E53: Attention Deficit Hyperactivity Disorder (ADHD): Background and Pathophysiology

Hello, this is your brain on drugs and this is the punk rock psychiatrist. Alright, well, so we finally moving on to the next season and as I mentioned at the end of the last season, I've decided to do two seasons together. I thought, you know, depression was definitely what we should do first. We got to depression. Please listen to those episodes. If you haven't, there's a 52 episodes where I go over depression, antidepressants, all sorts of stuff. And I thought, let's do ADHD because two reasons. It's what patients are really interested in and it's not really taught. So it's not, it's not, it's barely taught at all to, in med school or residency and things like adult ADHD are virtually not taught at all. So it's something of great interest that I think people don't know as much about as they should. And there's a lot of medications out there. And a lot of them, they're the same drug, but different formulations. There's just so many and I think most folks are just not aware of them. And we're going to cover them all. And I'll give you the pluses and minuses of every one of them. When I think you would, you should use one versus another. I certainly haven't used most of them, but I can imagine some situations where that might be the case. And I also, you know, as I've talked through in the last season, I'm very interested in lifestyle medicine and I'm very interested in obesity medicine. So I've combined the two topics into one series where we're going to talk about lifestyle. And so lifestyle stuff can treat just about anything, medical problems, mental health problems. And I'm going to be specifically addressing it on how I can help with obesity. But at the same time, it can also help with other disorders. So you'd use those same principles. And then of course, we're going to go into obesity medicine further. I'm going to cover all the medications for obesity medicine. So today, we're going to start off with ADHD. And just to get started, I'll go over kind of how we're going to cover this. So first, we'll talk about background and pathophysiology. So we'll just kind of give the background on where this comes from, some of the history on it. And then the pathophysiology, like kind of what's going on the brain that we think is leading to this. And that's what I'm going to talk about today. And then on subsequent subsequent episodes, I'll go over diagnosis. We'll talk about adult ADHD in particular. We'll talk about a medication treatment algorithm and all the insavouts of how to dose meds, how to time them, when to take them, how to do it different on different days, how to combat different side effects with dosing it and so forth. We'll talk about some non-pharmacological treatment. We'll talk about stimulants, we'll go over amphetamines, methylphenidate, other stimulants. We'll talk about their adverse effects. We'll talk about non-stimulants. And then at the end, I'm going to talk about how estrogen can affect ADHD. So that would be menstrual cycle and menopause. All right. So hope that sounds good to everyone. Let's go ahead and we'll do our intro episode today. We'll start with the background. So ADHD. Most common behavioral disorder in childhood. All right. So it's super common. Interestingly, they don't really teach it that much in pediatrics and a lot of programs, but it is the most common behavioral disorder in childhood. Approximately 8 to 15% of school-aged children have this diagnosis. All right. It's characterized by inattention, impulsivity, and hyperactivity. Now, I will mention that there's a lot of disagreement on this diagnosis. Is it a valid diagnosis? Does it actually exist? We're going to act like it does. All right. Because my main aim here is to tell you if you're going to treat it, how to treat it. If you're going to give these medications, how to do it? Now, a lot of folks won't prescribe these medications at all because they don't believe it's a real disorder. I think the evidence points in the favor that it is a real disorder. Right. But like a lot of the DSM diagnoses, they can be better or worse based on environmental factors, culture, and all sorts of things. And I don't necessarily necessarily think that it's any more invalid than a lot of the other diagnoses that we use. All right. So, inattention, impulsivity, hyperactivity, but of course, those symptoms could be associated with a vast number of other disorders. All right. So just because that's something you see, doesn't mean that we're dealing with ADHD. All right. So, some folks, and there's some papers out there that say that there is a difference between males and females when it comes to this disorder. Some studies say there is no difference. I'm kind of of the mind that it is a one-to-one male to female. More boys are diagnosed than girls about double. And some may say that this is because it's more it's more in boys than girls. And some might say that it's just not noticed in girls because they tend to not be as distracting of others as disruptive. And so oftentimes this diagnosis is picked up because a child is just rupting class, making it hard for others to learn, making it hard for the teacher to do their job, and or they are causing problems at home, and making it difficult for parents to do what they do. And just in general, boys cause these more problems more often than girls do. All right. And so it's more it's more often to come to light with boys. Boys are more likely to have the hyperactivity, which may or may not be associated with ADHD that makes this come to light, whereas girls may be just as likely to have the intention that makes it hard for them to learn in school, but because they're quiet and keep themselves and don't cause problems, but are just not doing as well because they're having difficulty paying attention may not be noticed as much. So there is there is some disagreement about whether it is an equal distribution between boys and girls, but I lean towards the camp that says that it's equal. All right. So there's also controversy. Once again, there's there's controversy on every single point on ADHD. Just bring it up is going to cause a lot of opinions in the room. All right. So do the symptoms persist into adulthood? Some would say no. And then some would say the range is 20 to 50%. At a lessons, 68% persist into adolescence. It's kind of generally thought that it's the most prevalent in the younger children, and it becomes less and less prevalent as the brain matures. Right. So as your neural networks and your brain are put in place a little bit more, you know, some people like this is thought of as kind of a it's a neurodevelopmental disorder. Right. It's something that you you have from an early early age, right? Whether it's noticed at that time or not, if you if you had it later and you actually had it later, it was there the whole time. It's not something that develops later. We'll talk about that in a minute, but as as the brain matures, this symptoms tend to become less and less of an issue, right? Because our brains do mature as we age. So some people are thought to grow out of this and other people are of the opinion that people never grow out of it. And so even though they may say that it persists in 20 to 50% of adults, you might say, well, some of those adults that don't have ADHD anymore, maybe they never had it. Maybe they were misnames. diagnosed as children and it was just that, you know, that, you know, they were slower to develop. Their brains were developing at the same rate as other people. They lacked maturity. They had difficulties at home, so on and so forth. But basically there are other explanations for their inattentioned impulsivity, hyperactivity symptoms that was not ADHD. And the fact that they don't have it as an adult means that they never had it. And as they matured and grew, they did not display those symptoms anymore. Others might say that as we learn new coping skills and learn how to social interact, even though perhaps the disorder is still present in the brain, we learn to cope with it in such a way that you don't meet the diagnosis anymore as an adult. I would lean towards both of these lines of thought. My thought is if you, if you don't have a ADHD later, perhaps you never had it in the first place and there's another explanation. Or if you don't meet the criteria for it now, it could be that you're compensating. You actually do have it, but you just don't meet the DSM criteria for anymore. And we know how much I love the DSM. You just don't meet the criteria for it anymore because you've come up with ways of dealing with these issues that you are unable to do when you're an eight-year-old child. Okay? So that's more of my thinking on it. But once again, research is mixed. Expert opinions are mixed. This is my own personal opinion from my experiences and what I've read. I'm not a scientist. I don't study these things. I'm just giving you my opinions on this podcast. All right? So I would say ADHD is a lifelong condition. And I know a lot of people would yell at me for that. I don't necessarily mean that you need to get treatment. And you know, I actually like have a lot to say about ADHD because the population that I treated in the military, these were people that were mostly mentally and physically healthy individuals. Otherwise, they would not have been allowed to be in the military. A lot of these folks had ADHD as children. And they were, there's rules that you can't take medication for something like two years if you want to join the military. So a lot of these folks get off of it so that they can join. A lot of people learn to cope without it. I mean, the whole thing is the military wants to make sure you can cope with that. But then they end up coming back to see me at some point. I find this in their history. And then it's like, Oh, you had this, you functioned for a while. And now you're not functioning, right? Because they wouldn't be seeing me if they weren't functioning, right? Like that's the whole reason that they come to see me. And often it's because they've been promoted to a certain point, maybe maybe when they were a young enlisted troop, and they were just turning wrenches on vehicles and things that, you know, for some folks, their ADHD would cause them to make mistakes in that sort of job. And those mistakes could be really, really a big problem. You know, if the screw is not turned appropriately in the wheel falls off, and you know, we have all sorts of problems, that would be an example. But other folks, they become hyper focused on that sort of stuff. They're really good at turning wrenches. They're very diligent at it. A lot of people with ADHD can actually focus very well when it's something that they're interested in or good at. You know, a few years later, they get promoted, they get put in charge of people. They have to do a bunch of paperwork. They're not turning wrenches anymore. And now they can't focus, right? So now the old ADHD symptoms that were there years ago, coming up and bubbled to the surface. So that is a presentation that I have seen quite frequently. So in the adult ADHD picture, where, you know, they functioned for a while, a lot of the time they didn't, they tried to function so that they could join. They quickly fall apart. And then if they see me, we get things back together. I get them back on medications that worked in the past and they begin to function again. Many of them are able to do fine. Maybe they, a lot of folks, you know, took the medications until they were 13 or 14. They came off of them, not because they were trying to join the military, but just because, you know, hey, maybe I don't need this anymore. And then, you know, things get harder later on. And they can't, they just can't task all these things at the same time. All right. So we'll talk more and more about this as we go through our ADHD series. All right. So I'm looking at a chart here of ADHD, aged 5 to 17 in the United States, boys, versus girls. And these are folks that have been diagnosed. So overall, on average, girls 8% and boys 14.5%. So I said that 8 to 15% range. That's where it came from. And then if you look at different age groups, you actually will see more diagnoses in the 12 to 17 year old group than the 5 to 11 group. And I think that's just kind of cumulatively more people, you're picking up on the diagnosis more throughout time. Maybe folks were missed because, I mean, the diet, according to the DSM definition, definition you have to have had symptoms before the age of 12. It used to be younger than that. I can't remember exactly. You used to be like nine or seven or something. But yeah, if you've got more people aged 12 to 17, that means that there were folks that were missed, that were like, oh, yeah, you had this the whole time. But now we've found it. So we've had more time to find it. So yeah, basically what it says in the 12 to 17 year old group, we've got 17.9 percent of boys 10, 10.4 percent of girls versus the 5 to 11 group 11.3 percent of boys and 5.9 percent of girls. So both of those have gone up. And this is this is a data that I've gotten from, I think it's from the CDC. It's from the NCHS data brief March 2024. I updated it before this, before this episode. And then I've got another chart from that same organization for ADHD, aged 5 to 17 in the US based on race. And so when we look at race, let's look at overall, let's see the overall 5 to 17 for Hispanic, it's 8.9 percent for Black non-Hispanic, it's 10.8 percent and for white non-Hispanic 13.4 percent. So as you can see, I mean, that obviously your race does not determine whether you have ADHD or not. And so there's just a lot of discrepancy here about like, who gets diagnosed and who doesn't? White kids are getting diagnosed at a much higher rate than Black and Hispanic kids are. And then Black kids are being diagnosed more than Hispanic kids. And I mean, this has to do with culture, it has to do with, you know, in the military we have a very diverse population. And I can say that generally a lot of my Hispanic patients will tell me that in when they were growing up, it was basically not allowed to talk about mental illness. And if you had it, you just kept it to yourself and, you know, your parents would be upset if you brought the idea up. And I mean, that happens in many households, but I did notice it happening more in the Hispanic households. So I can kind of see why Hispanic children might get diagnosed less. It's likely because, you know, the schools and the teachers might be bringing it up to the parents and saying, "Hey, we're concerned about your child. I think they should get diagnosed for this." And then they're saying, "They don't have anything. I'm not doing it." And like I said, that happens across the board with all races, but my guess on why the Hispanic is lower and the Black is a little bit higher, but still lower than the white population. And then you do have probably a lot more white parents that are, you know, thinking that their children are not achieving as much as they expect that they would and wanting to find some sort of way to get them where they think they should be. And they think, "Oh, my kid has ADHD. They need these medications. They need to do better at school." And you're probably going to see more of that kind of behavior in the white population. And that would be my guess on why there's more a diagnosis in the white population. But I would say that the diagnosis is very likely to be equal amongst boys and girls and equal amongst the races. But there are the reasons that I've discussed thus far that could explain why they are not diagnosed equally. All right. Next chart I've got here shows kind of the percent remission throughout time. And so it kind of shows the older that some somebody gets, there's a remission of syndromes, remission of symptoms, and a remission of functionality. But the functionality improvement remission is actually a very low-sloped curve. Whereas the syndrome is a high-sloped curve. And so basically what this chart is kind of saying is that functionally people may not be getting that much better. Symptomatically they're getting a little bit better, but syndromatically which is like they have the disorder. A lot of them are omitting. Now, once again this is probably a DSM issue where people are still having symptoms, but maybe they don't have enough symptoms to meet the criteria for the diagnosis. And we're going to go about how to diagnose it. I can't remember off the top of my head, but it's like you know you need X number of symptoms out of Y number of symptoms, like 5 out of 9 or something like that. That's what MDD is, but for this it would be different. But you need to have at least, I think it's 6, I think it's 6 for like adults and 7 for children out of the total number or something like that. And so say you slip down to 5. Well now you don't have the diagnosis of ADHD, you don't meet criteria, but you still have symptoms. So that would be the explanation. And because you have 5 symptoms, your functionality is still just about the same impacted. So that's I think what this chart is kind of saying. It's an older chart from 2000. I'll post these. I need to get the depression the most up-to-date depression slides up on the website. And I will post the ADHD slides that I have now, which I will update as I'm going along to the series, but I'll put this one up there as well. Probably since this is the first episode, I like to attach it to the episode. And so I'll I'll attach this to the episode. So you can see these charts that I'm talking about. You'll have these slides to like review. Yeah, what does it say here? It says at least 5 symptoms required for age 17 older. So yeah, maybe it's 5 for 17 up and 6 for younger than that. So they even decreased the amount of symptoms you need. All right. So let's talk about the this is another interesting thing. Let's talk about the history of the diagnosis of ADHD. ADHD is what we call it now, but it's been called many things in the past and by different different DSMs, which I I don't know I just find this amusing just that like obviously whatever disorders going on in the brain is exactly the same now as it was before, but that they come up with different names and different criteria. I know people are trying to do their best, but it's just kind of amusing to me. So let's go back to 1930 where it was called minimal brain damage. I love that. They basically what turned into it ADHD, the first thing it was ever called was minimal brain damage. So it was brain damage, but it was just a little bit of brain damage. Then a few years later, it changed into minimal brain dysfunction. So I we don't want to say it's brain damage is brain dysfunction. And then I don't have a year on this, but it's around the same time that sometimes it was also referred to as morbid defect of moral character. And that sounds great. 1937 is when the efficacy of infotomines was determined. And I'm going to get once we get to stimulants, I'm going to go through this history of like how it was discovered and how they figured out that the stimulants treated it. And it was actually interesting because they were they were looking at a population in this particular hospital that was completely different than ADHD, but that's how they ended up figuring this stuff out. We'll talk about that when we get to stimulants. 1950, they called it hyperactive child syndrome. And then was a sort of 1952 DSM one comes out and they call it minimal minimal brain dysfunction. I already had that back there in 1930s or something. Well, I guess they still called it that and by the time DSM one came out, they called it minimal brain dysfunction. DSM 2 comes out in 1968 and they've changed the name to hyperkinetic reaction of childhood. That's interesting because it's almost like they're they're just referring to it as the hyperactivity with that name. Hyperkinetic reaction of childhood and they're they're not so much noticing the inattention piece. They're they're focusing more on the hyperactivity piece with that name. And then see 1980 we get the DSM 3 and it's called attention deficit disorder plus or minus hyperactive state. So you could for those of you that grew up in the 80s like me and you remember it being called ADD. It was an ADHD. A lot of people still call it ADD because like that's what DSM 3 1980 grew up in the 80s 90s. You know you were using this ADD term. And so as attention deficit disorder and then you could either have hyperactivity or not have it. In 1987 they came up with the revised DSM 3R and that's when it was called ADHD. Attached attention deficit hyperactivity disorder and they also added the ability to have it diagnosed in adults. So it wasn't until 1987 that they even considered that this could be a disorder of adults. 1994 DSM 4 TR comes out and they talk about the 3 subtypes. So you're in a tentative type, you're hyperactive type and you're combined type which is you know you have both. Right. And then that's that's still what we we use today. So that was from DSM 4 TR. That's what I learned when I was med school in residency and then DSM 5 came out but they left they left this diagnosis the same in DSM 5 and then shortly thereafter I don't know this is 2004 I've got 2004 on here FDA approved adults for 80 out of all XR. All right so they included the adult diagnosis and then I don't know what if there were any meds approved for adults at that the point they added to the diagnosis or if it wasn't till this later time. But that's kind of the timeline of ADHD. Let's talk about etiology. So what is ADHD? Like physically in the brain like how does it happen? What's the what's the cause of this? So I've got like a list of four things and it could be a combination of these things or it could be one of these things. Right. So first first possible cause of ADHD. Neuro anatomic neurochemical. All right. So this is something that's just your brain is built in a way that that that you have these symptoms of ADHD right. So essentially they've done measurements of the brain and they've seen that folks that have ADHD have smaller cerebellar areas, temporal gray areas and total cerebral volume. Those are just kind of associations. We don't know I mean cerebellum has to do with balance. I'm not sure how that plays into ADHD but they've found an association with. So there are brain differences. We don't know exactly what those brain differences are but we do see that there are differences. The circuits to control attention appear to be smaller that makes sense. So they've actually seen when they when they do scans and look at these circuits for attention they are smaller. All right. So that there are neuro anatomic and neurochemical differences in folks with ADHD. Genetic origins. This is a very genetic disorder very much so. I can't tell you how many people I see it's like you know their parents had it or more commonly now like people my age as parents. I mean there weren't a whole lot of folks that weren't diagnosed with this back in those times. So what happens is and even a lot of folks my age I mean it was much more noticeable at that time but it's like our kids right people take their kids in their kids have it and they're like wait a second everything the doctor's saying I have maybe this has been my problem the whole time. So it often goes backwards. It's like yeah the parents have it and gave it and gave it to the kids genetically but they find out when their kids are being diagnosed that they've had at the whole time. I see that really that that happens a whole lot where people come in and tell me that you know they their kids were diagnosed and they'd like to get evaluated. So there's actually an up to eightfold increased risk for an offspring in a of a parent that has ADHD and it's been determined that it's 70 to 80% of of the genetic origins of ADHD are inherited from the parents. So that's huge actually. Even like schizophrenia is pretty heritable, but I don't think it reaches 70 to 80%. Like when they look at like identical twins with schizophrenia, it's a pretty high number. And with fraternal twins, it's high, but like 70 to 80% heritable. That's maybe the highest number in mental health that I'm aware of. Like that's almost guaranteed. Like if a parent has bipolar disorders, schizophrenia, there's probably a 50 or less percent chance that their children will have it. But if you have ADHD, the chances that your children are gonna have it are 70 to 80%. I mean, that's a eightfold increased risk. And when eight to 15% of people have it and eightfold increased risk is pretty massive. So very, very, very much genetically tied there. Here's another possible cause of ADHD, central nervous system insults. So that's not that you're like insulting the brain. It means that the brain was damaged in some way. So that could be while the baby is inside the mother, there could be some sort of brain injury that might be caused by an infection or trauma or blood, not flowing as much as it needed to be. Just something where the brain was not, was getting damaged in some way. Maybe nutrition, maybe there was some malnutrition going on. There's so many things that could be happening while that baby is inside that could affect the brain development that could lead to ADHD. Low birth weight is a two to three times increased risk of ADHD. So there's all sorts of things cause remember this is a neurodevelopmental disorder. So if the brain while it's developing gets insulted by some sort of toxin could be toxin or trauma or disease or blood clot or whatever, that increases your risk of ADHD. And kind of related to that would be the fourth etiology environmental factors. So exposure to cigarettes or alcohol in utero is a two to three times increased risk in utero means when you're inside the mom. And then also toxins later on in life. So lead poisoning, things like that that might happen after the child's born could, you know, and you know, is someone who has led poisoning is that ADHD or is that led poisoning? I would lean towards saying that, you know, this is where I don't follow DSM. If you have led poisoning and that's damaged your brain, is that really ADHD or is that you have led poisoning which has the same symptoms as ADHD, but it's led poisoning? That's not to say that you might not give a similar treatment, but you know, what I label it as ADHD, I'm not sure. And I'm also not sure that it matters. Now outside of the government where I work to get things covered by insurance, you kind of have to give it a disorder. If, you know, I could diagnose someone with led poisoning and give them a stimulant and no one would have had not. But if I were in the private sector in the United States and I did not give them a diagnosis of ADHD, their insurance would not cover the stimulant. So in many cases, in many cases, people are given diagnoses so that insurance will pay for treatments. And so that often leads to people getting diagnoses that they don't actually have and then they think they have it because they've been given the diagnosis, but really it was just done to help them out. And by help them out, I wouldn't say that it's fraud, right? I mean, that would almost be just, you know, suggesting that it would be fraud. Well, technically by DSM, they do have the symptoms. So it's not wrong to give them diagnosis. The diagnosis, does that mean that they actually have that diagnosis just because they meet DSM criteria? No, but can the insurance company argue with that? No. And if somebody, you know, if the drug company only gets FDA approval for certain disorders, even though the medication works in other disorders that have very similar symptoms and are related, does that mean that they shouldn't be able to get insurance coverage for the symptoms that they have? No. You know, something not mentioned on here that I've seen a lot of is that folks that have like a TBI, a traumatic brain injury often develop, this would be a case where you could develop ADHD as an adult. And I'll mention that. This is like the one exception, but is that ADHD or is that traumatic brain injury? And is ADHD is like a qualitative diagnosis that we can just make because you meet the symptoms, even though we know what the cause is. To me, the cause is more important. The cluster of symptoms is kind of something made up to me. If we know that you had a TBI, and perhaps stimulants might help you because you're having ADHD-like symptoms, I wouldn't want to call it ADHD, but if they're not going to get the medication covered, and they have the DSM diagnosis of ADHD, well, you might as well just say they have ADHD. But do they? I'm not sure. All right. This next chart is, this is like, these are some old studies. I've got study from 1971, 72, and 1990, that show the percent ADHD and first degree family members of children with ADHD control group versus ADHD group. And the control group, you just see, is like, wait, remember, I said it's an eightfold increase. So it's like the control group, first degree relative in children, it's like a really tiny percent of children that have it, that they don't have a first degree relative. And if they do, then it's a really, it's a lot. That's just kind of back up the thing already said. And then also from a genetic standpoint, there's a lot of complicated genetics that we don't really even understand. There's some genes implicated, just a list of few, DRD4, DAT, DAT is the dopamine transporter, DRD5, 5HT1B, that's a serotonin 15HTT, that's also serotonin, SNAP25. And there's more. And honestly, that stuff's not that important. But what's important to note is that there are genes-- and remember, I said that 70%, 80% of ADHD is heritable. What's the rest of it? Some of the rest of it is the CNS insults or the environmental factors. But some of it might just be some genes that there might be some spontaneous changes in the genes there that could cause something. But I mean, typically when we're talking about genes, we're talking about something that you got from your parents. All right, so that's the background. Let's go ahead and cover pathophysiology. And then we'll finish this episode up. So pathophysiology, that means kind of how it develops. We've already started to step into this. So we think that it has a lot to do with dopamine and norapreneference. So dopamine enhances signal in neurons. It improves attention, focus, vigilance, acquisition of information on task behavior, on task cognition, perception, norapreneference. It dampens noise. So it helps with getting distracted, shifting tasks, shifting thoughts. It helps with executive operations. It increases inhibition. So that would be dampening down hyperactive behavior. So behaviors, thoughts moving around. It inhibits that. So dopamine and norapreneference are involved. That's why the stimulants increased dopamine and orapreneference. That would be how they would be helping because perhaps this individual is having some problems with these circuits in their brain. And they need an enhancement to relieve that. There's been some neuroimaging studies done by functional MRI that have showed differences in the ADHD brain. So the anterior, singular, gyros showed activation in healthy subjects with memory tests, but not in ADHD patients. There's higher connectivity between subcortical and cortical areas. But it's not specific enough for us to use as a diagnostic tool. And there's other brain imaging has revealed smaller volumes than cerebellum frontal cortex and strion. I might mention that a little bit before. So what is the hypothesized neurochemical pathophysiology of ADHD? So the current theory suggests problems with the mesocortico-limbic dopamine pathway, so dopamine, and the locustsarillus noradrenergic system. So the dopamine and norinopreneference systems, right? And perhaps others as well. So there are tonins probably involved of the glutamine, anirgic pathway, colonirgic pathway, as anything, and we'll talk about the brain, it's very complicated, right? The psychostemulants, like amphetamines and methamphetamines, increase neurotransmitter activity in these systems, and that's how they can help relieve symptoms. All right? And here's another cause that I had mentioned before. This is something more recent. The use of Tylenol in pregnancy, so acetaminophen. There was a study in 2019 from Johns Hopkins that was in JAMA psychiatry, where they collected cord blood from 996 births and measured acetaminophen, which is Tylenol, and its metabolites, which is the chemicals it turns into, as it gets broken down by the body, and the amounts were classified into lowest, middle, and highest, thirds levels, I guess, in these 996 patients, they're like, what's the lowest third amount of acetaminophen is, metabolites the middle third and the highest third, right? And they compared the lowest third, middle third exposure, was associated with a 2.26 times risk of ADHD, and the highest third was associated with a 2.86 times risk. So that's really interesting. And I think pregnant women are told, "Tanol is the drug that you can take." Don't take ibuprofen if you're going to take something, take Tylenol. And now here we're seeing that, I mean, and remember, this is compared to the lowest third. So the middle third and the highest third, they're the ones that had the increased risk. So if you're only using it a little bit, that's probably not going to cause a problem. So the ASD autism spectrum disorder risk was also increased in this study. The middle third over the lowest was a 2.14 times increased risk and the highest third at 3.62 times increased risk. And sometimes when we talk about increased risk, oh, two times the increased risk may not be that big of a deal if it's a really, really rare disorder. So if it's something that only one in a million people get, you have a five times increased risk, that sounds massive, but that just means now it's five out of a million people to have it. That's pretty low. But if you've got a disorder that 5% of people have, and you increase that risk by twofold, now it's 10%. Okay, so ADHD, remember, it was 8 to 15%. So if you're increasing your risk by twofold, and then ASD, I mean, that's grown as we know. I think it used to be like 1%, and I think it's several%. Now, so if you're increasing your risk of AST by 2.14, 3.62%, that actually is a pretty substantial increased risk. And there's actually other studies that also support these conclusions. So the recommendation is limit use. I don't work in OB, so I don't know if this message has gotten out. On Tylenol, increasing risk of ADHD and ASD. But this is also, keep this in mind. The risk of a fever or pain that disrupts daily life is a higher risk than the risk of a scene of benefit. So just because you hear this, you're like, oh, I'm not going to take it at all. Well, if you get a fever, and you're really, really ill, and you don't take something to control the fever, that fever is going to do more damage to your developing fetus than the Tylenol was going to. All right? And if the pain you're having is so severe that the Tylenol would have relieved, that stress could actually cause more damage. And so basically what I would say is, if you have a mild fever, if you're a little bit sick, if you're in pain, but you feel like you can tolerate it, and you're thinking, this is something I would normally take Tylenol for, and I thought it was safe in pregnancy. I would think twice about that. I would discuss it with your physician. I know people would hear this, and they'll be like, I'm not taking this at all. I would not recommend that, because you could actually make things much, much worse. That's why it's important to have a conversation with your doctor. All right? So this was, I mean, 2019 study from Johns Hopkins in JAMA Psychiatry. That's the -- I think it was JAMA Stance for a Journal of American Medical Association. Yes, so that's like the premier psychiatry journal from one of the best medical schools in the United States. So this is something to really take into consideration. So I think this is something that all physicians, especially OB, should know about. And anyone that's going to be prescribing town all to pregnant women, so that would be a family medicine would be -- also would need to know this, all right? But then here, use less than eight days during pregnancy. So if you took town all less than eight days, there was no increased risk. So if you need to use it in a short term, it's not that much, and you really needed it, it's not going to cause a problem. However, I think folks were under the -- under the idea that it wasn't a problem back at all, and they were probably using it more often than they needed to. All right? So this is another possible etiology of ADHD. So let's summarize what we have learned, and then that will finish off this episode. ADHD is a neurobehavioral disorder with a complex etiology, right? Remember, we've got neuroendotomical and chemical effects. We've got genetic stuff. We've got environmental impacts. We've got CNS insults, right? So complex etiology and neurobiological basis. So we see the genes. We see the scans on the MRIs. We see the differences in the circuits that control attention and things like that, right? So this is something that we have -- we can measure. This is why -- I mean, I just don't really buy this idea that this is not a real diagnosis. I'd say it's just as real as anything else is. And a strong genetic component. That was the other one. 70 to 80% heritability. Massive. I don't know anything else that has that much heritability. They're genetic disorders that -- we say penetration. It's like how likely they are to get into off-string. Like, what is the penetration? If it's 50%, that means there's 50% change your offspring. You're going to have it. There's a lot of genetic disorders that have penetration of 50%, which is huge and scary. And these are -- I mean, things like -- I would think of things like hemophilia and Huntington's cystic fibrosis. I don't know if it's 50%, but it's high, maybe 25%. So, in this one, I mean, of course, this is not as lethal as those, but 70 to 80% is very, very large genetic component. 80 HD effects, millions of people of both genders. I think equally, some would argue with me. 8 to 15% of the population. It persists through adolescents and adulthood in a high percentage of cases. I might argue almost all cases. I think if you have a neurochemical developmental disorder of 80 HD, and it's legit, and you actually had it in childhood, that you probably have it as an adult as well. I would argue nearly all of the time, just because you don't meet the criteria for it, to me, doesn't mean that it's not still there. It may not need treatment. It may not be so severe that we need to do anything about it. I would say, you know, maybe you've come up with coping mechanisms or changed your life in a certain way that allows you to deal with it, in ways that were difficult when your brain was developing, but I would say it's probably still there in some capacity. And, you know, putting under the right stresses could rear its ugly head. And the last point, 80 HD can have a negative impact on multiple areas of functioning, and we'll go into a lot more detail on that when I talk about diagnosis. So, when we go through diagnosis, we'll talk about the DSM criteria, but I'll also go through, you know, a practical way to kind of go through this. I mean, you can't just tick off things, right? And in the case of ADHD, a lot of the time we use things like the Connor scales, you know, these are scales where we like, how teachers answer like 100 questions or more, and the parents and you kind of add it up and see what happens. But there's, you know, especially for adults, we just, That's not practical. And so the interview and how you ask questions and how you assess someone's life are very critical. And kind of seeing how that impacts the different areas of functioning of someone's life is really important. So we will get into that probably in the next episode or two. So I hope you enjoyed our introduction to ADHD and you're excited to learn more. I think I'm probably going to flip back and forth between the lifestyle of BC and ADHD. So my next episode maybe on that topic or it might be the next ADHD we'll just have to see. But I'm going to I'm going to kind of do those at the same time. And then just to put the throw out there the song for today is my brain hurts from the album my brain hurts by Screaching Weasel. It's a little it was a little hard for me to find like ADHD themed punk rock songs. And so I'm going to have to be a little bit more creative. And I may pull a lot of songs off the my brain hurts album just because I just kind of think you know you've got ADHD can't focus. It's like wreck in your life. It's like my brain you know it's killing me. It's like it doesn't work. So that was kind of my thought on why I picked that and the artwork today. I also have a little bit difficult to think about the artwork for ADHD so I kind of had like my character kind of having two thought bubbles between music because of the punk rock theme. And then like a book which is like working at a high-pasture. I can't get my job. I can't get the chance to do that. So hope you enjoy that. Hope you enjoyed the episode. I hope you all stay tuned for more. I will see you next time.