Good afternoon, everybody. My name is Antoine Ndwehi. I'm a professor of psychiatry and medicine at the University of Pittsburgh School of Medicine, and I've been an addiction psychiatrist for almost 25 years now, and my interests have been in the field of addiction as well as psychology of behavior change, and I've been involved in a lot of activities, clinical, research administrative, as well as also dissemination and implementation science. Today I will be discussing the Stimulant Use Disorder, and from the title, I'm going to review the clinical and practice implications. These are my disclosures and research grants. I get grant funding from NIDA, NIMH, CDC, SAMHSA, HRSA, as well as AFSP, and also royalties for academic books published by Oxford University Press, Pisai Publishing, and Springer, and as well I get some royalties from Oakstone CME. So what are the learning objectives for the presentation today? At the conclusion of this presentation, the participants will be able to, first of all, identify the different forms and types of stimulants that we have available, and learn briefly about the history of stimulants, which is really getting a little bit of a historical context is very important, and I will be summarizing the characteristics of different stimulants, and then I will be moving to describe the neurobiological mechanism and changes that have been implicated in the pathophysiology of stimulant use. Next learning objective would be to review the prevalence of substance use as well as substance use disorder, and I'm going to be using sometimes the abbreviation of STUD, and also participants will be able to understand the clinical manifestation of stimulant intoxication, withdrawal, and other medical as well as psychiatric consequences of stimulant use, and at the end I will review and discuss the pharmacological as well as psychosocial intervention for the stimulant use disorder. So the first learning objective is about differentiating all types of stimulants. So what specifically are we talking about when we mention stimulants? It's very much of a broad kind of a category of substances. First, the one that is the most familiar is the cocaine, then the amphetamine. Under the amphetamine, which is AMPH, I'm going to be referring to that. You have prescription medications that have been used for treatment, for example, of attention deficit hyperactivity disorder. You have methamphetamine, which is METH. So here we're moving towards one of the synthetic amphetamines, and then you have the multiple modified amphetamine products, combination of products and everything, and I will discuss that in detail. The other category of substances that are really classified under stimulants, too, are the MDMA. MDMA stands for methylenedioxymethamphetamine. It goes by Ecstasy, Molly, you hear that a lot, and this is a fascinating substance because it acts not just as a stimulant but is also psychedelic. It has hallucinogenic properties, often it's mixed with LSD, cannabis, PCP, and even heroin or even fentanyl. Molly is a crystalline power form of the MDMA. Others that are also very much synthetic products that have significant stimulant activities, you have the synthetic catinone, the cat and the synthetics, and you've heard about basically the bath salts or the MDKV, and in fact what's been sold out on the street is more of a Molly, which is really kind of a lab-made stimulant, and there are other types all over the place that we see, but keeping in mind these are really substances that can be extremely dangerous and people can really suffer significant negative consequences as a result of medical as well as psychiatric consequences as a result of even one-time use or multiple use, for example, the bath salts. In terms of also really the challenge with that is that it's been very hard to determine the prevalence and how often we see bath salts available and accessible, and it's sometimes very hard to determine the patterns of use, and then obviously you see it in adolescents and adults too, but as I mentioned, it's usually contaminated or it's sold as Molly, and it's another really synthetic product. So I mentioned about the context, the history of stimulants, which is really very fascinating, as I mentioned. I mean, sometimes it's kind of really helpful to avoid the use of psychostimulants, maybe amphetamines are preferable sometimes. Interchangeably, we use psychostimulants, amphetamines, you know, we go back and forth with that, and there are just basically three useful pharmacological options of the drug class. We're very well known and thoroughly explored in controlled trials. These are the three that have been looked at and explored and researched in this sense. First, the effects on attention span, as well as the cognitive performance, which is really why sometimes it's used by college students to really increase cognitive performance. The appetite suppressing effects is the second pharmacological action, and then the mood elevating effects, because it obviously is stimulant and it has a tendency to really elevate the mood and really, in fact, dysregulates the mood. Amphetamine was really first synthesized back in the 1887, and methamphetamine came after back in 1919, and during World War II, the amphetamine were widely used to keep people more awake, to keep ready soldiers really more awake and more cognitively alert. So and then obviously a lot of people ended up really getting addicted to it. The methamphetamine has a very limited medical use. At this point in time, what is currently available as a prescription for obesity, attention deficit hyperactivity disorder, ADHD, and narcolepsy is the Zoxin, and this is the only formulation at this point in time that has medical indications. So continuing in terms of the history of stimulants, you know, I mentioned about the synthetic MDMA, ecstasy, molly, or X, you know, even goes by that, the methylenedioxymethamphetamine. Initially it was used unsuccessfully in psychotherapy in the 70s and became very much popular in the rave scene in the late 80s and early 90s, and as you know now, you know, with the, you know, the event of the psychedelics, you know, and the pseudogenics, you know, there have been a lot of exploration of some of these substances that could have some potential therapeutic benefits. Crack cocaine, crack cocaine started appearing back in the mid to late 80s and started out in New York, Los Angeles, and Miami, and then spread around the East Coast particularly, and in the late 80s, you know, there was a smokable form of the methamphetamine that was created in Asia and then started surfacing in California in the 1990s. So I'm going to review, you know, the different type of stimulants that have been the most highly prevalent. So let's start with the cocaine, which as you know, still, unfortunately, a big problem, you know, and, you know, I'll tell you in our region in the, you know, Southwest Pennsylvania, you know, cocaine is really very highly prevalent still. It's a natural plant alkaloid, and originally it comes from the leaves of the cocoa bush, you know, and from the Indian regions of South America, the Peru, Colombia, Bolivia, as you know, a lot of now the drug seizing activities, you know, come from these countries and referring to the cocaine itself. It's a salt form, usually cocaine hydrochloride. It's powder, you know, as you can see it there. It's highly water soluble, and it's easy to dissolve for injection or absorption across the mucous membranes for snorting. This is how it originally had been used, is for snorting, because it's easy to dissolve for injection or absorption. So and then the different forms of cocaine start surfacing more and more, so it can be snorted, it can be smoked, it can be injected, and keeping in mind that, and I'll talk about it in the reviewing the neuropharmacological aspect, cocaine rapidly enters the bloodstream and penetrates the brain, which is really, in a sense, really dictates, you know, the highly addictive property of cocaine. You hear a lot about some terms like the freebasing or smoking crack, they're always, almost always used interchangeably, and at some point in time, it was frequently cut with levimizole, you know, which is the animal, the warmer, you know, it's a cutting agent to really kind of, in a sense, you know, make it in a way somewhat cheaper, you know, and when it is adulterated this way with the levimizole, you know, the biggest concern was during the COVID-19 pandemic, and we've seen a lot of cases of agranulocytosis and severe neutropenia. And also, let's keep in mind now, and we've been seeing it more and more also in our area too, but it's all over basically the U.S. too, is that cocaine can be adulterated with heroin and fentanyl. So again, what people get off the street is really totally unpredictable, and very hard to really figure out what's in, you know, they would think, you know, they are getting, what's in really that substance that they get, you know, so they believe, you know, they are getting a cocaine and they end up really overdosing, you know, and the overdose could have been also from the combination also of cocaine as well as heroin, in fact. How patients report in terms of the amount that they use, it's reported in grams, and usually a weekend user typically consumes one quarter of a gram, and because, you know, there are a lot of people who have that tendency to really use intermittently, occasionally, without necessarily having the full-blown, you know, substance, cocaine use disorder that is really more on the severe form. Regular users usually consume up to two grams a day, so that's why you can ask the patient particularly, like, how much do you believe you've been using, and what's the pattern of your use, and how often, and how much? And also, you know, some of the language that is used in that context is, for example, the eight ball of cocaine, which is one eighth of an ounce, it refers to 3.5 grams of cocaine, so let's remember that. One eighth of an ounce refers to 3.5 grams of cocaine, which is an eight ball of cocaine. So as I mentioned to you about the crack cocaine, the crack cocaine street name is for the free base, you know, cocaine, and this is a chemically processed form of cocaine, and so the cocaine hydrochloride that I talked about, the powder itself, can be converted back to the water insoluble base by heating it in an organic solvent at base pH. So what ends up happening, it would have, like, a relatively low melting point, and it can be administered by smoking it, and in fact, you know, the crack cocaine can be very, very highly addictive, and we need to think about that, and particularly because of the rush that happens immediately to the brain after people smoke it, and it's very much absorbed into the bloodstreams through the lungs, and it can be dissolved in vinegar in order to return to the form that can be injected. So again, you know, you can really kind of, in a way, play around with really the formulation or whether you would want to smoke it or you would want to end up injecting it by really playing around with water solubility and, you know, process itself. Methamphetamine, it goes by meth, chemically similar to the amphetamine, AMPH. It's usually white, odorless, and bitter-tasting crystalline powder, and how it's used, it's used in different ways, oral, smoked, snorted, injected, and it's made in illegal labs by chemically altering the over-the-counter medications, you know, and the pseudoephedrine. And methamphetamine is basically, in fact, very highly addictive, also stimulant, and if we look at now in the wave four of the opioid epidemic, we've been seeing more the heroin and fentanyl, which is now we see more, 95% probably is mostly fentanyl out on the street, is really very much mixed with methamphetamine. Ecstasy, you know, again, this is another kind of derivative, as we've talked about, you know, the MDMA, you know, X, you know, ecstasy, you know, or, you know, as you can tell, it's a derivative of the amphetamine, and some of the street names are E, X, Molly, Skittles, E. They have, as I mentioned earlier, two kind of properties, a stimulant property as well as hallucinogenic property, and initially it was synthesized by Merck, the German pharmaceutical company back in 1912, tested by the military in search for the truth drugs in 1953, and then it started getting made, you know, in illicit labs because it's a synthetic, you know, substance, and it may contain other really contaminants, you know, or even active substances such as amphetamine, methadrone, you know, the bath salt itself, methamphetamine, ephedrine, or caffeine, you know, they can mix all these things up, and some tablets sold as ecstasy do not even contain any MDMA, so you don't know what, you know, patients are getting off the street. I mean, they are told that this is an ecstasy pill, something, and then it turns out to be really not ecstasy, and or it is really kind of sold as ecstasy, and it does not contain any kind of MDMA, you know, which is really the component itself. The street names I mentioned, it could be E, X, Molly, Skittles, Adam, Essence, I mean, you can see all these, there are a ton of names, so you need to be kind of in a way familiarized with some of these street names, you know, so, and if you don't know when the patient reported, you know, to ask the patient what specifically are you referring to when you use that kind of particular name for that drug. So the prescription amphetamines, you know, these are the ones that have been used, you know, for the ADHD, you know, and you have the methamphetamines, Ritalin, Concerta, Bifentin, you have the dextroamphetamine sulfate, the Dexedrine, Generic 2, and you have also the amphetamine and dextroamphetamine combination, which is the Adderall and the XR, the extended release, and it could be also generic, and you have the Vyvanse, Vyvanse has been used more and more, which is in this dexamphetamine, and this is an important thing that I'm mentioning on the slide, is that there's a clear links between the molecular structure and the pharmacological mode of action, and in turn the efficacy and safety in humans, and it makes amphetamine like a textbook example of what we call translational validity. So this is really kind of, in a sense, really you see it, you know, out there, and there is a clear that connection that you can see between the molecular structure and the pharmacological properties, you know, and whether it's going to work or not, the efficacy part. So that's why we call it like a textbook example of translational validity. So now in terms of the next learning objective is about the stimulants and the brain. So these are some of the reward structures in the brain, the pathways, you know, and I believe you're familiar with a lot of that, but just to give you a very brief summary here, when activated by a rewarding stimulus, which is usually the three main ones of food, water, and sex, information travels from the VTA, the ventral tegmental area, to the nucleus accumbens, NAC, and then up to the prefrontal cortex. Prefrontal cortex, you know, where the executive functioning is. So this is how it kind of really, you know, the pathway really goes from VTA, NAC, and then PFC, which is the prefrontal cortex. So what ends up happening with the cocaine? When a person use the cocaine, you know, the cocaine starts concentrating in the VTA and NAC and the caudate nucleus. So it's really, you can see where really kind of mostly the concentration is there and which kind of explains a lot of also the consequences and the behaviors that we see. Let me go back a little bit here and describe a little bit also how cocaine also blocks the reuptake of dopamine. And what I'm referring to here is, you know, let me go back a little bit. So when a person ends up smoking or snorting cocaine, it travels really very quickly to the brain. I mean, and as I mentioned, the specific areas of concentration, they are there, the PTA and ACE and the caudate nucleus. And so they end up, the cocaine concentrates, especially in the reward areas that we have really talked about. So that's why sometimes what you end up seeing, a lot of the effects are really more kind of increased stereotypic kind of behaviors, like the pacing, nail biting, scratching. There's a lot of that. And that is really the result of where the cocaine is concentrating and how it is really kind of blocking, you know, the reuptake of the dopamine. So, let me kind of go here. So a result of the cocaine actions in the nucleus accumbens impulses, leaving the nucleus accumbens activate the reward system. So, and this is really very important. You see where really the turquoise, you know, the color is the cocaine. It binds to this uptake pumps and prevent them from removing the dopamine from the synapse. This results in more dopamine that is released and depletion eventually of the dopamine, significant activation of dopamine, you know, receptors and depletion of the dopamine system. So, I mean, this is in a nutshell how it really operates. So, when it comes to the brain and the stimulant use disorder, particularly with the cocaine. So initially there's a huge dopamine buildup. As a result of that, the dopamine buildup is really the result of the blockage of the dopamine reuptake. But what ends up happening too much of that end up really being, you know, in a sense depleted. That's why you end up seeing also a lot of the depression that is really correlated with heavy cocaine use. You know, and NAC is the most important side of the cocaine. In terms of the animal models, they found a lot of really changes in the glutamate system, elevation of the stress hormones, changes in the gene expressions, leading to even structural changes. You know, some of the brain structures, you know, including, you know, the NAC, you know, and VTA, you know, that they start really kind of morphologically, you know, they end up being really modified. So the long-term effects are changes also in the new cell structure. So you can imagine how cocaine use, particularly chronic cocaine use, can in fact, you know, destroy the brain in a nutshell. And what ends up happening also, there would be a lot of aging of the brain that can be sped up, you know, here. And there's always the question of vulnerability genes, like there are some people who are really more vulnerable than others to the cocaine effects and negative effects, you know, and negative consequences. So now how about the methamphetamine? What does the methamphetamine, methamphetamine, what do methamphetamines do to the brain? And stimulant use disorders when methamphetamine is used heavily and to a point of moderate to severe. There is an initial, initially the inhibition of the reuptake of the synaptic dopamine and promoting direct dopamine release, both, both actions. So there is a massive releases also of norepinephrine. There is also destruction of the neurons. There is also decreased white band. There is also changes in the cellular dysregulation and decreased gliogenesis. So there is a damage to the circulatory system in the brain. And it modulates three molecular cascades. There is the oxidative stress, neurotoxic stress and neuroinflammation, the Warburg effect. So you're talking about really multiple levels of really impact. And the compulsive drug effect is, you know, that impulsive compulsive, you know, in fact, there's an imbalance between the orbitofrontal cortex, the dorsomedial striatal, the ghost circuit, the ghost circuit meaning, you know, that, you know, that the brain continues to really be activated over and over and over again. And that is an opposing front striatal, which is a stop circuit. So the ghost circuit takes over the stop circuit. And the changes in the brain structure could really happen as it happens, you know, with cocaine, severe cocaine use, and which can lead to basically decrease in mental flexibility. So the question is always, you know, are these really changes reversible or not? In fact, if you treat the stimulant use disorder very early on, you can see the brain healing and getting much better. And some of these really consequences can be really, in fact, reversed. You know, but if the condition of the stimulant use disorder whether with methamphetamine or cocaine, particularly methamphetamine, leaders for a long time, what ends up happening is that it becomes much harder for the brain to heal as a part of the treatment. And if people are gonna continue using over and over again, you know, the ghost circuit continues to be activated and the stop circuit is gonna be really inhibited. And as a result of that, you know, the brain is gonna totally collapse. So what happened to the brain and the stimulant use disorder, particularly with ecstasy? So what it does, you remember I mentioned about the different mechanisms of actions that can happen. First of all, acutely it increases the serotonin by blocking the reuptake and directly releasing it. So which means, you know, basically there's gonna be depletion eventually of the serotonin. So there's an activation of the NMDA receptors and as well as the 5-HT receptors. Chronically, if ecstasy is used really on a chronic basis because some people, as I mentioned, you know, would use it here and there during parties or raves. But chronically, it decreases serotonin level by depleting serotonin stores and inhibiting even the synthesis of new serotonin. Other really kind of mechanisms of actions, inhibiting the dopamine transporters, toxicity, neurotoxicity, which could be multifactorial. And also the effects can be very significant on cognitive abilities, particularly memory and learning effects. Moving on now to talk about the prevalence. How prevalent is really the use of stimulants? Cocaine and amphetamine are the two most widely used illicit drug worldwide. The highest proportion of cocaine use is in North America. The highest proportion of amphetamine use, including methamphetamine and prescription stimulant, is also in North America. And there are specific populations that we need to keep in mind and related to behaviors. Men who have sex with men, the MSM, or people who inject drugs, sex workers, or people who use stimulants for occupational reasons, they have much higher proportion of people who use stimulants than others. So specific populations engaging in any particular behaviors could be at higher risk for really basically using stimulant than others. And these are, you know, the population that I mentioned. What a drug use is the norm in that kind of context. It includes cannabis, alcohol, and even co-injection of cocaine and heroin. They call it speedball, speedballing. And the co-injection of methamphetamine and heroin is called moveballs. And fentanyl, remember I mentioned, you know, that now we're in the fourth wave of really the use of fentanyl and methamphetamine. And there's definitely always to keep in mind as a part of the intervention, it has to be really focused on the fact that the risk of overdose is extremely high and the risk of mortality from overdose is extremely high. And let's not also forget here that when it comes to polydrug use, you know, benzodiazepine, I didn't really mention, but when benzodiazepine was also used in combination with all these stimulants, opioid, you know, that it could lead to really higher risk of overdose as well as mortality from the overdose, mortality as well as morbidity. So there are a lot of concern about the interaction between cocaine, methamphetamine, and fentanyl use because of the rapid increase in the fentanyl-related mortality in the U.S. So again, you know, as you see now, the people end up overdosing when they, you know, the autopsy report, you know, the coroner's report and everything, you know, always demonstrate multiple drug, you know, poisoning, they call it poisoning, you know, in people's system, you know, and that includes basically stimulant as well as fentanyl and sometimes also benzodiazepine on top of it. And this has really kind of in a way has been a major contributing factor to another epidemic, which is really related to the fentanyl, which is really the higher mortality. Just to give you an idea about where we are with, you know, the drug usership among Americans age 12 and older, and we're talking about really, this is from the National Center for Drug Abuse Statistics. And the NASA, you know, the 2020, and as you know, obviously cannabis is the highest, you know, but it's divided into used in a lifetime or used in the last year, which is the green part, which is the other color, you know, that not very, the light blue used in the last months. And if you can see also after the cannabis, cocaine comes as used in a lifetime is 14.2%, you know, and if you look at ecstasy, obviously it's lower, methamphetamine is lower, but also, you know, these kind of really numbers, these are percentages, also that are gonna depend a lot also on the geographical area, demographics, you know, are you talking about the East Coast, West Coast, you know, what it means. So there are a lot of variations, but the bottom line is that everything here is, you know, there is a high prevalence, you know, obviously of the stimulant, whether the cocaine, you know, we're talking about the ecstasy there. So if you look at the CDC, you know, and this is really, remember I talked about earlier, the stimulant use is shorter than opioid use is shorter. So there is, you know, the numbers have not really changed much in the past two, three, four years. The changes are not really very significant, but the bottom line is, you know, you're talking about around 53% of those are using methamphetamine in the past year, but the agnostic criteria for a use disorder and nearly 25% reported injecting methamphetamine within the past year, with the risk of obviously acquiring HIV and hepatitis C and hepatitis B. And that's the numbers that were estimated in 2019. There are 2 million individuals age 12 or older using methamphetamine, which was up from 1.4 million in 2016. And it's going up from 2019 up until now. If you look at, this is really fascinating. There's an, and I put it in the references too, a retrospective analysis that went on, you know, from 91 through 2020, found like an around 82.5% exposure to stimulant among people who have opioid use disorder. So people who have opioid use disorder have used stimulant at some point in time, whereas crack cocaine is 68.6%. Prescription stimulant 50.6%, methamphetamine 63.1%. So the, when you think about the percentage of exposure to stimulant, this is very significant. So we're talking about here, whichever way you're looking at it, this kind of a sort of data highlights the fact that there is a substantial prevalence of stimulant use among individuals who have opioid use disorder. But also there is a variability through which pathways of use occur. Could be in the context of crack cocaine use, or context of prescription stimulant, or in context of methamphetamine. So how about the prescription stimulant use? The numbers are really also very interesting here. And the numbers continue to fluctuate on some level. When you kind of think about really, you know, the among US adults from 2016 and 15 from the NASA, you know, data, you have a 6.6% annual average use prescription stimulant overall. Not all of them have a use disorder. 4.5% used it without misuse. 1.9% stopped misusing it with use disorder, which what I mean by that is, you know, when you misuse, you know, you take more than what you're supposed to take, or you sometimes, you combine, you know, using with other stuff. So again, the misuse is really, could eventually lead to a full-blown use disorder. And the use disorders is 0.2%. The one thing that is very important to keep in mind, the second point here on the slide is that the percentage of enrollees with one or more prescription stimulant fills increased from 3.6% in 2016 to 4.1% in 2021, which indicates, you know, that we are obviously prescribing more stimulant, psycho-stimulant or amphetamine. And a lot of people, you see the difference, you know, between 2016 and 2021. So people who have some sort of a vulnerability to developing a stimulant use disorder, you know, that's kind of very much riskier. And just to give you an idea also about the third point here is the percentages of females age 15 to 44 and males age 25 to 44 years with prescription stimulant fills that was increased by more than 10%. This is very significant during 2020 and 2021. And there is a fascinating also study that is cross-sectional study of students in secondary schools. The school level past year prescription stimulant, non-medical use ranged from 0% to more than 25%. Look at that massive increase of prescription stimulant that for non-medical use. And as I mentioned, one of the reasons, you know, these kids use them is to enhance cognitive performance. And the students attending school with the highest rates of stimulant therapy for ADHD, they have a 36% increased odds of non-medical prescription stimulant use compared to a student attending school with the lowest rates, which means if you end up, you know, treating, you know, the students, and there is a higher rates of the use of stimulant therapy for ADHD conditions. These students have a higher, way higher rates in a sense, way higher chances, odds, you know, of non-medical prescription stimulant use. And if you look also, I've already mentioned that before, you know, about the, you know, the 0.2%, you know, of the, I want to repeat that again, you know, which is really very crucial because that ties it to what we've been discussing before is also the misuse and the use disorder, you know, and it's associated with really a lot of really what we call the physician shopping type of, they are associated with increased likelihood of obtaining medications from physicians or drug dealers or strangers. The motivation for misuse mostly is related, as I mentioned, to cognitive enhancement, and that is associated with high risk. All right, moving on now to the next learning objective, which is reading stimulant intoxication. So what do we see? Some of these kind of manifestations of stimulant intoxication include signs or symptoms, tachycardia or bradycardia, pupillary dilation, elevated or lowered blood pressure, in fact, we see more elevation in the blood pressure, perspiration or chills, nausea, vomiting, weight loss that could be very significant, psychomotor agitation or retardation, usually we see more agitation. There's a muscular weakness, respiratory depression, chest pain or cardiac arrhythmias, which is really problematic because, you know, that can lead to basically heart attacks and as well as really a heart disease. And there's also the confusion that can happen as a result of that, seizures, a lot of abnormal movements problem that I mentioned because of the way, you know, the stimulants work in the brain, like dyskinesia and dystonia, and even, you know, the worst case scenario would be the cup. So what are the clinically significant problematic behavioral or psychological changes? Usually you see a lot of euphoria, but also you see kind of sometimes also dysregulations in terms of the affect, changes in sociability, there's hypervigilance to a point where it can become paranoia, and there's interpersonal sensitivity, heightened anxiety, significant tension, anger outbursts, stereotyped behaviors, and significant impairment of judgment and reasoning. So the question, how would you approach a stimulant intoxication? Well, fortunately, there are no really kind of particular medications or treatment. Obviously, you want to minimize the stimulation as much as you can. You know, treat symptomatically, you know, some of the symptoms, you know, that people experience, but most importantly, making sure you know that the patients are safe, and they are not engaging in any kind of risky behaviors, you know, and sometimes, you know, that requires, you know, hospitalization. So intoxications was wrong. Those wrong, you have a lot of patients will tell you that they are thrashing. And usually what you see is more dysphoric mood, severe depression, and you can see two or more of the following physiological changes that can happen within a few hours because, you know, cocaine gets eliminated or stimulant gets eliminated very quickly on system. To several days after cessation of prolonged amphetamine type substance, cocaine or other stimulant, you see significant lack of motivation, fatigue, no drive, unpleasant dreams, insomnia or hypersomnia. People engage much less when they are crashing in a way. There's an increased appetite or rebounds of the appetite that could happen, but also psychomotor agitation or even retardation. Again, you know, in terms of really treatment, what you're really doing, there is no particular, you know, medication approaches you treat symptomatically, and then you try to really minimize, you know, the stimulation that could really potentially worsen these symptoms. Stimulant psychosis, you hear a lot about that. So stimulant by themselves, they can cause treatment, emergent psychotic, or even manic symptoms, and patient with no prior history. So it would be like a stimulant-induced manic symptoms or psychotic symptoms. The risk of nuanced psychosis was approximately, in this one study, one in 660 patients who received a prescription for stimulant for ADHD. So the risk is there. The risk was about twice as high among patients who started amphetamine, as among patients who started methamphetamines. So we need to keep that in mind. And amphetamines can mimic psychosis, can present the same way, especially when taken recreationally above the approved dosages. Acute amphetamine intoxication can present as a substance-induced, similar to the cocaine, you know, methamphetamine, substance-induced psychotic disorders. Some people are more vulnerable than others to developing a psychotic disorder or psychotic manifestations with onset during intoxication that can persist. That kind of, in a way, creates a unique situation and a big challenge in younger adults when separating first-onset psychosis from a stimulant-induced psychotic disorder. So we're not totally clear here. Are we dealing with a stimulant-induced psychotic disorder, or are we talking about like a full-blown psychotic disorder, you know? And people, if they have that sort of a vulnerability, they could really move towards really developing, you know, like schizophrenia-like symptoms. So there has been always that sort of a question that has been floating around and that I would like to really address, which is, does methylphenidate treatment for ADHD increase the risk of psychosis in patients with and without previous psychotic symptoms? In fact, the studies did not demonstrate that. So the risk of psychotic symptoms did not necessarily increase, you know, with methylphenidate treatment in young people who are given methylphenidate to treat ADHD. At the same time, you don't know which patients could potentially be vulnerable, whether genetic vulnerability, whether neurobiological vulnerability, that even methylphenidate treatment for ADHD could potentially precipitate psychotic symptoms. So the issue of causality is not well-established there. It's not that because of this, you know, because they are getting, you know, the methylphenidate, they end up with a psychotic disorder. It could be because methylphenidate treatment has facilitated a process that led them to have psychotic symptoms or even a full-blown psychotic disorder. So the acute consequences. So neurologically, you have seizures and strokes. Very, very important to keep in mind. We talked about the cardiovascular system, arrhythmias, tachycardia, and myocardial infarction, hypertension, usually. Kidneys, you know, you can see a cocaine-induced rhabdomyolysis that can really kind of shut down the kidney functions. The hematology, I talked about the contamination with the levomizole, you know, which can cause angiocytosis. Reproductive system, placenta previa, the anti-nosebleeds, you can see that. Infectious diseases, sexually transmitted infections, cellulitis, bacteria, endocarditis, particularly obviously the people who have been injecting, you know, the stimulant. With ecstasy, you know, and we see it, you know, often in a way that the severe dehydration, hypothermia, and hyponatremia, hypokalemia, that could really lead to people passing out, you know, and eventually dying. So one of the commonalities in terms of clinical manifestations, you remember I talked about short-term, long-term. Short-term intoxication, withdrawal. Behavioral, psychiatric, cardiovascular, neurologic, and as well as withdrawal symptoms in general. The long-term is end-organ damage. Nutrition, you know, that because people are not gonna be really basically eating, you know, there's gonna be depleting, you know, their system from any vitamins, you know, there's gonna be a lot of deficiencies. And over the course of any chronic use of stimulant, you can see psychiatric problems as well as the infection. But also keeping in mind, when I talk about end-organ damage, what we're talking also about really the impact on the heart as well as the brain, the strokes, talked about the seizures, as well as really the heart failures, and as well as heart attacks. Again, you know, I want to reemphasize that suicide and overdoses are substantial causes of mortality, you know, and let's not undermine that people die, you know, from using stimulant. You know, they are at six times higher risk of mortality. And, you know, an additional three to 10% of new HIV and HCV in people who inject drugs in the next year could be attributable to each 10% increase in the prevalence of stimulant injection. And we've talked already about risk of psychosis, depression, severe depression, even violent behaviors in your elders are significantly elevated. So the stimulant-induced psychotic disorder, remember I talked about mimic, you know, the amphetamine use can mimic psychotic disorder but also can potentially, you know, precipitate. The causality is really kind of a very challenging, you know, issue to establish. Intoxication, you see psychotic disorder, delusions, paranoia, bipolar disorder, depression, anxiety, or CV because of the movement problem that I talked about, sleep disorder, sexual dysfunction. From the withdrawal, you can see, you know, obviously, picture similar to bipolar disorder or depression, anxiety disorder, OCD, and sleep disorders. So the case of co-occurring ADHD and SUD, remember I've asked that question before and I elaborated on it. Does a stimulant prescription have an impact on development of a stimulant use disorder? As I mentioned, the risk is not totally established, but it's neutral, more than protective, and not harmful. So this is something to really keep in mind. And in terms of using the stimulants for co-occurring ADHD and SUD, when there's a combination of both, there's no worsening of the SUD necessarily. The effect in amphetamine use disorder is not clear, not well-established, and there's more of a role in cocaine use disorder. There's a possible reduction of cocaine use, and I'll talk about it here, that possible treatment, you know, therapeutic benefits and ADHD symptoms, both the cocaine use improved as well as ADHD symptoms. So how do we establish the diagnosis? How do we identify, you know, the SUD? You know, always remember, you know, that you confirm, you characterize it through patient reports. I mean, and we've talked in the previous lecture about validity of people, of the self-report. There's screening tools that you can use, but always getting collateral information from family members, significant other concerns, significant others, symptoms and signs, and obviously, you know, drug screens, mostly the urine drug screens. When you talk about diagnosing stimulant use disorder, you use the DSM-5 criteria, and they use, obviously, as we know very well, it's gonna have to be leading to an impairment and distress. So treatment, now I already addressed the acute withdrawal intoxication. I wanna really bring up, you know, that really, very early on when the cocaine use disorder was very, very highly prevalent, you know, years, years back, NIDA established what we call a comprehensive drug abuse treatments that incorporate the behavioral therapy, even include group therapy, and counseling and pharmacotherapy, so more integrating both. And in terms of the psychotherapies, and I'll mention what exactly works, but let's always keep in mind, we're not talking about just people not using stimulants, we're talking about the different components and multidimensional aspect of recovery. Which is really the functioning, interpersonal relationships, you know, social functioning, the recovery in terms of multiple domains, the legal, occupational, spiritual, physical, psychiatric, you know, all these aspects. I wanna reemphasize here over and over again, no FDA approved treatments for STUD. I'm referring to no medication treatments. In fact, the therapies are really more psychotherapies. Obviously, recommending careful and ongoing risk benefit assessments every time you're gonna be prescribing any medications that is not FDA approved. Increase the monitoring when prescribing medications with high risk profiles, and I'll talk about it in a bit. Seeing patients more often, more regularly, a lot of clinical encounters, drug testing, pill counts, checking the PDMPs, always addressing co-occurring psychiatric and other substance use disorders if treatments are really valid, available, and FDA approved. And all medications discussed in the subsequent slides are gonna be off-label, not FDA approved. Typically, what we've had on leading kind of small studies with really methodological limitations and such as poor retention in these studies and completion rate, poor adherence to the medications, some positive effects in certain outcome measures. So the general principles for effective psychosocial interventions. Well, first of all, you know, it's very important to establish a therapeutic relationship. Using a motivation to viewing approach is really perfect for that. And the therapeutic components have to be integrated all together. Can be really kind of provided in a non-specialty and specialty settings. Usually, they are provided more in a specialty setting. Addressing recovery as a long-term process. Extending patient contact and engagement with healthcare practitioners and peer support, the recovery peer specialist with lived experiences, and peer navigators if it's needed to connect people into treatment and engage them in treatment and retain them in treatment. Remember, retaining in treatment for a lot of these patients is a huge challenge. Always involving family and concern significant others, providing whatever resources in the communities, and only remembering that medical care needs to be established. Patients have to have like a primary care physician that they can follow up with for any potential medical issues. So the psychosocial interventions, talk about the dual recovery approach is always important to address co-occurring psychotic disorder treatment concomitantly with the stimulant use disorders. And as I mentioned, that strong evidence for outpatient addiction counseling groups could be also intensive outpatient treatment like three days a week groups, partial program five days a week. Not as really kind of practical and available now and really supported by insurance companies, but mostly the IOP itself, but would be perfect if you can provide individual as well as intensive outpatient treatment. For intensive treatment, residential treatment program might be needed for patients with a lot of social instability. They need a lot of resources, patients who have out in the community very limited resources. So now the pharmacotherapeutic interventions, when is it really indicated? And we'll talk about it in a second, but in terms of therapeutic modalities, when you look at cognitive behavioral therapy, there's not enough evidence to support or discount the effectiveness. So kind of a neutral one, but there is sufficient evidence to support what we call the effectiveness of contingency management, which is the same as motivation incentives. You incentivize people for getting into treatment, staying in treatment, a negative, positive, excuse me, negative drug screens. You know, and unfortunately it has not been very easily adopted in a lot of the treatment programs. Motivational interviewing MI, the matrix model has been used with the methamphetamine, which really is a combination of motivational interviewing, case management, and contingency management. So it's a kind of a more of an integrated approach, which people would need a lot of training in and to implement in treatment programs. And they are mostly in specialized treatment programs. 12-step facilitation, which is an individual therapy to really facilitate people's engagement in 12-step, such as the LA, you know, and CA. And the family therapy, you know, that has been mostly the modalities particularly in youth and younger adults. So in terms of really the pharmacotherapy, and as I mentioned, off-label stuff and known as FDA approved, you know, there's consistent evidence that any drug is effective, you know, in absence, reducing use or improving retention has not been, we don't have it, unfortunately. I mean, we've done a ton of trials with multiple medications. So there is no consistent evidence. There is no strong evidence for that. Combination of pharmacotherapy possibly with contingency management could be promising. Again, no medication randomized trials have shown any efficacy for stimulant use disorders. A ton of medications have been explored, you know, in some trials, you know, with small numbers, bigger numbers, you know, not methodologically in good, you know, good designs. Antidepressants, nisulfiram, dopamine agonists, intracardiacs, anticonvulsants, anything you can ever imagine, even the psychostimulant, you know, the amphetamine themselves. I'll talk about in a second, and opioid agonists, and the NAC, you know, the N-acetylcysteine, but there's insufficient evidence to support effectiveness or sufficient evidence to discount effectiveness. Unfortunately, nothing is gonna really, you know, among those options, is gonna be really efficacious. I would like you to take a look at this newer guideline that came out, and I included the link there. The Clinical Practice Guideline on Management of Stimulant Use Disorder came out recently, you know, established by the ASAP and AAAP, and, you know, they talk about medications that have risks that may outweigh the benefits, and they made a very clear disclaimer saying that clinicians should generally avoid the use of psychostimulant medications. You know, again, I'm referring to the amphetamine medications to treat STUD in patients without a history of stimulant-induced mood disorders, so we need to keep that in mind, and there is always this important aspect of really evaluating risk-benefit analysis, and really the level of monitoring, and I would recommend that you go on the link and see the whole, really, document there. Just really briefly, what has been looked at in terms of the cocaine use disorder, non-psychostimulants, some evidence for bupropion and topiramate, not much for the psychostimulants, some evidence for modafinil, and the extended-release mixed amphetamine salts, such as Adderall, advantages, disadvantages. I talked about the risk and benefits, you know, but again, what you're really doing is that you're really testing these things out, and you're not gonna have any sort of a guarantee that this is really gonna work, and you would wanna be careful about patients having a tendency to misuse, particularly the stimulant ones, or even the non-psychostimulant, particularly the one I'm referring to as the bupropion. So now the amphetamine-type STUD, you know, the non-psychostimulant that have been exploration of different ones, combination of bupropion and naltrexone extended-release, mirtazapine have been looked at, topiramate, iripiprazole, you know, again, the studies are really very much limited on that aspect. What is fascinating is that now there has been some more and more recommendation of a potential evidence that it could really be helpful in work, is the extended-release metamphenidate, you know, and again, that would require close monitoring and high, you know, analysis of risks and benefits, checking, you know, PDMPs, you know, monitoring response, monitoring the dose, and all this. And these are the references. Thank you very much.

stimulant use disorder

Dr. Antoine Ndwehi

cocaine

amphetamines

MDMA

neurobiological mechanisms

substance use disorder

pharmacological interventions

psychosocial interventions

FDA-approved medications