616- ADHD Treatment and Substance Use Problems: The Latest Research on Stimulants & SUD

0:00Brian D'Onofrio, Ph.D.: From kickoff to the final whistle, trade the biggest moments in football on Kalshi, America's number one prediction market platform. Green Bay is currently trading at 42 % to beat Dallas, meaning a$100 trade pays out$228 if they win. Download Kalshi. Use code HOOPS to get$25 when you trade$25. K-A-L-S-H-I. Kalshi. Trade what's next. 18 plus only restrictions and eligibility requirements apply. Event contract trading involves risk and may not be suitable for all investors. Kaoshi products are not available in all jurisdictions. Prices, values, and available markets may differ from those mentioned.

0:34Brian D'Onofrio, Ph.D.: For more information, see kaoshi.com slash regulatory.

0:40Brian D'Onofrio, Ph.D.: Welcome to the Attention Deficit Disorder Expert Podcast Series by Attitude Magazine.

0:50Brooke S.G. Molina, Ph.D.: Hi everyone, I'm Carol Fleck and on behalf of the Attitude team, I'm delighted to welcome you to today's ADHD expert's presentation titled ADHD Treatment and Substance Use Problems, the latest research on stimulants and SUD. Leading today's presentation is Dr. Brooke Molina and Dr. Brian D 'Onofrio. Dr. Molina is a professor of psychiatry, psychology, pediatrics, and clinical and translational science at the University of Pittsburgh. She is also the president of the American Professional Society for ADHD and Related Disorders. Dr. Molina has been studying ADHD and substance use disorder throughout her career.

1:35Brooke S.G. Molina, Ph.D.: She serves on multiple journal editorial boards and on the National Institutes of Health review panels. Dr. Brian D 'Onofrio is a professor in the Department of Psychological and Brain Sciences at Indiana University. His research seeks to understand the causes and treatment of mental health and substance use problems across the lifespan. Recently, Attitude has devoted considerable attention to the association between ADHD and inflammatory disorders. We've just created a survey, which we hope you'll participate in, to help us better understand how these disorders, from allergies to POTS to hypermobility to connective tissue disorders, affect everyday functioning and whether they influence ADHD symptoms or treatment.

2:27Brooke S.G. Molina, Ph.D.: So without further ado, I'm so pleased to welcome Dr. Brooke Molina and Dr. Brian Donofrio. Thank you both for joining us and leading this important discussion.

2:41Brooke S.G. Molina, Ph.D.: Hi, everyone. Happy to be with you. I enjoyed reading all of the questions and comments that were sent by so many of you. Thank you for that. It gave me a sense of what was in your head. Some of those will be germane to the presentation that we're doing today. Some of them we might not be able to get to because they're a little kind of different from the topics that we're discussing. Somebody did specifically ask about whether we had any conflicts of interest, and it is standard for us to share that information. My research funding is all from federal National Institutes of Health and foundation funding.

3:19Brooke S.G. Molina, Ph.D.: I do not directly receive any funding from industry, from pharmaceutical companies. So there were quite a few of you who asked about pathways to substance use and substance use disorder. The why. The why do people with ADHD seem to have an elevated risk for substance use and for heavier levels of substance use and substance use disorder? And like with many human behaviors, there isn't one answer. there are quite a few different answers. And you'll see that that also has implications for what we do about it. So these six different blue bullets give you the general domains that we research as being the potential contributing reasons.

4:17So family effects.

4:19Brooke S.G. Molina, Ph.D.: We do know that within families, when there is ADHD, there is an increased likelihood that there is also a substance use or substance use disorder in the background of that family as well, and vice versa. There's a little bit of background noise. I don't know if there's something that needs to be muted. There is something that's really, really important that I also saw this in people's comments, there's variation in the way that people with ADHD respond to drugs and things that are potentially rewarding. So when you think about what motivates you or what feels rewarding, we all are somewhat different in that, right?

5:05Brooke S.G. Molina, Ph.D.: But we also know that people with ADHD, on average, have an altered sense of reward. And this does go back to the dopamine differences in the brain that engage or that are part and parcel of the reward system in the brain. So because of that, people with ADHD, we believe, have just an elevated likelihood of being susceptible to things that are especially immediately rewarding, be they, we were talking before the call started, be it ice cream, be it drugs that give you a big hit quickly, like alcohol if you drink a lot, or caffeine, or any kind of substance that has a potential feel-good aspect to it.

6:02Brooke S.G. Molina, Ph.D.: Temperament and personality, especially impulsivity. These are These are elements of human characteristics. You know, the idea of the apple doesn't fall far from the tree. We talk about people being shy or not shy or kind of generally kind of a nervous Nellie or not or outgoing. These are all aspects of personality. Temperament is the components of that that we see earliest at a young age that tends to kind of develop over time. elements of temperament and personality we've studied in the research literature for a very long time as being important for having vulnerability to substance use disorder and impulsivity is the biggest one that shows up again and again and again and as we all know most people not everybody but let's say many many people with adhd struggle with inhibitory control stopping yourself when you know you should be stopping yourself or just acting without thinking, the impulsive part of it.

7:11Brooke S.G. Molina, Ph.D.: Persistence of ADHD symptoms. That is something that we have shown is related. So the more your symptoms are persisting and not being managed, we know that that's important. People with ADHD have a hard time translating knowledge into action. This is really critical. It's not that people with ADHD don't know. They know. They know a lot. Many of them know way more than we know in particular areas, you know, and I'm often educated by even your questions that I read. And knowing isn't the same as doing. And that's where it breaks for people with ADHD. And that is really important for clinicians to be aware of.

7:54Brooke S.G. Molina, Ph.D.: You can't just take a standard treatment developed for something like PTSD or substance use disorder and drop it on a person with ADHD. It needs to consider the particular issues that go along with ADHD. Life problems. ADHD symptoms cause all kinds of life problems and those things like behavior problems, which we see more often in children, academic occupational, social functioning difficulties, those things are also substance use risk factors. There's your big answer. Lots of reasons we're researching all of these and have found support in one way or another for most of this. This is one study that we published.

8:37Brooke S.G. Molina, Ph.D.: I won't spend a long time on it. It just basically shows from the Pittsburgh ADHD longitudinal study where I work. We've been following children who were diagnosed with ADHD. You can see that in the first vertical bar. There were quite a few of them. You can see in the numbers at the bottom right. We have been following them for decades now. They're currently in their 40s. But in this particular paper, I'm showing you that when we measured whether or not they had ADHD in childhood and we followed them to an average age of 25, which is the middle bar, we found that on average, children with ADHD had lower levels of educational attainment, social difficulties, and of course, this was the persisting ADHD symptoms.

9:25Brooke S.G. Molina, Ph.D.: And those in turn predicted alcohol problems at a mean age of 29. So this is the point here is that not just ADHD symptoms, but also functioning. So when we're treating and intervening with people who have ADHD, medication is not going to be the only answer. It's an important part of the set of tools for helping people with ADHD. It's not everything because it doesn't necessarily always solve the problems that people have in their other areas of their life. Now, do stimulants increase risk of substance use disorder later? you all many of you were asking that question and that's the primary target of this talk today we've been asking this question for a long time and that's the point of this slide this goes back to 1998 and that's the only point we've been asking it for a long time it's a hard question to answer you'll see why i'm going to talk about clinical sample studies so what are they These are samples like the Pittsburgh ADHD longitudinal study, like a study that I'm going to tell you about called the MTA, Multimodal Treatment of Childhood ADHD, MTA.

10:44Brooke S.G. Molina, Ph.D.: These are samples where children were diagnosed in childhood with ADHD and followed up over time. This is different from the kind of study that Dr. D 'Onofrio is going to talk about. So that's what you're going to be hearing from us today is about clinical samples. Those are children who were diagnosed and followed over time. I mean, adults can be diagnosed too and can be a clinical sample, but I'm going to be principally talking about the childhood diagnosed clinical samples of individuals with ADHD. And I'm going to be talking about following them up over time. And what does that show us? We're going to be looking at, does stimulant treatment in childhood and adolescence predict later substance use or substance use disorder.

11:29Brooke S.G. Molina, Ph.D.: And that's going to be the focus of this, the slides that I present to you. So those of you who are asking the question, if I treat my child or my adolescent with stimulant medication, is that going to turn them into somebody who has troubles with substance use later in their life? That's the question that's being addressed.

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12:32Brooke S.G. Molina, Ph.D.: And it's important to understand the differences, okay? The studies that have been conducted have used rigorous research methods to diagnose those kids. So those are the ones that I'm talking about. So we know that they were very carefully diagnosed. That's a benefit of clinical samples. The kids were carefully diagnosed. Most of them were in childhood for these studies, some of them in adolescence. In clinical samples like this, we have a lot of information about these individuals because we interview them extensively and follow them over quite a long period of time. In the study you're hearing about, we follow them all the way into early adulthood.

13:15Brooke S.G. Molina, Ph.D.: we measure not just whether somebody had a disorder from substance use which is typically you hear this as abuse and dependence but we also measure their use so how frequently do you drink alcohol when you drink alcohol how much do you have this is really important because not everybody who drinks heavily will tell you that they're having problems and sometimes those problems don't show up until later, but the heavier or younger levels of substance use were important to measure. Otherwise, we miss it if we don't get at those things. So we really tried to do that.

13:58Brooke S.G. Molina, Ph.D.: As I mentioned, it's really hard to study this question. And why is that? It's because when we look at the connection between two variables like stimulant medication and substance use, there are other things that could be causing a connection between those two variables. We call those confounders, confounding variables. Here's an example. You could ask a similar question. Does drinking coffee lead to later heart disease? You might measure that in studies and show a connection. Oh my gosh, drinking too much coffee causes heart disease because they're correlated. But if you actually also measure how often those people smoked cigarettes and you put that into the analyses, that association, as you can see by the little circled X at the bottom, goes away.

15:00Brooke S.G. Molina, Ph.D.: So in this case, smoking is the confounder. It's really important to understand that. And as we know, correlation between two variables doesn't always mean that those things are causal, that one is causing the other. So what might be potential confounders when we're looking at the association between ADHD medication treatment and substance use? There's a whole bunch of things. Kids who are more severe are more likely to be treated younger and longer. In a family where children are being treated, there might be more likely to have parents who also have mental health difficulties. There might be a tendency in that family or by those parents to get more help-seeking, and help-seeking can also predict the likelihood of picking up on substance use problems later, not the stimulant treatment that might be causing it, but actually just the tendency to go, I think my kid has a drug use problem.

15:57Brooke S.G. Molina, Ph.D.: Can you please look at this? Family involvement and monitoring other resources like education, income, all these things, these are all things that are important to consider.

16:11Brooke S.G. Molina, Ph.D.: These are the studies that have been done so far. And across all of these studies, There are about 200 children, 2 ,000 children who've been followed. And there are a few things that I want to point out here. The Ps on the left side are the ones that suggest protective effects of stimulant medication, meaning when children are treated, they are less likely to use substances in a worrisome way or have problems from it. The Ns are the ones that show no association. There's one study that showed an adverse association, and frankly, that study tends to be fairly readily dismissed in the literature because it was less rigorous in its diagnoses of the kids.

16:56Brooke S.G. Molina, Ph.D.: It's pretty old. It was done before our current diagnostic methods were in place, and it wasn't replicated. You can see that there's a mix. This is one of the reasons why we keep studying this question, because there's a mix of findings. There also was a lot of variability in the extent to which they took the confounders into account. So this study that I'm going to tell you about was able to look at the confounders. So this is the MTA. It was a multi-site study. You can see the names of the universities at the top of the slide. 579 children were randomly assigned to four different treatment types at six different universities and you can see what the sample looked like reflecting the time this was in the early 1990s this is who was showing up for care so it was mostly boys and they were mostly white Although for the time, this still had quite a few people who were of other racial identities and ethnic identities, which was great, and 20 % girls, which was really quite unusual at the time.

18:19Brooke S.G. Molina, Ph.D.: This is how we followed them over time. We assessed them at baseline. You can see on the top left there, baseline 7 to 9.9 years old. We treated them for a little over a year, one of the four different treatment arms. And then we followed them all the way to 16 years later when they were on average in the top blue box there, 24.7 years of age. So 476 of them lasted through the whole study who had ADHD. And then we had another group, the LNCG, sorry for the long words, but that's what they got called. So they were a comparison group recruited from the kids' classrooms. we measured their stimulant treatment over the full 16 years.

19:06Brooke S.G. Molina, Ph.D.: We measured substance use. So heavy drinking, marijuana use, cigarette smoking, other substance use. And we had two main questions. Does medication in each year that we followed them or in the last year. So what if you were treated last year or the combination of those two things, you were treated last year, but you stopped, you weren't treated last year, but you started this year. What if you're treated both years? Does that relate to substance use at each of the time points through adolescence and adulthood? And then the second question was, if you're treated for more years, does that make a difference?

19:47Brooke S.G. Molina, Ph.D.: Because that's always a clinical question. Does treating for a longer period of time make a difference? we found something really really important that we you know some of this we kind of knew and expected that age is really really important to consider when you're looking at these analyses because here's what happens on the bottom of this box you can see ages they're really tiny font sorry about that but you can see at the bottom left they're 10 when we started on average and at the bottom right, they're 25 on average when we finished. The long bar on the left on the y-axis is percent. So as we followed them over time, they were less and less likely to be taking a stimulant medication to be treated in any way, actually, with medication.

20:40Brooke S.G. Molina, Ph.D.: You can see that drop. However, However, as they became older, they were more and more likely to be experimenting with and using substances. These are two patterns that we've seen in the literature for quite a few years, but they were never considered at the same time in the analysis. If you just take this on face value, you can inadvertently conclude, oh my gosh, stimulants goes away, stimulants go away, substance use goes up. There must be something going on there. they're more likely to use substances because they're not getting treated. So we were able to control for confounding variables, including these age trends, which is important to consider in the analysis.

21:24On the left side, if you do not control for age,

21:29Brooke S.G. Molina, Ph.D.: you get a correlation between medication and substance use. You think that more medication leads to less substance use or vice versa. Once you control for age effects, you can see in the little grayed out, X-ed out line between medication and substance use, there's no real relationship anymore. It goes away. It's no longer significant. It's an age effect. It's not a medication treatment effect or association.

21:57Brian D'Onofrio, Ph.D.: From kickoff to the final whistle, trade the biggest moments in football on Kalshi, America's number one prediction market platform. Green Bay is currently trading at 42 % to beat Dallas, meaning a$100 trade pays out$228 if they win. Download Kalshi. Use code HOOPS to get$25 when you trade$25. K-A-L-S-H-I. Kalshi. Trade what's next. 18 plus only restrictions and eligibility requirements apply. Event contract trading involves risk and may not be suitable for all investors. Kalshi products are not available in all jurisdictions. Prices, values, and available markets may differ from those mentioned.

22:32Brian D'Onofrio, Ph.D.: For more information, see Kalshi.com slash regulatory.

22:35Brooke S.G. Molina, Ph.D.: What about question two? Does taking ADHD medication longer lead to more substance use later in life? The short answer is no. So we measured how many years those individuals were taking stimulant medication over time, and we looked at that as a predictor of substance use in adulthood. We looked at whether taking medication for more years overall predicted substance use, whether taking it continuously without any breaks mattered, whether starting medication before they even started the study, so early and young, mattered. We looked at whether analyzing serious substance use problems versus just substance use made a difference.

23:18Brooke S.G. Molina, Ph.D.: Didn't find it for any of these. No associations found. The good news here, the good news is that a drug that has been found to be efficacious in so many ways, and Brian will talk more about that, Dr. D 'Onofrio will talk more about that, did not show signs in this study of increasing risk for heavy substance use or substance use disorder through adolescence and in adulthood. That's your glass half full result.

23:53Brooke S.G. Molina, Ph.D.: This is just an interesting study. We have looked at why people stop? People always ask, why do people stop? I can get into this in the Q &A period if it's helpful. But there's lots of reasons, all kinds of reasons, and you all probably know these. And we're still trying to understand if medications are so helpful, why do people stop? There are quite a few different reasons. A lot of people just don't like the way it makes them feel. So conclusions from my presentation is that stimulant medication in childhood and its continuation for some period of time does not predict substance use and substance use disorder at older ages from these clinical longitudinal studies from childhood.

24:39Brooke S.G. Molina, Ph.D.: And that is, I think the glass half full. you know one prediction we had was that it would protect you know because there's data that suggests that it should protect it our study did not support that so it's a it's a study that can answer certain questions and not others it can't address adulthood substance adulthood stimulant medication because as you saw most people were no longer taking stimulant medication as adults but when they were taking at a younger ages through adolescence it didn't make a difference so um i speculate that it might not make a difference then it's hard to know we just can't know we need more studies on girls and women obviously and we need more research on certain conditions so some of you asked what about if there's a family history of substance use disorder alcohol use disorder or um or whatever kind of substance use disorder we do need to research that question more we cannot say that there aren't people who have especially unique or heightened vulnerabilities.

25:43Brooke S.G. Molina, Ph.D.: It's entirely possible. We just don't have the answer to that question. And we can talk more about that in the Q &A. And I'm going to stop there. Oh, I do need to tell you about APSARN. So for those of you who are clinicians or practitioners, and those of you who aren't, I'm sure you would want to know if you might want to tell your practitioners about this meeting. This is the group that I'm president of. Our next annual meeting is in Washington, DC, and it's a three-day meeting where we bring the science to the practitioners. So feel free to look it up and or tell your providers about it. And with that, I will move on to Dr.

26:24Brooke S.G. Molina, Ph.D.: D 'Onofrio's slide.

26:27Brian D'Onofrio, Ph.D.: Great. Thank you, Dr. Molina. My task today is to give you some of the results from large-scale studies that are in contrast to the types of research that Dr. Molina just talked about. I just want to start with a thank you to my colleagues across the world who have helped with the research that I'm going to be presenting. In terms of funding, I've also been funded by the National Institutes of Health and other foundations, but I have not taken any money from the pharmaceutical industry or other industries, so I have no conflicts of interest. One thing that I want to highlight is that, Similar to Dr.

27:06Brian D'Onofrio, Ph.D.: Molina, I'm actually trained as a clinical psychologist. I actually don't prescribe. And what I do is I spend a lot of time talking with patients, with their families. I also spend a lot of time talking with practitioners, with nurse practitioners, family care doctors, primary care physicians, and psychiatrists to better understand what are the key questions that each of these groups have and how to do research that helps to answer those key clinical questions. And so for today, what I'm going to try to quickly do is just highlight some of the limitations of other types of research. Each research design has different limitations.

27:45Brian D'Onofrio, Ph.D.: And I'm going to talk about the limitations of how studies of medications are typically done. And that's randomized controlled trials. I will piggyback on some of the things that Dr. Molina talked about in terms of how do we analyze and do research when we're not randomly assigning people to take medication or not. And so I'm going to give you some examples of how we can use really large national surveys to help inform some of the questions that you raised in the questions that you posed and the questions that, again, that I hear from patients, from families and from physicians. I will then talk about how we analyze really large data sets from health insurers and use a design where we don't compare unrelated individuals, but we look what happens across time within an individual.

28:38Brian D'Onofrio, Ph.D.: And then I'll talk about data sets that use entire countries and data from people in entire countries like Sweden, where we try to emulate what would happen in a randomized controlled trial. I'll quickly review that, talk about some salient questions, and then the hope is that we leave a lot of time for questions from you all. So first, what are the major limitations of randomized controlled trials? These studies where you grab a number of people and you assign randomly half to take a medication and the other half not. Well, the first is that it's incredibly difficult to study rare but serious events.

29:17Brian D'Onofrio, Ph.D.: In contrast, for example, to some of the new obesity drugs where they're doing randomized control trials on 10 ,000, 12 ,000 individuals, the largest randomized control trial that we have in ADHD is 500 to 600, the MTA study that Dr. Molina talked about. But most are much smaller. So you can't study rare events like a nonfatal or fatal drug overdose or suicide. There are also questions about generalizability. So generalizability is the question is, what can we take from this particular study and infer about a different population? So Dr. Molina talked about this intensively studied group, the Pittsburgh ADHD study.

30:02Brian D'Onofrio, Ph.D.: I grew up in Pittsburgh. The question is, can you take what happened to me and my colleagues and friends and peers at that point and generalize that to other sections and to other people. And my friends here in Indiana would probably say, no, probably not. But in randomized controlled trials, it might be even worse. And so what we did is we looked across the entire country of Sweden and said, okay, who got ADHD meds? And then we said, well, among those people, who would have been excluded from randomized controlled trials who generally exclude people with other conditions? And that study found that one out of five children would have been excluded, a third of adolescents.

30:47Brian D'Onofrio, Ph.D.: And this is somewhat shocking. Three out of four adults who got ADHD meds would have been excluded from a randomized controlled trial. And we compared those people got excluded and they were way more severe. They had more comorbidities, meaning they had other psychiatric problems and a lot more impairment. And so we are questioning what can we infer from these randomized controlled trials that were done primarily on, quote, healthier individuals. There are also questions about the generalizability of patients who remain in the study. What happens, for example, when people drop out if they have side effects?

31:28Brian D'Onofrio, Ph.D.: What about the treatment? the doses that are given in randomized controlled trials are typically very different than those that are given just in the quote real world. And most randomized controlled trials are highly, highly structured, and the people who are prescribing those are highly trained psychiatrists. But we know that most people get prescriptions now from family care doctors, for example. people. So what we are doing is we are using observational data. This is data where we're observing who takes medication or not, again, not randomly assigning them. And as Dr. Merlina highlighted, if you want to study the effects of stimulant medications on substance problems or other problems, you need to rule out these other plausible explanations of why they would be associated.

32:17Brian D'Onofrio, Ph.D.: Again, they're called contracts. So you need to rule out the fact that people get ADHD medication primarily because they have ADHD and we know as Dr. Molina highlighted that ADHD in and of itself and the symptoms of it lead to more substance problems. We know that people with ADHD typically don't just have ADHD they frequently have other psychiatric problems so we need to understand does that explain the association? There are also there could be reverse causation where that substance problems leads to different use of prescribed medications. We know that there are psychosocial factors. There are things like stigma and discrimination and poverty and those sorts of things that could influence both of these.

33:07Brian D'Onofrio, Ph.D.: We also know that there are genetic factors like predispositions to impulsivity and other factors that could explain the findings. And as Dr. Molina highlighted, just developmental changes who stops taking medications primarily happens a lot during adolescence. So I'm going to walk you through a couple of examples of what large-scale studies have been able to tell us about the effects of ADHD medication. And the first thing I'm going to do is highlight national surveys. So here you rely on a big infrastructure where instead of just studying, for example, one high school, you rely on a research infrastructure that the government supports where you do surveys of all high school, not all high schools, a random representation of thousands of high schools.

33:56Brian D'Onofrio, Ph.D.: The advantage, you have more confidence in the generalizability of the findings. You have larger samples and you can study rare outcomes. You can study subgroups, particularly subgroups that haven't been studied before or have been excluded, for example, like females, which are not well represented in randomized control trials historically or the clinical samples. Some of the disadvantages. If you're just asking them once during high school, you're usually relying on retrospective reporting. They are retrospectively reporting on what happened when they were children. If you're not in school at that time, you can't participate.

34:33Brian D'Onofrio, Ph.D.: So there's questions about, well, what about people who have dropped out of school? When we're trying to rule out all of these other explanations, these confounding factors, we might not have been able to measure them. And just because we're measuring them once, it's really hard to understand the direction of the effects. So the first study that I'm going to do is I'm going to explain something from the Monitoring the Future study. This is a huge study. There's lots of studies on it. But this one in particular grabbed a sample of 10th and 12th grade students. So every year they would sample 10th and 12th grade students, but different students each year.

35:10Brian D'Onofrio, Ph.D.: And you can see the sample size is much, much larger. We're now talking around 11 ,000 individuals who received a stimulant medication. The exposure is the students' reports of when they started medication and how long they were on ADHD medication. The outcome, we're going to be studying their reports of using cocaine in the last year. Okay, this study had lots and lots of different measures, including stimulant misuse and methamphetamine use, but I'm going to just highlight cocaine use for the sake of brevity. And what they did is they wanted to see what is the association between the age and how long people are on their medication with cocaine use.

35:59Brian D'Onofrio, Ph.D.: And they use statistics to try to match and control for things like race and ethnicity and grade point average and truancy and other substance use problems. So what I'm going to do is I'm going to show you a lot of results on figures like this. This is an odds ratio. This is the magnitude of the association between medication use and cocaine use in the last year. And the reference group is going to be these controls. And what they did in this study is the people who were controls were people who did not have ADHD or unmedicated ADHD. And I think it's really important to highlight that this is a relatively rare event.

36:40Brian D'Onofrio, Ph.D.: Only roughly 2 % of high school students reported having cocaine use in the past year. Then they compared people with ADHD, but who got a non-stimulant medication. There's a drug, Adamoxetine, and there are some other antidepressants and alpha agonists that are also used. And they found that those individuals were at increased risk of cocaine use, almost a twofold increase in cocaine use in the past year. But this is not associated with stimulant use. They then said, OK, among those who use stimulants, who had an onset before they started medication before they were nine years old? and they broke it down in terms of how long they were on their ADHD medication.

37:35Brian D'Onofrio, Ph.D.: Some had six or more years all the way down to less than one year of duration and what they found is that those who started before the age of nine and who were on longer so those who had six or more years of duration were less likely to be using cocaine than those who had been on for just a short period of time, for example, less than one year. They then looked at individuals who started their medication between the ages of 10 and 14 years old. Again, they broke it down in terms of the duration. And similarly, you can see that those who were on ADHD stimulant medication for longer, like six or more years, okay, yes, they had an increased risk of cocaine use in the past year, but not as much.

38:27Brian D'Onofrio, Ph.D.: as those who had only been on for a short period of time. And those who started later after the age of 15, you can see that there's a roughly similar type of finding. So this study suggests that earlier age of onset of starting a stimulant medication and longer duration may actually be associated with less likelihood of using cocaine in the last year as a high school student. The next type of study is using health insurance claims data sets. And here the advantage or the method is that we take information when you go to the doctor, your insurance company needs information. and doctors and pharmacies provide this information so that you can get reimbursed.

39:22Brian D'Onofrio, Ph.D.: And we can take this data and we can look at individuals across time. And so what we're going to do is we're going to compare people when they're on their medication or when they have it to people when they don't. The advantages is we don't actually have to get people's consent. These are so large, we can't actually identify individuals. We get much larger sample sizes, as you'll see, and we can look at rare outcomes, look at subgroups, and we can account for more factors. The disadvantage is that typically this is done on people with private insurance. We have to rely not on people's reports, but on whether or not they were filling their prescriptions.

40:02Brian D'Onofrio, Ph.D.: And we're not able to perhaps account for everything that changes over time. So one study that used a large data set of people with private insurance, so roughly half to 60 % of adults, for example, have private insurance. We were able to study roughly 3 million people using this data set where we have information about their inpatient care, outpatient care, and field prescriptions. we could look at their exposure in terms of adhd medication which is primarily stimulant medication by their filled prescriptions the outcome is that we're going to look at something really serious and very acute and this is showing up in an emergency department or being hospitalized for a substance use problem okay and the method that we're going to do again is we're going to look at what is the risk when individuals have a filled prescription for ADHD medication to periods in which they do not have a filled prescription.

41:11Brian D'Onofrio, Ph.D.: So using the same figure, again, these are odds ratios and risk to the right suggest increased risk. And if it's to the left, it's a decreased risk. When we first just compared ADHD patients to non-ADHD patients, people with ADHC, are they more likely to have one of these really acute serious substance problems? We find that for both males and females, that yes, there's roughly a threefold increase in the risk of this serious outcome. Now, I want to highlight that the overwhelming majority of people with ADHD do not have these serious events. You can see for females with ADHD across roughly three years, about 2 % of them will have one of these events compared to just under 1%.

42:00Brian D'Onofrio, Ph.D.: And for males with ADHD, 3 % to roughly 1%. So we know that people with ADHD are more likely to have these serious events. The question is, well, what happens when we compare the risk, again, within individuals when they have their meds compared to when they don't? And we find that ADHD medication, primarily with stimulants, is particularly protective. Roughly a 30 % reduction in the risk of these serious outcomes. And because there aren't a lot of studies across the age range, particularly in adults, we looked at, well, what happens when you look at these different age groups? And we found that in general, that ADHD medication is protective, again, for these serious substance use outcomes, regardless of the age.

42:55Brian D'Onofrio, Ph.D.: We also wanted to know, well, what about people who had a prior substance use disorder, a particularly difficult group? Is it protective or risky among those patients? And we found that ADHD med is actually protective even among people with a prior substance use disorder. Okay, the last type of study, this is using large data sets from the entire country, for example, of Sweden. So everything that basically happens in Sweden basically gets put in the databases and we can link those using the equivalent of a social security number. And what you try to do is you analyze this as if it was a randomized control trial and you use statistics to try to account for those confounders.

43:41Brian D'Onofrio, Ph.D.: Again, the generalizability is much better, at least in Sweden. There are questions about what happens in Sweden. Does that it generalize to the U.S.? It's less likely to lose people. And there are other advantages that help with looking at observational data. Disadvantages. What happens in Sweden? Does it generalize? Again, you're using filled prescriptions, not self-reportive use. And again, we're not sure if we've been able to rule out every possible alternative explanation. So this Swedish study, roughly 150 ,000 ADHD patients from 2007 to 2020. The exposure is stimulant medication and non-stimulant, so particularly stimulant medication.

44:25Brian D'Onofrio, Ph.D.: That's how people in Sweden are generally treated. The outcome, there are two different outcomes that I want to highlight. One is mortality. They were able to look at is ADHD medication and starting ADHD medication is that associated with reduced risk of mortality, including cause-specific mortality that I'll highlight, or other really serious substance use like substance -related deaths, substance-related crime, or substance-related hospitalizations. And here, what we're doing is we're comparing those who are treated to those who are not, again, matching people in lots and lots of different factors.

45:06Brian D'Onofrio, Ph.D.: so here are the results okay so the first thing is that we're going to look at all-cause mortality okay this is really really rare okay across 10 ,000 person years those who started an ADHD medication roughly 17 people out of 10 ,000 person years died compared to 32 people who did not initiate medication. And you can see here that it's a reduction of about 15 % in terms of the risk of mortality for dying for any reason. We were then able to look at unnatural causes. Unnatural causes exclude things like cancer, and unnatural causes include accidents, suicide and homicide. And we found that ADHD medication, starting ADHD medication, reduces the risk of unnatural death.

46:05Brian D'Onofrio, Ph.D.: And we were particularly interested in accidental poisonings, and this includes drug overdoses. And we find that ADHD medication is particularly associated with a reduction in deaths due to accidental poisoning. We found this across two years and across five years, okay? Roughly a 50 % reduction in the risk. Now, these are very rare outcomes that you can't study in randomized controlled trials, but we think that this is really important. When you look at these serious substance use problems, so these are deaths or criminality or hospitalizations, they are more common. So out of every 1 ,000 person years, 58 % of the initiators compared to roughly 70 % of the non-initiators.

46:54Brian D'Onofrio, Ph.D.: And you get a very similar pattern of findings that is associated with reduced risk for a first event, for recurrent events, and even among people with a prior history of substance use problems. ADHD medication and initiating it is associated with reduced risk. Okay. I want to quickly summarize the association between starting and the duration of stimulant pharmacotherapy moderates the association between using medications and substance problems. That in adults and across the age range, concurrent ADHD medications is associated with a reduction in serious substance problems. And we still find these associations.

47:44Brian D'Onofrio, Ph.D.: It is still associated even among people who have a prior history of a substance use disorder. Okay, quickly some limitations. We can't make definitive causal conclusions because we're not randomly assigning people to these medications. There are measurement issues. Again, we're relying on either retrospective reports or whether or not they filled a prescription, and a lot of our outcomes are very, very severe events. There are questions about what about people who are insured by Medicaid and really vulnerable populations, and there are questions about long-term.

48:21Brooke S.G. Molina, Ph.D.: I wanted to get to our audience questions. Of course, we had quite a few. Well, we've had quite a few questions and comments specifically that many treatment programs won't treat people with ADHD. And in people who say they have a history of substance use, some have maintained sobriety, some have not, but they all have said that they needed stimulant medication to treat their ADHD symptoms, but they couldn't find a doctor who was willing to prescribe stimulants because of their history of drug use. Some said they were spiraling due to their untreated ADHD, what are people in these situations to do?

49:06Brooke S.G. Molina, Ph.D.: Do you want me to take that?

49:08Brian D'Onofrio, Ph.D.: You can start and then I can jump in at the end.

49:10Brooke S.G. Molina, Ph.D.: Okay. All right. So this is a huge problem, which is actually one of the reasons why in this slide I put this second bullet, U.S. guidelines for the diagnosis and treatment of ADHD in adulthood. These are being developed right now, entering their final stage of review. A big issue, a big problem that we have right now is that many, many, many practitioners were not trained in ADHD beyond childhood. So we have an enormous number of practitioners out there who just really are very uncomfortable treating ADHD, and they're scared of dealing with stimulant medications. and we're hopeful that as these guidelines get published and trainings that we offer by APSARD and other organizations get out there that more practitioners in the United States are going to become more comfortable with this.

50:06Brian D'Onofrio, Ph.D.: I also want to highlight that there are non-stimulant medications that can also be helpful and so with you know access to providers who won't prescribe stimulants, perhaps there's also the opportunity to use a non-stimulant medication like one of the SNRIs that I had amoxetine.

50:31Okay.

50:32Brooke S.G. Molina, Ph.D.: Someone writes, I have held off on getting stimulants for my son who is now 19 and has ADHD. He already has an extremely addictive personality when it comes to video gaming, speeding in a car, vaping, pot use, et cetera. So why would I ever consider putting him on a stimulant? What are better treatment options for people with ADHD who have an addictive personality? I know you just mentioned non-stimulants. Are there other options?

51:06Brooke S.G. Molina, Ph.D.: Or do you take issue with the premise of her question? Well, so I just wonder if this person would, how their question might be revised after hearing this presentation, if at all, you know, is I hope that across, even though all the studies have their limitations, that's the way science is. There is no one perfect study, but fortunately across these different kinds of studies, we're not showing that on average that stimulant medications increase risk for substance use disorder. um so i i do think that is something worth just bearing in mind and having a conversation with your prescribing practitioner about exactly that and about of course we can never give clinical recommendations for any given person here because we don't know the whole story so everything we say always needs to be couched with and talk with your provider about the particular circumstance that your your child is in there are psychosocial psychotherapeutic options for treating adhd that also target many of the vulnerability factors that I talked about in my kind of theoretical all the reasons slide that can be used, cognitive behavioral approaches, motivational, interventional approaches, school supports, all of these kinds of things can be potentially helpful.

52:32Brian D'Onofrio, Ph.D.: Yeah, I also want to highlight, you know, echoing what Dr. Lillian has said that we can't give recommendations for particular patients. But there are some stimulant medications that are less likely to be abused. They have less abuse potential. So those, for example, that are extended release rather than short acting. And then there are specific types of stimulant medications on top of that, different formulations that are harder to abuse. So I want to highlight that it is possible to abuse a prescription stimulant. And that is, I think, what a lot of people are concerned about, including a lot of the physicians that I speak to.

53:10Brian D'Onofrio, Ph.D.: But there are treatment options that help to reduce that risk. Okay. In addition to that, there are psychosocial interventions that can also help. Mm-hmm.

53:23Brooke S.G. Molina, Ph.D.: A teacher asks, how can teachers and counselors influence parents who worry about allowing their children with ADHD to use a prescribed stimulant medication because they fear it will lead to addiction problems?

53:42Brooke S.G. Molina, Ph.D.: Brian, you want to take a first stab?

53:44Brian D'Onofrio, Ph.D.: I would say have them try to download this presentation and then work it first. I mean, that's one of the advantages of attitude and in settings like this. Again, there's a lot of stigma associated with ADHD. There's a lot of stigma associated with substance use, mental health in general. And so we need to be very, very sensitive to that. And teachers are on the front lines. They're dealing with, you know, the students in front of them, some of them who are daydreaming and not causing too many problems. but daydreaming and not paying attention, as well as those who have lots of hyperactivity. And so my heart goes out to the teachers because they are on the front lines.

54:22Brian D'Onofrio, Ph.D.: But to try to educate them and give them the resources that they need, again, hopefully pointing them to a medical provider that can provide more guidance and maybe a trial of a different type of medication and or psychosocial intervention.

54:38Brooke S.G. Molina, Ph.D.: I also think it's just the approach is really, really important, you know, because, and And I've had lots of conversations with teachers about what they can and they cannot say. And you obviously can't tell a parent that they should put their child on a medication because that's not your job and your expertise. But you can say what experiences you've had. And you can say something like that may or may not be helpful for you. I don't know. but I do know from attending talks that I've attended, there are many, many studies that have been done on this, and maybe your provider could talk with you about that.

55:18Okay.

55:20Brooke S.G. Molina, Ph.D.: Someone asks, are young women with ADHD more likely to develop depression and anxiety and therefore more prone to substance use disorder?

55:35Brooke S.G. Molina, Ph.D.: this is your area do you want to highlight this yeah yeah sure um so while the literature on adhd and women is just really now starting to pick up in a really meaningful way and that's because we have seen a dramatic increase in in diagnosing of adhd and treatment of adhd in adulthood and And most of that is accounted for by women. So it's really quite amazing how many women are now showing up for diagnosis and clinical care. Interestingly, so there are studies that are coming out that are starting to suggest, this is really new, but starting to suggest that adults diagnosed with ADHD in adulthood, on average, are not more severe than individuals diagnosed at younger ages.

56:35Brooke S.G. Molina, Ph.D.: It's actually the reverse. And so we're kind of wrapping our head around what is this? And what it may be is that on average, people who wait all the way until adulthood to get a diagnosis in clinical care may partly have waited because they weren't so severe they weren't taken to a clinician as a child by their parent because it was because it wasn't as bad but when they got into higher demand situations as an adult then they really started to kind of struggle more and just decide on their own to go get assessed certainly depression and anxiety are co-occurring mental health conditions for everybody many people with ADHD and it is certainly something that we often see when we're looking at substance use as well so it is often part of the clinical picture okay well unfortunately that has to be our last question because we're out of time but Dr.

57:39Brooke S.G. Molina, Ph.D.: Molina and Dr. D 'Onofrio thank you so much for sharing your research and expertise with our ADHD community. We appreciate it. You're welcome. Happy to be here. And thank you to everyone here today. If your question wasn't answered during the webinar, we do share audience questions with our experts and yours may appear in a future edition of Attitude Magazine's advisor column. If you would like to access today's event resources, visit attitudemag.com and search for podcast 616. The slides and recording are posted a few hours after each live webinar. If you're listening in replay mode, simply click on the episode description.

58:22Brooke S.G. Molina, Ph.D.: Please know that our full library of Attitude webinars is available as a podcast. It's called the ADHD Experts Podcast, and it's available on most streaming platforms. Get alerts for future Attitude webinars by signing up at attitudemag.com slash newsletters.

58:41Brian D'Onofrio, Ph.D.: For more Attitude podcasts and information on living well with attention deficit, visit attitudemag.com. That's A-D-D-I-T-U-D-E-M-A-G dot com.

59:22Brooke S.G. Molina, Ph.D.: We'll be right back. Jerry could save over$1 ,300 a year. Switch with confidence. Download the Jerry app or visit jerry.ai slash libsyn today. That's j-e-r-r-y dot a-i slash l-i-b-s-y-n.