Amphetamine-based stimulants are more effective for ADHD than methylphenidate (Ritalin), but carry a risk of psychosis.
This risk, though uncommon, can have severe, long-lasting consequences.
Transcript:
John Kruse
Is, or generic methylphenidate, and there's dozens now of slow release versions, and there's even a patch, a skin patch instead of an oral version. Our definition of what a stimulant is, is really squishy and vague. In its broadest sense, it's any drug that has an effect in the body, like the sympathetic nervous system, which is a norepinephrine-driven fight-or arousal system. So by the loosest criteria, caffeine's a stimulant, wellbutrin's a stimulant, even though we classify it 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 Vyvanse. And again, there's a host now of newer branded extended release forms and methylphenidate. And we lump the two together. Probably most ADHD experts agree with, and this is where I'm going to 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 norepinephrine 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, let's just say, vesicle manipulator. So it's actually forcing a bigger release from the vesicles when they're synaptically released. So 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 norepinephrine and dopamine reuptake inhibitor, that's what Wellbutrin is. That's one of the, you know, 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 Adderall products, amphetamine, and methylphenidate products here and say, you know, they're here because they work better. This is, you know, success in reducing ADHD symptoms. And all of our stratera, adalmoxetine, walbutrin, I use Cymbalta a lot, Modafinil, Guanfacine, 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 the amphetamine products are head and shoulders above everything else. Methylphenidate is 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 effect that I worry most about, it's not at all common, it's one of the horrible ones, is amphetamine-induced psychosis. Now that we're finally looking at that a little more closely, because for years the ADHD experts have said, yeah, it's really rare, let's not look at it at all, let's not pay attention, Move along, don't look. With amphetamine Adderall products, and that's probably dose dependent, but it's close to one out of 500 people. And 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. So amphetamine-induced psychosis is a schizophrenic-like picture. Usually someone is really paranoid, really worried that their friends are manipulating them or the police are spying on them. I mean, if you drink too much alcohol, you can be batshit crazy. That's a highly technical term there. 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 of what you did. People will let you know. 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. So now we're studying this a little more. Well, with amphetamine-induced psychosis, about 20%, 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 a much higher risk of this for, I can get into it if we need 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 as my introduction to, you know, I'm happy to continue on this, but are you aware, to a person they said, no one ever told me that. Now, maybe they have ADHD and weren't listening, but it's so uniformly consistent that they didn't hear or know that that was a side effect. (Time 1:04:59)
Higher Psychosis Rates
Dr. Kruse encountered higher rates of amphetamine psychosis in San Francisco, partly due to pre-existing conditions like HIV and methamphetamine use.
Some individuals, despite experiencing psychosis, sought more stimulants, highlighting the potential for problematic use.
Transcript:
John Kruse
And one in 500 isn't a trivially small number. No, it's not trivial. And I mean, why I got alerted 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 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, there's a HIV-induced Dementia. So probably some of these people had brains that were compromised because of that and were vulnerable. Two, a high incidence of methamphetamine. So methamphetamine street speed is a chemically different molecule than amphetamine. It has 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. This 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 amphetamine-induced psychosis, a guy in his 40s, HIV Positive for years. This was back in early, mid-90s. Was able to finish school in his mid-40s, get a good-paying job in two years on stimulants, and then had a full-blown psychotic episode where his dad had died of a heart attack 10 years Earlier. He was threatening his mom because he believed his mom had poisoned her. He flew over to Rhode Island where she was living. He was making threats from a payphone. And because Rhode Island's so small, he was actually calling from out of state. So it was a federal crime. He got thrown in federal prison for this. And he stayed psychotic for months after he wasn't using anything. But it later turned out he had had a psychotic episode 10 years earlier on street meth, 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. And I was comfortable with the broader range of stimulant dosages than 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. And again, the numbers aren't huge, but at least five people with this general profile. But 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, you know, they presented, all of them also had ADHD. You know, they presented with ADHD. They'd say, I'd been on stimulants before, and, you know, I'm not working with that doctor because my insurance changed, or they had moved to the area. So they gave plausible histories. And most of those, within a month or two of restarting it, wound up back in the psychiatric hospital. Bright computer programmer, late 20s, calling me from inside the psychiatric hospital to try to get me to prescribe more Adderall 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.
Andrew Huberman
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. It feels like a manic high, the high dopaminergic state.
John Kruse
Yeah, and you put the word mania in there, manic, and lots of people define this as amphetamine-induced 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 going to 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 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. I think the second piece is how much of they, 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 that 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 they were the parents trying to take care of their (Time 1:10:55)
ADHD Medication Choices
Consider patient preferences and educate them on risks and benefits of different ADHD medications.
Amphetamines are more effective but carry a higher risk of psychosis.
Transcript:
John Kruse
Mean, some of this is just individual style rather than intellectually thinking one is better or not. 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 who are on disability from Medicare. I also worked with people who are on Medicaid and the city's insurance before Obamacare happened. So I've 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. We don't have potent antidepressants and non-partum. If it got FDA approved, it works in a certain range of likelihood. But with the stimulants, amphetamine-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 Wellbutrin 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.
Andrew Huberman
Do you worry about strain on the heart with amphetamine 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?
John Kruse
When you used that term, I was talking to Rob beforehand about running marathons. And when I ran the 100th anniversary of the Boston Marathon, they had some of the medical literature from the previous decades. And one of the medical warnings was, you know, maybe you could do one or two marathons in your life, but don't do more than that because your heart will wear out. And, you know run 100 and 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-stimulants that are affecting norepinephrine. So Welbutrin, Cymbalta, modafinil, it's less clear and we can get into that when we talk about modafinil, but clearly methylphenidate amphetamine, on average, 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 maybe a more slightly significant change. So 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 a stimulant. And almost every year there's a well-trained athlete, either a professional player or more often a high school or college player, who will take cocaine, take Ritalin, take prescription Stimulant, and drop dead of a heart attack. The risk of that's 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 on Adderall who dropped out of a heart attack. So part of it is, if you're in this rare genetic condition, almost always there's family members or you've had some other near-death or 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 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. Absolutely 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. 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. The 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. (Time 1:19:04)
Stimulants and Cannabis
Exercise caution when combining stimulants with cannabis, especially high-THC strains.
Consider the potential interactions and prioritize understanding cannabis's effects.
Transcript:
John Kruse
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. Or 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 madness that everyone who puffs a joint is freaking out? Clearly not.
Andrew Huberman
But again, it's much more potent than it was 70 years ago, I guess. Especially, as I understand, we had an expert from the cannabis research community on in edible form in particular. It's harder for people to control the dosage. Whereas when people use inhalation as a means to deliver, it seems like they kind of find the right plane without going overboard more often than with edibles in any case.
John Kruse
One other big factor is that CBD actually seems in some studies to have an antipsychotic effect. So 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 was a state with the most Close regulation and inspection, and almost a majority of what the labels say don't correlate with what you're really getting. So 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. (Time 1:29:28)
Nicotine and ADHD
Nicotine can improve focus and attention.
It uniquely both arouses and reduces anxiety, potentially offering benefits for ADHD.
Transcript:
John Kruse
So there's some well-done research showing nicotine is helpful for improving some of the executive functions of sustained attention. And I'm not sure which of 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 there 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 who say unique means one of a kind, so I can't modify it in any way. Unusual, 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 an important and useful part of their regimen. I have some people, small numbers, who prefer it to any other medications. And almost no, again, other than sort of the 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 (Time 1:35:15)
Drug Holidays for ADHD
Drug holidays for ADHD medication may not be necessary and haven't shown consistent benefits other than mitigating growth suppression in children.
Consider individual needs and demands when deciding on drug holidays.
Transcript:
John Kruse
Of that sort. Maybe I'll start with that. So for decades, particularly starting with kids, 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 growth years. And taking breaks that last for several months, like taking off during the summer, result in overcoming that decrement in height. I looked, and I still haven't, 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 was 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, and 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 where 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 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 asked 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, but how 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 with high doses, with a long extended release version, That may actually be more of a risk. But I'd say there's more concern, I think, in the basic science community from the immediate realist. And there's a tiny bit of data, but part of it overall is that we talked earlier 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 Adderall, who gets addicted to Ritalin, 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 it'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 Ritalin and it says take it one every Six hours apart during the day, and you acknowledge taking it on one day, eight hours difference, you're classified as a misuser by those studies. I mean, 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 addiction. 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. Some shorter, some immediate release lasts 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 3 that afternoon, you could take it at 2 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. (Time 2:19:40)
Time Perception in ADHD
People with ADHD experience time differently, not necessarily tracking it linearly but distinguishing between "now" and "not now".
This perception may relate to their interest-based attention and potential circadian rhythm disruptions.
Transcript:
Andrew Huberman
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? Good question.
John Kruse
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 I mean, there's a simple test, a time perception test, and you interrupt them after a certain period. I mean, say, you're going to be estimating how long you're left without interruption. And people with ADHD measurably, they're inconsistently inconsistent. 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 aberrant there, but there's also getting, you know, the real world aspect of not paying attention to cues or not noticing Other people have the room or not being distracted, which compounds the 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 chronically late to them? And particularly people who show up late to my office time after time. 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 we were talking, you know, are you regularly late? No, no, no. And I said, well, why was the boss so upset? And then I asked, well, when is the expectation? This is pre-COVID, pre-working. When is the expectation you're there? When do you usually show up? Oh, well, the office starts at 9, and I'm usually there by 9.15, 9.20. That's not late. In her mind, it wasn't late. So when you ask a question, are you routinely 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 improve time perception in that laboratory situation Of just can you estimate how much time has elapsed? I should know that, but I don't have that on top of my eye. 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 mainly a Danish 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 has a measurable impact as strong as medication. But there was 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 was that that was working because it was helping resynchronize 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 suprachiasmatic 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. (Time 2:29:55)
