that it could potentially be helpful to. There's a lot of back and forth about that at the drawing board, but ultimately I wanted it to be inclusive. And then we would just see what happened with that. Also, we included patients who were currently on naltrexone, who were new to naltrexone injections, and also even those who had had naltrexone injections in the past. And so those who were better suited for methadone or buprenorphine were not selected or even offered participation. And so our exclusion criteria included those who had high likelihood of incarceration, court mandated treatment, intellectual disability or cognitive impairments, any allergy or contraindication or intolerance to naltrexone, any active severe mental health issues and those who needed or were planning or preemptively needing opiate pain management. And so what we did for our contingency management portion, we used voucher-based incentives. And so patients would draw four slips from a bowl for each injection, and that would accumulate to a max of 16 draws for injections. So for month one, they would get four draws. For month two, eight draws. For month three, 12 draws. And then month four, 16 draws. And so it would continue if they even went for six months, 12 months, whatever, the max number of draws for injections were 16. If they missed an injection, the number of injections would return back to four and start from there. And so each contingency management session was monthly, and participants also received two bonus draws for group attendance and two bonus draws for having a negative opiate screen on your drug screen and also having a negative blood alcohol level. Some people may wonder why we included negative BALs, but it was not uncommon for patients to show up in our clinic with positive BALs. And we also had the daily methadone and buprenorphine dosing. And so it was not uncommon. Even patients would show up for their naltrexone injections intoxicated. And so we appreciated their engagement and met them where they were. And so for our prize bowl, we had 63 slips of words of encouragement, like good job, you can do it, we're rooting for you. And 136 slips worth $2 each, 50 slips worth $20 each, and then one jumbo slip worth $200 each. And these were for vouchers that were redeemable at the VA store, the canteen, the Patriot store at the VA. And so with our experiences with recruitment, we assessed and invited 27 participants to participate in this project, and two were excluded. One had court-mandated treatments and another one declined. And so 25 initiated the protocol with the contingency management. And so our most notable finding was adherence. And so at the second session, 72% of people received the second injection, 56% received the third injection, and 56% received the fourth injection. And if you'll recall, more than 50% of people usually drop out after the third injection. And then as far as the contingency management piece, there were an average number of five for receiving five consecutive injections. That was the average. There were a lot of people who received an injection, may have missed one, restarted. So that happens to several other people, but the average number of consecutive injections were five, but ultimately there were a lot more injections received overall. And the average number of prize bowl draws per injection was 15, and the average voucher amount awarded was about $80, but it ranged from 10 to 364. And out of the 25 participants, only seven of them received one injection. And I also noted that group psychotherapy attendance increased along with the contingency management participation. People who were not attending groups before, or once they learned that there were two bonus draws for attending a group, along with participating in the naltrexone clinic, most, if not all people, worked really hard at attending a group. And so the primary conclusion was that prize-based contingency management feasibly increased the adherence to extended release naltrexone in patient retention. And also a second part of this study, which I didn't include actual commentary about, was if this was even feasible to do. And I would just want to mention that the use of this contingency management enhanced engagement and care for both patients and clinicians. The nurses, myself, everyone involved, was super excited when it was time for patients to draw from the fishbowl. Like they just couldn't wait to see what they were going to get and talk about what they were going to buy from the Patriot store. Even one person wanted to buy a stereo, wanted to save his voucher so that he could do that. So that part was the most exciting and most engaging and allowed for a connection to develop with patients that other clinical settings didn't allow for. So to me, that was the most exciting, most impactful part of this project. And so my institutional PI, again, was Dr. Michael Hofer. And then my mentor through the RAMS program was Roger Weiss. And then also Steve Botkin and Ellen Herbst helped with this project at the VA. So thank you. Thank you so much. That was fantastic. Our final paper is by Albert Marius. Zonisamide reduces drinking in subjects with alcohol use disorder. Thank you, Albert. I'm Albert Marius. I'm Associate Professor of Psychiatry at Virginia Commonwealth University School of Medicine. I don't have any relevant financial disclosures that are related to this work. Everything I'm going to show you today was funded by the federal government. So today we're going to review and learn about the histories of Zonisamide as a potential treatment for AUD. We're going to learn about some recent study results from two studies and learn about the potential mechanism of action for the drug. Okay. So Zonisamide is proof that they are similar to pyruvate, meaning that they both have similar behavioral effects in humans. Also, Zonisamide is a cheap, widely available generic medication. Albert, are you, your microphone seems to be having some difficulty. Are you, is your hand over it or something? Let me hear it again. Yeah, we can hear you better now. Thank you. All right. So in addition to that, Zonisamide reduced drinking, similar to topiramate in rats. And it also reduced drinking compared to placebo in a small human laboratory study, which was an alcohol self-administration study. And so today there's been three placebo-controlled small studies that were pilot studies. The first of which was a pilot study that I did in 2010, a 12-week study with 40 people, 20 on the medicine, 20 on the placebo. And the medication was targeted, titrated over eight weeks to a target dose of 500 milligrams a day. And we found a significant reduction in drinks per week and heavy drinking days per week once the medication was titrated to the target dose. And then Knapp et al, 2015, it's a 12-week study, placebo-controlled randomized control trial, 20 on Zonisamide, 20 on placebo, 400 milligrams daily was the target dose. And they found significant effects on percent days, drinking percent days, heavy drinking and drinks consumed per day. And then this other study that Dr. Petrakis and our group that we did at the VA in veterans with AUD and PTSD, comorbid, where the medication and placebo were added to the cognitive processing therapy, that showed no additional benefit in medication. So that was a negative study. So how does it work? Well, it does a lot of things, but I think the most important things to note are that it essentially has indirect effects that facilitate GABAergic neurotransmission and also some indirect effects that block glutamatergic transmission. Kind of similar to opartamid, but not exactly the same. It does some unique things though. So it down-regulates GAT1 and it has reversible MAO-B inhibition. And clinically, so we think that this is going to help to stabilize and restore the brain of AUD patients, which have been allostatically modulated. So possibly it has effects on improving cognitive control or impulsivity. And we think from the previous studies though that it also reduces craving and it may reduce anxiety or things like that. So it's metabolized by the liver, largely extremely excreted. So half is the parent compound, half is metabolites. It has a really long half-life and it has really good bioavailability. Can dose it once a day easily with no problem. It doesn't induce the cytochrome P450 enzymes. So here's just kind of a general look at the typical side effects. Some sedation is pretty frequently noted. And other than that, some GI upset can be common. One thing to note is that it is a sulfa drug. So if you have an allergy to that, wouldn't want to take this. And there are some less common, but serious things that can occur like Stevens-Johnson syndrome, kidney stones, metabolic acidosis. All right, so here's the main event. So I'm just going to tell you about first, I'll tell you about two studies. And this was the main study for my R01. We did a large randomized placebo controlled trial of 159 civilians recruited from the community with alcohol use disorder. And they were titrated over seven weeks to a target dose of 500 milligrams a day of the medication. However, it was flexible dosing. So the patients could go all the way up to 600 if we thought it was helping and they were tolerating it. And as long as they could tolerate 200 milligrams a day, they were allowed to continue in the study. And in this study, we used a minimal behavioral component called medication management. And we did that to try to optimize the drug effect. And in a couple, in two of the three pilot studies that I showed you earlier, in one of them, everybody got CBT and then the other one everybody got CPT. So there was a lot of behavioral components of those. But we just wanted to isolate the drug effect here. And there were the primary outcomes. So the drinks per week or drinks per day, which is just a transformation of that, and that's focused on the last eight weeks. So after the medication has been titrated up to its target dose. And we also wanted to look at heavy drinking days per week, also focused on the last eight weeks. And people could enter the study if they had a goal of either cutting down or quitting, and no abstinence period was required. So they weren't required to say, you know, be abstinent for four days before they could start the medication, which is sometimes done in trials. So we just wanted to take people that would resemble, you know, the typical patient that you would see in a clinic. And I know this is a little tough to see, but so in general, the study was 37% women, 82% white, and there was no significant differences in the demographics. I think one unique thing about is that the sample had a lot of high earning individuals in it. And so there was a significant difference in early terminations or dropouts between medication placebo, with more in the medication group. However, only nine subjects noted that they dropped out due to medication intolerance. All right, so what did we find? Well, so there was a significant effect of the medication on the pre-specified primary outcome, average drinks per day, and the sample over the pre-specified last eight weeks of the trial. And so the placebo patients overall reported an average of 0.72 more drinks per day than zanisimide patients, which is a pretty small overall difference. But there was also a significant effect of sex and a sex by medication interaction effect, such that men had 43% fewer drinks in the last eight weeks when treated with zanisimide compared to placebo. And while, and there was no difference in women. So you can see that here, it's broken down by sex. And women, they drink less than men throughout the study. And you can see the difference in the last eight weeks here in the men, that's significant. And there's just nothing there in the women group. So there was also a significant interaction of medication by time on heavy drinking days per week, with the slope of the effect greater in the zanisimide group than the placebo group and the medication effect emerging after the first four weeks. So the main effect of the medication on heavy drinking days per week, comparing groups in the pre-specified last eight weeks, which is shown here, was marginally significant after Bonferroni correction. So it was significant at a level of 0.032. So if you Bonferroni correct that, it's not quite significant. So it's essentially superseded though, by the time interaction with the medication, which is significant after Bonferroni correction. And then finally, there was a trend for an interaction with sex on heavy drinking, with men experiencing a much greater reduction in the risk of heavy drinking with zanisimide compared to placebo than women. And again, you can see here, it's pretty obvious looking at it. There's a difference in the men and just no difference in the women at all. And so the overall odds ratio for reducing drinking on any given day in the last eight weeks of the study was 0.36. But for the men, it was 0.26 and the women 0.74. So to look and see if that was clinically significant. So we examined the correlation. Well, we wanted to do this without inflating alpha. So we examined the correlation of the endpoint short index of problems, which is a measure of psychosocial problems from alcohol. So we correlated that with endpoint cumulative drinking across all subjects. And the correlation was significant with a pretty large effect size. So just confirming that if you drank more in the study, you had more problems at the end of the study. And if you reduced your drinking, it came down. So the other thing, just looking at the size of the effect from the standpoint, so 43% reduction in drinks for the men after reaching the target dose and about one fourth odds of having a heavy drinking day on any given day compared to the placebo for the men, I think is clinically significant. However, it wasn't very helpful for women in the study. So I'll speed up a little bit here. So how does it work? So we also did this thing. It's called a daily process analysis. It's kind of like EMA, if you know what that is, EMA light. So we measure once a day, the patients made a call in and they gave some data about their mood, anxiety, stress, and impulsiveness in the late afternoon, early evening. And we were able to collect data separating the drinking into nighttime drinking and then daytime drinking. So we wanted to look at the effect of the affective measure in the late afternoon, early evening, and then how much they drank right after that in the evening. We used a multilevel modeling in M-plus and basically we found that there was pretty significant positive correlation between impulsiveness and craving that influenced nighttime drinking. And that's an SMI reduced craving and also reduced impulsivity in the trial. So we didn't find an effect on reducing stress, which we were thinking we're going to find, but it just wasn't there the way we did it. And so this might reduce craving significantly. And we were able to show that with a formal test of mediation and showed that it reduced the drinking by reducing the craving in part by reducing the craving. And that was significant. So, and then quickly, I just want to tell you about another, the other study that we did, the veteran study. So this was very similar, 16 weeks, same dose. The only things that were different were that they were seen more frequently by the study staff because we're concerned about safety because of the higher rates of psychiatric comorbidity. And also because of difficulty recruiting, we had to recruit a lot of times out of more intensive therapy settings like SATP, you know, day programs. So we found no significant difference on outcomes. There's a very high placebo response and many subjects did better regardless of whether they got the medication or placebo. And in general, it was fairly well tolerated. There were some severe adverse events. A couple of them turned out to be, a couple of the worst ones turned out to be on placebo. For the sake of time, I'm just going to, I'm just going to go ahead. So what's going on? Well, I think the medication is efficacious, but there does seem to be substantial heterogeneity in the response. We have one large positive trial suggesting a clinically significant effect, but only for men and not women. And one medium-sized negative trial now with a large placebo response. And I think what happened in that study is that there was a lot of concomitant care that they received probably washed out the medication effect. So I think this suggests that there's efficacy in having drinking out patients that want to cut down or quit. The question of whether it helps women remains, and there's one large trial that's ongoing right now at Washington State University. So that trial may help to sort of answer those questions. Its mechanism of action seems to be that it works by reducing craving primarily, but it also seems to reduce impulsiveness, which is a novel finding. And that's about all I've got to show you today, but I did want to take a moment and just thank and let everybody acknowledge the many, many people that helped and did a lot of hard work on these two studies, which went on over a little more than five years. So my mentors and co-investigators. And so Dr. Cobalt, site PI at UConn, University of Connecticut, Dr. Desai at the Bedford VA, Dr. Petrakis, et cetera, et cetera. You see all the names out there. I'm not going to read through them all, but so thanks to them. And- Thank you so much, Dr. Arias. I don't see a question for Dr. Hsu. Hopefully one will turn up while we're at, while we ask questions to the other presenters. Okay. So first question to Dr. Park, any speculation on, from Dr. Desai, any speculation on the reason for the rise in stimulant prescription, particularly among people with opiate use disorder? Yeah, that's a good question. This study wouldn't necessarily illuminate why we see this rise, but I think my best guess is that more and more people are getting identified with opioid use disorder. More and more people are getting into treatment. I mean, we obviously want more people to be getting into treatment, but it's possible that because more people are accessing treatment, ADHD, they're getting more assessments and ADHD is being identified at a higher proportion. I think that's the best guess. Another question to you was about what are your thoughts about prescribing stimulants and benzodiazepines in combination? I certainly have some patients on both, but I always feel a bit uneasy. Would it be important to distinguish between PRN benzo prescribing from daily benzo use? It seems we should be discussing this more given the work by CAST et al, supporting use of stimulants in SUD populations. Yeah, David, the uneasiness you feel is something that I feel as well, and I think a lot of other providers feel about co-prescribing these medications to people with opioid use disorder. That's because there's been a number of studies now that have shown that there is an increased risk of overdose combining benzodiazepines with opioid use disorder medications. A recent study that was just presented here at AAAP the other day found that there was an increased risk of overdose with prescription stimulant prescribing in people with opioid or I think buprenorphine. Then on top of that, there are some benefits in terms of treatment retention. Benzodiazepines and stimulants are now associated with increased treatment retention in people who are getting medications for opioid use disorder. There's benefits, there's risks. How those combine when it comes to benzos plus a prescriptive stimulant, it's hard to know. I think that it's safe to say though that some people are not going to do well on those combinations, and so you do have to be careful as a provider. Thank you. To Dr. Johnson, I see that you already answered David Hathaway's question about PEF instead of or in addition to BAL, and then I have a follow-up question about BAL. Okay, and I'll just respond verbally. We thought about PEF and other markers, and so we just didn't want to add an additional activity to our participants mainly because in our experience, even with obtaining urine drug screens, they were more easily obtained in our clinic than if we sent patients to the lab, and so that was the service we did provide. We would offer them the lab, but if they refused, we would offer in our clinic as well, and the nurses would just physically take the samples to the lab. We just decided just for this first goal that we would not offer those, but that was a great example again, Dr. Hathaway, of when we should use it and how it can help our patients demonstrate their success. I have a follow-up about that. You know how exciting to use contingency management for things other than stimulant use. What a great idea. Two practical questions. One is people often ask in terms of using contingency management, where does the money come from for the rewards? Part of it was there was some institutional vouchers that were donated to our clinic, like literally in a drawer, vouchers sitting there that we had to figure out how to use, so first we used those, and then secondly as a participant in the RAMS program, there was funding for projects, and so I used that funding as well. And it's wonderful to see how far a little bit can go. Okay, we have a couple of questions for Dr. Arias. Given a half-life of 63 hours, is less than daily dosing possible? That's interesting. You know, I suppose you could do that. You would probably want to load it up good first before you switch somebody over to less than once a day. I usually don't like to do that with anticonvulsants, but you probably could with this one anyways. And another question to you. This is related to the whole difference between males and females, and I had some follow-up questions about that actually, but this question was, were the pre-study craving levels similar in males versus females? You know, that's a great question, and I'm not sure off the top of my head, but you can bet I'm going to go back and look now. They might have been different, and so we've done some more work with this data. I didn't have time to show you everything today, and I don't want to spoil all of that, but one of the things we found in some of our follow-up work suggests that it really isn't sex that's dividing who responds and who doesn't. It's meeting some other variables, and craving was one of those things in that analysis, but I'm going to go back and look at and see what the baseline levels were exactly and look at it that way too, but I guess the main point of the stuff that we've done after this, the work we've done after this, is that probably there are women that will respond if they meet a certain profile, and it involves pharmacogenomics and then just regular measures like measures of craving, so I'll present that at another time. A follow-up question I had for you that wasn't so clear. Were one of the differences between men and women just quantity of use? Was it a question of high quantity users versus low quantity users in terms of how many drinks per day, that high quantity users responded more to the intervention than low quantity users? Yeah, and yes, and it looked like that, and so that's one of the things that confounds, is it really a difference between men and women? Is it some neurobiological sex difference, or is it just that the women that we recruited for whatever reason weren't as heavy drinkers, and so we can't tell the difference, but yeah, you're right, it did look like that. Their baseline drinking wasn't as heavy in amount and heavy drinking days. Finally, in our two minutes remaining, I'll take one for closing comments, but Dr. Xu, there weren't questions for you, and I think that's because your presentation was so comprehensive and answered so many questions, but because we were still keeping to 10 minutes when you gave your presentation, is there anything that you'd like to add or that you think would be important for us to know that you didn't have time to address? No, I think if folks have questions, feel free to shoot me an email. We are in the process of revising some of the data for a manuscript, so hopefully it will be out fairly soon. Okay, that's great. Well, anyway, that brings us to the end of our conference, the end of this year's annual meeting. Thank you for joining us, and please remember that all sessions are being recorded, and the recordings will be made available after the holidays, and we'll notify you via email when they become available. Continuing education credits will be sent via email at the end of the conference, and you must complete the evaluation by February 1st to claim your credits, and to learn more about CE credits, visit the virtual conference lobby, and there was one question asking, will this chat be available after the meeting? Oh, will the virtual lobby remain accessible after the meeting? John White, do you have an answer to that question? Yes, ma'am, the virtual lobby will be available for at least 30 days as continuing education is made available, but it can be made available for up to 90 days. All right, that's fantastic. Okay, that's a wrap. See you all next year in Naples, live or hybrid. you

presentations

naltrexone

contingency management

zonazimide

alcohol consumption

adherence

treatment response

substance use disorders

effective treatment approaches