Use Disorder series titled Medication Management for Stimulant Use Disorder, presented by Dr. Larrison Mooney. Before I turn things over to Dr. Mooney, I will go over some logistics and announcements. Next slide, please. This webinar is brought to you through collaboration between ASAM and AAAP. ASAM, founded in 1954, is a professional medical society representing over 7,000 physicians, clinicians, and associated professionals in the field of addiction medicine. ASAM is dedicated to increasing access and improving the quality of addiction treatment, educating physicians and the public, supporting research and prevention, and promoting the appropriate role of physicians in the care of patients with addiction. Next slide, please. AAAP is a national professional society that focuses on evidence-based prevention, treatment, and recovery approaches, particularly for people with substance use disorders and co-occurring psychiatric disorders. Their primary focus is to promote high-quality evidence-based prevention, treatment, and recovery approaches, strengthen addiction psychiatry specialty training, foster careers in addiction psychiatry, and promote addiction psychiatry as a recognized specialty. They also provide evidence-based substance use disorder education to healthcare trainees and healthcare professionals, and educate the public and influence policy on substance use, co-occurring psychiatric disorders, and related issues. Next slide, please. We begin our session today with a few brief announcements about how to use Zoom features. Please first note that attendees' mics are automatically set to mute. If you have any questions on the content during the presentation, please type them into the Q&A box in your Zoom control panel. We will have time for questions at the end, but you can submit your questions at any time throughout the presentation. If you experience any technical difficulties, please use the chat function to send a message and ASAM staff will help you with your technical issue. Today's webinar will include opportunities for audience members to engage through Zoom polls. So throughout the webinar, the Zoom poll function will be utilized. The poll will appear on your screen during various points of the webinar, so please participate and answer the polls in a timely manner. Next slide, please. A few ground rules before we start. Please take time to understand cases and participate actively, embrace diverse experiences, assume positive attentions of co-participants, monitor your participation, be accountable for your involvement, and seek clarification respectfully, and ask questions when perspective differs. I will now turn it over to Dr. Mooney. Great. Hello, everyone. Thank you very much. It's a pleasure to be here today. I am Dr. Larissa Mooney. I am an addiction psychiatrist at UCLA and a clinical professor of psychiatry in the Department of Psychiatry at UCLA. I also direct our Addiction Psychiatry Fellowship Program and our outpatient clinic. I hold a joint appointment with the Greater Los Angeles VA and for several years was the Substance Use Disorder Section Chief, and I'm involved in clinical research looking at interventions for substance use disorders. So I wear some different hats. I am also the immediate past president of AAAP, the American Academy of Addiction Psychiatry. And as was mentioned, this webinar is part of a series where we are disseminating our recommendations from the ASAM-AAAP Joint Clinical Practice Guideline for the Treatment of Stimulant Use Disorder, which was a really exciting project and collaboration between the two organizations. I was fortunate to co-chair the work group with Dr. Brian Hurley, and we had members from both organizations participating. The process of the guideline development was previously described on a prior webinar, but to reiterate briefly, we had a systematic literature review and applied grade methodology to determine the strength of recommendations and the quality of evidence to support the recommendations which are in detail in the guideline itself. And there was also a process of clinical consensus that informed our decisions. So our learning objectives today are to summarize guideline recommendations regarding medication management for stimulant use disorder. Other aspects of the guideline have been previously presented in the other three webinars, and I will be touching on importance of clinical monitoring and ongoing assessment of risks and benefits, particularly when prescribing controlled medications such as psychostimulants. And at the end, we will be applying the knowledge to a clinical case scenario. As an overview, I'll first review briefly some stimulant use trends, clinical effects, and general overview, then talk about the recommendations for pharmacotherapy for methamphetamine use disorder, followed by cocaine use disorder, and also how we think about using medications in the management of co-occurring psychiatric disorders together with stimulant use disorder. So that's a lot to cover, so I'll be really hitting on some of the highlights from the guideline and concluding with a case presentation. So as an introduction, we know that stimulant use disorder is a public health concern with clinical consequences and approximately 1.5 million U.S. adults having past-year stimulant use disorder. We also know that overdoses related to stimulant use have been on the rise in recent years, and many of these overdoses are in combination with opioids, including fentanyl and other potent synthetics. That's indicated by the yellow line in the graph, but also stimulant-only overdose deaths have also been on the rise. That's the lighter blue line in the graph. DSM-5 combines amphetamine-type stimulants, cocaine, really all stimulants into one category of stimulant use disorder, but when reviewing evidence-based medications that have some signal for the treatment of stimulant use disorder, these drugs have been studied separately, and some of the findings are different across methamphetamine use disorder versus cocaine. So it is helpful to briefly review some of the differences between methamphetamine and cocaine, namely methamphetamine is a synthetic. It has a longer-lasting effect because its half-life is 12 hours approximately. The mechanism of action of methamphetamine versus cocaine overlaps significantly, but the primary mechanism for methamphetamine is facilitation of dopamine release. We'll talk about that in a minute, whereas for cocaine, it's predominantly a blockade of dopamine reuptake. Medical uses of both of these drugs are uncommon nowadays, but methamphetamine does have a prescription form called disoxin, and methamphetamine is also considered to have greater potential for direct neurotoxicity than cocaine. Cocaine in contrast has a short half-life of about an hour with a shorter duration of intoxicating effects, and its medical use has been as a topical anesthetic, and it's not directly neurotoxic. Briefly, this figure is an image of the mechanism of action of cocaine, the dopaminergic neuron in the presence of cocaine, dopamine reuptake is blocked through the reuptake transporter, the net effect is an increase of dopamine in the synaptic cleft, and dopamine is our pleasure chemical and has rewarding and reinforcing effects, so net effect is to increase the dopamine availability. This image is a bit messier, but shows mechanisms of action for methamphetamine. Methamphetamine also blocks dopamine reuptake, but it also directly enters the dopaminergic neuron, and it facilitates the release of newly synthesized catecholamines from vesicles into the synaptic cleft, including dopamine and norepinephrine. Methamphetamine will also block the breakdown of dopamine inside the neuron, and this net increase in dopamine in the neuron is believed to be associated with its neurotoxic effects. We know that chronic stimulant use is associated with dysfunction in brain dopamine and learning systems. For example, on the left, in the presence of chronic methamphetamine use, we see reduction of dopamine transporters in the striatum, and this can be associated with greater impulsivity and diminished ability to respond to non-drug rewards. On the right, after chronic cocaine use, there is disruption in glutamatergic function in the orbitofrontal cortex associated with poor decision-making and less ability to resist urges and cravings. That's the learning center of the brain. So, shifting now to conceptualized treatment approaches for stimulant use disorder, and briefly integrating for context some of what was presented in the prior webinars, we really think about management of stimulant use disorder as ideally multidisciplinary and involving multiple modalities when possible. Of course, meeting the person where they're at and assessing what they are interested and willing to accept, but integrating components of medication management where appropriate to address cravings, withdrawal, psychiatric symptoms, some of the biological components of the disorder, together with behavioral treatment approaches, psychosocial support, and harm reduction approaches. And focusing on medication management and how that fits in, there are many aspects of medication management, not just the disorder itself, but considering management of other co-occurring substance use disorders. Does this person with stimulant use disorder also have alcohol use disorder, opioid use disorder? We know that fentanyl co-use is now very common and mixed into the drug supply. We use medications to manage co-occurring psychiatric disorders, also a very, very important aspect of treatment. And then, when thinking about medications for stimulant use disorder, which are all off-label, there are no approved medications at this time, there are a lot of people who at this time, considering the co-occurring disorders, but also the severity of use, the consequences of use, and whether the person has a primary amphetamine type stimulant use disorder versus cocaine versus prescription stimulant use disorder, that will influence what medications we might choose among the off-label options that have signals of efficacy. And really, is pharmacotherapy appropriate for everyone who is seeking treatment for a stimulant use disorder? It really needs to be individualized and taking these other factors into consideration. So behavioral treatment was covered in depth in webinar number three, but I do want to emphasize that behavioral treatment is still the gold standard treatment approach for stimulant use disorder, with contingency management having the most robust evidence of all behavioral treatment approaches. It's unanimously supported in reviews, and it's been studied in combination with other psychosocial treatments. There are other approaches with evidence of support, cognitive behavioral therapy for relapse prevention, community reinforcement approach, and also the matrix model. And of course, motivational interviewing is applicable across substance use disorders to help facilitate change, address ambivalence, and meet individuals where where they're at with their own goals. So as I start to address individual medications, considering offering behavioral treatment, if it's available in your clinical setting, or referring if it's not, would be an important component of treatment that can be readily integrated with pharmacotherapy. So what do the practice guidelines say about generally medication management for stimulant use disorder before we go through some of the individual medications? The guideline is clear that pharmacotherapies may be utilized off-label in the treatment approach for stimulant use disorder. The recommendations are they use the language can consider prescribing because the evidence is not robust, and we have no approved medications. So the language is really around low certainty evidence. In most cases, a couple have moderate certainty evidence, and the recommendation is that one may consider prescribing this medication for stimulant use disorder. And in the guideline, we recommend giving extra consideration for other indications for a given medication. So for example, if an antidepressant may be considered for the treatment of stimulant use disorder, you might give extra consideration to select that medication if the person has co-occurring depression. Similarly, for alcohol use disorder, tobacco use disorder, and ADHD, keeping the comorbidities and co-occurring disorders in mind when selecting medications might lend extra weight to select that medication. When prescribing controlled cyclostimulant medications, clinicians should closely monitor patients and perform ongoing assessments of risks and benefits, and this is a strong recommendation in the guideline. The type of monitoring might include needs to be individualized and take many factors into consideration, but more frequent contact, potentially pill counts, urine drug testing, and checking prescription drug monitoring databases to assess what other controlled medications are being prescribed for that individual. And also, there's a recommendation that cyclostimulant medication should only be prescribed for the treatment of stimulant use disorder by physician specialists who are board certified in addiction medicine or addiction psychiatry and physicians who have commensurate training competencies and capacity for close patient monitoring to really encourage a more nuanced approach and cautious approach with these medications. So moving now to methamphetamine use disorder pharmacotherapy, this is a summary slide of the medications that can be considered for the treatment of methamphetamine use disorder, and I'll touch on a couple of examples and from specific studies shortly, but bupropion does have a signal for methamphetamine use disorder, facilitation of use reduction, particularly among individuals with lower frequency of methamphetamine use at baseline, meaning individuals who are not using daily, and in fact, some of the studies had a cutoff of 18 or fewer days in the month prior to baseline. You might also give additional consideration if the person has tobacco use disorder or depression. Also, combination of extended release naltrexone, the injectable monthly naltrexone plus higher dose bupropion XL, we'll talk about that one in a moment. Two smaller studies that demonstrated efficacy for metazapine antidepressant with additional considerations there, also topiramate, particularly in individuals with lower level methamphetamine use at baseline, which would also have an additional consideration for alcohol use disorder, and extended release methylphenidate, the signal there was in individuals with higher frequency of methamphetamine use at baseline. So many of these studies have some secondary analyses looking at subgroups that suggest stronger signals. This medication would, of course, have additional consideration if the patient has attention deficit hyperactivity disorder. I want to say something about steady medication adherence and acknowledge that we could have possibly missed signals of efficacy in the past. In more recent years, there's been greater attention to assessing medication adherence over the duration of a trial. In this example of a study, this was a negative trial for bupropion sustained release. This was 150 milligram dose twice daily at the time. And overall, this was a negative study, there was not a significant difference between placebo versus medication. But when they looked at medication adherence, only about a third of participants were actually taking the medication on a regular basis via plasma levels. And in that subgroup, adherence was strongly associated with end of treatment methamphetamine abstinence, there was a significant difference in those who were adherent to the medication versus not. I want to mention a more recent study that was published by Trivedi and colleagues in 2021. That combined extended release naltrexone, the injection, monthly injection, administered every three weeks. So this was a slightly different dosing schedule than standard in combination with bupropion XL at 450 milligrams per day. So, at 450 milligrams per day, so higher dose bupropion. And this was a 12 week trial conducted in two stages, whereby participants who were non responders to placebo were re randomized to stage two at the end of stage one. And they just define response as those who produced at least three out of four methamphetamine negative urine samples. In the final two weeks at each stage, urine was collected twice weekly. And related to the last two bullets here just showing a figure from the study, they calculated the treatment effect, which, well, first, the weighted average responses were calculated across the two stages. And then the treatment effect was defined as the between difference in those weighted average responses. And this difference was 11.1 percentage points. Interestingly, in this study, the number needed to treat to have one patient respond was nine. Moving along, mirtazapine, as I mentioned, also has been shown to have a signal of efficacy in two separate trials dosed at 30 milligrams at bedtime, promising early studies in MSM populations. And this was even despite inconsistent medication adherence. The medication was not associated with significant improvement in treatment retention. But showing here a figure from the more recent study published by Coffin and colleagues, this was an RCT that enrolled 120 participants, again, mirtazapine 30 versus placebo, and they found significant reductions in methamphetamine positive urine drug screens in the mirtazapine group at all time points, even though only about 40% adherence was demonstrated using a pill dispenser that monitored adherence. This slide just summarizes the favorable odds of continuing methamphetamine use via toxicology testing favoring the medication mirtazapine over placebo. Topiramate for methamphetamine use disorder, studies have demonstrated more participants reducing methamphetamine use compared to placebo, not significantly different in terms of meth use cessation, so total abstinence. Topiramate is typically dosed in a gradual titration schedule, up to about 200 milligrams per day, sometimes higher depending on the study, really dosed to about 100 milligrams per day. Maximum tolerability, and we know that topiramate does have some adverse effects and can be challenging for participants to tolerate, and contraception should be discussed and provided. In one study, this shows a figure whereby those randomized to topiramate started to separate over time from placebo in terms of the percent with meth negative urine results. Sustained release methylphenidate is the psychostimulant that has been demonstrated in prior studies to show some benefit in methamphetamine use reduction. These are details from one such study published by Ling and colleagues, whereby sustained release methylphenidate was titrated to 54 milligrams per day with a 10-week active med period, randomized methylphenidate versus placebo, and both arms had a platform of cognitive behavioral therapy across both arms, and methylphenidate was associated with significantly fewer self-reported days of meth use and reduced cratings over the treatment period in the subgroup of participants who had reported greater than 10 days of methamphetamine use at baseline in that prior month. So this again was a signal for greater efficacy in individuals with higher frequency of methamphetamine use, but they did not find a difference in positive urine drug screen results across the two arms. So I'm going to pause here. This is a lot of information to take in. Let's do a polling question. What strategies are recommended, and this is related to the last medication I just discussed, for monitoring patients for prescribed psychostimulants to treat stimulant use disorder? Select all that apply so you can choose more than one response. Results are still coming in, so I will wait before we review. Okay, so the majority selected the various methods that we reviewed earlier around having more frequent contact follow-ups, urine or serum drug testing, checking prescription drug monitoring databases, and fewer selected random pill counts. But we would not suggest relying solely on patient self-report, even though that is a very important part of the history at each visit. So this was largely successful in terms of the results. I'm just trying to click out of them now. Move this box. Okay. So moving now to discuss cocaine use disorder pharmacotherapy and some of the clinical guideline recommendations and medications that have been found to be beneficial potentially for cocaine use disorder. This is a summary slide, again, of medications that can be considered. Modafinil, we will discuss in more detail in a moment. But the strongest signal here is for individuals without co-occurring alcohol use disorder. Specifically, topiramate in individuals with lower frequency cocaine use, should say cocaine use, and also giving additional consideration for alcohol use disorder. Also, the combination of mixed amphetamine salts plus topiramate, and then even earlier research just on the mixed amphetamine salts. So in terms of the psychostimulant that has shown the greatest signal of efficacy for cocaine use disorder as opposed to methamphetamine use disorder, it has been mixed amphetamine salts. The Modafinil story is interesting. In that there's been really a series of trials and work done with some mixed findings, but an early study conducted by Dacus and colleagues demonstrated greater abstinence periods, cocaine abstinence periods in participants randomized to Modafinil over placebo across eight weeks of the trial. However, this study excluded individuals that had a history of or current alcohol use disorder. And the issue there is that alcohol is commonly co-used with cocaine with rates of at least 60 to 80 percent. Alcohol use disorder is also a common comorbidity. So NIDA conducted a replication study across several sites where 210 participants were enrolled with cocaine use disorder and with and without alcohol use disorder. So they do not exclude alcohol use disorder. And in this study, they randomized participants to 200 milligrams of Modafinil versus 400 milligrams versus placebo. So two doses were compared on placebo. And in the end, the overall study findings were negative in terms of cocaine non-use days across medication versus placebo. However, when they looked at the subgroup without alcohol use disorder, there was a significant difference and separation between those randomized to active medication versus placebo. Interestingly, no difference, however, in 200 versus 400 milligrams, which is represented by the green and red lines here. So no dose difference, but difference separation from placebo. However, keep in mind that across multiple trials that have examined Modafinil, there really have been mixed findings with some negative studies, some positive, and overall slightly favoring Modafinil in facilitation of the cocaine abstinence. Similar to methamphetamine use disorder, there has been evidence for topiramate for cocaine use disorder. Again, keep in mind that this is also approved for alcohol use disorder, so could be given additional consideration if somebody has alcohol use disorder. But studies do favor effects of topiramate facilitating continuous abstinence compared to placebo. Extended-release mixed amphetamine salts plus topiramate, there have been two studies and they're both briefly described in this one slide. The initial study published by Mariani and colleagues included individuals with cocaine use disorder who were randomized to the combination of the two medications versus placebo for 12 weeks. And in this study, the mixed amphetamine salts were titrated to 60 milligrams per day, topiramate to up to 300 milligrams total in split doses per day. And the primary outcome was three consecutive weeks of abstinence. And this was significant for the combination medication arm. However, there was a greater signal in those who had used self-reported cocaine use more than nine days per month at baseline. So this effect was moderated by days of cocaine use. In a subsequent trial published by Levin and colleagues in 2020, this was a replication study where they enrolled specifically individuals who were self-reporting at least greater than nine days of cocaine use per month. And again, the results were replicated in terms of greater proportion of participants in the combination medication arm having at least three consecutive weeks of abstinence during the study. They also had a more end of study abstinence as represented by the figure on the right. The proprion for cocaine use disorder, I would say has a weaker signal and that then has been found for methamphetamine use disorder. In this study, this was specifically methadone maintained population. So slightly different early trial, the proprion titrated to 300 milligrams daily. And this effect was really found on consecutive abstinence when it was used in combination with contingency management. So it was a forearm trial and the solid squares on the top represent that CM plus bupropion group having greater percent of patients with consecutive weeks of abstinence in that combination. So we did make a recommendation for consideration of the proprion for cocaine use disorder and the meta-analyses also supported that. So shifting gears a little bit, this could be a whole topic on its own, but I'm going to share some of the recommendations for management of co-occurring psychiatric disorders specifically in combination with stimulant use disorder. The CPG strongly recommends that both stimulant use disorder and co-occurring psychiatric disorders are treated concurrently when possible. Integrated treatment has strong evidence in the literature. When considering individual psychiatric symptoms or disorders, it is important always to think about acuity and we do want to treat symptoms of mania or psychosis with appropriate pharmacotherapy. Whether or not you know that this is a substance-induced syndrome or the person has substance-independent bipolar or psychotic disorder, when those symptoms are present, we do want to treat them. The challenge of course becomes what to do with the antipsychotic when you're not sure whether the person has a substance-independent psychotic spectrum disorder. In some cases, if it's suspected that this could have been a stimulant-induced disorder and their symptoms are in remission, one would want to consider tapering off the antipsychotic after a period of symptom remission. This really will vary based on clinical judgment, presenting symptoms, severity of symptoms, and hopefully more detailed history obtained, but it might warrant a trial off of antipsychotics if substance-induced psychosis was suspected. When treating depression, anxiety, or insomnia, pharmacotherapy may be appropriate and one might consider what phase of methamphetamine use the person is in. Are they in an intoxication state or withdrawal state such that the symptoms might remit more quickly or you would also consider the severity of symptoms if somebody is severely depressed as suicidal ideation. You would want to be more proactive in considering an antidepressant. What setting are they being treated in? Is this an inpatient admission? Really, there's just a lot of clinical judgment and not a lot of evidence or robust studies to guide any of this decision making. Many of these recommendations in the co-occurring disorder section were driven by clinical consensus more so than evidence from the literature to guide these recommendations. The guidelines are transparent around this could be actually very weak evidence but still clinical consensus and stronger recommendation. Typically, the recommendation is to continue prior medication treatment for co-occurring disorders when initiating stimulant use disorder treatment when considering together risks and benefits. What this recommendation is describing is somebody coming in for treatment for their stimulant use disorder. They carry other co-occurring mental health diagnoses. Typically, one would try to obtain some history chart review collateral but in many cases continue that medication for the co-occurring disorder even if they are continuing to use stimulants and in active stimulant use disorder. ADHD specifically, the recommendations are to consider psychostimulant medication when the benefits outweigh the risks. Really, individualize the assessment and risk and benefit. For example, somebody with a known prescription stimulant use disorder and demonstrated vulnerability to lose control over their prescription stimulant use develop tolerance. That would be an example where risks likely outweigh benefits and may even be a contraindication in that individual case. Consider non-stimulant medications when benefits do not outweigh the risks and this might also include incorporation of behavioral treatment approaches. In fact, whether or not stimulant medications are initiated, behavioral treatment can be an effective adjunct. If the decision is made to prescribe stimulant medications for ADHD in an individual with stimulant use disorder, it's preferred to use and recommended to use extended release long-acting formulations and to also increase that monitoring as appropriate based on their risk profile. Again, that could be more frequent urine drug screens, checking the PDMP, more frequent visits, sometimes prescribing shorter duration of medication supply if there's concern. There isn't literature to specifically guide adolescent management of ADHD in combination with stimulant use disorder, but one might counsel families on safe storage. That also applies for non-adolescent populations. Safe medication storage is always a good thing to counsel on. And in some cases, consider arranging for direct medication observation. But it is important to address the ADHD and stimulant medications are approved and evidence based. Integrating some of the prior recommendations and applying them to co-occurring opioid use disorder together with stimulant use disorder. This is certainly arising in an emerging concern. Again, with the prevalence of fentanyl, it's really important to manage the opioid use disorder with approved evidence-based approaches. Prescribe medication treatment for opioid use disorder, even if there's ongoing stimulant use. Ideally, provide or refer to contingency management if it's available, acknowledging that many settings do not have availability of contingency management. Or refer to other evidence-based behavioral treatment interventions like cognitive behavioral therapy, community reinforcement approach, matrix model. Want to address the methamphetamine or cocaine use disorder clinically with the tools that we have while also offering the gold standard treatments for opioid use disorder. Some of the harm reduction pearls integrated here, consider fentanyl or drug test kits if available, prescribe naloxone for overdose prevention. So I'm now going to move to the case presentation and discussion, and we will still have time, plenty of time for questions. And within this case presentation, I have one more polling question. So this is a case of a 30-year-old woman who presents to outpatient substance use disorder specialty treatment program for treatment of methamphetamine use disorder. That is the treatment she's seeking. And you learn on history that she has attention deficit hyperactivity disorder that was diagnosed in childhood. She's had prior treatment trials with stimulants, including methamphetamine and mixed amphetamine salts when she was younger. And no history, no known history of prescription stimulant misuse or development of a use disorder related to controlled prescription stimulants. On intake, she endorses history of methamphetamine use for the past five years, typically three to four days per week. And use has increased to include IV use recently. She also endorses intermittent binge alcohol use. She denies other substance use. And you learn that she has in the past been treated with SSRIs for depression and anxiety. She's currently unemployed, estranged from her family. In the past year, she's had two prior ED visits for paranoia and agitation in the context of methamphetamine intoxication. On intake currently, she's endorsing some depression and anxiety symptoms. She's denying any psychotic symptoms. And she states that she last used methamphetamine And she states that she last used methamphetamine the day before, and has some ambivalence about long-term abstinence as a treatment goal, but does want help. So I'm going to first discuss the initial question, what other information would you want to obtain? And then the second question will be related to the polling question. So this is intentionally a shorter case synopsis to get us thinking and applying some of what we learned and thinking about how might medications be incorporated into our treatment approach for this patient. But in terms of other information, learning that she has previously had trials of SSRIs for depression and anxiety, brings up some of the questions that are often diagnostic challenges and dilemmas around substance-induced versus substance-independent disorders. We know that methamphetamine intoxication and alcohol use, which she's endorsing, can contribute to depressive and anxiety symptoms. So I would want to know more about the time course. When were these episodes of anxiety and depression in relation to substance use? Was she actively using substances at the time? When did she first start drinking alcohol? We know when she first started using methamphetamine. She's denying other substance use, but I would want a more careful history around any other substance use since a young age and that time course. Did she ever have these symptoms during at least a one-month period of abstinence from substances? Were the SSRIs effective? Would they help her? That might guide our selection of medications in this case. I would also want to know more about the consequences of her methamphetamine use. She's now endorsing IV use. Has she experienced any overdoses, suicidal ideation, suicide attempts? Has she had any evidence that fentanyl may be part of her drug supply currently? Either intentional co-use or use without her knowledge, but based on some clinical suspicion. I'd also want to know more about her family's psychiatric history, her current supports. Sounds like she's having a lot of social consequences and employment consequences, but more about her support network and history of trauma, of course, would be very important to ascertain and could really inform some of the therapeutic approaches to her care. Question number two, and you probably have other ideas around question number one that I omitted, but I tried to touch on some of the categories. What form of therapy would you consider? I'm going to move to the polling question now. Based on this history, based on what you do know, and here's the question. Would you select or would you consider Here's the question. Would you select or would you consider mirtazapine, extended release, uproprion, and or in combination with naltrexone, methylphenidate, extended release, or topiramate? Hopefully, we can open the poll. Yeah, I see it now. So it looks like the vast majority of responses favored bupropion extended release in combination with extended release naltrexone, with 54% selecting that combination. Second place was methylphenidate ER, followed by bupropion XL, and a few for modafinil or topiramate. It should have been actually mitazapine. OK, I'm going to get out of this box for a moment. Right, so yeah, I think those responses are all reasonable. The way I would think about the selection, of course, we'd want to get a sense of what symptoms are most distressing to her now around the depression and anxiety. What feels more severe? Is she having insomnia? Mitazapine might be an option if the insomnia and anxiety are very prominent. Bupropion extended release for depression. Is she also a tobacco use disorder? This might also steer towards bupropion. Is she having poor concentration, low energy? And it's true, the combination study, bupropion plus naltrexone, had some more robust results. Considering, though, what's available in a given facility, is she interested or willing to consider an injectable naltrexone? Some would even adapt if injectable is not available or not of interest, might consider the PO naltrexone, because these are clinical studies designed a certain way and at certain dosing intervals and regimens. But we don't know if other combinations that are similar might also be helpful to the patient. And methylphenidate ER, she has a history of ADHD. Unclear if it's active or predominant concern right now. I agree, I tend to favor non-stimulant options as first line, as I'm getting to know someone, particularly if they have other co-occurring disorders for which some of these other options might be helpful. And keeping in mind, and again, this is just my approach, might speak to somebody else who has a different algorithm. But I would really keep all of these in mind. And after trials and learning how effective different options are for her, we now have really a range of off-label considerations or some that are actually indicated for potential co-occurring disorders. We're not sure right now if her depression and anxiety are also related to recent methamphetamine use. Is she currently in withdrawal? How protracted or severe are those symptoms? All right, great feedback on that question. I'm going to go back to the final two questions here, which I'll cover briefly. What other treatments would you recommend? I'm going to get back to the behavioral treatment interventions. She's now in an outpatient specialty SUD setting. Not sure if contingency management is available there, but that would be a robust option that if there is a way to offer her contingency management program, that would be my top recommendation, in combination with other evidence-based behavioral approaches, CBT, CRA, if it's available. But getting her engaged in behavioral treatment for a stimulant use disorder would be recommended, no matter what medication we decide. And is outpatient SUD specialty treatment the right level of care? We would need to know more information, but it very well could be. There's no evidence that she's having active psychosis, agitation, didn't initially endorse suicidal thinking, where we would be concerned that we need to refer her to an inpatient setting. Starting in a more structured program, if she's willing to accept an IOP level of care, given some of the consequences, might be appropriate. But seems like it's worth a try. OK, now we are right on time to move to Q&A. I'm going to be looking through the Q&A section and selecting some questions to answer. OK, first question. What is contingency management? Contingency management is a behavioral treatment that it was covered in depth in one of the other webinars, if you would like to learn even more about it. But in brief, it's a method of reinforcing behaviors that incentivizing behaviors that you wish to reinforce. And it's commonly applied in stimulant use disorder as vouchers or gift cards, money given for methamphetamine or cocaine negative urine drug screens. It can be integrated in an intensive outpatient program where individuals are submitting urine drug screens as part of their existing treatment. It is endorsed nationally by the VA. It's not widely available in many settings because reimbursement and implementation challenges California, we now have a system to receive reimbursement for contingency management. But there are many applications and methods of administering contingency management. But in short, it's providing incentives for behavior that you are seeking to change. And in the case of stimulant use disorder has been found to be very effective over the course of treatment. And sometimes it's a 12 week or 16 week program. Why is modafinil not recommended for treatment of cocaine use disorder in individuals with co-occurring alcohol use disorder? The mechanism and reasons for this are not known. These are findings that were replicated in a couple of studies. I don't think we can conclude that it can't be used in individuals with co-occurring alcohol use disorder, but the signals were certainly stronger in the group that did not have co-occurring alcohol use disorder. But mechanistically, we don't fully understand the reasons. What about NPs or PAs prescribing psychostimulants? Is there a reason to exclude them? We do have, we're very aware that the guidelines, when you publish practice guidelines, there's a chance that people with varying expertise or training may say, oh, this guideline says you can do this or that. But we really want to be careful that individuals prescribing stimulants, which are the most controlled medication as Schedule II for the treatment of stimulant use disorder, that there has been addiction board certification or commensurate training to be able to adequately monitor and assess risks and benefits, really to mitigate harms, especially given that these medications are not approved. The literature is not robust for any of these medication options. There's always going to be some risk and benefit when prescribing a controlled stimulant medication to somebody with stimulant use disorder, taking those signals of efficacy in mind. I'm moving my box here. Would you ever consider bupropion doses higher than 450 milligrams per day for the treatment of methamphetamine use disorder? Has that been studied? Understanding seizure threshold for doses higher than 450. Yeah, I wouldn't prescribe higher than 450, and I don't typically prescribe it even for individuals who don't have stimulant use disorder due to the seizure warning and lack of study for these higher doses. And we know that stimulants can lower a seizure threshold in studies in which bupropion has been studied. There has not been concerns about increased adverse effects, but that's always a consideration to really mitigate and risk and minimize harms, maximize benefits. So I would keep at that 450 milligram cap. There is some discussion, however, about psychostimulants for the treatment of stimulant use disorder that perhaps in the studies that we have, dosing has not been high enough. And in the standard dose range, it really may not be adequately addressing the symptoms and tolerance developed by somebody who is using methamphetamine and perhaps higher than standard doses, which are also used sometimes off-label for other indicated conditions, might be more effective. And that's mentioned in the guideline as well. What is the theory about potential mechanism of action for mirtazapine and treatment of methamphetamine use disorder? That's a good question as well. This is a medication with serotonergic effects, but it also has indirect effects on the dopamine and norepinephrine levels. So indirectly increasing catecholamines may be the unique aspect of the mechanism of action for mirtazapine over standard SSRIs, which have not demonstrated signals of efficacy for stimulant use disorder. In fact, in at least one study, I can think of the methamphetamine use increased in the arm prescribed randomized to an SSRI. Also, mirtazapine is uniquely relaxing and sedating. It's dosed at bedtime, helps with sleep and anxiety. This may be another mechanism or at least symptom relief that may be very beneficial, particularly in the early abstinence period when withdrawal symptoms and early abstinence and symptoms from methamphetamine, mirtazapine may be targeting those effectively. This is what I'm thinking. We have time for about one or two more. Have you seen abuse of bupropion? I'm surprised to have at least two patients taking excess amounts of this medication. Like many medications, it can be misused. We've definitely heard of this in incarcerated settings and even non-incarcerated settings. I prescribe a lot of bupropion in individuals with substance use disorder. I haven't yet had that experience, but I've certainly heard of it. And same with many other medications we prescribe. Amphetamine, for example, gabapentin, but when indicated, we use them, we monitor, we try to have an informed consent process. Why was disulfiram for treatment of cocaine use disorder not included in the guidelines? Disulfiram is mentioned in the guidelines as a medication for which there was insufficient evidence to make a recommendation. And or some of the evidence is mixed, but it is very good point that I do acknowledge there is some evidence for disulfiram, but mixed and insufficient to make a recommendation around its use. These are great questions. I'm trying to take one more that's fast. Doses of modafinil that would be recommended for cocaine use disorder. In the studies, there've been doses ranging from 200 to 400 that were studied. And one trial was just 400 with the positive signal in those without alcohol use disorder. In another study that actually compared doses, they found no difference. So I would favor a more standard dosing of 200 milligrams per day, because there's no evidence that 400 is superior. However, like our other medications, we do sometimes tailor and adjust dosing based on tolerability and efficacy. Okay, we are out of time for questions. Thank you for such an interesting webinar, as interactive as we could make it in this setting and for your participation today. I'm going to turn this back to Taline to wrap up. Thank you so much, Dr. Mooney. You can go to the next slide. I wanna thank you all for attending today's session. I do wanna remind you that this is the last webinar of a series of four, and this webinar as well as the previous three are available on demand for free on ASAM's e-learning center. Next slide, please. And before we close, I did want to mention how to claim CE credit. So you will need to log into your ASAM account and complete the evaluation through the e-learning center in order to claim credit. You will also receive an email tomorrow regarding claiming credit. Next slide. And should you have any questions, you can always reach out to the education department at education at ASAM.org or 301-656-3920. Next slide. Thank you all so much for coming and we hope you enjoyed this webinar series. Take care. Thanks everyone.

Medication Management

Stimulant Use Disorder

ASAM

AAAP

Evidence-Based Prevention

Behavioral Treatments

Pharmacotherapies

Bupropion

Naltrexone

Methylphenidate