Adderall, Stimulants & Modafinil for ADHD: Short- & Long-Term Effects

Welcome to the Huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and Ophthalmology at Stanford School of Medicine. Today we're discussing stimulants, in particular stimulants for the treatment of ADHD or Attention Deficit Hyperactivity Disorder. As many of you know, there is tremendous interest in drugs like Adderall or Ritalin, Vyvanse and other stimulants, as well as non stimulant prescription drugs that have been shown to improve the symptoms of adhd, such as Modafinil, Armodafinil and Guanfacine. Today I'm going to discuss all of these compounds in the context of how they work to improve the symptoms of adhd. I'm going to address common questions about these compounds such as are they just speed? Are they similar to meth or methamphetamine? I'll talk about their addictive potential as well as their potential to cause psychotic symptoms both in the short and long term. And of course, I will talk about the scientific literature surrounding the most frequently asked question about these compounds, which is what are the long term consequences of taking any of them in childhood or in adulthood? Now, today's discussion centers around the use of these compounds both for childhood and for adult adhd. But of course I'd be remiss if I didn't acknowledge that there are a tremendous number of people that use these prescription drugs without a prescription in order to improve their ability to focus and indeed also use them recreationally. In fact, some surveys reveal that as high as 80% of college age young adults have used one or several of prescription drugs such as Adderall, Ritalin, Vyvanse or similar at some point and are doing so without a prescription. So they are either obtaining those drugs from those that do have prescriptions for them for adhd, or they are obtaining them through black market sources, which of course carries an additional and very serious risk related to the so called fentanyl crisis that is as high as 75% of black market drugs nowadays of various kinds, but certainly including the sorts of drugs we're going to talk about today are contaminated with fentanyl and therefore are very deadly. So today I'm going to describe what these various drugs really are, how they work at the level of neurons and brain networks, and how they change those brain networks in ways that really can allow people with ADHD to be able to focus better. I will answer the common question which is why is it that giving children speed? Because indeed several, not all, but several of the compounds I'm going to discuss are speed. They are amphetamine. Why would that cause a reduction in hyperactivity if speed is a stimulant? So I will answer that question for you, and I will also answer questions that are commonly asked, such as how these drugs impact things like sleep hormone health, reproductive health, as well as what is their impact on height. Indeed, it was one prominent hypothesis that these ADHD meds could actually restrict the height of children. I'll tell you whether or not that's actually true or not, and I'll discuss the data surrounding whether or not these drugs predispose people to becoming addicts to other sub substances. Even if people cease or continue taking the stimulants that can help them in the clinical sense for adhd. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. 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So for instance, I use Ketone IQ anytime I want to do extended bouts of focused work, preparing for podcasts, research writing grants, and if I ever want to exercise but I don't have time to eat or I don't want to have my gut full of food. Taking Ketone IQ and thereby increasing my blood ketones allows me to do cognitive work or physical workouts without getting hungry and with plenty of energy and cognitive focus. If you'd like to try Ketone IQ, you can go to hvmn.com huberman to save 20 off. Again, that's hvmn.com huberMan I'm pleased to announce that I will be hosting two live events in September of 2023. The first live event will take place in Toronto on September 12th. The second live event will take place in Chicago on September 28th. Both live events will include a lecture and a question and answer period, and are entitled the Brain Body Contract, during which I will discuss tools and science related to mental health, physical health, and performance. I should mention that a lot of that content will have absolutely no overlap with content covered previously on the Huberman Lab podcast or elsewhere. If you're interested in attending either or both of these events, please go to hubermanlab.com tour and enter the code Huberman to get early access to tickets. Once again, that's hubermanlab.com tour and use the code Huberman to access tickets. I hope to see you there. Let's talk about treatments for ADHD and why stimulant treatments in particular can be so effective. First of all, it's long been known that there are specific brain networks involved in what we call attention. Now, attention is not one thing. Actually, it involves several different cognitive operations, including the suppression of noise, that is, turning down the background chatter in our heads and turning down our attending to things outside us, like noises or visual cues that are not relevant to what we want to do. And it also involves ramping up or attending or focusing on particular things that are happening either in our immediate environment or in our head, or both. So if that all sounds rather complex, indeed it is. It involves several different networks operating in parallel. But what we know for sure, based on a lot of clinical and scientific laboratory data, is that the so called prefrontal cortex, the region of neural real estate in your brain just behind your forehead, is critically important for orchestrating which neural circuits are going to be more or less active at a given moment in order to bring about what we call focus or attention or task switching, or our ability, indeed to multitask. Because we can actually multitask to some extent. In fact, if you were to look at somebody and focus on perhaps the expression on their face, you could do that while also attending to a conversation that's happening nearby. It's energetically demanding. It's hard to do, but we can do that. That's actually referred as covert attention. You're covertly paying attention to something else, and then you can switch that attention back to just one thing or one small collection of things. The point being that attention is a powerful resource. It's what allows us to navigate through life with efficiency and to be adaptive in our behaviors. It's what allows us to learn and to build relationships and have successful school careers and professional careers and so on. But it is indeed expensive. It takes metabolic resources, you know, just at rest. If you were to think about essentially nothing or whatever just pops into your mind. With no dedicated effort toward paying attention to anything, your brain would consume about 25% of your daily caloric needs. And then when you lump on top of that your need or your attempts to focus on things, to pay attention to specific things, it should come as no surprise as to why that often can make us feel tired, as if we've been working really hard and we've been running a quote unquote mental marathon when trying to learn and attend to things. It's hard work for the brain, and yet we can pay attention because of that very precious real estate just behind our foreheads, the prefrontal cortex. Now, in people, both children and adults, that have adhd, their prefrontal cortex is not necessarily deficient in any specific way, except that it is not as good at orchestrating the activity of other brain networks operating in parallel with it. What do I mean by that? Well, if we take a step back and say, what is the prefrontal cortex really doing? The prefrontal cortex has this amazing ability, through what's called top down inhibition, to quiet other brain areas. So, for instance, if you are feeling agitated but you need to sit still, your ability to sit still, even if it takes a bit of work, is coordinated by your prefrontal cortex sending inhibitory suppressive electrical signals to the networks of your brain that are trying to generate physical action. In addition to that, if you are in a conversation that's either a difficult one or a boring one, or you are tempted to interrupt and you are actively holding back your desire to walk away or to yawn or to blurt something out, it's your prefrontal cortex that is controlling that active suppression. So in many ways, you can just think of the prefrontal cortex as an orchestra conductor that is essentially saying, shh, or not right now, be quiet. This is not the time to many different brain networks all at once. Now, in addition to that, your prefrontal cortex is coordinating with other brain networks that are involved in generating what's called salience or attention to particular signals. So the prefrontal cortex, in many ways is like a teacher or an orchestra conductor. It can point to in the neurochemical sense, that is, point to a given brain structure and say, you, I'd like to hear more from you right now. Yes, you, the student in the back, speak up and a moment later point to a collection of small students chattering in the back. Again, I'm presenting all this by analogy and say, hey, hey, hey, you guys, quiet down right now. So and so is going to come up to the front of the room and help us work through this particular math problem. So when we hear that the prefrontal cortex exerts what's called executive function, what that refers to is the prefrontal cortex's ability to quiet the activity of particular neural circuits and, and to enhance or increase the salience of other neural circuits that are involved in creating our spotlight of attention. And what we know for sure, based on many, many brain imaging studies, is that ADHD is not necessarily a deficit in prefrontal cortical function, but rather the prefrontal cortex's ability to communicate with other brain areas in the proper ways. And so what results in the brain, of a person, either young or old, with ADHD is that a lot of the background chatter becomes very, very loud. So, for instance, we have a brain network called the default mode network. This is a fascinating brain network. This is the brain network that is active when you just sort of sit in place and don't think about much, and then you start having ideas about what you might do next week. It tends to be very autobiographical. So you might remember an experience from the past. You might think about some of your desires, some of your dislikes. This default mode network, as it's called, is also involved in our imagination, in our spooling together of different experiences that we've had. It doesn't tend to be the thing that's really focused on anything external in particular, all at once. The default mode network is always active. But it's when we start to attend to something, especially things external to us, like something written on a page or a conversation or something, that we really need to learn something we need to pay attention to, that the activity of the default mode network is suppressed somewhat. And that suppression occurs not just by accident, but because the prefrontal cortex is actively suppressing it. In kids and adults with adhd, the default mode network is often still active at a very robust level, even while we're trying to attend to things. And that's why someone with ADHD will sit down and try and do some focused work, and they'll start thinking about something they want or something they dislike. Their internal state will. Will start to distract them. And of course, there are other networks in the brain. There's actually a. What's called a true salience network. There's the dorsal attention network. There are a bunch of different networks and brain areas. But again, when thinking about adhd, and especially when thinking about how the drugs that we're going to talk about today, work to alleviate the symptoms of adhd. And in thinking about why so many people use or even abuse these drugs for sake of learning or recreationally, we might say, you start to realize that everything centers back to the prefrontal cortex and the prefrontal cortex's ability to actively suppress and actively enhance the activity of these multiple brain networks, including default mode network, salience network, dorsal attention network, et cetera. So rather than overwhelm you with a bunch of names of brain areas and brain networks today, I'd really like our discussion to focus on, first, what the various drugs that are used to treat ADHD are, that is, how do they work at the level of neurons. Second, how they create a certain set of conditions that allow the prefrontal cortex to be a better conductor. Third, how that can be leveraged during development to actually teach the prefrontal cortex of a young child to learn to be a better conductor. Because that's really the hallmark of the use of these drugs is to try and enhance the activity of particular circuits and to create a sort of learning so that the prefrontal cortex is much more efficient at doing its job of conducting. And then fourth, we're going to talk about the various things that I think most people out there ask about when they hear about drugs like Adderall, Vyvanse and Ritalin, et cetera, which is, you know, are they addictive? Why are they addictive? Can one use them briefly or even from time to time and still be okay? What if I use them as a child and I don't want to be on them anymore? Should I put my child on these drugs, et cetera? It is, I believe, only by understanding the biology of how these drugs work and their potential both to improve brain function, but also some of the dangers associated with these drugs that one can really answer those questions for themselves or for their children. Okay, so let's start with a very basic but critical question, which is why in the world would amphetamines, speed, or other stimulants improve the symptoms of adhd? That's so critical to answer because if you think about it, the prefrontal cortex needs to coordinate the actions of these other circuits. And so just increasing the amount of activity in prefrontal cortex you can imagine would create a state of hyper focus. Perhaps, but actually that's not the case. If you just were to ramp up the activity of prefrontal cortex, what you would find is that somebody would become even less efficient at paying attention to what they wanted to, rather, they would pay Attention to whatever was presented in front of them with laser focus, they would lock on to essentially anything. And that's not good. One of the key things about prefrontal cortex is that it needs to be flexible. It needs to be able to pay attention to this, then it needs to be able to pay attention to that. Then it needs to go back to paying attention to the thing it was paying attention to previously, and so on and so forth. Life, that is an effective adaptive life, a good life consists of self directing one's attention most all of the time. So why would stimulants do that? Well, almost all, not all, but almost all of the drugs used to treat ADHD fall under the category of stimulants or what are called sympathomimetics. Sympathomimetic refers to the fact that we naturally have a component of our nervous system called the autonomic nervous system. The autonomic nervous system has two major components. One is called the sympathetic arm of the autonomic nervous system. Has nothing to do with sympathy, has everything to do with ramping up our level of attention and arousal. It is the so called fight or flight aspect of our nervous system. Or rather it mediates fight or flight, but it mediates a bunch of other things too, including sexual arousal, including excitement and focus about something that we want to learn, or somebody that we want to learn more about, or remembering a phone number or anything that puts us into a state of alertness and focus. The other arm of the autonomic nervous system is the so called parasympathetic arm of the autonomic nervous system. And that's often referred to as the so called rest and digest component of our nervous system. And yes, it controls rest, indeed it puts us into sleep. And yes, it's involved in digestion, but it's involved in a bunch of other things as well, including sexual arousal, including rates of digestion, including salivation, including all sorts of things that don't just have to do with resting and digesting. The way to think about the autonomic nervous system is it's a sort of seesaw. So it's always at a balance, someplace between either predominantly sympathetic or predominantly parasympathetic. But both the parasympathetic and the sympathetic arms of the autonomic nervous system are always active all the time. It's not as if one is completely active and the other shut off. Even in sleep, your sympathetic nervous system is not completely turned off. And even during a panic attack, your parasympathetic nervous system is not completely turned off. Drugs to treat adhd, which fall under the category of stimulants are sympathomimetics because they trigger the release of neurochemicals and the activation of components of our nervous system that very much resemble the activation of the so called sympathetic nervous system, the one that makes us more alert and more aroused. So that's why they're called sympathomimetics. And the word stimulant refers to a general category of drugs that are sympathomimetics. Now, the most commonly discussed sympathomimetic is one that fortunately is not prescribed for adhd and that's methamphetamine. These days we hear a lot about methods. Meth, which is methylated amphetamine, is an extremely potent sympathomimetic and it has tremendous abuse potential. Believe it or not, meth or methamphetamine is actually available as a prescription drug. But it is used very rarely because of its high abuse potential and all the terrible things that it can do in terms of cardiovascular health, in terms of oral health. Right. There's this stereotype that meth users have very degraded teeth and indeed they do. There's a reason for that related to how meth impacts the brain and body. I'm going to talk a little bit about methamphetamine a little bit later, but let's just place methamphetamine high on the shelf as the most potent sympathomimetic that's out there. Because even though it's not often prescribed for adhd, there are a class of compounds very similar to it that have a very similar pattern of action that is not quite as potent, but that leverages the same underlying mechanisms and they are very commonly prescribed for adhd, namely Adderall and Vyvanse. So first let's talk about Adderall and what Adderall is. Adderall is a combination of what are called amphetamine salts. Amphetamine salts refers to the fact that there are two major forms of amphetamine. There's a D amphetamine or dexaramphetamine and levoamphetamine or L amphetamine. So I'll refer to these as D and L amphetamine. And for you chemistry minded folks out there, the D and the L also refer to the fact that there is a L left handed version of the molecule and there's a D or right handed version of the molecule. This is only important to understand insofar as you know that the D And the L forms of the molecule look very similar, but they're mirror images of one another. And yet they can have very different actions in the brain and body. So Adderall is a 3 to 1 ratio of D amphetamine to L amphetamine. You should know that L amphetamine tends to be less potent in increasing certain neurochemicals in the brain. I'll talk about which neurochemicals they are in a moment than is D amphetamine. So D amphetamine is potent stuff. Not as potent as methamphetamine, but very potent stuff. L amphetamine a little bit less potent. L amphetamine tends to be the amphetamine that increases blood pressure and heart rate, what we call peripheral effects, because it happens in the periphery, outside the central nervous system. Peripheral effects like increased heart rate, increased blood pressure, sweating, et cetera, are mostly activated by L amphetamine, whereas D amphetamine tends to work mainly on receptors in the brain and therefore have effects mainly restricted to the brain. Now, what are these effects that I've been referring to? The major effect of Adderall and other sympathomimetic stimulants is to increase the activity of two neurochemicals. The first of those neurochemicals is dopamine, and the other of those neurochemicals is norepinephrine. First off, I want to be clear that when I say norepinephrine, I could just as easily say noradrenaline, because those are the exact same thing. And forgive me, even though I wasn't the one to name the same thing, two different things. I'll try and stay with norepinephrine, But I may say noradrenaline. They are the same thing. There's a whole story as to how they got named. Two different things, but it's the same thing. The major effect of Adderall and other sympathomimetic stimulants is to increase the transmission of dopamine and norepinephrine. So what is dopamine and what is norepinephrine? Well, both dopamine and norepinephrine are what are called neuromodulators. That is, they have the ability to increase or decrease the firing patterns, the electrical activity of particular brain circuits. Both dopamine and norepinephrine have separate roles in creating certain states within our brain and body. But they like to collaborate, meaning they tend to be released at similar locations in the brain in order to deliver us to a particular state of Mind and or body. So if we were to take a look at just dopamine, we would find that dopamine is released at sites within the brain and increases the activity of brain networks that for the most part, lead to increases in motivation, pursuit, and to some extent, mood. If we were to look at norepinephrine and where it's released in the brain, it tends to be released at many, not all, but many of the same sites where dopamine is released. And the main function of norepinephrine is to increase the activity of neural networks that are involved in attention and focus to particular things in our environment. So think of dopamine and norepinephrine as collaborators, because indeed they are. And actually they're very neurochemically similar as well. It actually just takes one chemical conversion to turn dopamine into norepinephrine. So they are very similar. They're like close cousins that work together to help us achieve a common goal that involves increased motivation, focus and alertness. So when we talk about attention in ADHD, or we talk about quieting the hyperactivity or impulsivity of adhd, one of the reasons why drugs that are effective in treating ADHD are so effective is because they increase motivation, focus and alertness. And they tend to do that at very focal locations in the brain. It's worth taking a couple of minutes to think about how sympathomimetics such as Adderall actually increase dopamine and norepinephrine. They do so by affecting a couple of specific operations at the so called synapse. What are synapses? Synapses are the communication points between neurons. They're actually the spaces between neurons. But that's where a lot of the action is when neurons, as we say, are stimulating the next neuron or activating the next neuron, or inhibiting the next neuron. The word neuron just simply refers to nerve cell. And so what nerve cells have is they have a cell body that contains their DNA and a bunch of other stuff. They have a long wire like process which is referred to as an axon. And at the end of that axon, there are a bunch of proteins in there that do really interesting things, things. So, for instance, there are proteins down at the end of the axon that package neurotransmitter into little spherical things that we call vesicles. Those vesicles can fuse with the end of the axon and vomit the contents, those neurotransmitters into the synaptic cleft. Into that little space between neurons. And then if enough of those neurotransmitters bind to receptors on what's called the postsynaptic side, which simply means the neuron on the other side, well, then the next neuron will become active, and then the signal will propagate from one neuron to the next. Now, I just described that whole process pretty quickly, and I like to think pretty simply, but it actually involves a lot of different protein bits and some pretty complex machinery in order to make that happen. I don't want to overcomplicate our conversation, but what I will tell you is that down in the synapse, in the presynaptic terminal, the neuron that is going to release neurotransmitter, there are what are called transporters, which sit there and suck up, or suck back up some of the neurotransmitter that's been released. There are dopamine transporters, and there are norepinephrine or noradrenergic transporters down in the synapse. What Adderall does and what other sympathomimetics do is to inhibit or disrupt the action of those transporters. And the net consequence of that is that when dopamine and norepinephrine are released into the synapse, more of it is allowed to stick around and to bind to receptors on the postsynaptic cell than would be the case if Adderall or the other stimulant were not present in the system. So one way that Adderall increases dopamine and norepinephrine is by disrupting the activity of these presynaptic transporters for dopamine and norepinephrine. The other way that Adderall increases dopamine and norepinephrine is that it disrupts the activity of a different piece of machinery in the presynaptic neuron, which is called a VMAT, the Vesicle Monoamine Transporter 2, if you really want to get specific, you don't have to remember these names, but what these VMATs do is actually really cool. What they do is they actually take whatever transmitter has been brought back up into the cell by transporters, and they package it into those vesicles that are then going to be released by disrupting the transporters that vacuum back up some of the dopamine or norepinephrine that's been released, and by also disrupting the packaging of dopamine and norepinephrine into vesicles themselves. What ends up happening is that there's a buildup of a lot more dopamine and norepinephrine in the presynaptic terminal, so that when an electrical signal travels down the neuron now the total amount of dopamine and norepinephrine that's released is increased. Okay, so what's happening when you take Adderall is that you're getting more out of the dopamine and norepinephrine that you're releasing, and you're releasing more dopamine and norepinephrine altogether. And there's a third mechanism by which Adderall increases the amount of dopamine and norepinephrine present in synapses and therefore can act on other neurons. And that has to do with disruption of the entire network between these different proteins. I'm not going to go into that in any detail because it gets somewhat complicated in terms of the cell biology and some of the biochemistry down at the tips of these axons. But suffice to say that Adderall is such an effective sympathomimetic, that is, it can increase dopamine to such a great extent, especially compared to other treatments for adhd, because of its ability to increase dopamine release and transmission and therefore action, as well as noradrenergic release and transmission and action down there in the synapse. And it's worth pointing out that most of the effect of Adderall is in increasing dopamine as opposed to norepinephrine. It does increase norepinephrine, but its major effects, or we should say the major effects that have made it such an attractive drug to so many people, both for the treatment of ADHD and for people to take recreationally or off prescription or for sake of studying or work, simply because they want to focus more and longer, is because of its ability to increase dopamine to such a great extent. I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic greens, now called AG1, is a vitamin, mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and the reason I still take Athletic Greens once or usually twice a day, is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road, in the car, on the plane, et cetera. And they'll give you a year supply of vitamin D3K2. Again, that's athleticgreens.com Huberman to get the five free travel packs and the year's supply of vitamin D3K2. Now, a bit earlier I mentioned that L amphetamine levoamphetamine is present in Adderall, but at one quarter the amount of D amphetamine. Okay, so there's a little bit of L amphetamine and a lot of D amphetamine in Adderall. Many of you are probably familiar with Vyvanse. Vyvanse is a commercial name for what many people think is extended release Adderall. But actually Vyvanse is not extended release Adderall. Vyvanse is a drug in which the pharmaceutical industry has taken one component of Adderall, just the D amphetamine component, and attached to it an amino acid called lysine. Now, the amino acid lysine is a big amino acid. And the attaching of lysine to D amphetamine, what we call Vyvanse, makes it what's called a prodrug, it actually can't have any effect on its own. But when one takes Vyvanse and it's broken down in the gut, but to a greater extent actually in the bloodstream, the lysines are cleaved off slowly over time. And as a consequence, Vyvanse is basically timed release D amphetamine. This is important because I think a lot of people think that Adderall, which again is D amphetamine and L amphetamine, and those two things operate quite a bit differently at the level of norepinephrine and epinephrine and cardiac versus brain effects. A lot of people think Vyvanse is just slow release Adderall, but it is not. What Vyvanse is is D amphetamine only, but in time release form. And Vyvanse was actually developed as a way to try and get around or rather prevent some of the abuse potential of Adderall and other drugs that contain D amphetamine. D amphetamine stands for dextra amphetamine. And in the 70s and 80s there were a fair amount of movies and there was a lot of trafficking and there was a lot of criminal activity related to what was called Dexedrine. Dexedrine is pure D amphetamine. So if we're going to be very direct, if I were going to just frame these things in the context of their neurochemistry, what I can tell you is that Vyvanse is time release Dexedrine. Okay? It's not time release Adderall. Now just because there were movies and reports of criminal activity related to Dexedrine, that doesn't necessarily mean that Dexedrine is not an effective and useful pharmaceutical. In fact, Vyvanse, which is time released Dexedrine, has proved to be very effective in the treatment of ADHD for a time long lot of people. And the reason for that is this time release does indeed prevent abuse in the sense that despite people's many attempts, from what I hear, to increase the rate of entry of the D amphetamine into their system by either snorting it or God forbid, even injecting it and things of that sort, the attaching of that lysine to D amphetamine really does slow the absorption. So when somebody takes Vyvanse, and hopefully people are taking it responsibly when they take Vyvanse, what they're really getting is a slow trickle of D amphetamine into their system and therefore a slow, long lasting increase in dopamine and norepinephrine. And indeed that's what happens. The effects of Vyvanse can extend over anywhere from 12 to 16, sometimes even 18 hours, depending on how quickly somebody metabolizes it. And I should say that there is no way to predict how quickly one will metabolize any of these drugs except by trying them. That's one of the sort of downsides of the state of things these days. There's no blood test or enzymatic test that will tell you whether or not you're going to be a fast metabolizer or a slow metabolizer. And that's why people just have to sort through different dosages, which we'll talk about in a little bit. They have to sort through different types of sympathomimetics. You know, some people try Adderall and they find that, you know, the quick time course of Adderall or at least quick for them of about six to eight hours is just too fast and then it wears off and they get into a slight slump in the afternoon. Other people find that one Adderall taken at 6am will have them going all day long and into the night and it's just too much stimulation and they need to come way, way down in dose or they need to think about other sympathomimetics for adhd. And we'll talk about what some of those other options are in a little bit as well. So the important thing to understand is that Adderall is really two drugs. Dnlamphetamine, Vyvanse is D Amphetamine which is also called Dexedrine but with this time released aspect created by lumping a lysine on there. And you may notice that I haven't mentioned one of the major drugs used to treat adhd and that's Ritalin or what's sometimes also called Concerta, depending on again the time, release forms, etc. Ritalin was very commonly prescribed for the treatment of ADHD early in the days of using sympathomimetics in order to treat adhd. So for instance, I went to college in the early 90s, so I started college in 93 and I graduated in 98. There was one year in there as a, let's call it a transition year. I can recall hearing that Ritalin was being prescribed for ADHD in kids. And I, like many other people, were wondering what are the long term consequences of this going to be. I also, like many other people was very perplexed as to why a stimulant sympathomimetic like Ritalin was being prescribed for hyperactive kids. That will become clear in a moment. But we don't hear so much about Ritalin nowadays. And I think that's because Adderall and Vyvanse and things like them have become so popular for the treatment of adhd. It's worth noting that Ritalin is not actually amphetamine. Ritalin is what's called methylphenidate. And methylphenidate works in a lot of ways that are similar to the way that Adderall and Vyvanse work, but there are certain ways in which it's different. Now, Ritalin methylphenidate does increase dopamine transmission at synapses and it does so also by inhibiting the function of that presynaptic dopamine transporter that would otherwise suck more dopamine back up into the presynaptic cell methylphenidate. Ritalin also disrupts the activity of the noradrenergic transporter, leading to net increases in the amount of norepinephrine at the synapse. But it is not as much a potent inhibitor of the noradrenergic transporter, and therefore most of the effect of methylphenidate is to increase dopamine at synapses. A lot of people don't realize this. A lot of people think that Ritalin is just very short acting Adderall and that's not the case. It is true that Ritalin, at least in its standard form, tends to have a pretty short half life and therefore its effects basically kick in about 20 to 40 minutes after taking it, sometimes a little bit sooner, sometimes a little later, and they last about four to six hours, as opposed to the six to eight hours typical of Adderall. But Ritalin is not short acting Adderall. Ritalin is mainly increasing dopamine and to some extent norepinephrine at synapses, whereas Adderall and Vyvanse are increasing both dopamine and norepinephrine to a much greater extent. And for those of you that are interested in the underlying cell biological reason for that, it has something to do with Ritalin's relatively lower affinity for the noradrenergic transporter. But it's also because, remember I listed off three mechanisms by which Adderall and by extension Vyvanse increase dopamine and norepinephrine transmission rate. Disruption of the transporter, disruption of the VMAT2, as well as a disruption of the whole kind of complex of communication between those proteins. Well, Ritalin is really only tapping into the drug's ability to disrupt the dopamine and noradrenergic transporter. So it's three mechanisms of increasing dopamine and norepinephrine for Adderall and Vyvanse and by extension Dexedrine. And it's only one mechanism for Ritalin to increase dopamine and norepinephrine, and therein mostly dopamine. So if we take a step back for a moment from all these drugs and all this cell biology of neurons and so forth, and we go back to the brain networks involved in attention. Remember the orchestra model or the teacher model, where the prefrontal cortex really sits in top seat in terms of coordinating the actions, both the shhh, the quieting and the yes, please speak actions of the brain, really bringing about what we think of as focused attention and task switching, all the stuff that that goes along with learning and focus and cognition. Well, what we know is that dopamine and norepinephrine, which are differentially increased by these different drugs that we've been talking about, also differentially impact the various aspects of executive function of the prefrontal cortex, increasing our attention for specific things. And while there is a lot of nuance in the literature about this, we can safely say a couple of things. First of all, increasing dopamine at particular synapses and networks in the brain can serve as what's called noise reduction. It can help further enhance the quieting of all that background stuff. That background stuff can be attention to things in your environment, like noises or visual cues. It could be some internal narrative that you had about yesterday or something that somebody said about you or something that somebody you like would like to say about you, or whatever it might be that's happening in your head that's distracting you, as well as your representation of your internal bodily state, what we call interoception. This is a really important aspect of attention that we don't often hear about, which is that we have the ability to attend to things outside of us, which is called exteroception, as well as an ability to attend to things inside of us, which include things like thoughts, but also includes, you know, for instance, how empty or full our gut feels, whether or not we're comfortable in our chair, you know, and when we think about the practice of focus and learning, or focusing as a verb, it involves often forcing ourselves to sit still. It often involves us suppressing the fact that our foot is a little bit cramped or that we might need to use the restroom for. You know, we might want to delay that for 10, 15 minutes, even though it might be fairly urgent. All these sorts of things are central to our ability to attend and focus. And so dopamine, while it does many different things in the brain, many, many different things, One of its main functions in the context of all this prefrontal cortex and attention stuff, is to quiet the amount of noise that is. It helps the prefrontal cortex suppress the signals that would otherwise distract us into thinking about, oh, yeah, I'm kind of thirsty right now, or I need to use the restroom, or I really want to make this call, or I really want to pick up my phone. All of that stuff, all of that suppression, that. Shh. That quieting down of all the background chatter related to things external and internal to us in our head and our body, is greatly facilitated by having more dopamine present in the Synapses that allow for what we call noise reduction. Now, in parallel to that is norepinephrine. Norepinephrine is released from multiple sites in the brain and body. But within the brain, there's one major site of neurons that manufacture norepinephrine. And the name of that site is locus coeruleus. It sits in the back of the brain. It's actually a relatively small collection of neurons, but they are very, very powerful. They extend their little axons, their wires, to multiple locations in the brain, and they release norepinephrine at those locations. So think of them sort of as a sprinkler system that originates from one very focal location, but that can sprinkle norepinephrine at multiple locations in the brain. And the amazing thing about locus coeruleus and that sprinkler system is that, indeed, the sprinkler system can be pretty widespread, where everywhere there's a sprinkler head, somebody's getting norepinephrine. But it also can fairly focally release norepinephrine at particular sites. So while in the context of today's discussion, dopamine is acting largely to impart noise reduction, norepinephrine has the ability to boost signals at synapses to increase the amplitude and frequency of communication between neurons. And in that way, in the context of today's discussion, norepinephrine, when released at the particular synapses in the particular brain networks that are related to attention and learning, is largely serving to increase signal. So what we have in the context of a drug like Adderall or Vyvanse or to some extent, methylphenidate, Ritalin, does this as well, is an increase in dopamine and norepinephrine that is leading to two things. Both a reduction in noise, a quieting of the circuitry that we don't want to hear so much from, and an increase in the signal of the networks that we do want to pay attention to. And the net effect of that noise reduction and signal amplification is what the engineers refer to as increased signal to noise. And the consequence of that is a heightened subjective sense or ability to decide what we want to focus on, sit down or stand there and just focus on it. So the way that we've been discussing drugs to treat ADHD and their ability to increase dopamine and norepinephrine, and thereby to reduce the amount of noise, so to speak, in the brain and to increase the amount of signal related to things that we want to attend to all presumes that the amount of dopamine and the amount of norepinephrine that's being increased is perfect for what we want to accomplish, which is increased focus and reduced hyperactivity and impulsivity. But of course, in the real world, that's not always the case. Depending on the dosage of the drug, one's sensitivity to the drug, even what stage of development across the lifespan a person is that things can really go haywire pretty fast. And what I'm referring to when I say haywire is if you think about dopamine and its ability to reduce noise, well, dopamine does a bunch of other things as well. And in fact, we know that if dopamine is increased too much in the brain of somebody that has ADHD or somebody that doesn't have adhd, people can become euphoric, people can become manic, people can even become psychotic. Likewise, if norepinephrine is increased too much, people won't just become alert. They will become very anxious, have panic attacks, and depending on the drug they're taking, they may even experience very serious peripheral symptoms, meaning elevated heart rate and sweating that is super uncomfortable, and on and on. So everything I've been discussing up until now is true, but I want to make it clear that it's true in the context of appropriately dosed prescribed drug for a given condition. Which leads us to the next question, which is why would it be that giving these drugs, which are in fact stimulants, why would that calm a kid down? Why would that calm an adult with ADHD down? And the answer to that is not completely straightforward. And it is worth pointing out that not everyone with ADHD has impulsivity and hyperactivity and therefore an inability to focus on. Some kids and adults with ADHD do have challenges with impulsivity and hyperactivity. Some do not. Some just have challenges with focus. And I did an entire episode about adhd, and we are going to have an expert guest on this podcast who specializes in the treatment of ADHD to talk about some of these issues further. But I just want to remind everybody that as in the general population, children and adults with ADHD are capable of. Of very concentrated periods of focus. The pattern, however, tends to be that children and adults with ADHD have a harder time getting into that state of focus.