Improve Focus With Behavioral Tools & Medication for ADHD | Dr. John Kruse

47:35Does that logically hold free? It's just a story Yeah, I was gonna say There's both those have some science background. So I'd say I'm glad it works and what's hard to sorting out as wide as working as one is you know potential placebo effect You're doing it because you're thinking or opening it works good and two I'd say maybe even more importantly than the placebo effect is the days that you're deciding to do this There's something different about those days to begin with because they're not doing it every day so those potential issues aside I'll jump into insomnia and Matthew Walker talks about some of this to me Maybe the biggest finding in insomnia sleep medicine in the last 20 years is it almost everyone Who has a problem with insomnia doesn't have a problem with sleep?

48:29Huh what that does sound like I'm contradicting myself what I mean is The sleep systems intact. It's there. It's waiting to arrive and put you to sleep each night What the problem and that this is from the sleep researchers With at least 90 % of probably more of people who have insomnia problems is the failure of the daytime arousal system to shut off properly So normally we have these two mutually inhibitory systems or waitfulness Arousal system and a Sleep sedation system and usually when one turns on the other turns off and with Most people's problem with insomnia. It isn't that sleep is weak or insufficient or not there It's sitting it's waiting there.

49:13It's just can't land on the landing pad because you're too arouser too weak I mean maybe that helps the arousal system to turn off better at the end of the day It's gotten more fully engaged During the day. I don't know but it feeds back more into some of the non -medication approaches to Helping with sleep and that is doing everything you can again Not just a forced sleep or push it because that doesn't work very well. It's getting rid of arousal It's dampening arousal so for people with ADHD one is you know deciding on what's a reasonable bedtime? You know having Thinking about this out of time and to um Eliminating any stimulation or I mean once so exercise.

49:58I'm a big fan of Marathon runner. I know you're heavily into exercise as well um Exercising too late in the evening can elevate body temperature disrupt falling asleep. So Physical arousal we don't want to be doing a lot of late in the day and emotional intellectual A cognitive arousal too. So The biggest single tool in modern life is do not have your phone in your bedroom And that's hard for lots of people to do but if it's there You're gonna be checking it. I mean studies have been shown even if you're not checking it if it's there You're thinking about it. They're looking at it just having it away Out of sight is better than having it visible and turned off Two is using if you have someone you're sharing a bed wet their family members using them to help reinforce Yes, it and it's really helpful to talk about this ahead of time Because the exact same words can either be sounding like a nag or someone trying to exert their power over you Rather than what people with ADHD we know need reminders They know they need some of that external structure And if you are on the same page and can have a partner your kid or someone else present A dad shouldn't you be turning off the computer and not into bed right now That can be helpful again.

51:25It can be destructive if it's not done in a Framework where both people are on board and it's Not fair to make the other person responsible for your own behavior But lots of people are usually Happy to help the person at ADHD be more organized in their life So we were also talking a little bit before one of my favorite tools for falling asleep is actually sickluxi I mean there are other box breathing and other techniques to help someone relax So we know sickluxi engages the parasympathetic nervous system our rest and digest system I mean one of the things that happens normally in the transition every night when you fall asleep is you're going from Primarily sympathetic tone to primarily parasympathic tone so anything that Is strengthening or putting in there already makes it easier um I know you have videos about sickluxi and I do too.

52:19I mean my own Experience which I was sharing with you before we started talking was not only does sickluxi help me fall asleep better It actually helped me stay asleep throughout the night better That's a remarkable thing because many people including myself have very little trouble falling asleep Especially given how I stack caffeine in the early part of the day and then Stop in the afternoon. It allows me to fall asleep within seconds Somewhere for me typically around 10 p .m. Somewhere between 10 and 11 p .m. Is my typical bedtime But then I consistently wake up at You know three in the morning usually get up use the restroom and then go back to sleep Most of the time without too much trouble provided there isn't a lot of stress in my external life and provided the phone is not in in the bedroom um But as we were also talking about before we uh turned on the microphones Um this idea that our bladders get smaller as we age is is complete nonsense right so that can't be the explanation why people wake up More in the middle of the night as as they get older.

53:22Yeah, I mean some might I mean some it may be a prostate issue with No, clearly that isn't accounting for half the population But I think it's much more the neurologic innovation of our bladder You know all our nerves start functioning not quite as well And they're just getting the signal that I really need to urinate right now when pretty clearly most of those people don't They could wait but the signal is arriving that says you have to and it's believable and you don't want to deal with it If it's you know you don't want to not listen to it if it is right so How much cyclic sign are you doing before sleep and how long before sleep is the cyclic sign done?

54:02So when I read your paper with speagle and others generate For years i've said I don't have a meditation practice most people think i'm sort of so chill or relax that i do I seem like a pretty mellow dude. I I haven't ever taken the time to do it which i'm embarrassed by so i said Read the paper i can do five minutes a day of cyclic sign And i tried and it was Some days i was getting it in and many days i wasn't getting it until bedtime which is the I slept really well till i was around 40 and not so well the next 20 years both that Mostly with the trouble falling asleep even though i knew of relaxation techniques and others So i wound up just consistently doing it to do it more for the general health and I'd rather slightly elevated blood pressure and relaxation and to see what effect it would have and it was clear So i do about five minutes and Much more than five minutes.

55:03I tell people And i might be doing it a little slower than most count out about 20 or 25 reps of it And if you lose track Doesn't matter to just go back to the lowest number because again everything we're trying to do is decrease a rousal If you have a timer on it and you do it for five minutes and then you're walking up You're reversing or mitigating some of the benefit of it doing it so My recommendation is do it for five minutes about but do it by counting reps and Don't focus or you know if it's six minutes of it's four. I mean there's so many Aspects of this and we know the exhalation has to be longer I was trying to find as you know is anyone systematically You know is a four second exhalation better than ten versus six And those studies would be so simplistic and easy to do but you know There's lots of variables that we can play with to see what's optimal I don't think we know it all it's optimal But we know what's good enough to work Oh delayed to hear that it's worked so well for you I am as people know i'm a huge fan of the physiological size and I take no credit for having discovered it It was discovered by physiologists in the 1930s point that I shared with you is that Prior to trying cyclicsai Sleep you mentioned earlier Encouraging people with ADHD or who think they might have ADHD to keep somewhat regular eating schedule or at least to make sure that they're eating and to not let their meals get fragmented into starting a meal and then finishing it later, like have for some people, it's breakfast, lunch, and dinner for some people, like myself, it's lunch, snack, dinner, whatever it is, keeping a regular schedule, exercise, aside from encouraging people to not exercise too late in the day, certainly not caffeine and exercise late in the day, are there any data about specific types of exercise being better for ADHD, independent of effects on sleep?

57:22I realize they're hard to tease apart. Yeah, there's a few studies looking at acute aerobic exercise. Hard of it is that it's hard to study people when they're exercising during many exercise. I mean, not gonna wire someone up when they're swimming, for example. So there's not a lot of studies in anyone approach and there's so much diversity that often it just gets lumped together. So there do seem to be some acute effects of measurably improving some of the executive functions associated with better attention from acute exercise and there seem to be some more general or longer term benefits from people who are consistently exercising, having, you know, being able to concentrate longer, being able to switch of attention more appropriately or effectively, and there's a huge body of sort of clinical literature of patients reporting.

58:17You know, I feel much more alert today. I get my workout in the gym and I feel better. You know, the week I took off from that was a big mistake. But I would say identifying at what's the most valuable or what's the best duration. I've ran through the data about a year or two ago and I could say that we can't make any conclusions and I would say at some level, try it and see what works for you and that's what's important. It doesn't work for everyone. Is there a relationship between ADHD and addiction because of the impulsivity component? Yes, and so the answer is, and these are really rough statistics.

59:00I actually, one of my pet peeves is people who quote, oh, the rate of this is 27 .43%. Well, it might have been in that study, but that's looking at one population, at one set it. So I use ballpark figures. The ballpark figure is Americans in the last 20 years, more than that, about 20 % of Americans run into some addiction, substance addiction problem, either alcohol or drugs. People with ADHD have a rate that's almost double, and it's higher in men than in women. Double. Almost double, almost 40 % risk. And that's for substance abuse. Not substance behavioral addiction. Yeah, that's substance abuse, and that's looking at abuse, and we can get into the related topic of what's misuse and versus abuse and pet peeves there.

59:49However, kids who are put on stimulant medications when they're young, and I should say the stimulants themselves do have a small potential for addiction, but putting kids on stimulants pretty much normalizes the rate of addiction problems. So it protects them. This is a really important point that I think maybe we just hover on for a second, because I think many people, including myself, assume that, well, if you're putting these kids on emphetamines of which, many of the medications for ADHD are that we're creating kids that are addicted to emphetamines or to a hyper stimulation period. But you're telling me it's actually protective to put kids with real ADHD on medication for ADHD.

1:00:39I can say not absolutely every study has found this, but several large meta -analyses have gone back, and most of them have found this fairly dramatic benefit to being on stimulants as a kid in terms of specifically reducing substance abuse risk. And some of them that have looked at us, when I said it, was a yes and it seems to be that it's not just the impulsivity traits, but some of the inattentive ones too. If your teacher's lecturing about the risks of alcohol are this and this, and you're zoning out to the window and looking at the plane flying by, you have less pertinent information on the topics.

1:01:17You may be less attentive to the negative effects that other kids are seeing among the classmates who are stoners at this age or X, Y or Z. So it seems that both inattentive sets of ADHD symptoms and the impulsive, you know, thrill -saking, not weighing the consequences, as heavily are all contributing to this heightened risk. I have this model in my head that is perhaps completely wrong, maybe partially wrong, and it goes something like this, that we know that the neural circuits involved in executive control and directing attention and maintaining attention and avoiding distraction, this kind of thing, use dopamine and epinephrine and nor epinephrine, at least to some extent.

1:02:10And we know that people with ADHD are capable of focus, as you said, it's a failure to direct that focus, maintain, et cetera. So I've heard from you before this discussion that, you know, people that, you know, tend to drink lots and lots of caffeine or who can drop into an activity but have a lot of distractibility that, you know, they might have ADHD. So what I'm imagining here is that the threshold to get dopamine, epinephrine and nor epinephrine released is either much higher or more complicated for people with ADHD. And so what they're seeking is these catacoleumines, these three chemicals, dopamine, epinephrine, nor epinephrine, and that if they're given a medication that puts them in that range where they're getting it, then they're good, they can stop seeking it, so to speak.

1:03:00And I'm raising this now because we're talking about addiction, addiction is a, you know, pursuit of things, essentially. And I guess what I'm saying is it seems to me that the model of ADHD that we hear about is that, you know, people can't focus, you know, their dopamine circuits are all out of whack and then you put them on this dopamine orgic drug and, you know, basically you get them addicted to that tunnel vision or something. But I have this model in mind now that what we are all seeking is to have portions of our day where we are directing our focus towards a meaningful bill, the things that are, you know, generative in our life, work, school, relationships, et cetera.

1:03:39And that whether or not it's pharmacology or exercise or what have you, that it's just about getting into this plane of consciousness and I say that in no woo or abstract terms. Is that right? I mean, are we really talking about here is a failure to access enough of these neuromodulators and these medications which we're about to talk about. Are really about putting us in the realm where those neuromodulators are just more accessible? I'll just say I can go with that. Okay, well you're the expert. I mean, I'm putting this together based on kind of what we're talking about it, like getting enough sleep to me is a way of being able to have enough arousal during the day.

1:04:17You know, exercise or these medications just different ways of being able to access arousal. Like if you don't sleep, you can't access arousal during the day. So, okay, well, I'm gonna hold that model in mind and I'm gonna keep testing it to try and destroy it as we go forward. Let's talk about the medications since you raised those. And, you know, the first one I ever heard about was Ritalin. Let's start with Ritalin. How often is Ritalin used nowadays? And what is Ritalin doing in neurochemically? And what are your thoughts on Ritalin as a useful drug for childhood and adult ADHD? And I'm happy to repeat those questions.

1:04:58So Ritalin is, or generic methylphenidate and there's dozens now of slow release versions and there's even a patch, a skin patch instead of a neural version. Our definition of what a stimulant is is really squishy and vague. And it's broadest sense. It's any drug that has an effect in the body like the sympathetic nervous system which is a norupinephrine -driven fight or flight arousal system. So by the elusive criteria, caffeine is a stimulant. Well, butions are stimulant, even though we classified as an antidepressant. Some of the decongestants are stimulants. But more often when we're talking ADHD medicines, we're using stimulant more specifically for amphetamine -based products like Adderall and ViVance.

1:05:49And again, there's a host now of newer branded extended release forms and methylphenidate. And we lumped it together, probably most ADHD experts agree with. And this is where I'm gonna be disagreeing with most of them. I don't consider Ritalin a full stimulant. So the neuropharmacologists differ a little bit but amphetamine is a strong dopamine and norupinephrine reuptake blocker. So it prevents what's already been released from being taken back up. So more is available longer. But in addition to that, amphetamine is a pretty potent, it's just a vesicle manipulator. So it's actually forcing a bigger release from the vesicles when they're synaptic to release.

1:06:33So it's not just that the signal lasts longer and is stronger because of that. It's a bigger signal. Depending on what study you look at, most of the studies suggest that methylphenidate is actually a pretty weak vesicular manipulator. And some studies don't find any impact there at all. Which means if methylphenidate is basically a norupinephrine and dopamine reuptake inhibitor, that's what well butren is, that's one or a component. It's, and so why I would further say, if you look at the efficacy data, how well do these work in resolving ADHD symptoms? All the meta -analyses lump, adderol products, amphetamine, and methylphenidate products here and say, you know, they're here because they work better.

1:07:25This is, you know, success in reducing ADHD symptoms. And all of our strutera at the, at a moxatine while butren, I use cymbalto lot, metaphenyl, grantficine, all these other things are down here as less effective. But if you actually look at any of the plots that I've looked at and separate out, methylphenidate is actually closer to the pack below. It's that amphetamine products are head and shoulders above everything else. Methylphenidates usually at the top of the rest of the crowd, but if you're just looking at the data objectively, there's a clear decision point. So in terms of efficacy, amphetamine products are stronger, but in terms of some of the side, that, you know, the side effect that I worry most about, it's not at all common, but it's one of the horrible ones is amphetamine and dosycosis.

1:08:19Now that we're finally looking at that a little more closely because for years ADHD experts have said, yeah, it's really rare. Let's not look at it at all. Let's not pay attention, move along. You know, don't look. With amphetamine at all products, and that's probably dose dependent, but it's close to one out of 500 people. And what's, I'm going off on a tangent here, but I'll keep following it because it's an important tangent. It's only one out of 500 people. That's uncommon, but this is a really bad condition because so amphetamine and dosycosis is a schizophrenic light picture. Usually someone is really paranoid, really worried that their friends are manipulating them or the place they're spying on them.

1:09:02I mean, if you drink too much alcohol, you can be batshit crazy, and that's a highly technical term there. I mean, you can be out of touch with reality. You can be hallucinating. You can be saying all sorts of nasty things. But if it's alcohol -induced, you fall asleep at the end of that night, you wake up the next morning, you may feel horrible at the hangover. You're not hallucinating. You're not psychotic anymore. Hopefully you're regretting what you did. Probably not remembering much about you. People will let you know. With amphetamine induced psychosis, on the other hand, classically and characteristically and what I've seen clinically, it continues for days, weeks, or months after stopping the medication, which means we've changed someone's brain and we don't have lots and lots of data and it's actually only come to us because people are concerned about marijuana causing a similar picture.

1:09:58So now we're studying this a little more. Well, with amphetamine induced psychosis, about, and these are again, rounding from different studies, about 20%. If you look 20 years out, about 20 % of those people are in a permanent psychotic state still. So again, it's uncommon, but it's such a bad outcome that we really should be alerting people to it and I've been, I saw much higher risk of this for I can get into it if we need a reasons in my population in San Francisco. But I've had people coming from all the most prominent ADHD clinics over the years, who just moved to the area. And when I'd say this, give this is my introduction to, you know, I'm happy to continue on this, but are you aware?

1:10:44To a person, they said, no one ever told me that. Now maybe they've ADHD and we're listening, but it's so uniformly consistent that they didn't hear or know that that was a side effect. And one in 500 isn't a trivially small number. No, it's not trivially. And I mean, why I got delerted to it is my rate in San Francisco is actually higher than one out of 100. And so I'll go into, I think a couple of different reasons. One is, I worked with a lot of HIV positive men and we know HIV, particularly in the days before we had effective antivirals, is a virus that goes to the brain and in fact, I don't know, there's a HIV induced dementia.

1:11:28So probably some of these people had brains that were compromised because of that and were vulnerable to a high incidence of methamphetamine. So methamphetamine, street speed is a chemically different molecule than amphetamine as an extra methyl group. And an extra methyl group can mean a lot. So it's a cousin, but methamphetamine we know has higher rates of psychosis, higher rates of addiction tends to be more rewarding. But again, in that population and many of them would hide that history from me, but I think that the very first person I had with them had a methamphetamine induced psychosis.

1:12:05A guy in his 40s, HIV positive for years. This is back in early mid 90s. It was able to finish school in his mid 40s, get a good paying job in two years on stimulants and then at a full blown psychotic episode where he is dead and died of a heart attack 10 years earlier. He was threatening his mom because he believed his mom had poisoned her. He flew to Rhode Island where she was living. He was making threats from a pay phone and because Rhode Island's so small, he was actually calling from out of state. So it's a federal crime. He got thrown in federal prison for this. And he stayed psychotic for months after he wasn't using him.

1:12:48But a later turned out, he had had a psychotic episode 10 years earlier on street math, which he lied about when I did the evaluation. So the other high risk group I had was, I was known in San Francisco as someone who worked with adults with ADHD at the early stages of recognizing ADHD. So and I was comfortable with the broader range of stimulant dosages and many providers are. So I had people who had, and they were all young white males, straight males who had history, and I don't know how many of those demographics are relevant, but who had histories of taking stimulants, having a psychotic episode, again, being really paranoid, all, and again, the numbers aren't huge, but at least five people with this general profile.

1:13:40But even though they were paranoid, even though they were severely impaired enough that each of them wound up in a psychiatric inpatient hospital, which is pretty hard to get into in this day and age, or even 20 years ago, they all liked something about the experience enough that they all wanted to get back on, and all of them knew enough to lie about this past. So they didn't tell me about, they presented, all of them also had ADHD. They presented with ADHD, they'd say, I'd been on stimulus before, and I'm not working with that doctor because my insurance changed, or they had moved to the area.

1:14:17So they gave plausible histories, and most of those within a month or two of restarting it wound up back in the psychiatric hospital. I had one guy, right computer programmer, late 20s, calling me from inside the psychiatric hospital to try to get me to prescribe more aderal to him. And not only that, he had convinced his inpatient psychiatrist that this was a good idea, that this was important to treating his ADHD and helping him retain his job. Wow. So these are, as you said, straight white males who have psychotic episodes on their ADHD meds, and continue to seek those meds because they, quote unquote, like the experience.

1:15:09It feels like a manic high, the high dopaminergic state. Yeah, and you put the word mania in there, manic, and lots of people define this as, I'm not mean to do this mania rather than psychosis. I don't, because one is uniformly and maybe other people are seeing more, that these people were paranoid, they were worried, they were anxious, they were delusional, but they weren't overtly enjoying it, they weren't having a great time, they weren't saying, I'm gonna party with all you friends and I'm only worried about the people there. And yes, they were talking more loudly, they were sleeping less, which is, could be characteristic of mania, but there was no positive affect that I or police reports or often families give you extensive history of everything that was going on, that there was nothing euphoric, they were describing about it.

1:16:08I mean, I think the second piece is how much of, it's unclear how much they actually remember or recall or either through psychological suppression of it or physiologic, they're in a different enough state, it didn't register properly, it's not clear, but they tend not to recall the paranoia, and by paranoia, it's persecutory delusions, I have people who assaulted family members thinking that they were being spied on, manipulated, when the parents were trying to take care of their kids. I'd like to take a quick break and thank one of our sponsors, Element. Element is an electrolyte drink that has everything you need and nothing you don't.

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1:18:03What are the options for people that think that they may have ADHD? Let me phrase it differently. Someone comes in and you, they have, you know, let's say an adult, they have five of the 18 criteria, criteria, they meet the criteria for ADHD. Do you tend to, well, after telling them about sleep, food, exercise, and relaxation, after that squared away, if the decision is to medicate, do you just, and assuming they're not on any other medications, which cluster in this two sets of clusters that you described before, the emphetamine type, the Adderall, ViVance, et cetera, versus the, I realize you put riddle in at the top of the bottom cloud, well, buterin, riddlein, Modaphanil, you mentioned Simbalta, which cluster do you go to first?

1:19:04I mean, some of this is just individual style rather than intellectually thinking one is better and my style is usually to listen as closely as I can to what the patient wants. That doesn't mean agree with them, but to explain in as much detail as I can, what I perceive the risks and the likelihood of those are and what I perceive the benefits to be. For years, just statistically, I had many more people who were on non -stimulants than stimulants compared to the general ADHD population and that's even accounting for, by many variables, I've always worked with a lot of people on disability from Medicare.

1:19:45I also worked with people who are on Medicaid and the cities insurance before Obamacare happened. So I worked with, not entirely, but a skewed more dysfunctional, more severely afflicted population, which, again, you would think would be a better match for the more powerful drugs. I'll jump back, but this actually is a situation where we have more powerful drugs. So often when I treat people with depression, they'll try one or two or three antidepressants and say, well, give me something that's more powerful and with depression, maybe we can put ketamine out of the picture and I know this is a side issue, but all of our antidepressants seem to work equally well.

1:20:28We don't have potent antidepressants and non -pricot FDA approved. It works in a certain range of likelihood, but with the stimulants, I don't think any of the based products really are more powerful and more so than with depression or many of our other conditions where it's more a categorical, this will help or not as long as you're above a threshold, there's a more linear relationship. If a little bit of well -beautiful helps, a lot is likely to help more. I mean, you might start getting more side effect issues and there may be good reasons to not keep going up, but there's a more linear dosage results relationship.

1:21:09Do you worry about strain on the heart with emphetamine products, just even if it's relatively low dose over time, just the strain on the calcium channels and on the heart, is it true that stimulant -based medications for ADHD can quote unquote weaken the heart? When you use that term, I was talking through a rub beforehand about running marathons, and when I ran the anniversary of the Boston Marathon, they had some of the medical literature from the previous decades, and one of the medical warnings was, maybe you could do one or two marathons in your life, but don't do more than that because your heart will wear out.

1:21:54And I've run 100 in my heart, I think, is still beating, so we know things we thought we know at one point. Common cardiovascular effects of not just the stimulants, but the non -stimiancid are affecting north, and I think so, well -butron, symbolta, marathons, it's less clear, and we can get into that when I talk about marathons, but clearly methylphenidate and fetamine, on average increase, at therapeutic doses, increase heart rate, a few points, increase blood pressure, a few points, but part of that obscures that probably 80 % of people don't have any change, and maybe 20 % have a maybe a more slightly significant change.

1:22:36So we know that there's some impact there. We know there's some people with extremely rare genetic, underlying conditions, usually related to the neurologic wiring of the heart, who are particularly vulnerable to dropping dead from the stimulant. And almost every year there's a well -trained athlete, either professional player or marathons, a high school or college player, college, who will take cocaine, take riddling, take prescription stimulant, and drop dead of a heart attack. The risk of that so uncommon, this is 15 years ago, when Adderall XR came out, the Canadian government was worried enough about this risk, that they banned Adderall XR for almost a year, and because they have a comprehensive medical system, they could look more extensively at the numbers, and this was looking at kids, the percentage of kids who dropped dead with Adderall was tiny, and not just tiny, it was lower than the kids, who aren't down Adderall, who dropped out of a heart attack.

1:23:48So part of it is, if you're in this genetic condition, almost always there's family members, or you've had some other, you know, death, there's a syncopal episode where you passed out. So history taking of the individual and family history, and if you're at all worried or concerned, you can do EKGs, which detect most of those electrical abnormalities, but the cardiology and lots of my colleagues practice, maybe a more conservative cover your ass medicine approach, where everyone has to have an EKG before they're on a stimulant, but even the cardiology associations have said, that seems to be a waste of resources.

1:24:30Absolutely do a thorough history, absolutely do a thorough family history, if there's anything of concern, or if the patient's anxious about it, get an EKG, but other than that, these should be generally safe for most people's hearts. So there was a meta -analysis that came out earlier this year on, so most of the studies looking at more serious, other than just mild hypertension or mild elevation of heart rate, haven't found much, but most of them only look, you know, a year out or a year of treatment, do we see rates of heart attacks, do we see rates of strokes, do we see rates of dangerous arrhythmias, and in general, they're looking at a young population, where these events are really uncommon anyway, and most of them didn't find any evidence of problems in a year or two out.

1:25:20The more recent study looked as long as 14 years out, and there they found measurable, statistically significant, increase in risk, that increased during the first three years of being on a stimulant, and increased at a much lower rate for the next 10 years, sort of plateaued out, but still measurably higher than people with ADHD who weren't on a stimulant, but the absolute rate is still really, really low. So for most people, it's not a risk. I mean, on the other hand, if you start these medicines when you're 10 or 20, and maybe on them for 60 years, we don't know whether potentially more people are getting into more trouble.

1:26:05So if somebody presents as having ADHD as an adult, and they've never touched stimulants, and would you start them on Ritalin, Will Butrin, or something in the adult's advance class? So thanks for bringing me back to your question. And I'm gonna jump through in that sort of qualifying phrase, never been on any stimulant in their life, or tried it or something. And what I would say is, what I would say is, lots of these drugs are fairly common in our society, both illicitly and illicitly. I mean, we know lots of kids, lots of adults with ADHD share their medication, lots of people have tried these things, even if it's just once or twice.

1:26:51And that itself is valuable clinical data, and if they felt too revved up from it, so if they have, I try to find out what dose was it, what did it do for you, what good things did it do for you, what bad things did it do for you? So my presentation is usually, you know, Adderals likely to be the most strongly effective, or I'm often are using diamonds. These are the other options, but Adderal also has, again, greater rare, but risk for these bad problems. What, you know, does that scare you? Some people are petrified, they're not gonna go anywhere near that. Some people say, yeah, I'm not that concerned about it.

1:27:33And most people do come in with some friends at work, family members, X, Y, or Z, you know, they think they know what the drug is likely to have as an effect on them. And I tend to, at least as a starting point, listen to that. And now, I mean, there are certain reasons I absolutely would not. I mean, my worry, again, I saw more of it than I think most people in a higher rate with the infetomean anger psychosis. But a friend from college was just trying to refer a friend's son who's 27 and had a psychotic episode on Marijuana.

1:28:15And those have ADHD and is in bed depressed, and not going to work, and is being evaluated by two North New York City doctors, but the psychiatrist kept him on Adderals. I absolutely, again, the likelihood of recurrence seems so high that if you have a family history of schizophrenia or psychosis, or you've had any experience of it, I would not prescribe a stimulant and infetomean -based stimulant. Could we go so far as to say, and I suspect the answer is no, but because nowadays we're hearing more about the possibility, I want to highlight possibility of high THC cannabis causing psychotic episodes.

1:28:57This is something I've stressed on this podcast, on social media. I took a lot of heat for this from the traditional press. And then ironically, they're now putting out information that essentially speaks to the same. I'm not saying this happens in everybody, but there's certainly a possibility there. Would you say that if somebody is a regular high THC cannabis user, that they are at greater risk to developing psychosis if they're taking these stimulant form ADHD meds? Yeah, I mean, you could actually play that both ways. I mean, you could claim that if they've already been on an agent without developing psychosis, then maybe they're more impervious to that as a potential side effect.

1:29:41Or where you were coming more from is if we're already on one agent that's pushing them that direction, why the heck would you ever add another that could also? I mean, my approach clinically would be more, what do you think the marijuana is doing for you? And might it be more helpful to just clear that out of the picture before we add anything new onto it, but depending on what they say or don't say? So my reading of the data is very clear that there is some, I mean, there's even at low THC, there's some risk. Is it, you know, refer madness at everyone I've said joint is freaking out, clearly not.

1:30:19But again, it's much more potent than it was 10 years ago, I guess. Yeah, especially as I understand we had an expert from the cannabis research community on an edible form in particular, it's harder for people to control the dosage, whereas when people use inhalation as the means to deliver, it seems like they find the right plain without going overboard more often than with edibles in any case. Well, one other big factor is that CBD actually seems in some studies to have an anti -psychotic effect. So, you know, maybe strains of marijuana 50 years ago that had a, whatever nature thought was a more balanced view, had less of a risk, but now that you can get pure THC products and I'm sure you've highlighted that a big problem with this whole industry is even in Colorado, which three years ago is the state with the most close regulation and inspection and almost the majority of what the labels say don't correlate with what you're really getting.

1:31:18So, this is not a well -regulated industry, even though states are trying to regulate their industries, so you may not know what you're getting. CBD again may have some protective effects, so getting pure and higher potency, THC may be particularly undesirable. So, in my own YouTube podcast series, I researched lots of subjects and most of them I wind up saying we don't have a lot of data on it and there's not a lot of data on marijuana. It's the one subject I've actually changed my mind from reading what was out there. And for years I would tell people, because being in San Francisco, even before the wave of legalization, lots of people are using it, lots of people felt to help them.

1:32:08And what I would tell them is the data we have, and these are from everyday users, is that there are measurable, you know, the characteristic of the classic stoner has a grain of truth there. So, measurably, lower motivation, or organization of thought, lower energy are strongly correlated with daily marijuana use. Why would anyone with ADHD want any of that going on? That seems like a perfect misfit or accentuating what's not working right. Over the years though, I had a handful of people would swear, it worked better for them than stimulants, it worked better than the non -stemyan alternatives.

1:32:49Clearly not everybody. And when I looked at the data, there is actually some tiny studies, you know, there are some that are funded by marijuana organizations, so that doesn't mean they're wrong, but it's harder to evaluate how objective they were. But there's some research that suggests there is some sub -segment, and I don't think it's eight people with ADHD in general, but some subset of that population who may actually do better. And most of the time they were looking at marijuana rather than pure THC, and what I was going to say is there's probably at least seven or 80 other psychoactive components to marijuana.

1:33:27Not most of them is in a higher concentration, it's a THC or CBD, but they're out there, maybe they are more important to even lower concentrations. I've heard this that for some people, cannabis can help them focus. And I'm certainly not one of those, but it certainly is interesting. As long as we're on cannabis, excuse me, as long as we're discussing cannabis, and either of us are on cannabis to my knowledge, maybe I could just ping you for the relationship between various compounds that people use that are available over the counter, or with online access to these compounds, and ADHD symptoms specifically.

1:34:15And then at some point I'd like to return to the emphetamine -based drugs. So let's just start with nicotine. So these days there's increased use of nicotine pouches, gums, not just smoking, vaping, dipping, and snuffing. And it's certainly a stimulant, and certainly a lot of people, in particular, young males are using it more often. The traditional media is now trying to create this kind of picture of nicotine being part of the kind of wellness and fitness community, but in my observation, many, many more people outside of that category are using it. So what in your experience happens when somebody with ADHD, let's assume they're not meditating in any other way, starts dabbling in nicotine use, and let's assume they're gonna do this in ways that do not cause cancer, because the smoking, dipping, vaping, snuffing part is what causes the cancer.

1:35:13Let's just talk about the compound nicotine. Yeah, so there's some well done research showing nicotine is helpful for improving some of the executive functions, so sustained attention, and I'm not sure, which is the executive functions, but they help people focus, be sharper, do better. There was actually a major pharmaceutical company who was developing a nicotine receptor product specifically for ADHD, and they abandoned that several years ago, and I haven't been able to find word as to why that was abandoned, whether it was some other side effect. It's worth throwing out there that, although nicotine in many ways acts like a stimulant, it actually is moderately unique, and I hate people, unique means one of a kind, so I can't modify it in any way.

1:36:05Unusual, maybe not the only one, unusual in that it both arouses people and reduces anxiety simultaneously. Not too many, most of our stimulants are again, banging away at the sympathetic nervous system, and that's banging away on good arousal and bad arousal. So nicotine, again, seems to be both calming and helping alert or focus people, and as long as they're taking it in a way that's not clearly detrimental to their health, which smoking and vaping and probably chewing are, well, not probably definitely are, and if it's affordable, because some of these products are pretty pricey, at least the chewing gums or the nicorette that was used for helping people with smoking cessation, I have some people who feel that it's been important and useful part of their regimen.

1:37:00I have some people, small numbers who prefer it to any other medications, and almost no, again, other than sort of a basic neurophysiology showing that it can have beneficial effects on executive functions, there's no research, at least as of a year or two ago, whenever I dipped my toe, not my anything else into the snuff. Looked into it, there's no clinical research showing does this help or not help. What about caffeine and in particular energy drinks? These days, there's just seems to be an explosion of drinks that include caffeine, but also fairly high dosages of things like touring, alpha GPC, thinning, you know, so it's irresisting.

1:37:50So, you know, things that are thought to generally amplify the production or release of neuromodulators like dopamine, a state of calling and so forth. So, the epidemiologist say that the most widely used psychoactive substance on this planet, and I thought it was alcohol for years, but it's actually caffeine because lots of groups outlaw alcohol, who won't outlaw caffeine? So, lots and lots of people use it, and this is a gross oversimplification, but this is what I tell people. Even though it's most widely used, if you used it as an equivalent dose to our stimulants, I mean, essentially, we're using it at a lower dose level.

1:38:33It's a pretty lousy stimulant. I mean, separate from that it's working primarily on adenosine and indirectly working on dopamine, but associated with higher levels of anxiety, higher levels of jitteriness, higher levels of cardiac toxicity, if you were to use it at a equivalent dose. But most people are using it at substantially lower dose, and the ADHD experts sort of historically have fallen into two different camps. Some of them have said, it's gonna interact with your stimulants or other medications that's complicated. We don't want it messing up the picture, stay off of it, and the other half say, it's a stimulant.

1:39:14You know, lots of people are using it with these other stimulants, you know, both full blown stimulants and non -stimulate ADHD medications, and as long as you know it's part of the picture and you're trying to be constant with your dosage or aware of it, then fine, and maybe it helps you get away with the lower dose of the prescription. The one little piece I'd add in there is that often you don't know what dose you're getting. So people have the common experience, as I was saying earlier, I've only had three cups of coffee in my whole life. So this is all anecdotal or research, not personal experience data, but lots of people have the experience, go to their local Starbucks or something, say, well, that feels way stronger than usual, and then invariably they say, oh, that must just be me.

1:39:59I'm more anxious already, I'm jacked up, or because they think Starbucks, you know, seven billion stores around the country, everything's automated and precise, they must be Starbucks, isn't, you know, they control for the aromas. Tiss -a -dee, they, how many minutes each bean is cooked, which side it gets flipped over on, they're not controlling for caffeine intake, which is wild to you and me. So at University of Florida study, Mrs. Several Years ago now, went into a Florida Starbucks, bought the same drink every day for three weeks, and compared the caffeine content, the highest day compared to the lowest days, was a threefold difference.

1:40:40Wow. And that's Starbucks, who knows what, smaller, so one is, you may think, you know what, you give, and maybe, you know, the bane of coffee drinkers, and maybe, Sanka, in a teaspoon that you're dissolving, maybe the most consistent there, but one of the risks with caffeine, and with pretty much any over -the -counter drug, is you may not know what dose you're getting. Very interesting. I mean, I, as I've said several times in this podcast, I think caffeine is a wonderful drug, mostly because I love the things that comes in a year -bomot -a, being my, you know, preferred source of caffeine, but also coffee, and it certainly increases my focus.

1:41:23It's a venerable plane, though. You know, it two -sips too many, and I can start feeling myself veer toward more lack of focus. It doesn't seem to have a very pervasive effect, and dosing it on an empty stomach, versus after eating, it's, I mean, I'm not that precise about it, but I don't see it as a very reliable stimulant. It's more to get to a plane of just normalcy for me, given how much I've been drinking it, since I was a teen, really. I think most people are similar. They drink it to feel normal. Yeah, normal. Well, and there's also lots of cultural and habitual, you know, if it makes, gives you your warm fuzzies or puts you in the right mode, or you're sure, you're thinking more alert, or you're listening to your favorite newscast in the morning as you're drinking it, that all is adding to its effect.

1:42:16In terms of combining with other over -the -counter things, there is some study looking at caffeine and altheanine together, and having some, at least in a tiny handful of studies, some measurable beneficial effect on, I think it's mostly kids that have been looked at, and nothing dangerous found across a pretty broad range of altheanine dosages, but it's, I'm not aware of any good research done with adding all the other things that are currently being added to it, and some logically may be doing something, some may be irrelevant, some may be more detrimental. Altheanine certainly is being added to a lot of caffeine containing drinks because it seems to take the jitters of, and the assumption being that people can consume more of that drink as a consequence.

1:43:08Yeah, there's a tiny bit of evidence of success. It may both, you know, help with anxiety, but it may directly have some beneficial cognitive, executive function benefits itself. Yeah, this is in keeping with the green tea hypothesis, which I believe green tea is enriched with the inine. You are somebody who, quite refreshingly to me, has talked not just about prescription drugs and behavioral tools for ADHD, but also, actually, I think years ago, you were the first person to first share with me the data about fish oil and the EPA omega -3s for depression. Those studies were starting to come out.

1:43:52We were talking about those studies. And nowadays, I think, while there's still a little bit of controversy out there about fish oils, I think most everybody believes that getting high quality omega -3s from good clean sources, including fish oil, is mostly beneficial or beneficial. What about fish oil for ADHD in particular? And what threshold dosages are relevant here? So just as with the fish oil for cardiac benefits, you know, there was a time period where the first few large, and they were pretty large well done studies, so benefits for cardiovascular health. The more recent studies with fish oil haven't shown in effect, or benefit, and strangely to me, and not very scientifically, the cardiology community sort of looks at the more recent ones and say, okay, that's what it is.

1:44:46Well, you have to reconcile all the data in the pool. The ADHD -fish oil story is a little opposite, and it's been almost everything with ADHD. It's been kids that have been most strongly looked at. The first few studies with fish oil and kids didn't show any benefits at all, and then subsequently there have been several studies that looked at benefits. And again, in the field jumps to the second set without reconciling, well, how do we, you know, do a good meta -analysis with everything in there? Or so, and I haven't looked closely enough to know, you know, where their methodological differences, dosage differences, population differences, it matter.

1:45:29I'd say unless you're taking so big a dose that you're probably at risk for heavy metal poisoning, which is a possible issue at big, big doses of fish oil. I mean, most of the recommendations are in the range that it seems, and I'd say that depression has been the most consistent field, and that doesn't mean every study there has been positive either, but the most consistent field for a mental health benefit or a health benefit. And there, the recommendation is usually target about 1 ,000 milligrams of EPA of icosopentanoacacid today. If you're seeing some benefit, but it feels like that there's more room for improvement, so this is my amount of, I tell people, then you could probably double it reasonably.

1:46:20I mean, some of the dramatic studies looking at fish oil for mania, people hospitalized with it, but and they use dosages as high as 7 ,000 milligrams a day. To treat mania? Yeah. And I'm not study, I think it was a Harvard area clinic that was doing it. The results were so dramatic that they ethically had to stop the study before it's intended completion, because the benefits seem to be so robust in the fish oil group compared to the unethical to not put everyone on fish oil. That's a lot of fish oil. You probably need to get it in liquid form to make it, so it wasn't so expensive. But I find this recency effect incredible, which you mentioned a few moments ago, that and I think this is helpful for people to hear.

1:47:10Certainly it is for me. We hear studies over the years of explored fish oil for cardiac benefits, and then more recently, as I understand, these are not, have not been demonstrated. And there seems to be a focus on the recent studies as if the old ones don't exist. That's essentially what you described for both cardiac and ADHD. I think it's really important. We hear this with alcohol too. I've been involved in this debate. I don't care if people drink one way or the other, provide they take care of themselves and others. And if you're an alcoholic, don't drink, and if your kid don't drink, but people want to drink a few drinks a week, I don't have a problem with it.

1:47:48But it's remarkable that every time a study comes out showing a mild benefit of moderate alcohol use, that seems to be the highlight and then everything else is forgotten. And the inverse is also true. One would think that the meta -analysis would include all as many good studies as possible, but I think it's important to understand that people hear that that's not always the case, just because there's a meta -analysis doesn't mean that it included all the relevant studies. So I'm just restating. Thank you. I make it a point to try and get one to two grams of EPA per day, just as a general mood.

1:48:21You know, I'm not clinically depressed, but just to support my mood, to support focus, to support well -being, including cardiac problems. So the other thing that I think is understudied with the fish oil issue is that, and it's a Harvard guy who has a proprietary brand of purified EPA that pushes it. So in nature, whether you're a whale or a human or a butterfly or maybe not insects, I'm not sure that across the mammal bird, dropped all kingdom, you may get threes are found in about a two to one ratio of EPA to DHA. I cost a pentahotinolic acid to cocaxinolic acid. And what I tell people is, I think mother nature is probably smarter than any Harvard professor.

1:49:07And the brain particularly is high in brain membranes of DHA. So I don't see, some people seek out EPA purified or so only EPA brands. That to me doesn't make a lot of sense. I would say we can still counter to the numbering based on about 1 ,000 milligrams of EPA, but don't worry that you're getting about 300, 400 milligrams of DHA, and probably that's better for you. I'd like to take a quick break and acknowledge one of our sponsors, Matina. Matina makes loose leaf and ready to drink yerbamate. Now I've often discussed yerbamate's benefits, such as regulating blood sugar, its high antioxidant content, the ways it can improve digestion and its possible neuroprotective effects.

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1:50:27I drink at least three cans of those a day now. I also love their loose leaf Matina, which I drink every morning from the gourds when I add hot water, sip on that thing, and I'll have some cobalbrews throughout the morning and early afternoon. I find it gives me terrific energy all day long, and I'm able to fall asleep perfectly well at night, no problems. If you'd like to try Matina, you can go to drinkmatina .com slash huberman. Right now Matina is offering a free one pound bag of loose leaf yerbamate tea and free shipping with the purchase of two cases of their cobalbrew yerbamate. Again, that's drinkmatina .com slash huberman to get a free bag of yerbamate loose leaf tea and free shipping.

1:51:04You're one of the first people that I ever heard discuss the gut microbiome in ADHD. This is me giving you credit for being way ahead of your time. I don't know how you are at receiving prayers, especially on camera and with microphones, but I just wanna say that it was over a decade ago that I heard from you about EPA and fish oil for depression and other things about circadian rhythms, an area that I'm familiar with, and just the critical importance of circadian health for everything that we're talking about today and more and on and on. And so, again, thank you for raising these points, even if they turn out to be minor effects.

1:51:46I think nowadays we hear about the gut microbiome. I may have actually heard the words gut microbiome first from you. Gosh, yeah, that would be well over, that would be almost 20 years ago, remarkable. So gut microbiome, what do we know about the gut microbiome and supporting it in ADHD? I'm gonna kind of pass on that by just saying, it's complicated and probably important and so many variables that it's hard to know what's really valuable in a day -to -day, real human living perspective. Do you do anything to support your gut microbiome just with your knowledge of the relationship between gut and mental health?

1:52:38Does it impact your behavior at all in terms of choices? Yeah, only to the extent of trying to have a very diet and eating somewhat regular interval intervals, but not more specifically. Great. That's where we're at, where that's where we're at. Before we go back to some drugs, I wanted to ask about behavioral tools for ADHD. I've seen some of the literature claiming that certain video games might actually be useful for training focus. I've managed to find a few papers that talk about focus and meditation tasks that kids, in particular, but adults may be able to get better at. Are any of these brain training games to get people better at focusing?

1:53:28Are any of them known to be worthwhile according to real data or clinical observation? So, for stepping back a little bit and broadening it, I'll get to the video game thingers, but one of the effective approaches that helps with symptomatic reduction with ADHD is cognitive behavioral therapy. So that's a form of talking therapy. And my quick overview of it is that it focuses on actions, thoughts and feelings, and that humans can have direct control of their actions and thoughts not too much over their feelings, but all three are affecting each other. And the traditional CBT was developed by Aaron Beck to treat depression probably 50 years ago.

1:54:15Maybe longer, 60s, I think, late 60s. Anyway, on the surface, it's a horrible match for ADHD, because we know it requires lots of repetitive boring homework doing the same thing involves introspection of being aware of what you're doing already, looking at those patterns, looking at what the triggers, to see if you can see triggers for them, and then doing lots and lots of repetitive homework, which, and when it's successful for depression or PTSD or other venues, we know it actually changes brain wiring and brain chemistry. So lots of people still think talking therapies are sort of up here doing something and chemicals and medications are really changing the brain.

1:55:00If your thoughts are changing, if your behavior's changing, your brain has changed. That's only place that thoughts and behaviors come from. But there have been at least two groups, Mary Salanto's and New York and Harvard Group, by I'm blanking on this for Safran and some other Rams, I had Pennsylvania, developed approaches using CBT techniques specifically designed for people with ADHD to help overcome some of those hurdles and barriers. And both of them encourage actually the use of medications and combination with it. So because many people with ADHD are too unfocused, too unable to sit down and do it, but these are approaches and both approaches are amazingly similar, although devised completely independently.

1:55:49At the core of both of those approaches is having a system of scheduling each day. That doesn't mean micro -managing each minute, but it's having the essentials in place, having blocks of time that you know what you're gonna do and having a task list in combination with that and ways of learning to prioritize and move things supper down. And again, with ADHD being interested in rather important, you may have a task, I mean, you probably have 17 task lists, one's New York coffee, one's at the grocery store, one, it's having one consolidated list because if it's everywhere, then it's nowhere. And two is the simplest triaging or organizing approach is having the things that are both urgent and important, so the half to happen today, those get in the A category.

1:56:45The things that are important, but aren't as urgent are the B category and all the other things are the C. And one of the temptations that people with ADHD have is how I need to be productive. You know, it's fun to go buy shoelaces and that's on my list, so I'll go to buy shoelaces because then I can cross something off my list, but I didn't move the car, I didn't do my taxes, I haven't done my homework, you know, all the important things remain undone. So it's a system for getting done, what's really needed to be done, and eventually, if your shoes don't work, the shoelaces will move up to that A category, but for most people, they're not really there and it's not a good use of your time to do them first.

1:57:27So the, and there's much more to it, so that CBT approach can work with decreasing procrastination, it can help with structuring your own workspace given that you probably have much more trouble doing that and not doing it spontaneously. It's how to eliminate distractions and modules on even extending your concentration time. So the answer with the video games, there is one product that's actually been FDA approved for use in ADHD and the really important thing to remember there is the FDA's system for addressing medications is much more rigorous, much more thorough, you have to demonstrate it really works and does something when the FDA approves devices, basically they're saying it's not gonna kill anyone, it might help tremendously, but having the FDA in premature for that doesn't guarantee that or mean that at all.

1:58:28Do you recall if the study of that device, or the study of that video game, it has a conflict of interest, was it run by the company? Yeah, yeah. So almost all of them have been run by the company. I mean, it's good people at UCSF who are at least partly involved in it. Oh, is this Adam Gazelle? He's a group. I think so. Yeah, I should just say that I've followed his work for some years, he's a neuroscientist, I know people who have been in his lab, he's known for doing very high quality and stringent work. Their product and some of the others can clearly show you get better at their product and you get better at tests that look exactly like their product, but in terms of real world, how much is this really helping ADHD symptoms on a day -to -day basis?

1:59:15Not a lot of data at all. So again, that doesn't mean it doesn't work, and I'm gonna get sideways and talking about neurofeedback because there's lots and lots of neurofeedback companies across the country that are making lots and lots of money and there was an article in the American Journal of Psychiatry in the last year, I'm not remembering which group did it. And it was another non -failure to find a significant impact from neurofeedback. And again, I'm not saying it doesn't have an effect, but I've had lots of people saying, writing me, keep spending hundreds of dollars each week as my insurance isn't covering this and the doctor's saying, oh, maybe 20 more episodes will retrain your brain.

2:00:05So this gets back to a topic you brought up earlier, how much are we retraining our brains with immersion in social media? And the evidence is we are rewiring our brains. So maybe anything pushing an opposite direction or maybe this is reinforcing some of the bad things we don't want. It's we're in a messy world without clear answers yet. I've made it a point to put social media on an old phone. So those apps are only on that phone. I don't even know the number of that phone if I need to post something, I air drop it onto that phone and this has helped tremendously in segregating that activity and limiting it.

2:00:47It also means that people send me something which would otherwise direct me to social media. It's much more difficult for me to go look it up to help tremendously. I just passed it on because it's one of the things that's really allowed me to restrict my social media time and yet still be in keeping with the fact that I think social media has its uses, I post there, et cetera. Yeah, so getting back to the scheduling, I mean, what I would recommend to people and one of my week, I don't know the specific apps but there are apps that will help shut you out of Facebook or Discord or TikTok or whatever it is.

2:01:21If you can't exert your own willpower, which again is harder to do if you have ADHD and if the app approach doesn't work, the next level up is there are all sorts of companies making lock boxes and physical devices where you can lock yourself out to your device for certain hours of the day. And I think that's a good idea for lots of people. I do too and I think it also helps, at least in my experience, to do things that are very different than social media as well, but still consuming content. So I make it a point to read from an actual physical book a bit each day or night also because I was raised doing that and writing by hand is just over in keeping with the way that my brain was wired.

2:02:06So maybe that's more specific to me in my generation. But I find that when I'm doing those other activities when I go onto social media, it feels more like a departure from the rest of life as opposed to the other way around. That's a good sign for preserving. I'd like to talk about some compounds that are not so typical, meaning some people may have heard of these, but most people probably haven't and they are somewhat novel to me. The first one is guanfacine. What is guanfacine and why is it sometimes used for ADHD? So guanfacine and a related drug called clonidine, which can be confused with clonipin and others.

2:02:54So clonidine and guanfacine are both alpha -2 agonists, so they work on a subset of the norupineference system. They're both originally anti -hypertensive for lowering blood pressure. And it was actually studies first in clonidine that suggested this could be helpful with people with ADHD. And I think it was just a serendipitous initial discovery. It wasn't seeking out its mode of action to see if that really worked. One difference between the two of them is clonidine jumps off the norupineference alpha -2 receptor really quickly and for people who skip a dose for the blood pressure medication or stop abruptly, it's not uncommon to have rebound hypertension and not to smile, but way higher than what you're being originally treated for at the dangerous levels.

2:03:46Guanfacine leaves the receptors more slowly and there've been formal studies trying to see if this is a problem or issue there. And particularly given that people with ADHD forget their medication or run out and don't fill it in time or just don't remember to take it, the rebound hypertension does not seem to be nearly as common with gondphacine and that's part of why the research has moved more towards the guantia vaccine. So there's extensive work by, I'm going to blank under the Amy Arden. Arden, she said, Yale, Arnston. Arnston, yeah. And her lab and related labs have shown that Guanfacines effects seem to deal with strengthening synaptic connections in prefrontal circuitry.

2:04:35So unlike most of our drugs that are just boosting or up in effron and or dopamine and work quickly and I'll throw in this, guess if we didn't really touch this, most of the ADHD experts still say stimulants, amphetamine, ridolin work quickly immediately because they boost dopamine right away. And our drugs like strotera, which is adomoxetine or symbolta or well -butron work slowly for ADHD because their antidepressants and antidepressants work slowly. There's still people saying this and for 25 years, I've been saying, this is just wrong from one of basic neuroscience point of view and wrong from don't you ever talk or listen to patients.

2:05:18So neuroscience view, how quickly does dopamine get reuptake, get blocked by well -butron or by adomoxetine strotera or by symbolta within minutes to hours of taking it. So you would expect if you're boosting nor up in effron or dopamine availability right away, you should see effects right away. And if you ask patients who these drugs work for and they don't work for anybody, all the ones I've worked with say, they don't work just like a stiny, I could tell, I took it and I walked out of your office and I mean one guy I have who loves symbolta said I took it in your office and I wasn't sure it was working and I got downtown to work 15, 20, maybe half hour later.

2:06:01And there was this guy coming at me on a state board on the sidewalk and I know in my normal ADD state, I would have just been flooded and not be able to process and I could just step out of the way. So it worked that quickly and dramatically. So that's the aside. So jumping back to Guantfacine seems to work slowly. So the synaptic strengthening building and it seems to be the alpha -2 receptors that are on, neurons that receive glutamate is a primary input. The alpha -2 receptor is modulating how glutamate is actually working and it's actually an MDA glutamate receptors, not the more common in the brain, ampute glutamate receptors.

2:06:50No, that's an important point. I'll just quickly throw in if I may, that the NMDA, the N -Methodeouspartate glutamate receptors are the ones that typically are associated with synaptic plasticity, so are the ampute receptors can do that too. But what Dr. Cruz is referring to is the fact that Guantfacine indirectly modulates those pathways. So the longer duration to get the effect it sounds like could be at least partially explained by a real change in neural wiring as opposed to with you use Symbalta and well buterin as examples of fast changes in neurotransmitters, neurotomodulators that led to this very quick effect in this patient that left your office, got downtown and was already experiencing effect.

2:07:38Put differently, sounds like Guantfacine and clonidine, not to be confused with clonipin. clonidine could help ADHD but might take longer for the effects to manifest than the other drugs that we typically hear about. Yes, so most often it takes two, three, four weeks and because of it, I mean with the stimulants you see effects right away. It's reinforcing and stimulants often in addition to having effects on concentration, attention, other, you know, do boost energy for most people, do boost mood for most people and can improve sleep if they're not taken too close to sleep. Guantfacine's most common side effect tends to be sedating so most people take it at night time which is why are you taking a sedating night time medication for your ADHD?

2:08:24It's because it helps it works slowly and directly. So intunive that the brand name extended release Guantfacine was approved in kids because again, most of the research on ADHD is still on kids. Fort treating ADHD as a solo agent, it clearly works in adults as well and even before intunive was approved, there were a handful of studies with either immediate release Guantfacine or extended release Guantfacine in the studies so far. The results aren't distinguishable, they both seem to work. So clinically because it's much cheaper, I actually use immediately release form and all of bedtime and again because it's my impression and it probably don't have a end that's big enough to do a rigorous study is the sedating effects are relegated to the night time and people are feeling okay during the daytime.

2:09:24I mean some of the rationale with the extended release is you're sort of smearing it over a longer time so it should be less sedating but depending on the time curve and how it works you could actually wind up with being more uniformly sedated day and night with the extended release. So I've seen good results in some people. I've had many who either didn't work or they didn't perceive result because again some part for some people of the stimulant benefit is I can feel it, I know it's working. So the majority at least in terms of prescription searches and what clinics tend to do, it looks like most people who are on Guantfacine are on in combination with either a stimulant or norupinephrine or dopamine promoting agent.

2:10:12Let's talk about Modaphanil and Armodaphanil by extension. We hear about Modaphanil a lot in communities like the tech community and communities where people are trying to quote unquote cognitively enhance. What is Modaphanil? What does it do? What doesn't it do? How might it be useful for ADHD? So we're going to jump back to the dear issue with the recent C &C and science and how to incorporate things. When some Modaphanil was a drug developed by a French company and approved their unused for decades for maybe a decade before it came to the US 25 maybe 35 years ago. And at the time all the research showed that it was an O -Rexan receptor antagonist.

2:11:03Right. Antagonist, agonist, now it works on the O -Rexan, the hypercretin O -Rexan system. So boosting activity but not working like all of our stimulant, the luring drugs which are working on primarily norupinephrine systems. So it was called the non -stimulant stimulant. Now most of the pharmacology literature refers to it as a dopamine acting drug and there's some people are debating whether it's O -Rexan that it's working via dopamine. I haven't seen anything that to me means it gives a clear consensus. So I stick with the O -Rexan because that's where I was taught. So O -Rexan getting back to the sleep wake and the brain in a row is all as I described but there's two ways to wake up in the morning.

2:11:52One way is the normal way that you just wake up and the other is being alarmed by an alarm clock, your neighbor starting the earth lawnmower, someone snoring, an earthquake, if you're an L .A. or Hawaii, being startled out of sleep. That wakefulness system is a sympathetic nervous system. The O -Rexan system is a more natural normal waking system and it isn't arousing you, isn't it's waking you but it's agitating you. Again the claims originally was that this is how a definal work, it was waking us you up but not overstimulating over revenue so that the other than being developed by this French company, the entity that spent most research funds looking into what this does or doesn't do was the US military because they have a big investment in wanting people to be alert and ready to kill 24 -7 but not being a hyperactive trigger -happy jittery like stimulants can do and this you know particularly in the early days this is really dating me of the Afghan war we dropped bombs on Canadian troops by accident in our friendly fire scenario things and the investigation, the pilot and the crew there, waned their trigger happiness on being revved up by methylphenidate.

2:13:16So for years the military has relied on traditional stimulants to keep people able to fight around the clock and they wanted an agent that would give you alert awake but not revved up, not agitated and I'd say there's some good evidence that that's really sort of how a definal works or performs so a definal is called Provigil for provigilants and then when they were losing their US patent like many drugs the Provigil is a Raseem McMister of left -handed and right -handed versions of the same Modephanol molecule they found that the Armadephanol, the right -handed version was the one that's doing most of the good stuff and has a longer half -life than the combined version so they got a new patent for Armadephanol which is new vigil so that's the only difference between the two that are the same active ingredients as far as we can tell.

2:14:16So and when it got approval in the US it was approved for narcolepsy where people are falling abruptly asleep during the day so it keeps them alert and awake there. It also got approval for circadian sleep shift work disorder where because you're on a shift schedule you're sleeping weirdly and it got approval for daytime sleepiness from sleep apnea but even at that time when it was approved there were dozens of studies that showed regardless of why you're sleepy whether it was sedating medication whether you had blueprints or MS whether you had some other condition it works pretty well for keeping people alert and awake.

2:14:57So more than keeping alert and awake there does seem to be evidence that it helps with some of the executive functions of attention, concentration, my clinical experience with it tends to be again with the amphetamine on top. Many fewer people describe it as being helpful or as as helpful. On the other hand there's one study and I'm forgetting the principal investigators of Brown University where they used some very clever sophisticated approach to try to sort out motivation versus pure cognitive functioning and their claim and it was a very well done study they were comparing it directly to an amphetamine product.

2:15:41Their claim was that Modephanel was the one that was actually boosting cognitive functions and not just boosting motivation whereas that most of amphetamines benefit for ADHD when we say it helps me concentrate, it helps me sustain focus, makes me less distracted. Their feeling, their analysis was that that stimulant was mostly working on motivation. It's a controlled substance but not nearly not the same schedule as amphetamine and riddled and so it's easier for some prescribers to prescribe even though it's the non -stimulant stimulant and I'd say most people do experience you know I feel more alert or awake or better but I don't feel rubbed up about 10 to 15 % of people that I've worked with and others have written about it so I don't think it's unique.

2:16:34We'll feel rubbed up when they take it the first few times and invariably the people I've worked with have said this feels like bad speed including people who haven't too who never even took speed so I don't know why they came up I mean it's just weird that people come up with the same terms but it's I mean my interpretation is that for some people this novel substance primarily may be tacking into the OREXAN system is serving as a signal kind of like a panic attack does that there's something weird something different or being rubbed up and that it's I think secondarily triggering the sympathetic system because for most of those people within a few trials within a few days they no longer had that overrev just effect and again the important piece for alerting people to that is if they're expecting taking this I'm not going to feel overroused and over agitated and they do then they're even less prepared and more freaked out.

2:17:36Even though I've never tried Modaphanel Providial that people that I know who have and I know one who has for treatment of real narcolepsy say he's narcoleptic but others who have taken it for ADHD and for work focus and cognitive enhancement. People who take Modaphanel and Armodaphanel really like it they I don't know if it has any reinforcing property but today's the first thing I've heard that has this dopaminergic aspect but they seem to really like it and rely on it have you seen a kind of a dependence form. I mean it is a controlled substance because some people are worried about the potential and there was a woman in the half late 2015 years ago who was Admodaphanel and said she had narcolepsy I don't know the birth but was disqualified from the Olympics because of it whether it has any real performance enhancing effects is not clear you know it was available in France for decade at least before it came to the US and they didn't see any rates of substance abuse or problems I mean it clearly does not have there on any tests or animal studies the propensity that the amphetamines do and I'd say it's to me not to conclude its subject whether there's any potential for addiction with it.

2:19:02What about within the category of Adderall, Vivance and the stimulant type treatments for ADHD I don't want to say what do you go to favorites because that makes it sound very non -clinical but you know what are the general trends that you've observed and that others have observed clinically or in any studies about preference for long long acting drugs versus shorter acting drugs and maybe this is also a good opportunity for you to be able to chime in about drug holidays you know taking weekends off or things of that sort. Maybe I'll start with that so for decades particularly starting with the kids that the dogma has been taking breaks from stimulants is a good idea because it will decrease the likelihood of developing addictions it will decrease tolerance and not a lot of rigorous research but one of the known side effects of stimulants for kids is growth suppression so height winds up being about two centimeters not big but measurably and consistently found there for kids who are routinely on these stimulants for their growths years and taking breaks that last for several months like taking it off during the summer result in overcoming that decrement and height.

2:20:32I looked and I still have whether there's any lower rate of addiction whether there's any lower rate of developing tolerance there's nothing that shows clinically I mean it may be true the other recommendation when I started out was and this is before the internet before constant plugged into everything and before kids had soccer practice and violin lessons and 400 activities is that kids should take it during the work days and not take it during the weekends and not take it during the summers and now for many years we've lived in a world where little Johnny has soccer practice and ballet and piano and has 42 things to get to or he's supposed to be performing and focused and behaving so the sort of excuse you could have downtime has diminished in many communities and again whether there's actual benefits to that or not other than for the the height decrement which again there is evidence that taking long breaks but probably not short breaks mitigates that I haven't seen any evidence clearly showing a benefit that doesn't mean it's not there nobody has really studied it rigorously sort of related to that you ask the question about short acting versus long acting and there's differences in the realm of what's clinically helpful or useful and then there's the issue of risks or side effects so again one of the claims is that part of what makes a drug more addictive is not just the level it reaches about quickly it's going in and out and that the short acting drugs may predispose someone to higher rates of addiction there are at least occasionally some people arguing on the other side that saturating the receptors for longer periods of time but tie doses with a long extended release version that may actually be more of a risk but but I'd say there's more concern I think in the basic science community from the immediate relisk and there's a tiny bit of data but part of it overall is that we talked early about global rates of addiction to any substance that we have fairly good data on because the CDC tracks it but in terms of very specifically who gets addicted to at all who gets addicted to a riddle and there's so little data and most people just sort the same numbers that oh maybe two to three percent of kids run into trouble and that's not common and that's it or they study a much broader question and that's the issue of misuse combined with abuse and misuse by the research definitions means anyone who didn't use their drug exactly as prescribed which means if you're taking a short acting riddle in and it says take it's one number six or six hours about during the day and you acknowledge taking it on one day eight hours difference your classified as a misuser by those studies I mean it's a I'm being maybe a little ridiculous because most of the exceptions aren't that narrow but there's a big blurring in the research particularly coming from the people who are worried about addicted I mean we should be worried about addiction but we shouldn't be overreacting or creating pretending it's a problem among those where that I would say is not addiction that's not abuse that's not using it as directed but people with ADHD by their very nature are not going to use things as directed either because they forgot or weren't organized enough to get it on time or forgot what you said in the office even though you wrote it down because they lost a sheet of paper it's written down on so getting back to patients experience of it so the advantages of the immediate release is they tend to work quickly you can feel it going in it's easily most people there's a lot of individual variability but let's say in the six to eight hour range we'll get benefit I'm some shorter some immediate release last all day but you know when it's on you know when it's off if you forget to take your medicines in the morning but you know you have a presentation at three that afternoon you could take it at two and still be able to sleep that night so it allows more flexibility it allows more pinpointing of optimizing it for points the day you want to be using it some people philosophically say that in itself is wrong or bad that you should be absolutely steady and constant because what we're trying to do is be consistent and reproducible and others would say we're trying to treat individuals who have different demands on them and have different patterns during their day so there are different philosophies about what's better worse one of the big downsides of the immediate release though is not only does it go in quickly it tends to go off quickly and most people not all but most experience some withdrawal as it's going off and although when we're using this for ADHD we focus on cognitive executive function benefits the focus the attention the concentration and people can experience that many people who weren't even aware of it increasing their energy feel my energy's crashing as I go off of it or many people who weren't aware that it was actually elevating mood to any extent feel oh my god I'm crashing and I'm crying and cranking and miserable now and with the extended release versions most of them go in more gradually so it can be harder to detect the last a longer period of the day and most of them go out much more gradually at the end of the day the one I like the most or for a long acting amphetamine product is vivants and vivants was designed as a slow release product it was designed specifically to be unattractive to drug abusers so vivants chemically links to dexerome phatamine molecule to lysine one of the amino acids it's a basic component of proteins and 20 essential amino acids and if you snort it or inject it you have an inactive prodrag you have the list X amphetamine your red blood cells actually need have an enzyme the cleavs of lysine and leaves you with the free active dexerome phatamine and that's the slow release mechanism is how quickly your red blood cells can do it and they have limited capacity to do that so although they designed it to be an anti drug abuse drug it actually turns out to be one of the sort of most consistently evenly entering the body for some people it goes in so slowly that they say I don't feel it and also towards the end of the day one of the best in terms of not falling off abruptly the potential downside is again that the capacity the red blood cells is limited so at some point for most people because that's a rate limiting step when you're adding more and more you're actually extending the duration of time more than you're getting a bigger peak because your red blood cells just aren't cleaving it fast enough to make more dexerome phatamine available almost invariably when I'll ask you know how did this compare to your adorol XR or to enhance your to they'll say smooth smooth they're getting it they're not feeling too jarred too rubbed up yeah we don't really have a language for these things right hence the uh bad speed um language before cracked out bad speed smooth um because what we're talking about here is the gushed salt of the subjective experience of all these uh neural and and uh chemical mechanisms very interesting thank you for sharing that I know that there are a lot of listeners and and viewers who have tried these things or who are considering or you know or one point use them and um a lot has evolved in in this uh realm of chemistry for ADHD but that's very helpful before we wrap up I want to make sure that I ask you about something that's been on my mind a lot in general but in particular as it relates to ADHD which is time perception and I'm basically obsessed with time perception I've long been fascinated by the fact that we can find slice time when our rousal is high that's what presumably gives people the kind of slow motion effect and you know high very stressful environments versus when we relaxed our frame rate on life goes down and um it's all very dynamic it's important our brains are able to do that but someone recently told me the following her partner has ADHD and she said that the big rescue to their relationship came when they together read read a book about ADHD and something in their read something like this that people without ADHD keep track of time whereas people with ADHD don't but they do know the difference between now and not now but they're not tracking time they know that what they're doing in the moment is not what they're going to be doing later or what they did in the past but they're not tracking time the same way and I think this ties back to this interest -based attention system what do we know about time perception in ADHD and by extension do you think that these drugs are working in part to change time perception?

2:30:17Good question so I'd say there's two different angles and I think I mean the one that's easier to objectively measure is putting people in a lab and there's a simple test a time perception test and you interrupt them after certain period I mean say you're going to be estimating how long you're you're left without interruption and people with ADHD measurably are they're inconsistently inconsistent or consistently inconsistent consistently inconsistent so it's not that they perpetually underestimate or overestimate but they are estimating incorrectly much more often than people without ADHD so there's something at a basic time processing level that's apparent there but there's also getting you know that the real world aspect of not paying attention to cues or not noticing other people left the room or not just you know being distracted which compounds a situation and I mean it's also interesting to the extent to which many people aren't so I often ask even though it's not one of the 18 symptoms are you conically late and particularly people who show up late to my office time after time so one of my favorite quotes is this person who the session before we had been talking that her boss was giving her threatening notices because she had come in two hours late one day and she had all sorts of good excuses of why she couldn't get out the door and I we were talking you know regularly late no no no and I said well why was the boss so upset let's say and then I asked well when do you when is the expectation this is pre -COVID pre -working when it's the expectation you're there when do you usually show up oh well the office starts at nine and I'm usually there by 915 920 that's not late and her mind it wasn't late so you know and so when you ask a question are you originally late you're going to get meaningless information on your little checklist unless you know what that means to the individual so the second part of the question I'm sure it's been done and I don't have the answer whether stimulants or other drugs measurably improved time perception in that you know laboratory situation of just can you estimate how much time is elapsed I I should know that but I don't have that on top of my and the more global question of how central that's sort of the time aspect of organization of thoughts and attention is to the content of disorganization I mean there are some research groups I think it's a many adenish group who's feeling that ADHD is primarily a circadian rhythm disruption that that's the central neurologic issue at play and there's interesting I got to do work in the early 80s on bright light therapy for winter depression which as a measurable impact as strong as medication but there is one or two studies done on individuals with ADHD without any seasonal depression without any depression at all and just those same bright lights showing them you know a dose of bright lights early in the morning measurably improved a broad range of ADHD symptoms and the claim is that that was working because it was helping re -synchronize internal rhythms which are out of sync in ADHD whether that's exactly the same thing you were getting at but certainly if you have I mean even though we have a sort of master clock in the super chiasmatic nucleus we also have clocks throughout our body and they're talking and interacting and ostensibly synchronized and working with each other but it could well be that for many people they're not and that getting that to work is essential thank you for those reflections and really I want to say thank you on behalf of myself and everyone listening and watching for doing the work you do you were invited here today because you have an absolutely encyclopedic understanding and knowledge of ADHD and the clinical treatments and I've watched your YouTube channel and we'll provide links to all your various resources I'm looking forward to your upcoming book however long it takes I'm sure it'll be spectacular you know when you talk about ADHD you're able to do it from so many different angles behavioral supplement based nutrition life an organizational life organizational aspects and of course the medication the pharmacology the neuroscience and the ways that those different nodes interact with one another because of course they do so I just want to be absolutely clear how grateful we are for you for sharing all this knowledge a lot of people struggle with attention issues with regardless of whether or not they have a full blown ADHD or not a lot of people who treated for it some people are still wondering if they should be or not and so today's discussion was nothing short of a spectacular so on behalf of everybody I want to just thank you for doing what you do and for coming here to educate us thank you so much thanks I'm God smacked so thank you for joining me for today's discussion with Dr.

2:35:41John Cruz to learn more about his work please see the links in the show note captions if you're learning from end or enjoying this podcast please subscribe to our YouTube channel that's a terrific zero cost way to support us in addition please click follow for the podcast on both Spotify and Apple and on both Spotify and Apple you can leave us up to a five star review if you have questions for me or comments about the podcast or guess for topics you'd like me to consider for the Hubertman Lab podcast please put those in the comment section on YouTube I do read all the comments please also check out the sponsors mentioned at the beginning and throughout today's episode that's the best way to support this podcast for those of you that haven't heard I have a new book coming out it's my very first book it's entitled protocols and operating manual for the human body this is a book that I've been working on for more than five years and that's based on more than 30 years of research and experience and it covers protocols for everything from sleep to exercise to stress control protocols related to focus and motivation and of course I provide the scientific substantiation for the protocols that are included the book is now available by pre -sale at protocols book .com there you can find links to various vendors you can pick the one that you like best again the book is called protocols and operating manual for the human body if you're not already following me on social media I am Hubertman Lab on all social media platforms so that's Instagram X formerly known as Twitter Facebook linked in and threads and on all those platforms I discuss science and science related tools some of which overlaps with the content of the Hubertman Lab podcast but much of which is distinct from the content on the Hubertman Lab podcast again that's Hubertman Lab on all social media platforms and if you haven't already subscribed to our neural network newsletter the neural network newsletter is a zero cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three page PDFs that cover everything from how to optimize your sleep how to optimize dopamine deliberate cold exposure we have a foundational fitness protocol that covers cardiovascular training and resistance training all of that is available completely zero cost you simply go to Hubertman Lab .com go to the menu tab in the top right corner scroll down to newsletter and enter your email and I should emphasize that we do not share your email with anybody thank you once again for joining me for today's discussion with dr john cruise and last but certainly not least thank you for your interest in science