E63: ADHD: Introduction to Stimulants

[Music] Hello this is your brain on drugs and this is the fungurks psychiatrist. So today, getting back to the ADHD series, we're going to start talking about stimulants. And so I'm going to do an introduction to the stimulant medications. I'm going to talk about which ones there are, kind of some general features, how they work. And then next time I'll start talking about individual medications and I'll go over kind of the differences. Right, so there's so many of them, there's like 20 some odd. And so I want to kind of give you an idea of when I would use each one and how they differ from each other. But today, just an overview. So there are actually seven types of FDA approved stimulants, four of them are infetomines, and three of them are methylphenidates. And then there used to be one called magnesium pymoline. And the one that I'm bringing with silo, however it was drawn from the market in October 2005 due to life threatening hepatotoxicity. So there was some evidence that it harmed the liver. So that one's no longer available. There used to be the three stimulants FDA approved. Now we only have two types. There are four types of infetomines. So there's just regular infetamine base. There's just infetamine. There is mixed infetamine salts. So that's the one that you guys are probably the most familiar with. That's Adderall falls into that category. It's mixed infetamine salts. And then there's dextrone infetamine, which is just the right, you know, dextrone means right. And so that's the right handed in antimere. It's right, we've got racemic mixes of left and right. But the interesting thing about the infetomines is that unlike a lot of medications like cytolopram, which is a one to one mix of left and right. The infetamine base, they're supposed to be like a mix of one to one left and right. But not all of them are some, I'm a little confused on that, but that's what infetamine base is supposed to be. It's an even racemic mixture of one to one left and right in antimere. Mixed infetamine salts vary. They tend to be like 75% right to 25% left. And that's because it's a mix of salts because you've got like four different salts or there's one that's like 3.2 to one. We'll go into all that stuff. But dextrone infetamine, which is the more effective of the two in antimere is also a product in and of itself, just the dextrone infetamine. Whereas the mixed infetamine salts do contain some of the left handed in antimere in there as well. And then there is Liz dextrone infetamine. However, Liz does not mean left. Liz means lysine. So this is dextrone infetamine that has a lysine group of text to it. That's the 5-Ans. I think people might not realize this, but dextrone infetamine, and this is Liz dextrone infetamine. So they've dropped the tro, the dextrone, and just shortened it to dextrone. And then they've changed the pH and infetamine to an F. So I don't know if any of you have noticed that, that they chose to spell dextrone infetamine, not the same as dextrone infetamine. We'll talk about that one. And then we've got three methylphenidates. So we've got methylphenidate itself, which is the racemic mixture of left and right. And then we've got dextrone methylphenidate. So you guys know what that is now. That's just the pure right handed in antimere. That's focal in. And then there is a newer one called serodextmethylphenidate. And that is kind of similar to Liz dextrone infetamine. It's got, I believe that serous serine group attached to it. But it's actually a mix of, it's actually got some other infetamine mixed into it. It's like two, it's got the serodextmethylphenidate. And it's got like, I think dextrone methylphenidate. If I remember correctly, it's like kind of that mixed together. And so that's one of the newest ones that has come out a few years ago. And so we'll talk about that one. And so when we talk about the stimulants, those are essentially the four we're going to talk about. And we're going to go through each one of those seven categories. And I'm going to tell you each medication cut that's inside. There's more than one dextrone infetamine. You've got, and the differences between the different ones in here are kind of the difference between short acting and long acting. So like with methylphenidate, you've got like a short acting, metalitmedium. There's like four acted, you know, four lengths of time acting on methylphenidate. And then with dextrone methylphenidate, you've got like a short and long serodextmethylphenidate. There's only one lixanemphetamine. There's only one. Then you've got ones like with the infetamine, some of the infetamines you have different products. So you have like a product that is liquid or chewable or things like that. And so we'll go through all that. And that will all make sense to you when we go through it. I just want to kind of give you an overview that there are those seven. And then next, I just kind of want to tell you what to expect when we have stimulants. So we've given a stimulant to someone. What symptoms are likely to respond well versus ones, which ones maybe are not going to respond too well and what could we possibly do about that? So the symptoms that respond best are like the symptoms that you would kind of think about when you think about having poor attention. So distractability, right? So when someone is easily, their attention is easily kind of put onto something else rather than what that they were trying or wanting or supposed to pay attention to. So it helps focus them in on the thing that we want them to pay attention to. Mind wandering, which is kind of similar to distractability. I think of distractability more like something happened and that caught your attention. Whereas mind wandering would be more like you just stopped thinking about, it's like day dreaming, which is actually the next one. But mind wandering just kind of like, oh, you're just kind of going from thing to thing to thing and you're not really paying attention to what's going on. And then daydream is kind of similar to mind wandering. Just kind of like, I think of mind wandering more like you're going from thing to thing to thing where it's daydreaming is more like you're just thinking about something else. And then there's something you want to think about. Just a story in your head, right? Next sticking with boring tasks. So you're doing something that is not very interesting to you, but you're able to plow through it, right? Inpatients. So just the inability to wait your turn or wait for someone to stop talking or wait to be able to like do the thing that you want to do, right? So it's going to help with that. And then impulsivity, impulsivity and restlessness. So that's kind of the hyper activity, right? So the impatience is kind of tied into the hyper activity, but the impulsivity and the restlessness is also kind of tied into that where you just can't hold it in. You just have to say something. You just have to do something without thinking or restlessness where you're like bouncing your leg, moving around that kind of stuff. And then the last one I have in symptoms that respond well, and I would say this is the one that responds the least well out of all the ones that I've listed thus far would be procrastination. So that's right, you can't finish a task, right? You put it off for later. You kind of think, oh, I'm kind of bored with this. I'll finish this later or I won't even start this. I'll do it later. The medications can help a little bit with that, but I would say less. And then the next symptoms I'm going to talk about are the ones that maybe your expectations for the medications are that they might not work too well at these things. So disorganization, so like executive functioning type of stuff, disorganization, poor planning, so just kind of keeping things organized and planning and having your schedule and sticking to times and schedules and keeping things organized in an order by which you could like complete the tasks and move through things. The medications, that's more of like a skill that I think the medications might help you to develop that skill, but they're not going to give you that skill. Okay. All the other things we kind of talked about were like what you think about of attention deficit, like not having attention and hyperactivity, like impulsivity in patients, things like that. That's why I said the procrastination is not as good because I feel like that's also more of like a self-discipline type of thing, whereas these other things are more like just like you can't really help it. You can't control that you stopped thinking about something. help but blurt something out. You can't help but wait your turn. But procrastination, you know, that's something that you kind of have to work on, right? And disorganization planning, these are all executive functioning things and I think the medications help you to be able to do this better, but it's something you're going to have to work on. That's why, you know, therapy is all typically like goes hand in hand with anything and so having some coaching and mentoring, like some of the non-pharmacological stuff I talked about in a previous episode would be really useful. Another one are kind of the the oppositional defined disorder, the ODD type of symptoms, so like oppositional behavior where you're opposing someone, you're disagreeing just to disagree because you know, that's just what you feel like doing, right? Or what the patient feels like doing. And then you've got argumentativeness where, you know, it's kind of similar where you just like want to quibble your point, right? So we're going to talk later about like what would respond better to this. So I would say like the Alpatoagonist would probably work better for your argument and miss an oppositional behavior. And then the disorganization and planning and the these executive functioning things, I think the coaching techniques and therapy and things like that might help more with that, all right? So I'm going to go ahead and list all the stimulus that we're going to talk about in the next several episodes and I want to kind of give you an idea of like how long they last. So I've got four categories here. I've got short acting, so we have meds that work about four to six hours and then we've got meds that work, which we call like intermediate, which lasts about eight hours. And then we've got some long acting, 10 to 12 hours. And now more recently, and these are like a lot, these are newer meds. We have even longer acting where they can go up to 16 hours, all right? So let's just go ahead and review through these real quickly and we'll go into details later just so you kind of have an idea, right? So for the short acting, the four to six, these are some of the first medications that were developed. These are medications that we might give to the smaller children. These are medications that will typically need to be dose twice a day, and we might do that to kind of establish what what met and what dose we're going to use and then maybe convert someone over to a longer acting. And these are also meds that we might add on later in the day. Sometimes every day, sometimes it's just a PRN as needed if we need a little bit longer action. Okay, so that's what I use the short acting for. And those are Dex methamphetamine. Also known as Foculin. Methylphenidate known as ridolin and also methamphetamine. These are the NBN names. Dexteramphetamine. We've got Dexterostat, Dexterin, Procentra, Zenzetti. And then we've got Dexteram phetamine and amphetamine. So this is mixed-and-fedamine salts. Sorry, this is mixed-and-fedamine salts. It's Dexteramphetamine andphetamine. So that's the the emphetamine base. That's evikeo. And then we've got the mixed-and-fedamine salts, Adderall, Adderall IR. Just like this would be focal in IR. This would be riddle in IR. These are all the IR preparations. So those are all our short acting. There's quite a few. All right. Next, we've got a few intermediate acting. The ones that are about eight hours. So only methamphetamine is in this category. We don't have any emphetamines in this category. So there is a ridolin SR sustained release. We have several different ridilins. So we had the our first ridolin methamphetamine which is IR. This is ridolin SR. And there's a couple other branded products that are basically the same thing. Meditate ER and methyl in ER. I'm not even sure if these are produced anymore. A lot a lot of the time once the branded products have been out for a long period of time, they stop making them. And the only thing that's available is to generic and see this would be like methylphenidate ER is what is what the generic would be called. Right. So it can be a little confusing because the branded product might be SR within the generic products ER. But when I go through this and I talk about what's generic and what's not, I'll tell you what the name of the generic products are so that you can kind of like understand what those are. Next, we've got the long acting. And these used to be our longest acting ones 10 to 12 hours. So these are kind of like the XR preparations of the meant of the IR meds. Okay. So here we've got mixed-and-phetamine salts. This is where Adderall XR is. Okay. So then we've got the Dextra andphetamine andphetamine. So that's the infetamine-based Racimic mixture. We've got Dynavel XR and it's in this ER. So at ZNS ER, it's in this XRODT, those are kind of the same acting product, but they are different formulations of how how you take them. And then we've got Dext, Dextmethal Phenidate ER that's focal in XR. We've got Methyl Phenidate ER which is Medidate CD, Ritalin LA, Concerta, DeTrona, Quillavan XR, Quilletue XR, Cotimpla XRODT, Jorn APM, lots of Methyl Phenidate ERs. And then the next one we have is Dextra andphetamine which is Dextrogen Spancels and Zelstrom. And then lastly, we've got Lysdex andphetamine 5-Ans. So lots of long acting preparations and you've got liquids, you've got Chouables and it's so cool that we have long acting liquids and you're probably wondering how can a liquid be long acting? You're going to find out. So lots of stuff to choose from in that category. And then we've got a few here that act extra long. So we've got a few. There's around 16 hours, Methyl Phenidate. There's Apptencio XR and Adhanceia XR. And then you've got, remember I mentioned the Serdex Methyl Phenidate and I said it was combined with something else. I was right. It's Serdex Methyl Phenidate mixed with a Dextro Methyl Phenidate ER and that's called Astaris. And then and that's because it kind of is it's got that Serdex Methyl Phenidate which is a long acting preparation and it's got that short acting Dextro Methyl Phenidate added on at the end to kind of give it that extra boost. And the next one's similar. So the the the the emphetamine version is Dextro andphetamine and then it's emphetamine mydeus and it's kind of a long it's like a triple acting formulation. So we've got a few of the long acting but a lot of these are still on patent and they're expensive and so I would be more in favor of combining like generics. All these long acting ones are expensive. So I would go are the longest acting ones. So I would probably if I needed that, add a short acting onto a long acting to be easier to prove and save money for the medical system. So those are all the meds that we're going to talk about in the upcoming episodes. So now that we kind of got that out of the way, let's talk about the history behind these meds. They've been along for a long around for a long time. Now when we talked about any depressants, they started around the 50s. The same can be said for the anti-psychotics. Bensit azapines I think were around that same time barbituids came out a little bit earlier. The oldest psych drugs we have are opiates if you want to include them in stimulates. All right. So emphetamine is one of the oldest meds really that's still used today. Aspirin is another one. These are meds that came from the 1800s. They've been around forever. Aspirin and emphetamines and opiates are, I don't know which specific opiates, but those are the three that come into my mind that were actually like isolated and kind of maybe their use was a little bit after that, but they're discovery. Lithium and Velproic acid were actually discovered around that time, but their use wasn't, it didn't come until much later. So emphetamines originated from a plant called a federal gyrus. It's known as Ma Wang in China. If you are aware of Chinese medicine or you've ever heard of Ma Wang spelled M-A-H-U-A-H-U-A-N-G, that's kind of where these came from. All right. A fedron was isolated from the plant. So the plant's name is a fedraval gyrus. That's it's like genus species. A fedron is the chemical that is the stimulant that's in the plant. It was isolated in Japan in 1885 and then a synthetic analog which we think about as emphetamine. So amphetamine is a synthetic analog of a fedron. So when you think about the opiates, you've got like the natural opiates And then you've got the synthetic opiates. Synthetic like fentanyl would be a synthetic opiate a lot of them are synthetic, okay? so They synthesize something that was similar to a fedron called it amphetamine It was a synthesized in Germany in 1887 Its stimulant properties were discovered in 1927 and then amphetamine was actually sold as a branded product known as benzidrin in 1933 as a nasal decongestant right so that they actually work for that It's kind of like how the opiates were used for diarrhea when when they first came out And if you if you know about emotium emotion is actually an opiate that does not get absorbed very well at all unless you take it in really high doses It's actually an opiate, but it's over the counter because it doesn't get into the brain. It can if you take enough of it Of course, I don't recommend that but that's actually an opiate. They're used for diarrhea and The stimulants are used as a nasal decongestant right when you think about What do we use at the store for for nasal decongestants right? The the phenylmphrens which don't work are the pseudo-affedron right so remember a fedron was the chemical pseudo-affedron is kind of similar to that It's a little harder to get now because you can actually make amphetamines out of it right that is the nasal decongestants And I think you can understand now. Oh, that's that makes sense that amphetamines were first used as nasal decongestants However, that was in 1933 the FDA banned it was benzardium was an over the counter counter product But the FDA banned it in 1965 and limited to prescription only I Have to assume that's because they realized that it had the properties that we know that it has now the stimulant properties which could be abused Later this medication so first use as an acetylchongestant later it would be used for narcolepsy obesity hypotension libido pain and depression Now the beneficial Effects on children for attention were first discovered in 1937 so this was also a very early use of the medication Now if you if you guys are familiar with the story I'll tell it so there were there was this Bradley home Which was run by this doctor Charles Bradley? Okay, it was in Connecticut and there were these children there these are children that you know it's like a foster home and You know as people did back in the day they experimented on The less fortunate and children and I mean that's that's how we got the smallpox vaccine the very first vaccine that was ever developed Some but somebody gave cowpox to an eight-year-old. This is just kind of how things were done back in the day So doctor Bradley performed LPs so that's lumbar punctures Which is not a pleasant procedure on all children In his in his Bradley home with the thought that it might elucidate their developmental disorders and Then the children got these headaches Lasting one to two weeks after the procedure right because you get you get a you get a headache after you have your cerebral spinal fluid drained out of your Your spine and then you have lower pressure And that you know that causes a headache so doctor Bradley Hypothesis that benzidrin right or the nasal decongestant might relieve the headaches Just kind of a gas. Hey, maybe this will relieve the headaches and then he noticed that their academic motivation improved significantly while taking the medication Hence was born stimulants to treat ADHD. All right How was methamphetamine where that come from well that was in Switzerland so Dr. Leandro Panazone At Siva which is now known as Novartis he altered emphetamine molecules to produce methamphetamine in 1944 it was initially Was the idea was to use it to reverse a barbiturate induced coma So you induce a coma to per you know to do a procedure on a patient or whatever you need to do with a barbiturate and then you want to wake him back up And so we use this methylphenidate and And then as researchers did back in the day Dr. Panazone actually experimented on himself and his wife and his wife's name was Margarit He called her Rita And you see where this is going So she said that it helped with her tennis game and So he named the drug after her Readle then right riddle in so that's where we got that name from It was then approved in for ADHD and children in 1961 But it really took off in the 1990s So emphetamine and methylphenidate were also extensively used on both the allies and the Axis powers during World War 2 to keep troops awake and we all know that Hitler was on a boatload of stuff he He was on uppers downers inner's outers like I don't know he was on a bunch of drugs And I mean if you watch him it kind of looks like he was He was on infetamines he was on opiates. I mean I can't remember what else he was on but These were used a lot for for stimulants I remember when I was Kid my mom used to tell me that like actors and actresses would take they would take barbicchewits to put themselves down and they would take Amphetamines to ramp themselves back up for their like long performances and and so forth So that that's how they were abused and still are So there was actually a mixture of methylphenidate and amphetamine or sorry not methylphenidate There was a mixture of methamphetamine all right, so that's what we actually know is like the dangerous drug today, right? methamphetamine How many of you realize that it's actually a schedule to prescribe a full substance and we're gonna talk about it on the next ADHD episode so Meth met met methamphetamine and amphetamine mixture product was sold as obitrol And obesity obitrol right for weight loss in the 1950s and 1960s The FDA withdrew the approval in 1973 and then it was reformulated without the methamphetamine in there rebrand is aterol and approved for ADHD in 1996 So I mean the long history that we have of these drugs going back to the 30s and we only had methylphenidate approved for ADHD in 1961 and aterol approved in 1996 and those were our first two meds When I was a kid everyone was on Ritalin everyone called it Ritalin Ritalin Ritalin, right? There was no aterol when I was a kid. It wasn't approved until 1996 so Ritalin was the the the Ritalin IR was pretty much all there was There there were some other substances that there was a Dexamphetamine substances Dexadrin etc. And we'll talk about that but aterol was actually not approved until 1996 So that's the history of the stimulants and then I want to wrap up today's episode by talking about how the amphetamines work and the methyl and the methylphenidate work, okay? So you can kind of see the difference between the two because they they have some overlapping stuff but the amphetamines do a lot more They actually have a lot of things they do and this is what I've talked about before and I'll talk about it again. I generally Think of amphetamines as a slightly more likely to work I'm more likely to give them to adults because they tend to need more and I tend to give methylphenidate to kids because they cause less effects, alright, so How do how do the amphetamines do what they do? All right, we're gonna it is good a lot of technical chemistry stuff here. So I don't you guys heard of the tar one receptor. So that's the TAR Trace amine associated receptor one so amphetamines are a full agonist at this receptor That means that they basically Act as the natural compound that would light this receptor up, right? So what lights it up tracing amines do? And if that means a trace it isn't it isn't amine so it it has a full agonist at the TAR one and so it's a little complicated How this what effect this has but? It goes through protein kinase A and C get phosphorylated This results in the dopamine reuptake pump and the nor the dopamine reuptake pump nor nor per nephrine Reuptake or the transport is the dopamine transporter nor per nephrine transporter getting internalized into the cell and Then that decreases dopamine and nor per nephrine reuptake All right, so that makes sense so when you agonize the the tar one receptor. This leads to a cascade of protein kinase AC phosphorylation. And that phosphorylation takes those receptors that are on the outside of that cell membrane of that neuron that those dopamine and norapornepernetferent transporter proteins and it pulls them into the cell. Right. And the job of those proteins, we've talked about this with the antidepressants, right. Because we talked about the serotonin transporter pump, the dopamine transporter pump and the norapornepernetferent transporter pump, what they do is they pull those chemicals from the cleft in between the neurons where they're going to do their job and light up the next neuron and they suck them back into the cell that release them. And if they get sucked back in, they're not going to get used. Right. And so this thing about how the SSRI worked, they block that transporter, right. Serotonin reuptake inhibitor. So they block that pump from being able to suck that serotonin back up into the cell. This works a little bit differently. Um, actually, in fetamines also do that on the norapornepernetferent dopamine transporter pumps. But in addition to that, we haven't got to that part yet. But they also take those pumps and just pull them inside the cell so that they can't transport. So that this is why they have several ways of keeping more dopamine and norapornepernetferent inside the cleft so it can do more of what it does, right. So through the protein kinase, C mediated phosphorization, it induces the dopamine transporter, no upper and different transporter, reverse transporter function causing efflux. So it also does that. So this tar one, it pulls those things back in so that they can't transport those chemicals back up into the cell where they won't be used. But it also causes them to like reverse what they do. So instead of sucking up the dopamine in norapornepernetferent back up into the cell, it causes them to spew them back out again. So it's kind of a double action. One, we kind of remove those by pulling them in so that they can't do their job. And then on some of them, we end up reversing them so that we're shooting more dopamine and norapornepernetferent back into the cleft, all right. So that's what that tar one full agonism does. Next, there's several functions here of amphetamines. Next one, the the secular mononamine transporters. So that's V-mat 1 and 2. It gets inhibited. Now you probably have heard of V-mat 1 and 2 if you're a psychiatrist because that's how these newer meds, newer, they're like 10 years old now. The ones that we use for Tarte of dyskinesia to help with that side effect of amysycotics, we have the V-mat 2 inhibitors. Well, amphetamines actually have some V-mat 1, 2 inhibition. And what that does is remember you've got your what is that, right? So you've got these vesicles and a vesicle is like a little bubble that's inside the cleft. So we're not we're inside the end of the terminal of that neuron. And we've got our little vesicle, our little bubble in there. And what that vesicle does is it packages dopamine and norapornepernetferent into the storage vesicles. And so the the V-mat 1 and 2 pumps are what sucks the dopamine and an orapornepernetferent that are in that terminal into the neuron and puts them in the vesicles. So when they're in the terminal, they're still not being used, but they could be ejected out into the cleft. But if they get packaged in the vesicle, they're even less likely to be used. And so what amphetamines do is they block that V-mat 1, 2 so that it can't suck that dopamine and norapornepernetferent into the vesicles so that they're in the cleft so we can more likely to shoot them out into the not in the cleft in the term in the end of the terminal so that we can shoot them out. So hopefully that makes sense. You've got it's it the vesicles kind of like a cell within a cell, right? You've got the neuron, which is a cell and it houses these chemicals. And with the with the tar one, we're like one we're reversing its action so that we're shooting out more dopamine, dopamine, norapornepernetferent and then we're sucking up the things that are going to like take it out. But then on the V-mat side of it, we're actually preventing more of it from being put into storage vesicles where it can't be used, right? So that it'll be out there so that we can shoot it out, right? And so then we've got V-mat 2 uptake. So amphetamines actually pass through the V-mat 2 that's that transporter, right? That's on those vesicles and it induces a collapse of the vesicular pH gradient. So in which results in releasing dopamine in norapornepernetferent. So this is kind of similar with the tar one. Remember, so the tar one had this effect of internalizing that receptor, but also reversing it so that we put more out there. Well, the effect that has on the V-mat 2 is one, it blocks the V-mat from transporting the chemicals into the vesicle, but then the amphetamine actually goes through the V-mat to a transporter and causes the vesicle to collapse so that it releases the dopamine in norapornepernetferent that happened to be stored in there in the first place. So one, it makes it hard for it to store it and two, it takes whatever was stored in there and shoots it out, right? So kind of a double action there. And then the next thing that it does is it's an NDRI. It's a norapornepernetferent dopamine reuptake inhibitor. Okay, so now our action is actually on that dopamine norapornepernetferent transporter pump. So the amphetamines actually enter the cell through that pump and that competes with dopamine and norapornepernetferent so it essentially blocks the reuptake. But when we talk about the NDRI, the norapornepernetferent dopamine reuptake inhibition effect of this medication, this is the effect that causes there to be more norapornepernetferent dopamine in the synaptic cleft to have action on the post synaptic terminals. Okay, for the next neuron. There is a difference between dextramphetamine and levonphetamine. Dextramphetamine has a KI value on the norapornepernetferent transporter of 6.6 to 7.2 versus a dopamine transporter of 5.8 to 24.8. And levon has on the norapornepernetferent 9.5 for the norapornepernetferent transporter and 27.7 for the dopamine transporter. So what you'll notice is the lower the number of the stronger it is. So to break that down, relatively, the levonphetamine has a little bit more effect on norapornepernetferent reuptake inhibition, which is going to have a little bit more the cardiovascular effects of increased heart rate and increased blood pressure. Dextramphetamine has more effect on the dopamine transporter, about 3 to 4 times more than the levon, which is that's where we get our central nervous system stimulation, kind of the effects that we're trying to get to treat the ADHD. So the dextro works more for ADHD. Now that's not necessarily something that we want with every patient. And so this is another difference that we're going to find in a lot of these amphetamine products is the ratio of dextro to levon. Some of them are a 50/50 mix, some of them 75/25, and some of them 100 percent dextro. Okay, so it does a lot of things to those pumps. It blocks, it blocks them from working. It takes them up so that they don't even exist. And then it causes them to reverse function and shoot the stuff out the other direction. So and then it works on the vesicles as well in a couple of ways. So amphetamine do a lot of stuff. I mean, I'll just tell you what methamphetamine does right now. It does the NDIRI and that's it. It doesn't do any of this other stuff. It doesn't affect tar one. It doesn't affect the MAP one to none of that. It just does the NDIRI. Okay. So if the the amphetamines are mostly having their effect on dopamine and norapreneferin, but they can have some effect on serotonin as well. But it's much less and you'd have to take a lot more. All right. And then at high levels, it actually can act as an MAOI as well. So it's got some monoamine oxidase inhibition activity at high levels. Okay. So that you know, that's that that was a type of any depressant that we talked about. So those two last functions are not something that you need to worry about a lot at the doses we're giving patients, but people that are like abusing this, that they may be getting some of that function as well. All right. So and then I've if you've got this if you've got my slides, I've got this drawing that I actually stole from Wikipedia and it shows all this. It shows the internalization of the pump. It shows the the e-flux. It shows the vesicle or you can just go and Wikipedia yourself and find this cool drawing. I think it does a good job of illustrating the pk a the pk c the the the tree samines the emphetamines the dopamine the phosphorization, all that. You can kind of trace it. All right. But then like the emphetamine can actually like, it can go through the transporter pump, but it can also just diffuse across the membrane. All right. So emphetamines can get all up and everything. All right. So that's, that they're pretty, they're pretty intense. And that's why, you know, they're abused. You don't really hear about methylphenidate being like a street drug. Okay. Because it's just an NDRI. And so you may be thinking to yourself, isn't buproprian just an NDRI? And didn't I mention before that buproprian is like, fourth line for treatment of ADHD? Well, if it's exactly the same thing as methylphenidate, then like, why is it so much like less effective? Well, it has to do with a lot of stuff, right? Because I mean, these drugs, they have different half lives. They have different intensities of effect. They have, you know, that they have, they may be stronger on different things. And so a couple of things that I've been able to actually dig up is that one, when you look at the KI values, which we talked about a long time ago at the beginning of the depression series, so the lower the KI, the stronger that a chemical interacts with that receptor. Right? So when we look at methylphenidate, its KI for the dopamine receptor is actually probably about, you know, seven times higher than that for the noraponephrine one. So 121 versus 788. And then focalin, which is dextrometalphenidate, is about 206 to that and 161 to that. Dopamine versus noprenephrine. Buproprian is like, doesn't have as much dopamine reuptake inhibition. So methylphenidate does quite a bit more on the dopamine side of things. And that's where we're getting the majority of our benefit. But there is benefit from the noprenephrine as well. That's why I mean, tricyclics used to be used. Not so much anymore. They've got a lot of side effects. But also they just like don't work as well because they don't have the effects on dopamine. But another thing is that the methylphenidate is actually an inverse agonist at the dopamine transporter versus an antagonist, which is what Buproprian is. And I want to put together a whole episode where I talk about all the different ways that drugs work, where I explain inverse agonist versus antagonist. And I explain all these different effects you can kind of put it together and have that as a reference. But I'm working on that. But I'll just briefly explain this. So an antagonist blocks the pump. It basically blocks it from working. But an inverse agonist like extra blocks it. So it basically does it more so that it has like a stronger effect if that makes sense. So it does more than just block it. And so it has a stronger effect on that receptor. So therefore it's stronger than Buproprian. And so doing these things on the noprenephrine dopamine reoptic inhibition can increase alertness, reduce fatigue and improve attention. Those are the effects that we're getting. And then methylphenate, I've already mentioned it was initially used as a barbiturate induced coma, but also narcolepsy and depression. And we still use stimulants for narcolepsy and often at higher doses to try and keep the patients awake so that they don't have the sleeping spells. And so we'll talk about narcolepsy when we get into the insomnia series. And I'll talk about all the treatments for that, but this is one of them. We use sedatives and there's some newer meds out there too. So a methylphenate was also used to treat memory deficits in the elderly. And as I said, it began use in the 1960s for ADHD and children and was actually in fetamines were actually a little bit earlier. They came about in the 50s. And so on the next episode, I'm going to try and go in chronological order as best I can, but there will be some jumping around because I'm going to go by category. And because amphetamines got approval first, I'm going to talk about them first. And so we're going to kind of go in chronological order and we're going to go by, remember I talked about the four different types of amphetamines. You had the base, the list X amphetamine, the mixed amphetamine salts, and the dextromanphetamine. And we'll talk about the drugs in those categories. We'll talk about how they're different, which ones are available, which ones aren't anymore. When you would use them, but hopefully this was kind of a good intro for you. And you're looking forward to actually, I don't know if I'm going to get through all the amphetamines on the next episode or if I'm going to have to break those up until a part one and part two. We'll see how far I get. There's quite a few of them. But we'll go ahead and go through those. And just to kind of tell you what the song and the reason for the song I picked today, I went with Disconnected by face to face. I've used a face to face song in the past. This is probably their most famous song. It's my favorite song of theirs. They put on both their first album and their second album. It's really its own. But I just think the idea of Disconnected is like somebody could be a ADHD-like thing to you know. They're Disconnected in different ways. So thank you for joining me and I will see you there. [Music]