I'm Derek Plevens, I'm an addiction psychiatrist and an assistant professor at Columbia University, and this will be a series of webinars that will focus on stimulant use during OUD treatment. The title of the webinar series is Integrating Screening Brief Interventions and Treatment for Stimulant Use Disorder During Buprenorphine Treatment for Opioid Use Disorder in Primary Care. And this project is supported by the Opioid Response Network. The Opioid Response Network is SAMHSA-funded. It assists states, organizations, and individuals by providing the education and training they need locally to address the opioid crisis and stimulant use. Technical assistance is available to support the evidence-based harm reduction, prevention, treatment, and recovery of opioid use disorders 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. Each state or territory has a designated team led by a regional coordinator who is an expert in implementing evidence-based practices. To ask questions or submit a technical assistance request, you can visit the Opioid Response Network website that's listed here, email ORN at AAAP.org, or call 401-270-5900. Here is the funding statement for ORN. And finally, the overall mission 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. And these will be the four different talks that will be covered in this webinar series. We'll start out today with Introduction, Stimulant Use, and OUD Treatment. That will be followed by Screening, Diagnosis, and Brief Intervention, then Behavioral Treatment Approaches, and finally, Pharmacologic Treatment Approaches. So to start with today, we'll talk about what stimulants are, what defines a stimulant, stimulant pharmacology, stimulant use disorder neurobiology, some of the epidemiology, and then the impacts of stimulant use or stimulant use disorder on physical health, mental health, and OUD treatment. So what is a stimulant? There are a couple of different ways to define this. One is the DEA's definition of a stimulant, which is a substance or drug that speeds up the body's systems. And if you look at the four different DEA schedules, you'll see in Schedule 1 that includes drugs like cathinones or bath salts, as well as MDMA. And just as a note here, MDMA has both stimulant and hallucinogenic or empathogenic properties, but it does in some ways act like a stimulant. Schedule 2 drugs include amphetamine, methylphenidate, cocaine, and methamphetamine. Schedule 3 include drugs like benzephetamine and fen-dimetrazine, both of which are appetite suppressants or have been prescribed for weight loss. And then Schedule 4 drugs include modafinil, armodafinil, and phentermine. NSDA has a different way of describing, defining stimulants. So cocaine, methamphetamine, and prescription stimulants act in similar ways to stimulate the brain. These drugs can produce stimulant effects such as increased alertness, wakefulness, or energy, and physical side effects of rapid or irregular heartbeat or increased blood pressure and temperature. And these are some notes on what is really meant by the DEA scheduling. So Schedule 1 drugs have no currently accepted medical use and a high potential for abuse. Schedule 2 drugs have high potential for abuse and potentially lead to severe psychological or physical dependence and are considered dangerous, but may have medical or do have some medical uses. Schedule 3 have moderate to low potential for physical and psychological dependence, and Schedule 4 drugs have low potential for abuse and low risk of dependence. So here are the main examples of stimulants. So you see here powder cocaine, oppressed, what is sold as Adderall or amphetamine pill, crack cocaine, methamphetamine, and prescription stimulant pills. When we think about the pharmacology of stimulants, so cocaine and methylphenidate act actually in the same way, the same mechanism. They both block the dopamine transporter pump. So the dopamine transporter that's on the presynaptic neuron that pulls dopamine back into the synapse so that it doesn't remain in the synapse is blocked by cocaine and methylphenidate. And this results in an increase in dopamine in the synaptic cleft. Amphetamines including methamphetamine also have the same mechanism. They block the dopamine transporter pump, but they have two additional mechanisms that do differentiate them from cocaine and methylphenidate. So at higher doses in particular, they reverse the dopamine transporter pump, meaning they put more dopamine into the synapse instead of pulling it back into the presynaptic neuron. They also inhibit VMAT2, which is the transporter that pulls dopamine in the presynaptic neuron into the vesicle. So more of the dopamine is available in the cytoplasm that can then be pushed out into the synapse. There are some other kind of practical differences, pharmacologic and practical differences between methamphetamine and cocaine that are important clinically. So both are stimulants. Methamphetamine also acts as a local anesthetic. Methamphetamine is entirely man-made, whereas cocaine is derived from a plant. When someone smokes methamphetamine, it produces a very long-lasting high compared to smoking cocaine, which is a very intense but brief high. And the half-life of methamphetamine is much longer than cocaine. So about 50% of the drug is removed from the body in 12 hours compared to one hour for cocaine. Both increase dopamine and block dopamine, and methamphetamine blocks dopamine reuptake. Methamphetamine has pretty limited medical use for ADHD, narcolepsy, and weight loss. And cocaine's medical use is really limited to it being a local anesthetic that's used in some surgical procedures. In terms of the neurobiology, what does the brain look like after someone has used cocaine chronically over longer periods of time and often at higher doses? So one thing that we see is that cocaine reduces the orbitofrontal cortex functioning. So that's what you see here in this imaging of a control, so a person who does not have cocaine use disorder compared to someone who does have cocaine use disorder. And we see that area of the orbitofrontal cortex not lighting up as much in someone who has chronic cocaine use. This may lead to poor decision-making, inability to adapt to negative consequences of drug use, and a lack of self-insight. Another thing that we see of people that use cocaine chronically and at higher doses is reduced D2 receptor, D2 is a dopamine receptor, so reduced D2 receptor availability in the striatum, which is part of the brain's reward circuitry. And this may lead to low sensitivity to natural reinforcers. And this is likely due to prolonged cocaine exposure, but it's not possible to rule out an underlying vulnerability to the development of cocaine use disorder. And methamphetamine use disorder, we see similar changes in the brain. We see reduced binding of dopamine in the striatum, although this reduction in binding actually can be restored after 14 months of abstinence. So these changes that happen as a result of methamphetamine use disorder do not have to be permanent. They can be reversed with a period of abstinence. And now just to mention a few things about stimulant use and stimulant use epidemiology. So this is data from the NSDUH from 2022, the data are from 2021. And this is looking at past year illicit drug use. So not a drug use disorder, but illicit drug use. And not surprisingly, marijuana is the highest, so the highest number of past year users. And then as you go down the list, you see that cocaine, about 1.7% of the U.S. adult population used cocaine at all in the past year, compared to 1.3% used prescription stimulants and 0.9% used methamphetamine. And this data is pretty stable over the past number of years, with the exception of methamphetamine, which has increased from about 0.6% in 2017. So from 0.6 to 0.9 of past year methamphetamine use. There's not a lot of crossover between the types of stimulants that are used or misused. So among all CNS stimulant misusers, only 2.5% use all three. So methamphetamine, prescription stimulants, and cocaine. About a third used only cocaine, a fourth used prescription stimulants, and about 18% use methamphetamine. So the highest amount of crossover is actually between cocaine and prescription stimulants, which you see represented in the green, in the green shaded space. And that represents about 7.6% of all stimulant users. That's followed by about 5% who use or have used both cocaine and methamphetamine, and then 3% who have used methamphetamine and misused prescription stimulants. This is just to visualize cocaine use trends. So this goes from 2017 to 2020. And what we largely see is that past year use has been relatively stable, and maybe even some reduction in the 18 to 25 year old age group. However, we see the opposite is true in methamphetamine use trends, where we see increases overall among age 12 and up in past year methamphetamine use since 2017. And in particular, in the 26 and older age group, we see a pretty big jump of past year methamphetamine use. This data actually goes 2016 to 2019, not up to 2020. They don't have this data visualization available through NSDA. But just to point out that among lesbian, gay and bisexual adults, methamphetamine past year use is much higher. So this 3.6% bar that you see on the far right is in comparison to 0.8% in the overall population. So this is a very important difference among subpopulations of people who use stimulants and methamphetamine in particular. And then lastly, for prescription stimulant use, what we mostly see is the data are pretty stable. The 2021 data did show what appears to be a jump, but there was a change in the methodology of NSDA from 2020 to 2021, that they asked the questions differently. So you actually can't compare the most recent NSDA results for prescription stimulant misuse with prior years. So they essentially asked all people who are prescribed a stimulant to answer questions about misuse. And this reflects a jump in reported misuse. And now thinking about substance use disorder, not just substance use, and we also see that meth use disorder increased from 2016, where it was 0.3% to 0.4% in 2019, and now up to 0.6%. So we're seeing pretty significant increases in methamphetamine use disorder. Cocaine use disorder increased from 0.4% in 2019 to 0.5% in 2020. And that has been stable then in 2021. And again, if you compare years, it does look like prescription stimulant use disorder increased from 0.3% in 2020 up to 0.5%. But again, there were these methodological differences, so you can't actually compare those two numbers. But we are seeing significant increases in methamphetamine use disorder. And what does this mean in terms of the drug overdose crisis in the United States? We see that after synthetic opioids, primarily driven by fentanyl, that the next second and third categories of overdoses are psychostimulants and cocaine. So psychostimulants is this yellow-orangish line, and then cocaine is the orange line. And when we separate the two out, cocaine and methamphetamine, what we see is that cocaine and fentanyl combination deaths have really sharply risen since 2015, which you see here represented by this yellow line on the graph. Cocaine alone, cocaine overdose alone remains fairly stable, but it is higher than the 2008 to 2015 period. So it does appear that most of the cocaine-involved overdose deaths are being driven by the co-use or combination of fentanyl and cocaine. This is actually different than what we see with the methamphetamine data, that methamphetamine alone deaths have risen steadily since early 2010s. So that's what you see, this light green line on the graph, this increase since around 2010. But then we've also seen this really stark increase in combination of methamphetamine and fentanyl deaths since about 2016. And then very sharply from 2019 to 2021, again, you just see that this turn in the yellow line around 2019. So this is an issue when we're thinking about treating people that have opioid use disorder, because there is a lot of comorbidity between stimulant, in particular cocaine use, and opioid use disorder. And it can have impacts on, of course, physical and mental health, but also on the treatment of the opioid use disorder itself. So in this graph, what I'm showing here, the top line that's shaded in gray is just the general population rates of different substance use disorders. So we see again that 0.5% of the population has a cocaine use disorder of the general population. And then looking at three other sort of three different ways here. So one is heroin use disorder from NSDUH data that goes back a bit further that where they analyze the comorbidity prescription opioid use disorder from that same data set. And then the last line here is a VA sample of opioid patients with opioid use disorder. And what we see is that nicotine use is the most, nicotine use disorder is the most highly comorbid substance use disorder with opioid use disorders followed by alcohol in all of these groups. So heroin use disorder, prescription opioids overall and then the VA sample of opioid use disorder. And then after that for heroin use disorder the next highest is cocaine use disorder at about 20%. This is flipped for people who are prescription opioid use disorder. So we have a higher cannabis use disorder comorbidity followed by cocaine. But in this VA sample, this is consistent with the heroin use disorder comorbidity that first we see alcohol and then followed by cocaine as being the two higher substance use disorders in that sample. So this is really an issue because while nicotine and alcohol use disorders have some or a few different types of FDA approved treatments, we don't have FDA approved treatments for cocaine use disorder or for cannabis use disorder. So for nicotine use disorder of course nicotine replacement therapy, varenicline, bupropion and now repetitive transcranial magnetic stimulation are approved treatments. For alcohol use disorder, we have naltrexone, acamprosate and disulfiram, but for cocaine and cannabis, we do not have any medication or other types of FDA approved treatments. And why is this an even bigger problem? Is that there is an association with stimulant use and with overdose deaths among people who have opioid use disorder. So those with concurrent use of stimulants had more than twice the hazard of a fatal overdose compared to having opioid use disorder alone or using opioids alone. And that the hazard of death actually increases over time in that population, the people that use both opioids and stimulants. In this rural sample, about 63% co-use methamphetamine and opioids. And among those for non-fatal overdose deaths, there were 22% were co-users, 14% with just opioids and 6% with methamphetamine. And in addition to being at much higher risk of a non-fatal overdose death, they were much more likely to have tried and failed to access treatment. So 44% of the sample tried and failed to access treatment for their substance use disorder. And then when we think about the physical health impacts of stimulants and this is without the comorbid or concurrent contribution of opioids, they can cause weight loss or malnourishment. They can cause any number of cardiovascular effects, infectious disease, and in particular the risk of HIV infection and the acceleration of neuro AIDS development in that population. Other infectious diseases and sexually transmitted diseases, gastrointestinal issues that come from some of the cardiovascular effects, rhabdomyolysis that can lead to kidney failure, seizures, stroke, intracerebral hemorrhages, and then lung issues. And in particular, when we think about stimulants, we really think about the cardiovascular effects. And this I think was a very good graphic to understand why cocaine in particular is so problematic for the cardiovascular system. So at lower doses, we see this enhancement of sympathetic activity, which results in increased heart rate, increased blood pressure, increased contractility, and over time can lead to cardiac ischemia and ultimately infarction or death. Now, when someone uses cocaine at higher doses, we see this other effect of it reducing sodium transport. So it actually depresses some of the cardiovascular parameters, can lead to left ventricular dysfunction, arrhythmia, and QRS or QT prolongation. And then when you start combining these things, you really increase the risk of death from these effects of lower doses and also higher doses. Cocaine also causes vasoconstriction and platelet aggregation and clotting that can further contribute to the cardiovascular disease and death. So specifically for some treatment considerations, when someone has cocaine-associated chest pain, hypertension, or myocardial infarction, it's managed similarly as non-cocaine related with a few exceptions. So one is to avoid beta blockers. Beta blockers may worsen vasoconstriction by shunting norepinephrine to alpha adrenergic receptors. And typically the use of IV benzodiazepines is preferred over beta blockers for this reason. Nitrates may confer some additional benefits in this patient population compared to the non-cocaine-associated chest pain. And fentolamine is also useful for persistent hypertension in this population. You also want to think about avoiding QT prolongation meds and or monitor for QT prolongation, especially if someone is on medications that can prolong the QT interval. And more regular EKG and laboratory monitoring may be necessary in this population. And then thinking about some of the mental health impacts. So first is just the immediate impacts of stimulant intoxication. So it can be a euphoric experience, but it can also cause negative psychological experiences like anxiety, interpersonal sensitivity, tension, anger, or violence, or aggression, or impaired judgment. And the withdrawal state can look a lot like depression sometimes, can cause insomnia or hypersomnia, changes in appetite, changes in dreaming, fatigue, or low energy, psychomotor slowing, and in some cases can lead to suicidal ideation. And this is not uncommon to experience in an emergency room setting when someone comes in with cocaine withdrawal. And then beyond that, cocaine and methamphetamine can cause what we call stimulant-induced disorders. So these are DSM diagnoses that result in typically the chronic use of a stimulant that can lead to a psychotic disorder, bipolar disorder, depressive disorder, OCD, sleep disorder, sexual dysfunction, and mild neurocognitive disorder. So some of the things that we do know about cocaine or stimulants' mental health impacts that they worsen bipolar disorder. They worsen positive psychotic symptoms like paranoia, auditory hallucinations, and delusions. Methamphetamine can cause in particular a persisting psychosis that would last longer than we would normally expect, given our knowledge and understanding of the half-life of the drug, as well as sensitization, so that if someone uses even a much smaller amount, they may experience psychotic symptoms due to this phenomenon of desensitization with methamphetamine or with sensitization with methamphetamine. And then they can cause executive dysfunction, so problems with learning and memory, and those may have broad functional impacts, including limited progress in cognitive therapies and dropout from treatment. So some treatment considerations for the mental health aspect is consider underlying psychiatric disorders and treat those disorders when appropriate, and particularly if it's clearly preexisting. So mood disorders, psychotic disorders, ADHD, and PTSD, really thinking about screening for those disorders, and if they existed prior to the stimulant use disorder, to treat them with evidence-based medications and or psychotherapies. If the symptoms though appear substance-induced, but persist four to six weeks after abstinence initiation or significant reduction of substance use, then consider evidence-based treatments at that point. So it may be worthwhile to give the person some time, but then you wanna consider after four to six weeks, certainly strongly consider medication treatments like antidepressants, mood stabilizers, antipsychotics, and in some cases for patients with ADHD, stimulants or atomoxetine or alpha-adrenergic agents. Though, if the relationship is not clear and there's no progress with abstinence or reduction of use, then also still consider appropriate psychiatric treatment options. And one consideration again here is to avoid beta blockers if they might be useful for anxiety disorders, anxiety states like social anxiety or performance anxiety, that this would be contraindicated for someone who's actively using cocaine. The main principle though, is really thinking about and treating co-occurring disorders concurrently. And now thinking about the impacts of OUD treatment more specifically. So overall, a 30% reduction has been observed in medication for opioid use disorder initiation in clinical trials. And if you look at buprenorphine and extender release naltrexone separately, you see a 33% reduction in buprenorphine initiation and a 51% reduction in extender release naltrexone. And when you generalize this to the target populations, we see similarly about a 20 to 30% reduction in MOUD initiation when someone is actively using stimulants or has a stimulant use disorder. And there are greater impacts of stimulants among rural people with IV drug use. In a large VA sample of patients with OUD, one or more other substance use disorders was also associated with more substance use disorder visits, but less buprenorphine and methadone for opioid use disorder. So more visits, but less received evidence-based treatments for OUD. And another large insurance claim sample of patients with OUD, patients were less likely to be started on buprenorphine and had no changes in naltrexone either orally or intramuscular long-acting monthly injection. This was a systematic review and meta-analysis of medications for stimulant use disorder among patients with OUD. This was a collection or analysis of 34 trials. They actually didn't demonstrate any difference in cocaine abstinence among any of the medications. Antidepressants and disulfiram seem to actually worsen treatment retention. Stimulants may have reduced cocaine use, so prescription stimulants may have reduced cocaine use, but methadone resulted in more cocaine abstinence than buprenorphine when they were compared head to head. And again, this was an analysis of clinical trials for stimulant use disorder, but they did do an analysis comparing methadone and buprenorphine and showed that those on methadone had more cocaine abstinence. However, this study had slightly different results. So this was a systematic review and meta-analysis of buprenorphine versus methadone for opioid use disorder. And some of the findings that they observed in this study were retention was higher with methadone. There were less opioid positive urines with buprenorphine in particular in the randomized controlled trials. And some other things that are reduced with buprenorphine treatment compared to methadone were cocaine use, cravings for opioids, anxiety, and cardiac dysfunction. So these are two different methodological studies. One looking at treatments for stimulant use disorder, the other comparing buprenorphine and methadone outcomes, sorry, comparing outcomes of buprenorphine versus methadone. But the take-home message here is that it does appear that both methadone and buprenorphine can be helpful in this patient population with comorbidity between opioid use disorder and stimulant use disorder. And then in a large insurance claim sample of patients with opioid use disorder, the following medications were associated with reduced odds of stimulant-related hospital admissions. So a 41% reduction was observed in patients on methadone, 35% reduction with naltrexone, a 33% reduction with buprenorphine, and then a 23% reduction with bupropion and a 10% reduction with an SSRI. So again, medications that treat opioid use disorder do result in more positive outcomes when it comes to stimulant-related adverse events or sequela. So in summary, stimulant-related overdose deaths have increased significantly, particularly in combination with fentanyl. Stimulant use is common among people with OUD. Stimulant use is associated with greater risk of overdose among people with OUD. Physical health, mental health, and OUD treatment are all impacted by stimulant use disorder. MOUD, so medications for opioid use disorder, may improve stimulant-related outcomes. And there are no FDA-approved treatments for stimulant use disorder, but there are effective behavioral treatments and some off-label medications have evidence of efficacy in this patient population. Okay, and that concludes this first topic out of four for this series. The second topic will be screening, diagnosis, and brief intervention.

stimulant use

OUD treatment

stimulant pharmacology

stimulant use disorder

neurobiology

epidemiology

physical and mental health