Hi, I'm Derek Blevins. I'm an addiction psychiatrist and assistant professor of psychiatry at Columbia University, and this is the final fourth webinar in this series titled Integrating Screening, Brief Interventions and Treatment for Stimulant Use Disorder During Buprenorphine Treatment for Opioid Use Disorder in Primary Care. And this project is sponsored by the Opioid Response Network, which assists states, organizations, and individuals by providing education and training locally to address the opioid crisis and stimulant use, and technical assistance is available to support the evidence-based harm reduction, prevention, treatment, and recovery of opioid use disorder and stimulant use disorders. The ORN provides local, experienced consultants in prevention, treatment, and recovery to communities and organizations to help address the opioid crisis and stimulant use. ORN accepts requests for education and training, and each state or territory has a designated team led by a regional coordinator who's an expert in implementing evidence-based practices. To ask questions or submit a technical assistance request, you can visit the ORN website, email ORN at tripleap.org, or call 401-270-5900. And here is the funding statement for ORN, which is funded by SAMHSA. And the overall mission of ORN is to provide training and education via local experts to enhance harm reduction, prevention, treatment, especially medications like buprenorphine, naltrexone, and methadone, and recovery efforts across the country addressing state and local specific needs. So the final topic in this series is Pharmacologic Treatment Approaches for Stimulant Use Disorder. And as a disclaimer, there are no FDA-approved medications for stimulant use disorder, so all medications discussed in that context are presented as off-label. As an overview, we'll talk about some of the pharmacologic targets for stimulant use disorder, talk about some of the evidence for MOUD, medications for opioid use disorder, and stimulant use disorder, and then we'll talk about some of the specific off-label medications, which include classes of medications like antidepressants, antiepileptics, psychostimulants, anti-craving medications, and then different combinations of medications. So in terms of the pharmacologic targets, so there are multiple neurotransmitter systems involved in the development and maintenance of addiction, as well as withdrawal processes. Cocaine, methamphetamine, amphetamine, and methylphenidate all directly increase dopamine, which results in euphoria and reward. And glutamate is a really important neurotransmitter that's involved in the maintenance of addiction. Other neurotransmitter systems include norepinephrine, serotonin, and GABA. And when we think about medications for opioid use disorder and stimulant use disorder, there are a few interesting features of methadone and buprenorphine that would potentially make them treatment options for stimulant use disorder or may improve stimulant use outcomes. So for methadone, when we're using it to treat OUD, it is, of course, because it's a full MOUD agonist, but it also has this additional mechanism of being an NMDAR antagonist. So an NMDA receptor antagonist, which results in glutamatergic modulation. And this may have some effects on stimulant use disorder. Buprenorphine, similarly for OUD, is a mu-opioid agonist, but a partial mu-opioid agonist. And then for stimulant use disorder, it may also have some effects by blocking the kappa opioid receptor and blocking dynorphin from having effects. And these are a couple of slides that we saw earlier in this series. This one was the systematic review and meta-analysis of medications for stimulant use disorder, specifically among patients with opioid use disorder. And it looked at 34 different trials. The results of this meta-analysis were that there were no differences in the different medications that were tried for stimulant use disorder in terms of cocaine abstinence. They did observe that antidepressants and disulfiram seemed to worsen the retention. Again, this is among patients with OUD. And stimulants, psychostimulants, may have reduced cocaine use in these trials. And then when they compared actually methadone and buprenorphine head-to-head, they showed that methadone resulted in more cocaine abstinence than buprenorphine did. Another trial, so a different methodology. This was a systematic review and meta-analysis of buprenorphine versus methadone for opioid use disorder. So they were looking at primarily opioid use disorder outcomes. They showed that retention was higher with methadone. There were less opioid-positive urines, actually, with buprenorphine, but specifically in the randomized controlled trials. And in some secondary analysis, they also observed that some other outcomes were reduced in the buprenorphine group specifically. And one of those was cocaine use. They also observed reduced opioid cravings, reduced anxiety, and reduced cardiac dysfunction in the buprenorphine group compared to the methadone group. So really, when you look at these two studies, while the outcomes were slightly different, one seeming to indicate that methadone results in more cocaine abstinence, while this study indicating that buprenorphine resulted in less cocaine use, the takeaway point here really is that medication treatment for OUD on its own can be an effective treatment to address stimulant issues or stimulant use. So patients with comorbid stimulant use and opioid use disorder do better on medication for OUD in multiple domains, and appropriate medication treatment of OUD, including at adequate doses, may help patients reduce stimulant use without adding an off-label medication for stimulant use disorder. So when we think about stimulant use disorder treatment specifically for medications, there are no FDA-approved medications for either cocaine or methamphetamine use disorder. There have been more than 60 trials of medications that have been done for cocaine use disorder, and many of those have been tried for methamphetamine. There are some problems related to outcome measures for stimulant use disorder trials compared to alcohol, opioid, or tobacco use disorder medication trials. And just some of those things are varying focus on abstinence versus reduction and how much reduction is a significant enough reduction of cocaine or methamphetamine use to say that it is a positive outcome. These studies have very high dropout rates, often as high as 70% or more, and the meta-analyses are difficult to interpret due to a small number of trials with variable outcome measures. So this makes it more challenging to really understand the landscape of medication treatments for stimulant use disorders. Some of the clinical considerations, you know, as we're thinking about potentially prescribing an off-label medication for a stimulant use disorder. So first is what is the target? Are we aiming to reduce the patient's cravings for cocaine, to reduce their subjective drug response so that they take, if they take the cocaine, they don't feel the same euphoria or the same high, or to minimize or reduce withdrawal symptoms so that they're less likely to relapse. What's the comorbidity? So do they have another substance use disorder, alcohol, opioids, or tobacco, again, are three that have FDA approved medication treatment options. Do they have other psychiatric comorbidity like depression or ADHD? Do they have any other medical comorbidity like seizure disorder or migraines? And then how do we measure the impact of treatment if we do start an off-label treatment? Is the goal abstinence? Is the goal improvement of functioning or is the goal improvement of quality of life? And then how do we measure each of those things? And if the goal is less than abstinence, so if the goal is moderation, is that even safe? Is that something that is something that we can support as clinicians specifically considering that some of the stimulant drug supply, particularly cocaine, has been adulterated with fentanyl and there have been overdoses associated with fentanyl adulterated cocaine among people that don't have tolerance to opioids. And then levamisole is also a common adulterant. This is an anti-helminthic agent that we talked about in one of the former webinars that's often used to cut cocaine. And then does stimulant use lead to other substance use or vice versa? So does the person start with using cocaine and ultimately use methamphetamine or vice versa? Do they use GHB for other reasons either to come down off of the cocaine or because they're using it in a sexual context or partying? Similar question about ketamine, benzodiazepines. It's not uncommon for people to use benzodiazepines when they feel like they have used too much cocaine and are experiencing some of the adverse effects or alcohol along with similar contexts, starting with alcohol, using more cocaine to be able to drink more, and then this sort of cycle of repeated alcohol and cocaine doses. So these are all things to consider when we're thinking about prescribing an off-label medication for stimulant use. So if you go to UpToDate, what you'll see is an algorithm that is proposed of medications to treat cocaine use disorder in this order. So first, starting with topiramate, second, long-acting amphetamines, third, the combination of topiramate and long-acting amphetamines, and then fourth is the other medications. And the three that I will talk some about are modafinil, disulfiram, and antidepressants. So we're going to really focus on these particular medications in this section of the talk for cocaine use disorder. So topiramate is FDA approved for seizures, migraines, and obesity when it's combined with phentermine, which is another type of stimulant, a lower schedule stimulant. It's used off-label to treat mood issues, medication associated weight gain, binge eating, and alcohol use disorder, and actually has similar effect size as naltrexone for alcohol use disorder, though it does not have the FDA approval. The assumed mechanism we don't exactly know of topiramate is that it enhances GABA functioning and blocks glutamate release to the AMPA receptor. So again, remember that glutamate and the NMDA system are important in the regulation of addiction, so this may modify that in some way. However, it does have a lot of adverse effects. Lots of patients report cognitive dulling, having difficulty finding words, more difficulty in school or at their jobs, and it can also cause a number of physical side effects, including kidney stones and acute angle closure glaucoma. It has a long list of side effects in addition to these, but these are often concerns that patients have or things that we need to consider when we're prescribing topiramate. And then if we're thinking specifically about adding this to the medication regimen of patients who are already on buprenorphine for OUD, one thing to consider is that both of these medications can cause some CNS depression. This is not profound with buprenorphine certainly, and typically patients develop some tolerance to that, but when you're combining the medications, it is one thing to keep in mind, especially if the patient is driving or operating heavy machinery, things like that. So looking at some of the evidence for topiramate for cocaine use, there was a trial that showed that patients had more cocaine non-use days, so about 13% versus 5%, and more cocaine-free weeks, so 16% of cocaine-free weeks versus 5.8. Another study showed more continuous abstinence from cocaine in just a cocaine use disorder population and also in a population that had comorbid alcohol use disorder. There was a secondary analysis done that showed greater response with higher baseline impulsiveness So topiramate has been used, and you see some of the other off-label uses of it, that these are disorders that share at least one thing in common is that there is some loss of impulse control. So people with higher baseline impulsiveness actually benefited more from topiramate in terms of their cocaine use outcomes. When it's prescribed, we usually start with 25 to 50 mg per day, erring on the side of starting at 25 mg per day most likely to improve the tolerability, especially the cognitive side effects, and titrating it very slowly, so 25 mg per week with a target dose between 150 to 300 mg per day, and usually that does necessitate split dosing just for tolerability when you get to those higher doses. After the person achieves that 150 to 300 mg, the standard practice would be to evaluate that for about three months for an effect, and if there is, to continue it longer term, but if there's not, to taper it by 50 mg per week. So the overall message here with topiramate is that it may help with reduction in abstinence from cocaine, but tolerability may be treatment limiting. The next category or class of medications I'll talk about are amphetamines and methylphenidate. So in that algorithm, the second option was long-acting amphetamines, but I do want to include some evidence around methylphenidate in this discussion as well, since they're both prescribed psychostimulants. So these are medications that are approved for ADHD, narcolepsy, and cancer fatigue, and are sometimes used off-label for treatment-resistant depression. The adverse effect profile is important for stimulants. So one is there is a FDA black box warning for amphetamines specifically for sudden death, likely through some cardiac mechanism, but this is the wording of the black box warning for amphetamines that does not exist for methylphenidate. Both of these medications can be associated with addiction or dependency. They can cause cardiovascular issues or hypertension and appetite or weight loss. When you add amphetamine to buprenorphine, it's actually possible that you would see an increased analgesic response from the buprenorphine. So the idea of prescribing amphetamine or methylphenidate for cocaine use disorder is similar to agonist therapy for OUD. So similar to prescribing buprenorphine or methadone for OUD, but there are also a lot of differences. When you look at multiple different trials, and that's what this graph on the right here is showing, it does look like amphetamines are better than methylphenidate for treating cocaine use disorder. So you see in this top line here, this diamond shape falling on the side of favoring the active drug, whereas you see similar for modafinil that we'll talk about and falling slightly on the side of favoring placebo for methylphenidate. There are better outcomes with higher dosing for cocaine use disorder, and I'll talk about that a little bit more on a future slide. But as I said, there are a lot of differences compared to agonist therapy for opioid use disorder, like safety and diversion concerns. There are not clinics set up where people come and get dosed once a day as they do with methadone, and it does not have the same sort of partial agonist effect of buprenorphine. You're going to have the same sort of full effect of increasing dopamine, especially at higher doses of amphetamines. And then really thinking about the differences between long and short acting formulations where the trials have focused on long acting formulations with this idea of it being more like agonist treatment for opioid use disorder and with less increases and decreases in the amount of dopamine and potentially making the longer acting formulations less addictive and also usually having a lower lower street price. So amphetamine, again, I want to focus on this for cocaine, just because most of the research has been has been more positive for amphetamine and methylphenidate, there was a study that showed that it reduced cocaine positive urines at one month in both d-amphetamine, which is dextroamphetamine, sustained release groups. So they had two different dose dose ranges, 15 to 30 milligrams and 30 to 60 milligrams. But there was significantly more reduction in subsequent months on the higher dose and that 30 to 60 milligram range. And dextroamphetamine is one of the more active enantiomer in the mixed amphetamine salt. Another study showed reduced cocaine positive urines, so on a sustained release formulation, 20, 29 percent compared to 66 percent on the immediate release and 60 percent on a placebo. Now, there wasn't a statistically significant difference between immediate release and the placebo, even though the immediate release number appears it appears that it's worse than a placebo. But this was not a statistically significant difference. But we do see a lot fewer cocaine positive urines in this trial on the sustained release formulation. And then a trial looking at concurrent methadone and heroin assisted treatment. So this was done not in the United States and in a country where heroin assisted treatment is an available option for people with OUD and showed that that the amphetamine reduced the days of cocaine use from 45 or sorry, 45 versus 61 days. Another study looked at comorbid ADHD and showed that the amphetamine mixed amphetamine salt improved continuous abstinence in the last three weeks on mixed amphetamine salts at 80 milligrams was 30 percent and 60 milligrams was 18 percent compared to 7 percent on placebo. So again, this is 30 percent of people on the higher dose received three weeks of continuous abstinence compared to 18 percent on the lower dose and 7 percent in the placebo group. So. The most common longer acting formulation of amphetamines on the market is mixed amphetamine salts extended release. The typical regimen would be to start 20 milligrams per day and increase by 10 milligrams per week up to 60 milligrams per day. The literature does support benefits of doses greater than 60 milligrams per day, although the 60 milligrams per day is the FDA recommended maximum, and this does really require more safety precautions, especially around cardiovascular parameters. So after the person is titrated up to the 60 milligrams per day, you would evaluate for three months and then if it's ineffective, taper it over several weeks. There is a role for your toxicology testing to monitor compliance and effectiveness in a similar way that we use your intoxicology and buprenorphine treatment for OUD. And these cardiovascular and hypertension risks, particularly if the person is continuing to use cocaine, so you want to monitor with an EKG and pretty regular blood pressure and pulse checks. Lisdexamphetamine is a long-acting prodrug, so this means it requires oral ingestion for it to become activated, so it can't be snorted, it can't be, or if it's snorted it doesn't become activated. But one thing to know here is that the maximum FDA-approved dose of Lisdexamphetamine, which is 70 milligrams, is a lower equivalency than the max FDA dose of mixed amphetamine salts extended release. So the 60 milligrams of the mixed amphetamine salts, the equivalent doses of that is much higher than what you can achieve with the Lisdexamphetamine. There can be challenges with insurance coverages, particularly for long-acting formulations and using them off-label. Insurance may require that patient have a diagnosis of ADHD in order for them to cover this medication because of cost. So the bottom line really for amphetamines is that long-acting formulations may help with the general, or with general cocaine use disorder and with subpopulations. So people on methadone maintenance for OUD and patients with comorbid ADHD, that really does require close monitoring. And then the third option in that algorithm was the combination of amphetamine and tapiramide. So there, in the couple of clinical trials that have been done, the doses were 60 milligrams of mixed amphetamine salts and 100 milligrams twice a day of tapiramide. The first trial demonstrated a 33% of the patients with any three weeks of continuous abstinence during the trial. And that was compared to 17% of patients that were on the placebo combination. So placebo amphetamine and placebo tapiramide. A replication trial demonstrated similar positive results. A lower number achieved abstinence, but an important distinction between those two trials is that this was during the last three weeks of the trial. And this is generally considered a higher bar to consolidate abstinence in the last three weeks of the trial. So 14% achieved abstinence in that study compared to 0% in the double placebo arm. A couple of other things to know about this trial is that it did require people have nine out of 28 days of cocaine use at baseline for enrollment. So they were more severe cocaine users. And 20% of people in the active group did discontinue or were discontinued from the study because of cardiac safety parameters being exceeded. Typically, this is related to blood pressure and pulse. So for amphetamine and tapiramide, it does appear that more severe use does result in greater improvement. But we're talking about two medications with tolerability issues that may create create some additional challenges and need for more monitoring like EKG, blood pressure and labs. And another thing in these trials that the dose titration for the tapiramide is much slower. So it takes about six weeks to achieve that 100 milligrams twice a day, compared to titrating the amphetamine up over a course of two weeks. Okay, and now shift to talking about modafinil, which was another sort of in the fourth, fourth option of other medications that you might consider for cocaine use disorder. It's FDA approved for narcolepsy, shift work sleep disorder and obstructive sleep apnea as an adjunct. And then has some off label uses in ADHD, fatigue from depression or multiple sclerosis, and bipolar depression. The typical dose range is 200 to 400 milligrams and usually taken once a day in the morning. That presumed mechanism we don't exactly know is that it's a dopamine transporter inhibitor. So increasing the amount of dopamine available in synapse. It does have a few adverse effects, headache and GI or appetite changes when combining it with buprenorphine. So if it's being used in patients on buprenorphine for OUD, you may see a moderate reduction of buprenorphine levels. It is an inducer of the cytochrome P3A4 enzyme, which which metabolizes buprenorphine. So you would want to monitor for any potential withdrawal or increase in craving for opioids, especially if the person is on a lower dose, you know, in that 8 to 12 milligram range of buprenorphine rather than, you know, 16 to 24 milligram range. So some of the trials for modafinil demonstrated more cocaine for urine samples, so 42% versus 22% on 400 milligrams per day for eight weeks. However, a follow up trial to this was actually negative. When they removed patients that had comorbid alcohol use disorder, though, they did see a positive statistically significant difference between them and dafnil placebo groups. So this then was a trial that was conducted with patients without comorbid alcohol use disorder. And they did again demonstrate more continuous abstinence, so 23% of the sample versus 9% on 300 milligrams per day for eight weeks. Though another trial, a range from 200 to 400 milligrams for cocaine use disorder without alcohol use disorder was again negative. And this, the authors hypothesized could possibly have been related to greater cocaine use severity at baseline they had, they tested positive. And this seemed to be associated with poor outcomes in the modafinil group. So lots of mixed evidence, studies, certainly that looked very positive and then follow up trials that that contradicted those results. So modafinil does not appear to be effective for all populations, but it may be an option for some populations, in particular those without alcohol use disorder, men and some of the secondary analyses seem to benefit more than women. And those with less severe cocaine use disorder may benefit more. It does have less abuse potential and less adverse effects than traditional stimulants. So it may make it a more appealing option as a first medication to try. Some of the the prior authorization issue may exist from modafinil, although it is available as a generic. And, in my experience has been easier for patients to access than long acting stimulants in terms of cost. And then disulfiram is another medication that was in this sort of other group in the algorithm, it's an FDA approved medication for alcohol use disorder, and is prescribed at 500 milligrams a day for the first week and then 250 milligrams per day. The mechanism being that it's an irreversible irreversible aldehyde dehydrogenase inhibitor. So you get backup of acetaldehyde, which causes the negative effects of that disulfiram reaction. Some of the adverse effects are liver toxicity, neuropathy or neuritis, and then some lower risk of mania or psychosis. When combining with buprenorphine, there's not really any specific interaction between disulfiram and buprenorphine. For off label indications, really the only one is for cocaine use disorder through a different mechanism. So it's presumed to be a dopamine beta hydroxylase inhibitor, which prevents the breakdown of dopamine so allowing more dopamine to be available in synapse. The evidence though is pretty limited, similar to modafinil initial positive early trials and then repeated trials were not significant. And another important thing of course is that the patient has to commit to total abstinence from alcohol. They cannot have had any alcohol 12 hours before starting disulfiram and up to two weeks after discontinuing it. So if a person is not interested in in total abstinence from alcohol, this would not be a medication option for them. But I think it is important to consider the potential relationship between alcohol and cocaine use. As I mentioned before, it's not uncommon for one substance, the use of one substance to lead to another and alcohol and cocaine do seem to be pretty intimately tied to each other in that regard. So I would really consider if there's a relationship between alcohol and cocaine use for an individual patient and recognizing that absence from alcohol, even if the person doesn't have an alcohol use disorder may help with abstinence or reduction in cocaine use. And as a side note, combining alcohol and cocaine may actually worsen some of the physical effects of cocaine by prolonging its half-life. You result in this cocaethylene being produced when you combine cocaine and alcohol. And this is another potential talking point when you're having those motivational interviewing discussions with patients. And then the last medication that I will talk about for cocaine use disorder before talking about methamphetamine use disorder is bupropion. Remember in the algorithm, it mentioned antidepressants. So this would fit into that category. It is FDA approved for depression and for smoking cessation. It is used off label sometimes for ADHD. And the dose, so there are a few different formulations of bupropion. There's a sustained release, that's a twice a day dose and an extended release or sometimes called the XL formulation that's once a day. So for the XL or extended release, it's 150 milligrams per day for the first three days at least, and then increasing to 300 milligrams per day for two to three weeks. And then it can be maximized at 450 milligrams per day. The sustained release, again, the twice a day is started at 150 milligrams in the morning for three days, then 150 milligrams twice a day, and then can be titrated up to 200 milligrams twice a day after several weeks. And just as a note, the sustained release formulation is actually the one that was given the FDA approval for smoking cessation. Some of the common adverse effects, it can cause some insomnia, agitation or anxiety, and there is a risk of seizures, especially among patients with a seizure disorder or history of seizure, or at higher doses, especially doses above the FDA recommended max. The mechanism of bupropion is it's a norepinephrine dopamine reuptake inhibitor, sometimes called an NDRI, and also is a nicotine acetylcholine receptor agonist. And probably both of these mechanisms, but in particular, this nicotine receptor agonist mechanism is what makes it effective for smoking cessation. No interactions when combined with buprenorphine. There is pretty limited evidence for its use in cocaine use disorder, aside from a possible effect from patients who are depressed at baseline. The tolerability and safety profile, though, is much more appealing than some other prescription stimulants. So it may be useful with comorbid depression without a severe comorbid anxiety, and or with comorbid cigarette smoking and among those with lower severity cocaine use disorder. So this bupropion is often tried kind of as a first line, especially in non addiction specialty settings. One because of the safety profile, and the concerns about diversion and misuse, but also because it doesn't really require any additional monitoring. Okay, now switching gears to some of the evidence for methamphetamine use disorder, which is a bit more scant than for cocaine use disorder. But if you go to up to date, you'll see a similar recommendation for an order of medications to try. So the first is the combination of bupropion that we just talked about and naltrexone. The second is mirtazapine, which is a antidepressant sort of in its own category. And then the third is methylphenidate. So another prescription stimulant, I just put an asterisk on the bupropion plus naltrexone combination, because of course, this will be contraindicated if patients are coming to you for their buprenorphine prescription, because it's an opioid blocker. So it would cause them to go into withdrawal or with methadone. So this was just information that was presented on a previous slide about bupropion, again, for depression, smoking, and no interactions with buprenorphine. For naltrexone, it is on its own FDA approved for alcohol use disorder and opioid use disorder. Some of the adverse effects are liver toxicity and injection site reactions or infection for the long acting once monthly injection, upset stomach, GI issues and anxiety or insomnia. It is a new opioid antagonist. And again, if the person is concurrently being prescribed buprenorphine, it would be contraindicated. So there was a study that was published fairly recently, looking at the combination of bupropion and extended release naltrexone. So they use not the oral version, but the injectable that's usually given once a month at 380 milligrams. But one difference in this study is they did give the injection every three weeks instead of every month. And the extended release bupropion or XL formulation was titrated up to 450 milligrams per day. They started at 150 and actually titrated it to 450 in three days, so faster than what the FDA label recommends. They demonstrated greater end of study abstinence from methamphetamine, so 14% versus two and a half percent. And you can see that the absolute number of 14% abstinence on its own, of course, it does not sound extremely impressive. But when you compare that to two and a half percent in the placebo group, it is a quite a significant difference. So this is a possible strategy for comorbid methamphetamine and opioid use disorder, if the patient is motivated to be on extended release naltrexone or is already on it, but likely is not a justification to switch from buprenorphine to to, sorry, from buprenorphine to this regimen, if their opioid use disorder is stable on buprenorphine. Now, there have been some studies done prior to this study that looked at bupropion alone, that the studies were the sustained release, so the twice a day dose at 150 milligrams. And they did show that they that it may be helpful for people with lower methamphetamine use, but probably not helpful for people with moderate or severe methamphetamine use. So the second medication in the methamphetamine algorithm was mirtazapine. It is FDA approved for depression and is used off label for insomnia and anxiety. Typical dose range from 15 to 45 milligrams taken at night because it is quite sedating. It can cause a significant amount of weight gain quite a bit more than most other antidepressants and can also cause dyslipidemia and sedation, which is sometimes why we prescribe it to help people with sleep. The mechanism is that it's a central alpha-2 antagonist and this results in increases in norepinephrine and serotonin. When combined with buprenorphine, like other CNS depressants, there is some possibility of increasing sedation. And just as a note, it does have an opposing mechanism with clonidine. So clonidine is an alpha-2 agonist. So if you're using clonidine for withdrawal, then it may not make sense to use clonidine and mirtazapine simultaneously. So a few studies have shown improvements in specific populations. So this study showed a reduction in positive urine samples in two different trials. So 29% on the mirtazapine versus 4% in one trial and 19% versus 3% in the other trial. And these were among sexually active men who have sex with men and among cis men and trans women who have sex with men. Though it is also important to note that these trials did not demonstrate great adherence to the medication. So it was less than 50% in the trials. For dosing, you usually started at 15 milligrams for a week and then go up to 30 milligrams nightly. That has been the protocol in these trials also. Evaluate for three to six months. You want to monitor their weight and lipid profile. So mirtazapine certainly you want to consider for depressed and or sexual minority populations and you will monitor for adherence to the medication and any weight gain or consequences of weight gain like dyslipidemia. And then finally, for a methamphetamine use disorder, I want to talk a little about methylphenidate. So it's FDA approved for ADHD and narcolepsy. Use off label for treatment resistant depression and cancer fatigue. And the orosmethylphenidate, one of the formulations, there are many formulations of methylphenidate. This is one of the long acting versions and the dose range is 18 to 72 milligrams per day. Adverse effects like other stimulants are like amphetamine, cardiovascular hypertension, appetite or weight loss and potential for addiction or physical dependency. And there's no interaction with buprenorphine. So this is different than amphetamines. There was some potential for increasing analgesia on amphetamines, but that is not an interaction with methylphenidate and buprenorphine. So in trials, small reductions in positive urines have been demonstrated in a few studies, and it may benefit those with heavier methamphetamine use more than those with lower use. So this is the opposite of bupropion where we saw that it was maybe helpful for lower methamphetamine users, but not for higher. Methylphenidate may be more beneficial for those with heavier methamphetamine use. And the long acting osmotic controlled release delivery system, this orosmethylphenidate may have some lower abuse potential and could be considered for those with comorbid ADHD or having failed other treatment options for methamphetamine use disorder. So in summary, cocaine and methamphetamine use disorders have no FDA approved treatments. Buprenorphine and methadone have demonstrated positive effects on cocaine use outcomes among people with OUD. For cocaine use disorder, topiramate, long acting amphetamines and the combination of those two drugs have demonstrated the most robust evidence, while modafinil, bupropion and disulfiram may benefit some patients. For methamphetamine use disorder, the combination of bupropion plus naltrexone, mirtazapine and methylphenidate have demonstrated some evidence. And patient physical or mental health comorbidity and goals may help guide off label medication trials. And some of these medications require much more safety monitoring due to adverse effects and diversion or addiction risks. And these are important considerations when considering what medication to start or to try to treat a patient's stimulant use disorder off label. All right, and that completes the four series of this, this webinar series. And I'll just show some references slides. Thank you.

Pharmacologic Treatment Approaches

Derek Blevins

MD

Assistant Professor of Psychiatry

Columbia University

webinar

stimulant use disorder

MOUD