Adderall
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Welcome to another episode of the chemical collective. The chemical collective offers you your weekly dose of Drug Facts while dispelling fiction. Today, we're diving into a topic that sparked a lot of discussion in both scientific circles and mainstream culture, Adderall. I am Dr Dustin Hines. I'm April Contreras, and I'm Missy buffalo. All right, all right, all right. Let's jump in. Let's start with a drug class and the class that Adderall belongs to. So Adderall belongs to a class of drugs known as central nervous system stimulants. The term stimulant, known colloquially as uppers, is an overarching term that covers many drugs, including those that increase the activity of the central nervous system in the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. By sympathomimetic effects, we mean effects that mimic the actions of the sympathetic nervous system, preparing the body for actions so stimulates, activate those same receptors as natural chemicals released by the sympathetic nervous system, like epinephrine and norepinephrine, causing similar effects such as increasing heart rate, blood pressure and breathing rate. Stimulants work by affecting the levels of certain neurotransmitters like dopamine, norepinephrine, serotonin, histamine and acetylcholine in the synapses between neurons. So by increasing their availability, you're going to have more neurotransmitter binding, which will then produce a range of effects, from mild stimulation to euphoria depending on the specific drug dose, route of administration and individual factors. Okay, so that sounded like a lot of science, but really I think about the fight or flight system, these are things that are going to kind of put that into place. Is that correct? Got it?
Unknown Speaker 2:16
Yeah. And stimulants themselves actually have a long history of use, both for medical and non medical purposes, which we'll kind of touch on throughout this show. But largely when one thinks about Adderall, they're probably thinking about how Adderall is used to treat Attention Deficit Hyperactivity Disorder or ADHD. It's also commonly used to help treat narcolepsy and help combat fatigue. So that's interesting to me too, because you think some of the history of stimulants, at least, my exposure to them, the first place was people during World War Two, bombers on large flights needed to stay awake. Then it was the 60s and 70s. You know, people trying to lose weight. It's all kind of the same molecule. And now it's people trying to focus, which is kind of crazy. Yeah, there's a lot of history of, you know, it being used for anxiety, and it's kind of a complex history that we're gonna have to unpack. Yeah, it's gonna alleviate for some and I think what Missy said originally with the personal factors, some people, it's gonna make more anxious. Some people, it's gonna be make less and I think that's why it's been used in many forms for many different disorders. Yeah, it's been used as recreational drugs, performance enhancing substances and cognitive enhancers by students, athletes, artists, soldiers, like Dr Hines said, so yeah, there's a lot of different uses for the same substance. So Adderall, specifically is an amphetamine. The term amphetamine refers to any combination of the enantiomers, Dextroamphetamine and levomphetamine. And when we say enantiomers, those are pairs of molecules that are mirror images of one another, so they're very similar. Listeners may have heard of methamphetamine, which we'll get into more in future episodes, but I just wanted to briefly say how similar methamphetamine and Adderall really are, that's such a big point, because people like, I'm taking my Adderall, it's like, you're taking speed, right? You might need it. It's useful when it's prescribed, but it is speed, or even that Methamphetamine is as, like, quote, unquote crazy on the streets, like, it really is very similar to amphetamine. It just has
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an addition of a methyl group, which makes it more lipid soluble, so it can then cross the blood brain barrier faster and in larger quantities compared to Adderall, which leads to a faster and higher release of dopamine, so it's more addictive and more neurotoxic. But again, while methamphetamine has a faster onset, more intense effects and a longer duration due to that extra methyl group, the effects of Adderall and methamphetamine are quite similar. Yes, I want to talk more about that and those effects, but first, let's really discuss this history, because it's really fascinating how long this has been around. It's not just even again, my exposure to it was the history of it from World War Two, but it's long before that.
Unknown Speaker 5:00
What was at first synthesized as and by and who and where and when. Yeah, some of the earliest recorded history is it starts in 1887 so the discovery of amphetamines was discovered by Romanian chemist Lazar edinalu through but the medical potential amphetamines wasn't recognized until the 20th century. And then in the 1920s and 30s, amphetamines were synthesized for more of a therapeutic use, and their stimulant effects were initially studied for a variety of conditions, including asthma and narcolepsy. And then into the 60s, amphetamines were first marketed under the name albitrill, primarily as a treatment for obesity, because its appetite suppressing effects made it a popular weight loss drug. However, as concerns about the misuse of amphetamines for weight loss grew its use, its usage for this purpose really started to decline. Yeah, I think the big sorry, missy, the big drug that I remember back in the day was dexedrine, and I think it's still around, right? You can still find these drugs.
Unknown Speaker 6:06
And then the shift to using amphetamines for ADHD came in the 90s, when the drug was rebranded as Adderall by Rex our pharmaceuticals, when researchers discovered that amphetamines improve focus, attention and impulse control, particularly in individuals with ADHD. So as ADHD diagnoses rose, and we'll talk more about why that is, Adderall became one of the most commonly prescribed medications for the disorder. Yeah, and something to layer on there, too. Really, what happened is the patents ended. So when the patents ended, their open up gain, and then people say, Okay, you patented this for obesity, but we're going to repatton this For Focus, attention and impulse control. We can get a new 2030, year patent, same drug, more money to come in.
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It all goes back to capitalism,
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typically by the late 90s and early 2000s Adderall use exploded in the United States, again largely driven by the increasing recognition of ADHD as a neurodevelopmental disorder that affects both children and adults. And today, it's still a mainstay treatment for ADHD, but it's carefully monitored due to the potential for misuse independence. Yeah, and I gotta tell you, at least in my generation going to college, it was heavily misused. Don't know from conversations now it still is. So how does then Adderall help people with ADHD? So in the context of ADHD, dysregulated dopaminergic and noradrenergic neurotransmission is widely implicated in ADHD pathophysiology, and Adderall helps individuals with ADHD by increasing levels of dopamine and erepinephrine, and these neurotransmitter systems are really critical for maintaining focus, motivation and attention. And then people with ADHD, it's currently thought that brain areas like the prefrontal cortex struggle to effectively regulate communication with other brain regions, leading to excessive background chatter, and this can make focusing on tasks really difficult. Yeah, like April said, Adderall can enhance the prefrontal cortex ability to suppress distracting brain networks and enhance task relevant ones, improving an individual's ability to focus and stay motivated by creating a better balance between different brain networks. So by boosting dopamine and norepinephrine levels, the drug strengthens communication in circuits responsible for cognitive control, attention regulation and behavioral inhibition, which can lead to clear thinking, improved decision making, and greater emotional stability, helping to alleviate the core symptoms of ADHD. So let's get mechanistic. Then, how does Adderall work at the synapse? And more, more to the point, how does Adderall exert its effects pharmacologically? So at the synapse, Adderall increases the availability of dopamine, norepinephrine, and again, these transmitters are really important for attention and focus, so it enters the presynaptic neuron through dopamine enterrepinephrine transporters, dat and net, which usually reabsorb these neurotransmitters from the synaptic cleft. And Adderall can kind of trick dopamine andrepinephrine transporters because its structure is really similar to these neurotransmitters, and amphetamine the active ingredient, and Adderall has a molecular structure that really resembles dopamine and norepinephrine, allowing allowing it to bind to their respective transporters. And once bound the transporters, mistake Adderall for these and move across the cell membrane into the cell
Unknown Speaker 9:39
and Adderall is going to be doing a couple of other complex things. Yeah, in addition to what April said, Adderall inhibits the reuptake of dopamine and norepinephrine, so instead of being if there's too much hanging around, it'll be taken back into the cell. So Adderall stops this, so that you have more dopamine and norepinephrine in the synapse. So if there's more.
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On the synapse, more is going to bind to receptors, enhancing their signaling effects. So again, as a result, the postsynaptic neuron is stimulated more intensely, which can lead to improved focus and attention. Adderall also affects the vesicular monoamine transport two, also called VMAT two, within the neuron. So VMAT two usually packages the neurotransmitter into vesicles for release into the synapse. But Adderall disrupt FEMA, two which causes dopamine and norepinephrine to accumulate in the cytoplasm, again, increasing the release of these neurotransmitters into the synaptic cleft. So many mechanisms for increasing dopamine and norepinephrine in the synapse, leading to more binding in the postsynaptic neuron leading to improved focus and attention. Okay, so, like always, we have a format, and you know, it's a little mundane here, but how do you take Adderall? Obviously, it's in a pill form, but April, maybe you could talk more about that. Yeah. And before this show, you know, I knew that Adderall was taken in the form of a pill, but I actually didn't realize there's a couple of different types of pills and mechanisms that change how Adderall is absorbed into the bloodstream. So Adderall is prepared in the form of tablets for immediate release and capsules for an extended release, or ER. And the active ingredients in these tablets are a combination of the amphetamine salts we talked about, which are chemically synthesized and processed into so sorry. Let me get that straight. We have the IR and the XR version is that we're saying Yes, exactly, thank you. And then so for immediate release tablets, the IR tablets, the powder is compressed into this, a really solid tablet form, but compared to these tablets, the extended release, or XR tablets, the powder is placed actually inside capsules that contain beads. And these beads are dissolved at different rates, and the capsule itself contains different beads with different coatings, so that the active ingredients are released gradually throughout the day, and this technique allows for a sustained control of symptoms without the need for multiple doses. Unlike that immediate release tablet, and the process of preparing Adderall really involves precise chemical engineering to ensure the correct ratio of amphetamine salts and proper time release mechanisms in the extended release version. Yeah. And as people use Adderall regularly, their brain can start adapting to the drug's effects, a process known as tolerance. So over time, the same dose can become less effective, because the dopamine receptors in their brain become desensitized, leading users to feel they need higher doses to achieve the same therapeutic benefits, which results in doctors increasing the prescribed dosage to maintain ADHD symptoms effectively, but it also raises concerns about dependence and long term side effects.
Unknown Speaker 12:51
So one of the things we talked about earlier is that this is really popular,
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and I guess I'm kind of spoiler alert, I know it's even more popular in the US. So why is this and what are other countries' relationship with these drugs? Well, again, yeah, you caught on to something that is really interesting, that Adderall is pretty popular in the United States. It's a primary treatment for ADHD. And the US actually has a really high rate of diagnoses of ADHD compared to other countries, and stimulant medications like Adderall are commonly prescribed due to their efficacy, and other factors that contribute to its popularity include awareness of ADHD
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culture in The United States that's very pro medication and the pharmaceutical industry's marketing efforts. And in many other countries, Adderall is viewed as more potent and has higher risk of abuse compared to Ritalin, and consequently, Adderall is often more tightly regulated or not as commonly prescribed. And there's a couple of pretty recent studies, like from
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groups all around the country that kind of compare the efficacy of Adderall in ADHD in the US, and the rising diagnosis rates since the 1990s appears to have contributed greatly to Adderall widespread use and the diagnosis of ADHD in the US, starting in the 90s, has continued to rise since so between 1997 and 2016 the percent of children diagnosed with ADHD rose from 6.1 to 10.2% according to CDC reports, and this rise In diagnoses was accompanied by a surge in Adderall prescriptions. For example, between 2002 and 2010, stimulant projections for prescriptions for children increased up to 45%
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with Adderall becoming, yeah, that's just insane, becoming one of the most prescribed medications for ADHD, according to the NIH and so.
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Have taken together increased awareness better diagnostic tools, and a broader recognition of ADHD and adults has really contributed to this trend. Yeah, so the WoW kind of has me on the idea that, you know, unfortunately, of a compound that the properties that make it effective also make it prone to misuse, so that 45%
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upset me. So Missy, can you speak to some of that misuse potentially? Yeah, so individuals who misuse Adderall are often looking for an increased energy focus in euphoria, and they particularly use large doses and use without a prescription. These effects are particularly appealing to college students where Adderall misuse is prevalent, with reports showing that up to 30% of students in the US have used Adderall at least once, non medically, for academic performance, and that was in 2019 so statistics show that Adderall misuse is a growing issue in the United States. According to the National Survey on Drug Use and Health in 2018 around 5 million people over the age of 12 misused prescription stimulants, including Adderall, again, primarily in college settings. Studies show that misuse often stems from the pressure to enhance academic performance or stay awake longer for studying, but also for weight loss or just recreational purposes.
Unknown Speaker 16:19
College and universities in the US, again, are hot spots for Adderall misuse. Students often take the drug without a prescription. They can obtain it through peers who then themselves have an ADHD diagnosis. Adderall is seen as a study drug on campuses due to its ability to increase focus and cognitive endurance, so it's extremely popular during exam periods like finals. Unfortunately, though, this misuse leads to potential health risks like addiction and adverse mental health effects like anxiety, paranoia and depression. Yeah, and actually fascinating to me as a professor, that most students that are taking this, maybe even abusing it, in some cases, as we've said, they're taking it to study.
Unknown Speaker 17:02
You know, this is a drug that should be taken to go to class, to learn, so you can focus. So even our understanding of the brain and all these chemicals is just so far off. Yeah, and in recent years, there's all this use of Adderall by multiple populations, has led to an Adderall shortage, and it's really compounded the issue as those with legitimate prescriptions for Adderall face difficulties in accessing the medication, and this shortage often has been attributed to increased demand, supply chain issues during the pandemic, that was a big thing, and Adderall was kind of folded into that, and tighter regulatory controls have also driven up illegal sales and further contributed to the misuse of Adderall. And people with ADHD who depend on the drug to function effectively are largely impacted, while others resort to obtaining Adderall through more unauthorized channels. So I'm still stuck on this 45% so if we think about the diagnosis and how many people are getting this, there's way more people getting this than are diagnosed with it. So let's talk about something that
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I think is a necessary evil, but is currently not done well, and this point speaks to exactly let's talk about scheduling. How are we looking at this drug? Who are we giving it to? What are some of the scheduling criteria? So in scheduling, we look at the abuse liability of a drug, which is determined by evaluating several factors, like the drug's potential to cause addiction, its capacity to induce euphoria in the likelihood of non medical use or misuse. And this assessment often focuses on how the drug interacts with the brain's reward pathways, the development of tolerance and dependence in the drug's reinforcing properties, which then encourage repeated use. So Adderall has a moderate to high abuse liability, and this is mainly due to its effects on dopamine. Adderall was classified as a schedule two controlled substance in the United States under the Controlled Substances Act, meaning it has medical use, but also a high risk of abuse. That scheduling reflects concerns about Adderall, stimulant properties, which again enhanced dopamine norepinephrine levels, making it effective for treating ADHD, but again, the same things that make it effective make it also prone to abuse, especially when taking higher doses than prescribed. So the decision to categorize Adderall as scheduled to in the United States, it's also influenced by the chemical similarity to methamphetamine, like we were talking about, which has an even higher potential for abuse. Got it.
Unknown Speaker 19:37
And I think scheduling in general is such a rabbit hole that you could go on. And when I think of Adderall and compare it to some other drugs, like psilocybin, so psychedelics, which are classified as schedule one, we always find a way to talk about psychedelics. There's always a way. Well, because psychedelics,
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being in Schedule One, are indicated to.
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Have no accepted medical use, a high abuse potential, even though research shows very clearly that psychedelics have a low abuse potential, they're actually really helpful in treating addiction and have massive therapeutic effects for depression, post traumatic stress disorder and other mental health
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disorders. And this discrepancy really highlights the inconsistency in how certain stub substances are regulated despite differing risks of dependency. Psychedelics are rarely linked to addiction, yet remain highly restricted to compare to stimulants like Adderall, which very clearly have high rates of misuse, especially in the US. Okay, so
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one of my biggest pet peeves, a game that we talk about every show, is there is no one to one drug action. So when you take a drug, other things happen, and we mislabel that side effects. So what are some of the off target or side effects of using Adderall? Yeah, so some of the off target effects of Adderall use are, there's quite a few. The most common are insomnia, loss of appetite and dry mouth and Adderall side effects occur due to its action on dopamine and norepinephrine receptors in the brain and body. Like Dr Hines says, it doesn't just bind where you want it to. It binds wherever those receptors are. So by increasing the levels of these neurotransmitters, Adderall stimulates various parts of the central nervous system. For example, insomnia occurs because of the elevated norepinephrine levels, which promote wakefulness, thus disrupting sleep. And loss of appetite is a result of Adderall stimulating the hypothalamus, which is the brain region which is responsible for many functions, including hunger signals. There are some cardiovascular side effects like increased heart rate and high blood pressure, because Adderall enhances sympathetic nervous system activity, triggering a fight or flight experience or response. So this is why individuals might experience anxiety or restlessness after taking the drug, due to overstimulation of the brain's arousal pathways. There's some more serious side effects like psychosis or paranoia, which can occur when dopamine is excessively elevated, particularly in the mesolimbic pathway, which is involved in emotion and perception. This overstimulation can mimic the symptoms of psychiatric disorders like schizophrenia, especially when the drug is abused or taken in high doses, and then long term effects like tolerance and dependence arise, because with repeated use, the brain adapts to elevated dopamine levels, which leads to dopamine receptor desensitization. So you then need higher doses to achieve the same effect, causing a crash when dopamine levels plummet. So I again devils in the dose, always we say, and anytime I hear and this, this isn't necessarily correct thinking, but I thought about this about Zins. Do you guys know what Zins are? There are those new at least in Europe. I don't know if they're here yet. Caffeine pouches, they come in three, six and nine milligram sizes. And soon as I hear that, I'm like, there's a lot of tolerance problems there. Here we have the IR, the XR, right? So tolerance becomes a big, big thing. So in that it seems like the drug needs to be on board at the right time the right amount. Is there a crash for somebody who's using this that goes off it or with and without ADHD? What does that affect? Yeah, so this crash occurs in people with and without ADHD. This Adderall crash can differ based on baseline dopamine and norepinephrine levels, so individual differences and kind of the brain chemistry and individuals with ADHD, Adderall helps to normalize these neurotransmitter levels, so when the drug wears off, the drop may not feel as extreme, but for those that are taking Adderall without ADHD, you know who have what someone might say, typical or normal neurotransmitter functioning, whatever that means, this sudden spike In dopamine caused by Adderall, can lead to a noticeable crash when the brain tries to restore homeostasis, which results in this intense fatigue and a low mood.
Unknown Speaker 24:11
Okay, so always bring it back to psychedelics. There's a lot of controversy in psychedelics now we know they have a lot of therapeutic benefit. They open a critical window. People that have clinical windows are typically kids. Should you give psychedelics to kids? You know, possibly a terrible idea. We protect kids, but in Adderall, we give a lot of kids Adderall. So the use of Adderall in kids with ADHD is also somewhat of a controversy. Missy, could you weigh in on this? What you were able to find and what we know about this? Yeah, so it's almost a paradox, the best time to treat is the scariest time to treat.
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So critics argue that exposing a developing brain to powerful stimulants like amphetamines carry significant risks, including potential impacts on brain development, emotional regulation and.
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Susceptibility to addiction, concerns about long term side effects, such as changes in appetite, sleep disturbances and potential cardiovascular issues, further complicates the debate, and the idea of medicating children to manage behavior raises ethical questions about whether ADHD symptoms, particularly in younger children, is that pathology? Is it being over diagnosed?
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Yeah, again, the developmental period represents a critical window for therapeutic intervention. ADHD interferes with cognitive, social and emotional development, which may have lasting impacts if left untreated. So early and effective treatment, including medication, can help children better manage their symptoms and improve their academic performance, peer relationships and their overall quality of life and research to just that, when carefully monitored, stimulants like Adderall do significantly reduce ADH symptoms, potentially allowing children to establish more stable developmental trajectories. So while the timing of treatment may pose risk, it's also when interventions can be the most beneficial in helping children manage the challenges posed by ADHD, for sure. So we've covered the effects of Adderall, and now you're bringing up cognition and emotions. What about the long term effects then on the brain itself? And you know this critical period idea, the idea that the brain has plasticity. Yeah, so there's some evidence to suggest that long term use of stimulants like Adderall can promote neuroplasticity, so the brain's ability to reorganize itself by forming new neural connections, and when dopamine andrepinephrine levels are properly balanced. These neurotransmitters can help strengthen these pathways in the brain, especially those involved in focus and attention. Okay, so we've touched on Adderall, and we've talked, talked about people with AEG, but let's talk about, you know, how the medication may work purely as a cognitive enhancer for people who really don't have anything. There's all kinds of people saying, you know, it's a nootropic. It's a game changer. It makes them smarter. Yeah, Adderall is frequently misused by people for the perceived cognitive enhancing effects, and while it is true that the drug can improve focus, alertness and motivation, temporarily, the effects on higher cognitive functions like creativity, complex problem solving or working memory can vary. Research shows that while it may help people maintain attention for longer periods, it doesn't necessarily improve learning or retention. Got it. I've also heard about people again we're kind of abusing this potentially, and even people that, let's say, are on it, but maybe don't really need it as much as they think. Taking a drug holiday, which is a terrible idea if you've been prescribed something. What are drug holidays from Adderall? What does this all mean, and what is the debate here? So a drug holiday is a deliberate break from taking a medication often used in the context of stimulants like Adderall. So for people with ADHD, the idea is to take short breaks, maybe during the weekend or school vacations, when you're not in class and needing to focus on particular tasks to reduce the risk of tolerance, dependence and side effects, like those that disturb sleep or your appetite. Got it. We've also, you know, talked a lot about its effect on focus and attention. What about other cognitive functions? What does it do to decision making and multitasking? Beyond just improving focus, Adderall has a significant effect on what's known as executive functions, which are higher level cognitive processes that include planning, problem solving, decision making and even self regulation. So for people with ADHD, these functions are often impaired due to dysregulation in the prefrontal cortex. So Adderall enhances the brain's ability to prioritize tasks, which is crucial for managing multiple responsibilities. It helps people block out distractions and stay on task, which is why individuals with ADHD often report not only being able to focus better, but also feeling more organized in their thoughts and daily activities, and this is due to the increase in dopamine and norepinephrine in the prefrontal cortex, again, which makes it easier to control impulsive behaviors and then make thoughtful decisions. Okay? And then again, back to what we just talked about a second ago. What about people without ADHD? Is this really having the same effect on their executive function? Well, in people without ADHD, the effect appears to be a bit different, since their dopamine and norepinephrine levels are already balanced.
Unknown Speaker 29:36
Awesome. So that's a wrap for today. Thanks for another episode of the chemical collector you.
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