Welcome to the huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew huberman and I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine. Today, we're discussing stimulants in particular stimulants for the treatment of ADHD or attention deficit hyperactivity disorder. As many of, you know, there is tremendous interest in drugs like Adderall Ritalin Vyvanse and
ER stimulants, as well as non-stimulant prescription drugs that have been shown to improve the symptoms of ADHD such as modafinil armodafinil and guanfacine. Today, I'm going to discuss all of these compounds in the context of how they work to improve the symptoms of ADHD. I'm going to address common questions about these compounds such as are they just speed? Are they similar to meth or Methamphetamine? I'll talk about their addictive potential as well as their potential to cause psychotic symptoms.
Both in the short and long term and
of course I will talk about the scientific literature surrounding the most
frequently Asked question about these compounds,
which is what are the long-term consequences of taking any of them in childhood or in adulthood. Now, today's discussion centers around the use of these compounds, both for childhood and for adult ADHD, but of course, I'd be remiss if I didn't acknowledge that, there are a tremendous number of people that use these prescription drugs without a prescription.
Ian in order to improve their ability to focus and indeed also use them recreationally. In fact, some surveys reveal that as high as 80% of college-aged. Young adults have used one or several of prescription drugs such as adderall Ritalin, Vyvanse, or similar at some point and are doing so without a prescription. So, they are either obtaining those drugs from those that do have prescriptions for them for ADHD, or they are obtaining them through Black Market sources, which, of course, carries an
Channel and very serious risk related to the so called fentanyl crisis. That is as high as 75 percent of black market drugs, nowadays of various kinds but certainly including the sorts of drugs, we're going to talk about today, are contaminated with fentanyl and therefore are very deadly. So today I'm going to describe what these various drugs, really are how they work at the level of neurons and brain networks and how they change those brain networks in ways that really can allow people with ADHD to be able to
Focus better. I will answer the common question, which is, why is it that giving children speed because indeed, several. Not all, but several of the compounds, I'm going to discuss our speed. They are amphetamine. Why would that cause a reduction in hyperactivity if speed is a stimulant. So I'll answer that question for you. And I will also answer questions that are commonly asked such as how these drugs impact, things like sleep hormone, Health reproductive Health as well as what is their impact.
Don height, indeed, it was one prominent hypothesis that these ADHD meds could actually restrict the height of children. I'll tell you whether or not that's actually true or
not and I'll discuss the data surrounding whether or not these drugs, predispose people to becoming addicts to other
substances even if people cease or continue taking the stimulants that can help them in the clinical sense, for ADHD. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring
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Cam huberman to save 20% off again, that's hvm n.com huberman. I'm pleased to announce that I will be hosting to live events in September of 2023. The first live event will take place in Toronto on September 12. The second live event will take place in Chicago on September 28. Both Live Events will include a lecture and a question and answer period and are entitled the brain-body contract during which I will discuss tools, and science related to mental health, physical, health, and performance. Now, I should mention
In that, a lot of that content will have absolutely no overlap with content covered previously on the human
Lab podcast or elsewhere. If
you're interested in attending either or both of these events, please go to huberman, labs.com tour and enter the code huberman to get early access to tickets. Once again, that's huberman, labs.com, slashed or and use the code huberman to access tickets. I hope to see you there. Let's talk about treatments for
ADHD and why stimulant treatments in particular
can be so effective.
First of all, it's long been known that there are specific brain networks
involved in what we call attention. Now, attention is not one thing actually.
It involves several different cognitive operations,
including the suppression of noise that is
turning down the background chatter in our
heads. And
turning down our attending to things outside us like noises or visual cues that are not relevant to what we want to do. And it also involves ramping up or
Attending were
focusing on particular things that are happening either in our immediate
environment or in our head or both. So if that all sounds rather complex, indeed it is and involves
several different networks operating in parallel.
But what we know for sure based on a lot of clinical and scientific laboratory data is that the so-called prefrontal cortex the region of neural real estate in your brain just behind your forehead is critically important for orchestrating.
Ting, which neural circuits are going to be
more or less active at a given moment. In order to bring about what we call Focus or attention, or task switching or our ability, indeed to multitask because we can actually multitask to some extent. In fact, if you were to look at somebody and focus on perhaps their expression on their face you could do that while also attending to a conversation that's happening nearby, it's energetically demanding, it's hard to do but we can do that. That's actually
For to his covert attention, your covertly paying attention to something else and then you can switch that attention back to just one thing or one small collection of things.
The point being that attention is a powerful resource. It's what allows us to navigate through life with efficiency and to be adaptive in our behaviors it's what allows us to learn and to build relationships and have successful School careers and professional careers and so on. But it is indeed expensive. It takes metabolic resources just at rest.
If you were to think about essentially nothing or whatever just pops into your mind with no dedicated effort toward paying attention to anything, your brain would consume about 25 percent of your daily caloric needs. And then when you lump on top of that your need or your attempts to focus on things to pay attention to specific things, it should come as no surprise as to why that often can make us feel tired as if we've been working really hard. And we've been running a quote-unquote mental marathon, when trying to learn and attend to things, it's hard.
Work for the brain and yet we can pay attention because of that, very precious real estate. Just behind our foreheads, the prefrontal cortex.
Now, in people,
both children and adults that have ADHD their prefrontal cortex is not
necessarily deficient in any specific way
except that it is not as good at orchestrating the activity of other brain
networks operating in parallel with it. What do I mean by that? Well,
if we take a step back and say, what is the prefrontal cortex
really doing
The prefrontal cortex has this amazing ability
through, what's called top-down inhibition to
quiet. Other brain areas. So for
instance, if you are feeling agitated, but you need to sit still your ability to sit still. Even if it takes a bit of work is coordinated by your prefrontal cortex. Sending inhibitory suppressive electrical signals to the networks of your brain that are trying to generate physical action. In addition to that if you are in a conversation that's either a difficult one or a
Bring one or you are tempted to interrupt and you are actively holding back your desire to walk away, or to yawn or to blurt something out.
It's your prefrontal cortex. That is controlling that active suppression.
So in many ways you can just think of the prefrontal cortex
as an Orchestra conductor
that is essentially saying
or not right now. Be quiet. This is not the time to many different brain networks all at once.
Now in addition to that
your prefrontal cortex is coordinating with other brain networks that are involved in generating what's called salience or attention to particular signals. So the prefrontal cortex in many ways is like a teacher or an Orchestra conductor. It can point to in the neurochemical sense that is point to a given brain structure and say you, I'd like to hear more from you right now. Yes, you the student in the back speak up and a moment later point to a
Small students chattering in the back again, I'm presenting all this by
analogy and say, hey hey you guys quiet down right now.
So and so is going to come up to the front of the room and help us work through this particular math problem.
So when we hear that the prefrontal cortex exerts,
what's called executive function,
what that refers to is the prefrontal cortex is ability to quiet, the activity of particular, neural
circuits, and to enhance or increase the
salience of other neural circuits that are involved in creating our
spotlight
Of attention.
And what we know for sure, based on many, many brain Imaging
studies is that ADHD
is not necessarily A deficit in. Prefrontal cortical function. But rather the prefrontal cortex is ability to communicate with
other brain areas in the proper ways. And so what results in the brain of IT person, either young or old with ADHD.
Is that a lot of the background chatter becomes very, very
loud. So for instance, we have a brain Network called the default mode.
Work. This is a fascinating brain Network. This is the brain Network that is active. When you just sort of sit in place and don't think about much. And then you start having
ideas about what you might do next week, it tends to be very autobiographical so you might remember an experience from the past, you might think about some of your desires, some of your dislikes,
this default mode Network as it's called is also involved in our imagination or in our spooling together of different experiences that we've had. It doesn't tend to be the thing that's really focused
on anything.
External in particular all at, once
the default mode network is always active. But it's when we start to attend to something, especially things external to us
like it, you know, something written on a page or a conversation or something that we really need to learn something. We need to pay attention to
that. The activity of the default mode network is
suppressed somewhat and that
suppression occurs, not just by
accident but because the prefrontal cortex is actively suppressing it
in kids.
Adults with ADHD, the default mode network is often still active at a very robust level even
while we're trying to attend to things and that's why someone wanted to ADHD will sit down and try and do some
focused work and I'll start thinking about something they
want or something, they
dislike their internal state will start to
distract them. And
of course, there are other networks in the
brain, there's actually a what's called a true salience Network. There's the dorsal attention Network.
There are a bunch of different networks and brain areas.
But again when thinking about ADHD and especially when thinking about how the drugs that we're going to talk about today work to alleviate
the symptoms of ADHD
and in thinking about why so many
people use or even abuse these drugs for sake of learning or recreationally. We might say you start to realize that everything centers back to the prefrontal cortex. And the prefrontal cortex is ability to actively suppress and actively enhance the activity of these
Brain that networks including default mode network, salience network, dorsal, attention, Network, Etc.
So rather than overwhelm you with a bunch of names of brain areas and brain networks, today I'd really like our discussion to focus on first what the various drugs that are
used to treat. ADHD are that is how do they work at the level of neurons?
S how they create a certain set of conditions
that allow the prefrontal cortex to be a better conductor
third? How that
It can be leveraged during development to actually teach the prefrontal cortex of a young child to learn to be a better conductor because that's really the Hallmark of the use of these drugs is to try and enhance the activity of particular circuits to create a sort of learning so that the prefrontal cortex is much more efficient at doing its job of conducting. And then fourth, we're going to talk about the various things. That I think most people out there ask about when they hear about drugs like Adderall Vyvanse, and Ritalin etcetera, which is, you know, are they
Detective. Why are they addictive?
Can one use them briefly or even from time to time and still be okay what if I use them as a child and I don't want to be on them anymore. Should I put my child on these drugs Etc? It is I believe only by understanding the biology of how these drugs work and their potential, both to improve brain function. But also some of the dangers associated with these drugs that one can really answer those questions for themselves or for their children. Okay? So let's start with a very basic
Like, but critical question, which is why in the world would amphetamines speed or other stimulants improve the symptoms of ADHD.
That's so critical to answer because if you think about it the prefrontal cortex needs to coordinate the actions of these other circuits and so just increasing the amount of activity in prefrontal cortex, you can imagine would create a state of hyper Focus perhaps but actually that's not the case. If you just were to ramp up the activity of prefrontal Cortex, what you would find is that somebody would become even less efficient at paying attention, to what they wanted to rather. They would pay attention to whatever was presented in front of them with
Laser focus, they would lock on to essentially anything and that's not good. One of the key things about prefrontal cortex is that it needs to be flexible. It needs to be able to pay attention to this, then it needs to be able to pay attention to that, then it needs to go back to paying attention to the thing. It was
paying attention to previously and so on and
so forth. Life that is an effective adaptive life, a good life, consists of self-directing, one's attention, most all of the time. So why would stimulants do that?
Well almost all not all but almost all of the drugs used to treat ADHD fall under the category of stimulants or what are called sympathize memetics sympathize mimetic refers to the fact that we naturally have a component of our nervous system called the autonomic nervous system. The autonomic nervous system has two major components. One is called the sympathetic arm of the autonomic nervous system has nothing to do with sympathy as everything to do with ramping up our
I love attention and arousal. It is the so-called fight or flight aspect of our nervous system where rather immediates fight or flight. But immediate a bunch of other things, too, including sexual arousal, including excitement, and focus about something that we want to learn, or somebody that we want to learn more about or remembering a phone number or anything that puts us into a state of alertness and focus.
The other arm of the autonomic nervous system is the so-called parasympathetic arm of the autonomic nervous system and that's often referred to as a so-called rest and digest
component of our nervous system and yes, it controls
rest. Indeed it puts us into sleep. And yes, it's involved in digestion, but it's involved in a bunch of other things as well, including sexual arousal, including rates of digestion, including
salivation, including all
sorts of things that don't just have to do with resting in.
Digesting
the way to think about the autonomic nervous system is it's a sort of
seesaw so it's
always at a balanced someplace between either predominantly sympathetic or predominantly parasympathetic. But both the parasympathetic and the
sympathetic arms of the autonomic nervous system are always active all the time. It's not as if one is completely active in the other shut off, even in sleep, your sympathetic nervous system is not completely turned off, and even during a panic attack, your parasympathetic nervous system is not completely turned off.
Drugs to treat ADHD, which are fall under the category of stimulants are
sympathize memetics because they trigger the release of neurochemicals and the activation of components of our nervous system that very much resemble, the activation of the so-called sympathetic nervous system. The one that makes us more alert and more aroused so that's why they're called sympathy memetics and the word stimulant refers to a general category of drugs that
at our sympathy memetics. Now, the most commonly discussed sympathomimetic is one that fortunately is not prescribed for ADHD, and that's methamphetamine these days. We hear a lot about meth meth which is methylated, amphetamine is an extremely potent sympathomimetic and it has tremendous abuse potential.
Believe It or Not meth or Methamphetamine is actually available as a prescription drug but it is used very rarely because of its high abuse potential and all the terrible things that it can do in terms of cardiovascular health in terms of oral health, right? There's this stereotype that meth users have very degraded teeth and indeed they do. There's a reason for that related to how meth impacts the brain and body. I'm going to talk a little bit about methamphetamine a little bit later, but let's just place.
Them feta mean high on the Shelf as the most potent sympathy, mimetic, that's out
there because
even though it's not often prescribed for ADHD,
there are class of compounds very
similar to it. That have a very similar pattern of action, that is not quite as potent, but that leverages the same underlying mechanisms. And they are very commonly prescribed for ADHD, namely, Adderall and Vyvanse. So first, let's talk about Adder.
Roll and what Adderall is Adderall, is a combination of what are called, amphetamine, salts and fed amine salts refers to the fact that there are two major forms of amphetamine. There's a DM feta, meaner dexamphetamine and levo amphetamine or LM feta mean. So I'll refer to these as a D and L amphetamine and for you chemistry minded folks out there, the DM, the L. Also referred to the fact that there is a l left-handed version of the molecule, and there's a d or right-handed version.
The
molecule this is only important to understand in so
far as you know that the D and
the L forms of the molecule look very similar but they're mirror images of one another and yet they can have very different actions in the brain and body. So Adderall is a three to one ratio of DM feta mean to LM. Feta mean, you should know that LM feta mean tends to be less potent in, increasing certain or chemicals in the brain, all talk.
About which no chemicals are in a moment then is DM, feta mean, sodium. Feta mean is potent stuff not as potent as methamphetamine, but very potent stuff. L amphetamine a little bit less potent, LM feta, mean tends to be the amphetamine that increases blood pressure, and heart rate. What we call peripheral effects because it happens in the periphery outside. The central nervous system peripheral effects like increased heart rate, increased blood pressure sweating, Etc.
Are mostly activated by LM feta. Mean, whereas DM feta mean tends to work, mainly on
receptors in the brain and therefore have affects mainly restricted to the brain. Now, what are these effects that I've been referring to the major effect of Adderall and other sympathy? Mimetic stimulants is to increase the activity of to neurochemicals. The first of those neurochemicals is dopamine and the other of those neurochemicals is norepinephrine first off. I want to be clear.
That when I say norepinephrine, I could just as easily say noradrenaline because those are the exact same thing and forgive me, even though I wasn't the one to name the same thing, two different things, I'll try and stay with norepinephrine, but I may say noradrenaline, they are the same thing. There's a whole story as to how they got named two different things, but it's the same thing.
The major effect of Adderall and other sympathy. Mimetic stimulants is to increase the transmission of dopamine and norepinephrine. So what is dopamine? And what is norepinephrine? Well both, dopamine and norepinephrine. Are what are called neuromodulators that is they have the ability to increase or decrease the firing patterns. The electrical activity of particular, brain circuits, both dopamine and norepinephrine have separate roles in
Creating certain States within our brain and body,
but they like to collaborate. Meaning they tend to be released at similar locations in the brain, in order to deliver us to a particular
state of mind and or
body. So, if we were to take a look at just dopamine, we would find that dopamine is released at sites within the brain and increases the activity
of brain networks.
That for the most part lead to increases in motivation Pursuit
and to some extent,
Food.
If we were to look at norepinephrine and where it's released in the brain, it tends to be released that many not all, but many of the same
sites where dopamine is released
and the main function of norepinephrine is to increase the activity of neural networks that are involved in attention and focus to particular things in our environment, okay? So think of dopamine and
norepinephrine as collaborators because indeed, they are and
actually, they're very neurochemically similar as well.
It actually just takes one chemical conversion to turn dopamine into norepinephrine. So they are very
similar like close cousins that work together
to help us achieve a common goal that involves increased motivation, focus and alertness. So, when we talk about attention in ADHD or we talked about quieting, the hyperactivity or impulsivity of ADHD. One of the reasons why drugs that are effective in treating ADHD are so effective is because they increase
Motivation, focus and alertness. And they tend to do that at very focal locations in the brain. It's worth taking a couple of minutes to think about how sympathy mimetic such as adderall, actually, increase dopamine and norepinephrine. They do so by affecting a couple of specific operations at the so-called synapse, what our synapses, synapses are the communication points between neurons there, actually the spaces between neurons but that's where a lot of the action is when neurons as we say, are stimulating the next neuron, or activating the next neuron or inhibiting?
Next neuron, the word neuron just simply refers to nerve cell. And so what nerve cells have is they have a cell body that contains their DNA and a bunch of other stuff they have a long wire like process which is referred to as an axon. And at the end of that acts on, there are a bunch of proteins
in there that do really interesting things. So
for instance, there are proteins down at the end of the axon that package neurotransmitter into little spherical things that we call. Vesicles those vesicles can fuse with the end of the Axon
On and vomit. The contents. Those neurotransmitters
into the synaptic cleft into that little space between neurons.
And then if enough of those neurotransmitters bind to receptors on What's called the postsynaptic side, which simply means the neuron on the other side. Well, then the next neuron will become active and then the signal will
propagate from one neuron to the next.
Now, I just described that whole process pretty quickly and I like to think pretty simply but it actually involves a lot of different protein.
B and some pretty complex Machinery in order to make that happen.
I don't want to over complicate our conversation, but what I will tell you is that down in the synapse in the presynaptic terminal, the neuron that is going to release neurotransmitter, there are what are called Transporters, which sit there and suck up, or suck back up. Some of the neurotransmitter that's been released.
there are dopamine Transporters and there are norepinephrine or nor adrenergic Transporters down in the synapse, what Adderall does and what other sympathy memetics do is to inhibit or disrupt, the action of those Transporters and the net consequence of that, is that when dopamine and norepinephrine are released into the synapse, more of, it is allowed to stick around and to bind to receptors on the postsynaptic cell
Then would be the case, if Adderall or the other, stimulant were not present in the system. So, one way that Adderall increases dopamine, and norepinephrine is by disrupting the activity of these presynaptic Transporters for dopamine and norepinephrine the other way, that Adderall increases dopamine and norepinephrine is that it disrupts the activity of a different piece of Machinery, in the presynaptic neuron, which is called a v, Matt, the vesicle mono, I mean, transporter to, if you really
Get specific. You don't have to remember these names,
but what these V mats do is actually really cool. What they do is they actually take, whatever transmitter has been brought back up into the cell by Transporters and they package it into those. Vesicles that are then going to be released by disrupting the Transporters that vacuum back up some of the dopamine or norepinephrine that's been released and by also disrupting the packaging.
Of dopamine and norepinephrine into vesicles themselves. What ends up happening is that there's a buildup of a lot more dopamine and norepinephrine in the presynaptic terminal. So that when an electrical signal travels down the neuron now the total amount of dopamine and norepinephrine. That's released is increased okay? So what's happening when you take Adderall, is that you're getting more out of the dopamine and norepinephrine that you're releasing and you're releasing more dopamine and norepinephrine?
For an altogether
and there's a third
mechanism by which Adderall increases the amount of dopamine and norepinephrine present in synapses and therefore can act on other neurons and that has to do with disruption of the entire network between these different proteins. Not going to go into that in any detail because it gets somewhat complicated in terms of the cell biology and some of the biochemistry down at the tips of these axons. But suffice to say that Adderall is such an effective sympathomimetic.
That is it can increase dopamine to such a great extent especially compared to other treatments for ADHD because of its ability to increase dopamine release and transmission and therefore action as well as nor adrenergic release and transmission and action down there in the synapse and it's worth pointing out that most of the effect of Adderall is an increasing dopamine as opposed to norepinephrine. It does increase norepinephrine but it's major
We should say the major effects that have made it such an attractive drug
to so many people, both for the treatment of ADHD. And for people to take
recreationally or
off prescription, or for sake of studying or work. Simply because they want to focus more and longer is because of its ability to increase dopamine to such a great extent.
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To get the five free travel packs. And the year supply of vitamin D3 K to now a bit earlier, I mentioned that LM feta mean levo amphetamine is present in Adderall, but at 1/4 the amount of DM, feta mean, okay? So there's a little bit of LM feta mean, and a lot of DM feta mean in Adderall? Many of you are probably familiar with Vyvanse. Vyvanse has a commercial name, for what many people think is extended-release adderal. But actually Vyvanse is not extended release. Adderall, Vyvanse is
A drug in which the pharmaceutical industry has taken one
component of Adderall, just the D amphetamine component
and attached to it, an amino acid called lysine. Now, the amino acid lysine is a big amino acid and the attaching of Lysine to DM. Feta mean, what we call Vyvanse makes it what's called a prodrug. It actually can't have any effect on its own, but when one takes Vyvanse, and it's broken down in the gut, but to a greater extent, actually
we in the bloodstream, the lysines are cleaved off slowly over time, and as a consequence Vyvanse is basically timed release D, amphetamine. This is important because I think a lot of people think that Adderall which again is DM. Feta mean end. LM feta mean, and those two things operate quite a bit differently, at the level of norepinephrine and epinephrine. And cardiac versus brain affects a lot of people think Vyvanse is just slow release, Adderall, but it is not. What Vyvanse is, is
DM feta mean only, but in time release form and Vyvanse was actually developed as a way to try and get around or rather prevent some of the abuse potential of Adderall and Other Drugs that contain DM. Feta mean, DM feta mean stands for Dexter and feta mean and in the 70s and 80s, there were a fair amount of movies and there was a lot of trafficking and there was a lot of criminal activity related to what was called dexedrine dexedrine is pure.
Per diem feta mean. So if we are going to be very direct, if I were going to just frame these things in the context of their neurochemistry, when I can tell you is that Vyvanse is time, release dexedrine, it's not time release Adderall. Now just because there were movies and reports of criminal activity related to dexedrine. It doesn't necessarily mean that dexedrine is not an effective and useful pharmaceutical in fact Vyvanse, which is Time released dexedrine has proved to be very effective in the treatment of
Th e for a lot of people. And the reason for that
is this time, release does indeed prevent abuse in the sense that despite people's many attempts. From what I
hear to increase the rate of Entry of the DM feta mean into their system by
either snorting it or
God forbid, even injecting and things of that sort. The
attaching of that lysine to DM feta mean really does slow the absorption. So when somebody takes Vyvanse, and hopefully people are taking it responsibly
When they take Vyvanse with, they're really getting is a slow trickle
of DM feta mean into their system and therefore, a
slow long
lasting increase in dopamine and norepinephrine and
indeed, that's what happens. The effects of Vyvanse can extend over anywhere from 12 to 16,
sometimes, even 18 hours depending on how quickly somebody metabolizes it. And I
should say that there is no way to predict how quickly one will metabolize any
of these drugs except by trying. That's one of the sort of, downsides of the state of things these days. There's
Blood test or enzymatic test that will tell you whether or not you're going to be a fast metabolizer a slow metabolizer. And that's why people just have to sort through different dosages which we'll talk about in a little bit. They
have to sort through different
types of sympathy memetics. You know, some
people try Adderall and they find that, you know, the quick time course of Adderall or at least quick for them of about six to eight hours is just too fast and then it wears off and they get into a slump in the afternoon. Other people find that one Adderall taken at 6:00 a.m. We'll have them going all day long and into the night, and it's just too much stimulation. And then
Need to come way, way, down in DOS, or they need to think about other, sympathy memetics for ADHD and we'll talk about what some of those other options are a little bit as well. So the important thing to understand is that Adderall is really to drugs, DNL amphetamine, Vyvanse is DM, feta mean, which is also called dexedrine. But with this time, released aspect created by lumping a lysine on there. And you may notice that I haven't mentioned one of the major drugs used to treat ADHD and that's ritalin or
Sometimes also called Concerta depending on again, the time release forms Etc.
Ritalin was very commonly prescribed for the treatment of
ADHD early in the days of using sympathy memetics in order to treat ADHD. So for instance, I went to college in the early 90s. So I started college in 93 and I graduate in 98. It was one of your in there, as a, let's call it a
transition here, I can recall hearing that Ritalin was being prescribed
for ADHD in kids.
And I like many other people were wondering, what are the long-term consequences of this going to be? I also like many other people was very perplexed as to why a stimulant sympathy memetic. Like Ritalin was being prescribed for hyperactive kids that will become clear in a moment but
we don't hear so much about Ritalin nowadays and I think that's because Adderall and Vyvanse and things like them have become so popular for the treatment of ADHD. It's worth noting that Ritalin is not
Actually amphetamine Ritalin is what's called methylphenidate and methylphenidate Works in. A lot of ways that are similar to the way that Adderall and Vyvanse work, but there are certain ways in which it's different. Now Ritalin methylphenidate does increase, dopamine transmission at synapses and it does so also by inhibiting, the function of that presynaptic dopamine transporter that would otherwise suck more dopamine back up into the presynaptic cell.
Methylphenidate, Ritalin also disrupts, the activity of the noradrenergic transporter, leading to net increases in the
amount of norepinephrine at the synapse.
But it is not as much a potent inhibitor of the nor adrenergic transporter. And therefore, most of the effect of
methylphenidate is to increase dopamine at synapses. A
lot of people don't realize this. A lot of people think that Ritalin is just very short acting Adderall
and that's not the case. It is
Is true that Ritalin, at least in its standard form tends to have a pretty short half-life and therefore its effects basically kick in about 20 to 40 minutes after taking it sometimes a little bit sooner. Sometimes a little later and they last about four to six hours as opposed to the six to eight hours. Typical of Adderall, but Ritalin is not short-acting, Adderall. Ritalin is mainly increasing, dopamine and to some extent norepinephrine at synapses where as adderall
And Vyvanse are increasing both dopamine and norepinephrine to a much greater extent. And for those of you that are interested in the underlying cell biological reason for that, it has something to do with riddle ends relatively lower affinity for the nor adrenergic transporter. But it's also because remember, I listed off three mechanisms by which Adderall, and by extension Vyvanse increase, dopamine and norepinephrine transmission, right? Disruption of the transporter disruption of the vmat2, as well as a disruption of the whole kind of
Lex of communication between those proteins will Ritalin is really only tapping into the drugs ability to disrupt the dopamine and norepinephrine, erdrich transporter. So it's three mechanisms of increasing dopamine and norepinephrine for Adderall and Vyvanse and by extension dexedrine, and it's only one mechanism for Ritalin to increase, dopamine and norepinephrine, and they're in mostly dopamine. So, if we take a step back for a moment, from all these drugs and all this cell biology of
Odds and so forth and we
go back to the brain.
Networks involved in attention. Remember the orchestra model or the teacher model? Where the prefrontal cortex really sits in top seat in terms of coordinating? The actions, both the, the quieting and the, yes, please speak actions of the brain. Really bringing about what we think of as focused, attention and task switching all the stuff that goes along with learning and focus and cognition.
Well, what we know is that dopamine and norepinephrine which
Are differentially
increased by these different drugs that we've been talking about.
Also differentially impact the various
aspects of executive function of the prefrontal cortex, increasing our attention for specific things. And while there
is a lot of nuance in the literature about this, we can safely say a couple of things. First of all increasing dopamine at particular
synapses and networks in the
brain can serve. As what's called noise reduction, it can help.
Further enhance, the quieting of
all that background stuff,
that background stuff can be attention to things in your environment like noises or visual cues.
It could be some
internal narrative at about yesterday or
something that somebody said about you or something that somebody you
like would like to say about you or whatever it might be, that's happening in your head. That's distracting you as well as your representation of your internal bodily State. What we call interoception, this is a
A important aspect of a tension that we don't often hear about, which is that we have the ability to attend to things outside of us, which is called XT reception, as well as an ability to attend to things inside of us, which include things like thoughts. But also includes for instance, how empty or full our gut feels whether not we're comfortable in our chair. You know, when we think about the practice of focus and learning or focusing as a verb, it involves often forcing ourselves to sit, still It Off.
Balls us suppressing the fact that our foot is a little bit cramped or that we might need to use the restroom for, you know, we might want to delay that for 10-15 minutes, even though it might
be fairly urgent, all these sorts of things are Central to our ability to attend and focus. And so, dopamine, while it does many different things in the brain, many, many different things. One of its main functions in the context of all
this, prefrontal cortex and attention stuff is too quiet. The
Amount of noise. That is it helps the prefrontal cortex
suppress the signals, that would otherwise distract us into thinking
about you. I'm kind of thirsty right now or I need to use the restroom. I really want to make this caller. I really, really want to pick up my
phone, all of that stuff, all of that suppression that show that
quieting down of all the
background chatter related to things external and internal to us in our head. And our body is greatly facilitated by having more dopamine present in the synapses that allow for
What we call noise reduction. Now, in
parallel to that is nor epinephrine norepinephrine is released from multiple sites in the brain and body. But within the brain, there's one
major site of neurons, that manufacture norepinephrine and the name of that site is Locus coeruleus. It's sits in the back of the brain.
It's actually a relatively small collection of neurons, but they are very, very powerful. They extend, their will axons. Their wires to multiple locations in the brain, and they release
Norepinephrine at those locations. So think of them sort of as a sprinkler system that originates from one very focal location but that can sprinkle norepinephrine at multiple locations in the brain and the amazing thing about Locus coeruleus and that sprinkler system is that indeed. The sprinkler system can be pretty widespread. Where everywhere? There's a sprinkler head, somebody's getting norepinephrine, but it also can fairly focally release norepinephrine at particular sites so while
Context of today's discussion dopamine is acting largely to impart. Noise reduction norepinephrine has the ability to boost signals at
synapses to increase the amplitude and frequency of communication between neurons.
And in that way in the context of today's discussion norepinephrine, when released at the particular, synapses in the
particular brain networks that are related to attention
and learning is largely serving to increase signal.
So what we have in the context of a
drug like Adderall or Vyvanse, or to some extent, methylphenidate, Ritalin does this as well,
is an increase in dopamine and norepinephrine that is leading to two things. Both a reduction in noise, a quieting of the
circuitry that we don't want to hear so much from
an increase in the signal of the networks that we do, want to pay attention to and the net effect of that noise, reduction and Signal, amplification is what the engineer is referred to as increased.
Not to noise. And the consequence of that is a heightened subjective sense, or ability to decide what we want to focus on sit down or stand there and just focus on it. So the way that we've been discussing drugs to treat ADHD and their ability to increase dopamine and norepinephrine and thereby to reduce the amount of noise. So to speak in the brain and to increase the amount of signal related, to things that we want to attend to all presumes that the
The amount of dopamine, and the amount of norepinephrine that's being increased is perfect for what we want to accomplish, which is increased focus and reduced hyperactivity and impulsivity. But of course in the real world, that's not always the case, depending on the dosage of the drug. One sensitivity to the drug. Even what stage of development across the lifespan a person is at things can really go Haywire pretty fast and what I'm referring to when I say Haywire is if you think about dopamine
Its ability to reduce
noise. Well, dopamine does a bunch of other things as well. And in fact, we know
that if dopamine has increased too much in the brain of somebody that has ADHD or somebody that doesn't have ADHD, people can become euphoric, people can become manic, people can even become psychotic likewise if norepinephrine is increased too much. People won't just become alert. They will become very anxious have panic attacks and
depending on the drug they're taking they may even experience very serious peripheral symptoms.
Meaning elevated, heart
rate and sweating, that is super uncomfortable and on and
on so everything I've been discussing up until now is true, but I want to make it clear that it's true in the context of appropriately.
Dosed prescribed drug for a given condition, which leads us
to the next question, which is why would it be that giving these drugs, which are in fact stimulants, why would
that calm a kid down? Why would that comment adult with ADHD down?
And the answer to that is
Completely straightforward. And it is worth pointing out that not everyone with ADHD
has impulsivity and hyperactivity and therefore an inability to
focus. Some kids and adults with
ADHD, do have challenges with impulsivity and hyperactivity. Some do not
some just have challenges with focus
and I did an entire episode about ADHD, and we are going to have an expert guest on this podcast, who specializes in the treatment of ADHD to talk about some of
these issues further. But I just want to remind everybody.
That as in the general population children and adults with ADHD are capable of very
concentrated periods of focus, the pattern. However, tends to be that children and adults with
ADHD have a harder time getting into that state of
focus. And perhaps most importantly, they have
a very hard time getting into a
forced state of focus for things that they don't enjoy doing. I'm sure many of you are also thinking wait I don't like to do certain things and it's harder to focus.
On those things then on the things I like, of course, does that mean I have ADHD? And the answer is not necessarily. So
kids and adults with ADHD exhibit and extreme
variation in their ability to focus such that if there's something they really, really
like doing. They can indeed Focus, however, for many, many other activities that are required in order to develop, I guess we'll just call it normal life advancement. So sitting still listening to conversations that we may or may not be.
Particularly interested in, that's where the challenge has come about. So, the point is that these brain networks and these neuromodulators like dopamine and norepinephrine that we've been talking about in Fairly straightforward terms as it relates to a drugs ability to crease their transmission and therefore an improved ability of focus presumes to things that presumes that the dosing is, right. That is that the levels of increases in these neuromodulators is just right. And I also just want to acknowledge that ADHD is first of all, not an inability to focus at all.
All it is immense challenges in focusing on lots of different things as required for normal life progression.
And it's also the case that there is no one specific pattern of ADHD that applies to everyone with ADHD some people both kids and adults will exhibit the hyperactivity but not the impulsivity. All those two things tend to go hand in hand some people will have a challenge in focus without hyperactivity impulsivity and so forth and all this just really speaks to the complexity of ADH.
She and yet, and yet we can confidently say that there are more drugs to treat ADHD than any other psychiatric condition. We talked about a few of those now, but among those Adderall Vyvanse, Ritalin also called methylphenidate, there are time release versions. There are different variations on those time, release versions, there's even straight dexedrine, which is prescribed for ADHD in some cases and on and on and you might also find it interesting to know that that very large.
Kit of drugs all of which least the ones we talked about so far, sympathia mathematics or stimulants
are more effective at
treating ADHD. Then are any other collection of drugs for treating other psychiatric
disorders. So what all of that diversity of
symptomology and ADHD, as well as differences in sensitivity to drugs and individual variation. What all of that speaks to is that the large kit of drugs that's out, there is designed to be assessed with the careful.
Assault of a very qualified psychiatrist in order to allow the child or adult to arrive at the specific drug and the specific dosage that's ideal for their particular pattern of ADHD and that issue actually gives rise to the answer to that. Now, somewhat age-old question as to why giving stimulants to a kid that is hyperactive would calm them down and the answer is that the hyperactivity impulsivity and focus issues present in ADHD in children and adults.
Are the consequence not necessarily of deficient
activity of neural circuits in the prefrontal cortex or deficient activity of the default mode Network, or
deficient activity of the
salience network Etc.
What appears to be the case, based on a lot of high-quality neuroimaging data? Is that the brains of children and adults with ADHD have all of
these networks functioning?
But those networks are actually hyper-connected
that is
They tend to be coactive at times when
ordinarily
meaning in kids and adults without ADHD, they would not be coactive.
So that's an important point because it's easy to get the impression that ADHD is
just a deficiency in dopamine and norepinephrine and that's simply not the case. If you
recall, dopamine and norepinephrine are neuromodulators. They modulate the activity
of other neural circuits and they can
both increase and
decrease activity within those circuits.
So you
Don't necessarily want to think about dopamine and norepinephrine just as molecules that
increased neural activity. And you certainly don't want to think about ADHD is just a deficiency in dopamine or deficiency in norepinephrine.
The way these drugs work when they are used effectively to treat ADHD is to tune the amount
of dopamine and norepinephrine that are present in
particular. Brain networks in order to allow the person to arrive at just the right
balance between the activation of these different neural
circuits, causing them largely
to be
less synchronous in their firing.
So this takes us back to this question of why giving stimulants to a kid would calm them down. It's not so much that you're giving a stimulant to a kid to place them into a state of calm. I think that's a common misconception rather by increasing dopamine and norepinephrine these drugs. Yes, increased
levels of overall autonomic arousal. They are after all sympathize memetics, but
more importantly to the treatment of ADHD symptoms
Are activating the prefrontal cortex in a way that allows it to be more of a coordinator of that Orchestra conductor. Or if you
prefer the analogy to a teacher in the classroom to ramp
up the activity of certain neural circuits in a given moment
and quiet down the activity of other neural circuits, such that the default mode Network can still performance incredible actions. After all, the default mode network is involved, not just in
self-referencing, and kind of daydreaming, but also
creativity and Imagination. That's been well, described in the literature
ER,
as well as the salience network in these other networks that are designed to drop
us into very narrow. Trenches of attention. These
drugs for the treatment of ADHD are indeed stimulants. But the goal of prescribing, these drugs to a
child or adult with ADHD is to adjust dosage
timing and the duration over, which somebody takes it in their life span, in order to allow those neural circuits to work in the proper way, meaning for the conductor to activate the
It's in that little symphony or band in the appropriate order in order to
arrive at the right music as opposed to all the instruments playing at once. Which would just be complete noise or if again if you prefer the classroom teaching analogy for the teacher to call on one student while the others are quiet and then, to call on a different student. Have one soon returned to their seats to have the students work in small groups. Again all of this by analogy, the point being that dopamine and norepinephrine are all allowing these networks to be activated to the precisely correct.
Levels and in the precisely correct sequence. Now, the other key aspect of drugs like Adderall Vyvanse, Ritalin, and similar to treat, ADHD has everything to do with these neuromodulators dopamine and norepinephrine but it has to do with their other incredible feature. Besides just their ability to reduce noise and increased signal Within These brain networks. And that incredibly important feature is what we call neuro plasticity or the brain and nervous systems ability to
Change in response to experience.
I've done entire episodes of the huberman loud podcast on neuroplasticity, what it is and how to access it at different stages
of development. And in adulthood, by the way, you can find those episodes of huberman Lab.com by simply searching plasticity in the search function. But the important thing to understand about plasticity in the context of today's discussion is that while there are many different ways to induce neuroplasticity almost all of them almost
Not all of them involve strongly activating certain brain networks. And in that case also strong or elevated release of certain neuromodulators,
Now we've talked about dopamine and norepinephrine they are but two of many neuromodulators others include serotonin, acetylcholine. And each of the neuromodulators does different things at different synapses in the brain and there's some Global statements that can be made about each of them. We made some of those earlier. Like dopamine is broadly involved in motivation, craving and pursuit, and norepinephrine, and Signal detection and drawing of focus or salience to something in our environment, or in our body, or inner experience.
Serotonin does other things acetylcholine does other things.
But what's really important to understand is that any time there is a dramatic elevation in, dopamine and norepinephrine relative to Baseline relative to what was happening with dopamine and norepinephrine. Just prior to that that has a tendency to promote neuroplasticity at particular synapses. So here is where it's appropriate to remind everybody that
Laters are different than neurotransmitters. Neurotransmitters are chemicals that just like dopamine and norepinephrine or released between neurons. And they are what actually contribute to the electrical signals going up or down between different neurons. And again, dopamine and norepinephrine modulate that activity causing a given amount of neurotransmitter to have an even greater effect for instance. So when we hear about dopamine and norepinephrine and we hear about motivation or focus at cetera, that's all fine, and good.
But it's also important to remember that when dopamine and norepinephrine are increased, there is a higher probability of strengthening
connections where dopamine and norepinephrine are increased. And what that means is that later, even if levels of dopamine and norepinephrine are not increased, if they go back to Baseline, it's often the case that if in our prior history or the history of a given set of neurons in our brain, there was more dopamine or norepinephrine.
Around. It's very likely that the connections where that took place are strengthened and therefore more easily activated and this takes us back to the really original purpose of prescribing. These some pasta mimetic stimulants to children with ADHD during development. It was yes designed to try and help them Focus to reduce their hyperactivity and help them Focus. But it was also designed to help the brain networks that are responsible for Focus to undergo neuroplasticity.
That is for the
synapses involved to strengthen, so that those networks could function more efficiently later on even after cessation of the drug. This is an absolutely crucial point that I think is not often discussed when people, for instance, a should I put my kid on
ADHD meds
or should I take my kid off of
ADHD meds as they transition from adolescence to their later teen years and into college? I mean after all no child or parent or adult for that,
Mater wants to achieve a bunch of benefits with
a drug and then lose those benefits. Later, nor does any parent or child
want to take a drug that they don't need to take when they could access other
routes to improving the neural circuitry or the function of some health system in the body. Because I don't think anyone really wants to medicate their kids, unless they have to, I would hope not.
And I don't think any kid wants to be medicated unless they absolutely need to be medicated. So, increasing, dopamine and norepinephrine with these
Like Adderall
Vyvanse, Ritalin, and similar is causing several things. And some of those things, actually, provide some general answers as to whether or not parents should put their
kids on these compounds in the first place. Obviously, they're going to do that in the under the careful consult of a qualified psychiatrist. I would hope and only under those circumstances but also whether or not the child should stay on those drugs over time and here's what we do know for sure. I did a vast
Just search within the literature in order to arrive at what is very clear, which is that children with ADHD, true ADHD, who are diagnosed with ADHD and are treated with appropriate doses of drugs like Adderall ritalin or Vyvanse.
Fair far better both in childhood and later in life when it comes to Performance in school performance in terms of focusing on anything and in terms of General outcomes. So for instance a lot of people have wondered and worried about whether or not treatment with these drugs early in life will set up a predisposition for illicit drug abuse or craving an addictive potential later. And it is very clear from the studies that have emerged over the last really fit
Teen years but
mainly within the last five
years. So that's when most of the data. I've arrived that
children with ADHD who are
not treated correctly, both with drugs and behavioral treatments because really the combination of drugs and behavioral treatments is the optimal situation.
So kids with ADHD who are not treated with drugs and behavioral treatments to deal with their ADHD. Have a much higher tendency towards illicit.
Drug use and addictive drug potential in their adulthood. Okay, so there is a real danger to not treating ADHD during childhood. And the reverse is also true, which is that children with ADHD, who take prescription drugs that are sympathy memetics. So yes, as you've heard, they are speed. Amphetamine is speed. Although I should say, if they take, methylphenidate, ritalin or Concerta or something of that sort. That's not amphetamine, nonetheless. It's a stimulant, it's a sympathy.
Medic. Also,
these are kids that are taking these drugs during development and therefore levels of dopamine,
levels of norepinephrine are being increased in their brain and body. And you might say, well, wouldn't that
lead to a craving for these things later in
life and that does not appear to be the case. In fact, there's some
very nice, neuroimaging studies, mainly positron, emission tomography, studies that I'll provide a link to in the show notes captions that showed the early treatment with these drugs, actually leads to combinations of increased.
Dopamine Transmission in the forebrain later in life at a lower level or a lower threshold. I should say, in a way that essentially says there's normalization of the circuits Across Time by the application of these drugs early in life. Again, in the case of children that have diagnosed ADHD I in no way shape or form, want to imply, that all children should be treated with these drugs, that is quite clearly. Not going to be a good idea. So all of this really speaks to the critical importance of
Getting an accurate diagnosis of ADHD
diagnostic criteria, include many things in children, their multiple
there. More than nine diagnostic criteria for each of the
categories relating to impulsivity hyperactivity and so on. So a well, qualified
psychiatrist will do several things, they will. First of all, do a careful diagnostic evaluation of a child. And in addition, one would hope that they would think about prescribing, both appropriate, pharmacologic treatments for Ada.
HD but also be aware of, and prescribe the various other types of prescriptions, meaning behavioral prescriptions. So there are clearly certain learning tools and things that kids can do in order to improve their ability to focus. And to be less impulsive that combine especially well with drug treatments as well as new advancements in the realm of nutrition and supplementation that are constantly coming online and the best psychiatrists are going to be tuned into all of those aspects of treatment for ADHD. Not
Prescription drugs but also behavioral treatments also nutritional guidelines also supplementation and also updating each and all of those things as a child matures from each stage of development to the next. I'd
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Now, the other common question is, if a child has been treated with these ADHD meds during development, do they need to
continue?
You on those drugs indefinitely
and the short answer to this is it
depends and that can be a somewhat frustrating answer, I
realize. But the good news is it's something that can be assessed in a fairly straightforward way. Let's recall that the use of these drugs to treat ADHD is designed to
accomplish two things. It's designed to improve the function of those neural circuits that allow a child to focus and it's also designed to increase.
Reese, the strength of those circuits to effectively, teach the circuits, how to learn what focus is. In other words, these drugs are designed in some cases to be used. And then withdrawn later because the circuits that they helped build up our functioning. Well,
In some cases, however, the circuits that underlie Focus are not going to be able to function
at the level required for normal healthy life progression unless there's continued application of the drug. So how would this work in the real world context? Well, I think any child or adolescent or person younger than 25 that's taken these drugs has no doubt achieve some level of neuroplasticity of the neural circuits related to all the things we call Focus.
And I want to be very clear. There is no single brain area or set of brain circuits for what I'm referring to as Focus because after all focus is most task-switching Focus involves all sorts of different cognitive operations depending on what we're focusing on. The focusing on a sport is basically a practice of directing one's attention in different locations at different moments, focusing on studying is an entirely different pattern of focus all together. But the point being if a
In 25 years or younger takes a drug that increases dopamine and norepinephrine and assuming that things are working. Meaning
the dose is right there achieving better ability to focus etcetera.
Those circuits are going to get stronger and it seems entirely reasonable. In
fact, it was supported by
the psychiatrist
that I spoke to you prior to this episode
that people have been on ADHD meds for any point of time, prior to 25 talk to their psychiatrist about what tapering off.
Off those drugs in order to examine whether or not they still need those drugs would look like. Now I mentioned the word taper because there is a withdrawal potential of Simply stopping these drugs very quickly because they do ramp up dopamine and norepinephrine. Even though they increase plasticity of the neural circuits for focus and mood and motivation. If one very abruptly cease is taking any of these drugs, it does not feel good that drop in dopamine.
One inevitably experiences is
almost always associated with lethargy, with depressed mood, with
feeling not good, in a number of ways and of course, challenges in Focus.
So anytime one is going to go off one of these drugs are sample,
what it is to even reduce dosage that has to be done in close communication with a board-certified psychiatrist.
At the same time, it was made very clear to me
from ADHD expert psychiatrists
that reductions in dosage
over time often.
Are optimal for a
patient.
Okay? And this gets to the whole
issue of dosage. Generally, you know I
spend a good amount of time talking to somebody who prescribes these drugs both to children and adults about dosage ranges. And I don't want to spend too much time on this from the perspective of how much one
should take. In fact, I don't want
anyone to think that what I'm about to say
should dictate what they should take specifically. Because that's something that really has to be worked out on an individual
basis, but it is worth noting that you look at the
studies
on Adderall and Methylphenidate.
You'll see is a pretty broad range in those studies. And that's because some of the studies used people that were already taking these drugs and ask them to participate in neuroimaging
studies, other studies actually put people on these
drugs for the very first time or adjusted their dosage. And so you'll see a tremendous range of drug doses. Explored for instance, you will see
anywhere from 10 to 40 mg of Adderall per day.
You'll see anywhere
From
10 to 60
milligrams of Ritalin per day. And here we could easily be talking about studies on children or adults
with respect to
Vyvanse. You'll see that the dosages tend to be
much higher in part that's because Vyvanse
has fewer called. It's that lysine which is a big molecule
stuck on, DM, feta mean, which is a smaller
molecule. And so the dosages of events tend to be in the
hundreds of mg
ranges, but
most of that hundred
milligrams of Vyvanse is not going to be the
Feta mean it's going to be the lysine, which doesn't do anything in the context of treating the brain, it's just there to control the slow release. So it's thought that 100 mg of
Vyvanse translates to roughly 9 milligrams of Adderall and on and on and actually it's pretty hard to translate between dosages of different drugs in any direct way. And in speaking with a psychiatrist expert in ADHD in preparation for this episode, he made very clear that it is extremely extremely difficult to predict how a child or adult will.
Back to a given dosage of any of these drugs so much. So in fact that he anecdotally reported to me that one of his patients is a male 300 pounds, diagnosed with ADHD and who achieves tremendous relief from just two point five milligrams of Adderall per day.
And at the same time, he has to patients both of whom are sisters. So they're genetically related who are in the 120 240. Pound range who did not respond well at all for the treatment of their ADHD until their dosages were very, very high. And if I tell you these dosages, I just want to warn you in advance. I am not suggesting anyone explore these dosages. Without, of course, the approval of their psychiatrist, turns out that neither of these, two young women were
Bonded at all to ADHD medication until they achieve dosages in the range of
180, in the case of one, sister and
240 milligrams, in the case of the other sister per day which is an
astronomically high dose on the face of it. But this physician again board certified physician expert in Ada. She verified for me that indeed neither of them experience any discomfort or side effects that led them to not want to take the drug but of course that amount of Adderall.
All could send somebody else into an absolute psychotic fit could potentially even cause cardiac arrest. I mean it's remarkable the ranges of Adderall that are used effectively in children and adults and this is true for a lot of the other. Sympathy mimetics used to treat ADHD and of course a good psychiatrist will always assess dosage as it relates to positive benefits, you know, relief of symptoms. So relieved of impulsivity relief of hyperactivity
Ability to focus, and of course, they are going to consider side effects. Any uncomfortable, adverse effects that come from taking the drug at a given dosage or taking the drug at all. Now, of course, this all begs the question of why such tremendous variation is this due to genetic differences in the amount of dopamine norepinephrine that people make it appears that the major underlying factor for why people require such a vastly different dosages of these. Sympathy memetics for the relief of ADHD.
Has to do with the different enzymes or levels of enzymes that people make, which metabolize these drugs, both in the brain and body. And unfortunately, there is no simple, blood, test or saliva, test, or test of any kind that can predict how someone will respond to these drugs. So, the most logical and safe way to assess dosage is to start with the lowest possible effective dose and to increase only as necessary in order to achieve the positive benefits while of course, paying attention to any side.
That might arise a
question that comes up from time to time when discussing the long-term effects of drugs like Adderall
Ritalin and
Vyvanse is whether or not they can negatively impact height or growth or development in some other way. This is a logical question to ask because after all these drugs are effectively mimicking stress in the body and most everyone is heard by. Now, that while stress can help us in the short term, it helps us deploy immune molecules to protect us against.
Action. It sharpens. Our visual focus in our ability to respond to things for survival. Chronically, elevating our stress over long periods of time. We know, reduces the effectiveness of our immune system and can actually, cause certain forms of brain degeneration. And while there aren't a lot of longitudinal studies on the heights of kids with ADHD. And of course, we never can tell how tall someone would have grown to be if they were treated with a drug because we don't have a perfect control experiment.
Even in the case of identical twin experiments and they're in there aren't that many of those examples where one twin was treated for ADHD in the other wasn't etcetera
but here's what we know. It does not appear that treatment with
sympathy. Mimetics during development provided the dosages are kept in the appropriate, ranges is going to limit overall height. In fact, if you look at the data, it appears that children with ADHD who are treated with ADHD meds actually arrive at sea
Slightly higher BMI is body mass indexes compared to age-matched peers. Now, of course, body mass index doesn't necessarily correlate with height, right? Someone could not achieve a full height, but could be heavier either through bone or fat, or muscle or combination of all three. But what we know is that the appropriate use of ADHD meds during development is not stunting development in any kind of overall way. It's not preventing maturation of the body in ways that are leading to reduced.
Just wait or somehow impaired growth
overall, with that said, long-term elevations of sympathetic nervous system activity does carry some risk. And one of the primary risks that people have wondered about is cardiovascular risk and it makes perfect sense, right? When you increase the activity of the sympathetic nervous
system, you increase, blood pressure, you increase heart rate, you increase in some
cases peripheral sweating, you know, all the things that we
associate with stress. So you can imagine that a child or adult with ADHD, that takes these
He's sympathy memetics everyday, even if the dosage is kept in a Range that doesn't allow them to experience any immediate untoward side effects. So they're not feeling miserable, they're just feeling like they can focus
better but one
always wonders what's going on under the hood, so to speak.
There is as far as I know. One major study that's addressed this and the conclusions of that study were a little bit hard to put into a single category. It did point to a subtle
In cardiovascular risk.
But the results did not point to anything. So dramatic that the authors of the study warned against taking these drugs or encouraging
people to cease taking these drugs. Again, provided they're being prescribed by a board certified physician for ADHD and at the appropriate dosage for that person
that said, I think this all again, speaks to the
importance of arriving at minimal effective dosage and it stands to reason that if you're somebody who's taking ADHD,
Meds or if your child is taking ADHD meds, that
one would want to do all the other things that they could
do, in order to try and improve cardiovascular health or at least not put it at additional risk. So those are going to be the obvious things like avoiding smoking or vaping nicotine. Regular exercise is going to be encouraged and things of that sort and that
dovetails into a bunch of other
questions that are often asked any time, the topic
of Adderall or Ritalin comes up, which is what about
Alcohol. You know, he's drinking alcohol at the same time or at different times even going to be problematic. If one is taking these drugs, is taking benzodiazepines going to be a problem. Etc, etc.
There's a very straightforward answer to this which is it's very clear that alcohol certainly in children but also in adults is best not consumed. I didn't Tire episode about alcohol which got into this and the data for this if you've heard that having
Some alcohol and particular red wine is better for you than no alcohol. That is simply not true. Sorry, it's not true. Most adults who are not alcoholics can probably have up to two. That's right. Two drinks per week, and still be on the safe side of Health. Although 0 is better than two, and once you get passed to you start seeing effects on various systems, including increased cancer risk, especially brain neuron loss and degeneration risk. I covered all of those data in the episode on alcohol that you can find at hubermann
Dot-com
combining alcohol with sympathy memetics even though they reside in very different Pathways within the brain. In
fact, the same path of my Medics are
driving up sympathetic nervous system activity. Whereas alcohol is actually doing the opposite, it's depressing it. And yet
all the data points of the fact that combining alcohol with sympathy memetics such as Vyvanse, Adderall Ritalin, it or any kind of amphetamine, is going to be more detrimental to the brain and body.
Body than simply taking those drugs on their own
put differently and more directly. If you are taking any of the drugs that we've been talking about to treat ADHD, or if you just happen to be taking them, for whatever reason, you are going to want to avoid
drinking alcohol at any time. And you're
going to want to avoid benzodiazepines and similar. Unless they've been prescribed to you by your physician, in advance of this episode, I put a call out on social media for questions about Adderall Etc. And
Got a lot of questions about whether or not their impacts of these drugs on the hormone
systems of the body. And if they impact the reproductive system in particular, I also got questions about whether or not these drugs impact,
sexual behavior, or
libido, or anything of that sort
in reviewing, the literature. What I can tell you is that there are
very few studies, unfortunately of the long-term effects of these drugs on the endocrine or hormone systems of the body.
But we do know a few things for sure.
Sure, first of all, when you increase the activity of the
sympathetic nervous system for long periods of time,
you are very likely increasing levels of cortisol. Cortisol is a quote-unquote stress hormone, but cortisol also plays some really
important positive roles in your body. In fact, you
want cortisol released, especially early in the day, you don't want cortisol release so much late in the day. This actually relates back to timing and schedules of taking drugs. This is something again that needs to be worked out with your psychiatrist or your child psychiatrist.
But one of the reasons why there are so many different drugs,
for the treatment of ADHD is that each? And all of them has a different time course of action. So Ritalin is very short-lived, which might sound bad because then you have to take it multiple times throughout the day, but if you think about it from the perspective of
sleep and the importance of having low
cortisol at night and these drugs, increased cortisol, and the importance of getting sleep. Because after all sleep is the foundation of mental health, physical health, and performance in kids and adults. It's responsible for growth. It's when neuroplasticity happens, it's just so vibrant.
Vitally
important. A lot of the drugs that we've been talking about, can severely limit one's ability to fall, and stay asleep. And so a short acting drug. Like Ritalin is actually attractive from the perspective of being able to take it in the morning and still get to sleep at night or taking it in the morning and in the afternoon and maybe even again in the evening, depending on the person
and then still being able to fall asleep at
night whereas long-duration. Release of DM, feta mean, which is
what you get when you take Vyvanse for some people is
To inhibit their sleep, they'll get a nice steady
rise and Improvement in focus and reduction and
hyperactivity, but they might have a lot of trouble falling asleep at night
and Adderall having a somewhat intermediate time course of action between ritalin which is short-lived and Vyvanse, which is very long-lived.
Perhaps is going to be the best solution for somebody else where they can take it early in the day. Perhaps a low dose may be again later in the day, low dose, and then still fall asleep at night, but I've spoken to people and I spoke to this clinician.
It in
ADHD, who told me that some people will take as little as two point five milligrams of Adderall at 6 a.m. and have a hard time falling
asleep later that night at 11 p.m. So, again, vastly different sensitivities to these drugs, leading to vastly different requirements of dosage and timing of intake, and which particular drug somebody might choose to or choose not to take. So how does that relate to hormones and sex and reproduction? Well, cortisol itself is a whore.
It can act as a bit of a hormone and a neurotransmitter in the brain, but for the most part, it's acting as a hormone in the brain and body and it does a number of things. First of all, it can enhance your levels of focus and alertness. It can activate your immune system. I know the immunologist out there, just cringe. When I say activate the immune system, your immune system is always doing various things. So it's always active just as your nervous system is always active, but it can to be specific, it can
Amplify or mobilize, the release of anti inflammatory molecules in your brain and body to combat different types of bacterial viral. And fungal infections is doing an enormous number of positive things. It's also involved in setting mood has interactions with thyroid hormone Pathways. I've done entire episodes about cortisol and cortisol regulation,
To paint all of that with a very broad brush and briefly. Now it's advantageous to have your cortisol release high in the early part of the day and to taper off toward the end of the day. In fact, late-day, elevations and cortisol are a strong correlate of depressive symptoms. This was demonstrated by my colleagues David Spiegel and Robert sapolsky at Stanford school of medicine, but that is not to say that cortisol is bad. It's to say that the timing of cortisol release is key. So do these sympathize with
Drugs disrupt the endocrine system. Well, they can if you are very awake and very alert regardless of whether or
not, you're taking your sympathomimetic treatment for ADHD early in the day or late in the day, you are very likely experiencing elevations and cortisol late in the day, so it is important. Even for those of you that like to study and need to focus in the evening and nighttime hours that you try and limit your levels of overall alertness and certainly stress late in the day because doing that day after day after day.
For several weeks or months or years can indeed disrupt other hormones in the endocrine system. And again, that's because cortisol is interacting with thyroid hormone and testosterone and estrogen. In fact, cortisol in many ways competes with, or can out-compete for the production of testosterone and other so-called steroid hormones. Remember, cortisol itself is a corticosteroid hormone. So when we hear the word steroids often times, people just think about athletes and steroid, abuse in sports, but steroid,
aah moans includes a lot of different types of hormones which are good for us. Are endogenous steroid, hormones are vital for all sorts of things Vitality, reproduction etcetera. And the way this works in general terms is that the cholesterol molecule is used to create testosterone and cortisol and estrogen. If we make too much cortisol, we in many ways are reducing the total amount of testosterone that we make or that is active, it's not
Exactly that straightforward. But
we can make that statement with, with confidence. For instance, if you spike your cortisol, just briefly during the day because you have some sort of stressful event, that's not going to inhibit your testosterone. In fact, it probably is going to boost your testosterone level somewhat. However, if your cortisol levels are chronically elevated. Yes, indeed. It's likely that you're going to suppress your total and or free Unbound forms of testosterone and downstream to that, you will experience effects such as
Reductions and libido reductions in muscle and bone mass reductions in all sorts of aspects of testosterone, related, psychology and bodily biology. This is true for both males and females and the same thing could be said for estrogen. Now, what's impossible for us to say is whether or not taking a given treatment for ADHD is going to, for instance, prevent a woman from ovulating that could happen through, chronic elevations and cortisol. But there's no direct link. Meaning there are no studies at least that I'm aware of showing that
Will that take Adderall have irregular ovulatory Cycles? Where that they cease menstruating entirely? I don't think there's any evidence for that
whatsoever. Nor is there any evidence that people that take Adderall or other Sympathy memetics for the treatment of ADHD have lower overall testosterone? In fact, you can imagine all sorts of instances in which the opposite was true. That a child or young adult or adult who has ADHD, but then goes on these meds to improve their symptoms is now focusing and achieving more in life. We know that happiness
This can impact dopamine and vice versa and testosterone levels and productivity itself and reaching our goals can feed back on the hormone system. So anytime there's a discussion about hormones or a study that shows that doing Acts or not doing why impacts hormone levels of a given type, we have to be very careful to make sure that we're talking about causality because all of these hormones are in a very intricate cross talk with one another. We can however make a very general statement, which is that when you are in state,
Stress for long periods of time, that is not a favorable condition for your immune
system. Your hormone system
or frankly, any other system in the brain and body. So the treatment of ADHD with these drugs should never be done at the expense of these other critical biological systems. Another common question, and concern is whether or not kids. And I suppose for that matter, adults that take medication for ADHD are basically being predisposed to psychosis and or other forms.
Of addiction. And earlier we talked a bit about the risk for addiction and the take-home message there is very clear that kids and adults that are treated for ADHD appropriately. So with the appropriate dosage of the appropriate drugs, under the supervision of a board-certified qualified psychiatrist are at less risk for forming addictions to other substances in adulthood or other substances generally. I think a lot of people also wonder whether or not those kids and those
Adults that take the easy ADHD, meds become addicted to the medications themselves. That's a
bit of a tricky issue to resolve any time, one stops, taking a drug or even tapers off a
drug. That's used to treat something where they feel better on the drug.
They are going to experience. Two sets of effects in these two sets of effects are often confounded with one, another one is the withdrawal effects. So the effects of removing the drug, that makes somebody feel less good than Baseline. So for
Since a kid that takes ADHD meds until their late teens or early 20s decides, they're going to taper off, they do that and they're feeling lousy during the taper or when they reduce their dosage, 20 their foggy brain. They can't focus that you feel a little bit depressed. Mood it's unclear whether or not those are withdrawal symptoms, or whether or not. Those are the consequence of not having the systems in their brain activated, the way that those systems were activated before I
For some of you that might seem like the same thing, but that's not necessarily the same
thing. And probably the best analogy would be something along the lines
of a hangover, right? If somebody drinks too much on a given night, the next morning, they have a hangover, The Hangover makes them feel lousy. It's or it is actually a
withdrawal from alcohol
affect, but then when they recover from The Hangover, they realize that they're sober State feels pretty good. It doesn't obviously feel the same as being on alcohol, but that's sober state is not a state of
Draal. Okay, if we were to look at removal or tapering off of ADHD meds, there's going to be a period of withdrawal symptoms. But then the real question is, how does somebody feel after they get through those withdrawal symptoms. So, that's an important issue to highlight. Now, in terms of psychosis, this is a very interesting and very important literature. First of all, any amphetamine whether or not, it's DM, feta mean, LM feta mean, and also methylphenidate for that matter. Ritalin can induce psychosis. Now, there are a number of
Factors that are going to predispose somebody to
psychosis having a first relative who's had psychotic episodes either schizophrenic episodes or bipolar episodes is certainly a strong predisposition. Of
course, if an individual themselves have had psychotic episodes that's the
strongest to predisposition that one could imagine.
So having a first relative with schizophrenia or bipolar depression or
it's sometimes called bipolar disorder, sometimes it's also just called
bipolar these days
Is going to be a strong predisposition for psychotic
episodes. Made much
greater anytime. One takes a sympathic mimetic drug such as
amphetamine but also methylphenidate Ritalin is going to increase that likelihood of psychotic episodes.
Then comes the question of if somebody has a psychotic episode as the consequence of taking any of
these drugs whether or not it's been
prescribed for ADHD or not, will those psychotic symptoms go away after the person stops
King the drug there appears to be a divide in the literature or rather a divided. According to drug
such that people that take Ritalin methylphenidate and have a psychotic episode often, not always. But most often if they stop taking methylphenidate, The Psychotic episode will cease not always the case, but most often times, it will cease. Whereas in individuals who have a predisposition to psychosis or even if they're not aware of a predisposition of psychosis and they take Adderall
Roll which as you recall is a combination of D and L amphetamine they can have psychotic episodes that sometimes are very long lasting even after the cessation of the drug. And while that might sound kind of shocking and really scary and indeed it is scary. It perhaps shouldn't shock us that much because if you recall DM feta mean which there's a lot of in Adderall it's a very potent way of increasing dopamine and anytime you potently increase dopamine in a
Person who has a predisposition to psychotic episodes.
You are shifting the whole system toward greater propensity for
psychosis. This would also be the appropriate time to
talk about meth methamphetamine.
Again, methamphetamine is considered an illicit drug, a drug of abuse. It is
responsible for a lot of The Misfortune and tragedy that you see on the streets of major cities and even outside of major cities and rural areas, it has all sorts of negative effects on
Health, including oral health cardiovascular health. It is
neurotoxic to serotonergic neurons. So it kills serotonin neurons. That is absolutely clear. It kills dopaminergic neurons. That is absolutely clear. One of the ways that methamphetamine creates so many of the problems that it
does inning effects on the
body abuse potential, addictive
potential. The fact that methamphetamine can
spark psychosis in those that have a predisposition to psychosis but also that it can create
Kostas in individuals who have no predisposition to psychosis and all of this points to methamphetamine, just being a terrible drug all around. And yet, if you recall back to the beginning of the episode, there is one form of prescription methamphetamine, but its uses are extremely narrow, and it's probably best left out of this conversation because it's used as are. So, so narrow in the clinical sense, I managed to talk to One expert. This is a board-certified psychiatrist, who is expert in ADHD, who is also very familiar.
With the psychosis symptoms induced by methamphetamine and by various ADHD drugs and people who have the predisposition. They made it very clear that any of the sympathia mimetic ADHD drugs that are of the amphetamines in variety so that would be Adderall and extended-release Adderall. OB Pure dexedrine or any variance that include amphetamine are going to have higher likelihood of inducing psychosis and people that have a
Predisposition to psychosis and yet, they did
assure me that at appropriately
prescribed and safe dosages that the total incidence of psychosis in people that take those drugs is still fairly low and not that much greater than in the general population. Although there is an increased risk, it's not that severe. And they also highlighted, the fact that methylphenidate, Ritalin carries a lower potential for inducing psychosis, not zero, but a lower level of inducing.
Psychosis then for the, in feta mean type sympathomimetic. So now one exception is a
Vyvanse that long release DM, feta. Mean that we talked about
earlier, there does seem to be something protective about that long duration. Release of DM feta mean that occurs with Vyvanse, which is not to say that there's zero abuse or addictive potential with Vyvanse. I was
told by this same individual that indeed, they've had knowledge of patients, trying to increase the rate of
absorption of Vyvanse
Release a Vyvanse or technically of the DM feta mean in order to get more of a high from Vyvanse as opposed
to just the extended-release but they did assure me. However,
that Vyvanse seems to be associated with fewer psychotic
episodes and less abuse and addictive potential overall, which again is not to say that it's a perfectly safe drug but
really this just highlights the fact that the kinetics or the time course of dopamine and norepinephrine
released that's caused by a given drug is going to
correlate very
strongly with its abuse potential and addictive potential.
And its potential to induce psychotic episodes. And this is where the discussion about meth becomes especially relevant. One of the reasons why meth is so dangerous in terms of its addictive potential and its potential to induce a psychotic episodes is,
first of all, how
much dopamine it releases again, five times more than any of the other drugs that we've been talking about, but also
how fast
that Peak comes on. It's a very fast on set, and that's true, whether or not people are
snorting it without they're taking it orally or
especially if they inject it intravenously. But,
Meth because it increases dopamine so
fast in to such a great degree. And then the, the
peak and dopamine comes down very
fast as well, and it drops below the Baseline levels of dopamine that were present initially. That's one of the reasons why methamphetamine is so dangerous in terms of addiction. And in terms of psychotic episodes, this gets back to a bunch of issues. We've talked about before on the huberman Lab podcast about dopamine kinetics. And I've done two episodes on dopamine that I'll refer you to one is called dopamine motivation and drive which is
All about dopamine and regulating dopamine. And the other one is about optimizing dopamine. It's more of a toolkit focused episode. Both of those, you can find a huberman lab.com but the general takeaway that's relevant for what we're talking about now is that with dopamine, it's not just about the absolute levels of dopamine that a reach. But how long lasting those increases in? Dopamine are so with Vyvanse, even though Vyvanse is DM feta mean it's fairly potent. Not as potent as meth but fairly potent at increasing dopamine,
The norepinephrine,
it's a long
extended release in dopamine and norepinephrine,
which reduces its
overall abuse potential because it doesn't tend to create that immediate Euphoria and high and then crash below Baseline. A lot of you will hear that it increases dopamine a lot and then stays up as translating to okay, well, then you're just euphoric for 16 hours but that's not the case. When it comes to dopamine, it's an issue of How High that Peak is and whether or not that Peak is stable.
Or we're not comes down again and when it comes to psychotic episodes or addictive potential, it seems that any drug or behavior the increases dopamine very quickly. And then brings dopamine down very quickly is what sets the high potential for addiction and abuse and for inducing psychotic episode. So, that's why I'm talking about these two things in parallel. And now, it should be very clear, why Vyvanse doesn't have so much addictive and abuse potential and has at least lower potential for it.
sings psychotic episodes and it should also be clear to you that for people who do not have ADHD as a child or for people that do not have ADHD in adulthood if they were to take any truly, any of the compounds that were talking about thus, far, methylphenidate, Ritalin Adderall, Vyvanse, dexedrine and certainly methamphetamine, what we observe from neuroimaging studies is that these people get enormous
Creases in dopamine, they're not familiar with these drugs. So that increases in dopamine are just Cosmic for them. They experience a lot of euphoria. Even if the dosage is Arlo the Euphoria is associated with it, very heightened degree of focus. They've never really felt before here, what I'm talking about is a lot of the recreational and off prescription use of Adderall and things like it. And what we know is that that sets in motion, both a potential for abuse and addiction to that feeling.
Substance, as well as a higher
potential for psychotic episodes down the road. Okay, so put differently
children who have ADHD and are prescribed any of these drugs or adults who have ADHD and are prescribed any of these drugs who take them for some period of time are actually at lesser risk to all of the issues related to having chronically elevated and greatly elevated dopamine as of kind of first-time event or as a
Or event, whereas anyone who takes these drugs without a prescription and decides, okay? I want to focus more. I'm going to use this to stay up for a couple of days in other words, using it recreationally, or using it for quote, unquote performance enhancement is that far greater risk for addiction to these substances because of the amplitude, and the time course of dopamine that results when one takes these drugs, just out of the blue. And so for that reason, I really want to caution everybody against.
Seeing any of the compounds that I've discussed thus far, unless it's been prescribed to you by a physician for the specific purpose of ADHD.
Now, I'm sure someone out there is screaming from the back. Wait. If a kid takes these drugs because they're prescribed them for ADHD.
The very first time they take them, they're going to have a
huge amplitude, dopamine
response or if an adult goes in and talks to their
psychiatrist and says, you know, I'm having issues with focusing in their prescribed. One of these meds for ADHD and they
I take it, they're going to
have a huge amplitude, dopamine response. Isn't that going to set in motion? All the same things that somebody who is using these drugs
recreationally would have. And indeed that's one of the reasons why a lot of psychiatrist will start with a very low dosage or the lowest
possible dosage to see how somebody responds to that low dosage. And then over time might or might not increase that dosage. In fact they might even bring it down further, depending on how sensitive somebody is to the drug
but equally important
Is the fact that it is, the repeated taking of that drug by the child
with ADHD, or by the adult with ADHD,
that actually leads to lesser and lesser Peaks and dopamine each time, which is not to say that the person becomes entirely desensitized to the effects of the drug, but rather that the system equilibrates through what's called homeostatic, plasticity. It sometimes referred to broadly as habituation to a drug, but there are systems in the brain and body that regulate the connections between neurons.
So that if dopamine and norepinephrine are elevated above Baseline levels for a while the system normalizes. So that instead the connections between neurons become stronger, and there isn't the critical requirement for all that increase in dopamine and norepinephrine. I realized that might sound a little bit technical, but basically what I'm saying, is the response that somebody has to taking a drug for the first time is far in a way different than the response to a drug that somebody has if they are taking the same drug day.
After day after
day, this gets to another issue which is not discussed that often these days. But that is really important. If you go back to the
original clinical literature on these empathic memetics, what you'll find is that the original use of these. Sympathy memetics to treat childhood ADHD suggested that children not take these drugs every single day. Now I'm not recommending that kids take drug holidays because I'm not a clinician I'm not promoting any specific dose or dosing regimen.
But in speaking again to a psychiatrist expert in ADHD who, by the way, is going to be a guest on this podcast in the not too distant future. What he told me was that many of these drugs were designed to be taken during the school week for children with weekends off, or during the school year with weekends off. But then also with vacations during the summer holidays and that these days rarely if ever is that the pattern of intake that these kids are following and why that is
Interesting, sociological and financial explanations, not alluding to any kind of conspiracy here, but this is an aspect of the dosing with these drugs that is or Fallen away in recent years, but I think is really interesting and it's something that actually was
supported for the treatment of adult ADHD
as well. Again, there is a very different
biological and neuroplastic response to taking a drug once versus taking a drug for say, five days. And
I'm taking weekends off to taking
a drug over and over again every single
day for a pattern of years. And
when exploring the literature in preparation for this episode, I confess it was a bit dizzying to find answers to what are the long-term effects of taking Adderall or what are the long-term effects of taking Vyvanse Etc. In fact, most of the literature on the long-term effects of taking
drugs to treat ADHD
has focus on methylphenidate on Ritalin. There are studies on Vyvanse and adderall and actually those were the studies that
will link in the show notes, captions primarily because that's where most of the interest is these days. The reason why so many of the studies have focused on methylphenidate on Ritalin is largely because that was one of the first drugs
used to treat ADHD. So in terms of addressing long-term
effects of kids, treated with ADHD meds, those kids are now adults
and therefore can be neuro imaged and assess where as a
lot of kids that have been prescribed Adderall or Vyvanse or similar
Have not yet, made it to stages of life in which we can answer that question
directly. There are a few studies and I've made it clear to include those studies in my description of
results today. In particular,
the result I talked about earlier where there's an
improvement in executive function, in kids, that have taken ADHD meds, or
adults that have taken ADHD meds for a longer period of time, anywhere from months to years. Those studies did include
both Adderall and Vyvanse and methylphenidate. And again, I'll link to those studies.
But by and large, most of what we know about the long-term effects of any of these drugs has to do
primarily with studies of
methylphenidate. I'd like to spend a little bit of time, talking about
some compounds that are not considered amphetamines at all, but that are now being used to treat ADHD, both in children and adults more
frequently. The major drug in this category of non and feta mean treatments for
ADHD is modafinil, which is also called by its commercial name. Provigil,
there's
Is a variant on this, which is our modafinil,
which goes by the brand name, new vigil, the major difference between
modafinil and our modafinil aside from having a slight chemical difference, is that modafinil was released first or modafinil is the second in the generation of these drugs and modafinil tends to be very
expensive. That's one of the reasons why it's prohibitive for some people to take, it can be as expensive as twenty-five dollars a pill or more. So more than a thousand dollars per
month and our modafinil tends to
Far far less expensive. I've talked to a couple experts about whether or not there
are any genuine differences between these two drugs and they report, no, although consumers of these drugs for whatever reason, whether or not it's Placebo or not report. Yes, there is a different when I say Placebo, I in no way mean that
these drugs are just acting as Placebo. I just mean that,
you know, people tend to get very attached to
certain drugs and whether or not the brand name or the generic version works better for them there.
Is all sorts of lower
about this. In
fact, there are a lot of people out there who strongly feel that brand name Adderall works better than generic Adderall for
them. There are a lot of people out there who say the same thing about Vyvanse there. A lot of people out there who say the same thing
about Ritalin, and all sorts of drugs, whether or not that's true or not is unclear, it is clear that generic versions of drugs can use, binders and other things that are in the pill or capsule that are different than what the
Name. Pillar capsule uses as binders to hold the drug together and that can
impact rates of release and Metabolism,
Etc, but a lot of this is just Laura. In fact, I went into the literature to try and find any real concrete support for the idea that generic adderall is less potent or less effective than brand-name, Adderall. And despite the tens of thousands of people who will say to the contrary, I could not find any peer-reviewed published data about that. So, who knows? Maybe it's a belief effect as it's called
Umm, maybe there's a real difference there, nowadays and modafinil, and are modafinil, or prescribed for a huge range of daytime, sleepiness issues. We were talking about narcolepsy but there are also people who suffer from daytime sleepiness related to dementia daytime, sleepiness related to post surgery anesthesia. So there's this thing where people have surgery and then they come out of surgery and they feel better for a few days. But then they find that they aren't recovering their normal levels of wakefulness. So,
Describe sometimes to try and get people back into a normal state of
wakefulness. It's been prescribed for a traumatic head injury after stroke again. All of these prescribed uses have to
be carried out by a certified physician. You really don't want to start cowboying, the use of modafinil armodafinil or any other prescription drug for that
matter, must say that in discussing all these different drugs. During today's episode, I have zero knowledge of any of
these drugs from a first-hand experience,
except for our
Modafinil back in 2017. I was prescribed a very, very low dose of our modafinil. For jet lag, for daytime sleepiness issues, really? When I was traveling overseas to give a talk so our modafinil was given to me in a 25 mg tablet. It was advised to me that I take a half or even a quarter of that. So I started with a quarter, I am a believer in minimum effective dose. I'm also somebody who's fairly hypersensitive to most medication so I took
I measured out to be five to seven milligrams of our modafinil and what I experienced was pretty profound. Certainly, it relieved. Any daytime sleepiness, in fact, it made me feel extremely alert for a period of about four to six hours. I can't say it was the most comfortable State, although I did not
feel as if I had racing heart or anything of that sort. I basically felt as if I was in a narrow tunnel of attention for that entire period. One thing I did not like about the experience.
Is that it was a very hard experience to come down from, there was no
crash but I found that that high
arousal State didn't taper off for many hours later even though it was
most heightened for four hours. I would say anywhere from 8 to
12 hours later I still felt like I was you know blinking once every four minutes or so. And I've certainly been accused on this podcast and at other times of blinking too seldom to my knowledge.
I don't have ADHD.
I've never been prescribed ADHD meds. I've never
been tested for ADHD. I don't think I
have ADHD.
And
yet, taking our modafinil, certainly
increased my levels of attention. But at least by that, one experience, it's not something that I would want to repeat again. I certainly would not want to be in that state for learning new material.
When I sit down to research a podcast or research papers in my lab or forage for information or learn
from people or books or lectures or podcasts. I want to be in a state of alertness but calm where I can really consider the ideas where I can script things out by hand. I'm a big believer in writing, things out by hand, to remember them later.
Drawing little diagrams. I would not want to be in the state that even that very low dose of our modafinil. Put me in in order to learn and I should mention that both modafinil, and our modafinil are associated with good number of side effects. If they don't agree with you, or if the dosage is too high, things like decreased appetite, people can get a runny nose headache. There's this instance of skin rashes. In fact, one of the reasons why modafinil, and our modafinil aren't more broadly. Prescribed is that there's a very rare skin.
Condition in which people who have taken certain drugs. Not just mowed a field or are
modafinil have developed these
very severe burn type blisters. And in some cases
this can be fatal. This is again
very rare and it was observed in at least one patient, who
took modafinil as part of a trial for modafinil as a treatment for ADHD, it's called Stevens-Johnson syndrome, please. If you are squeamish to images of skin abrasions and lesions and things of that sort,
Please don't look it up on the internet unless you're able to handle that and maybe not at all. But the point here is that one of the reasons that modafinil and our modafinil are not more widely prescribed for ADHD and that is still only prescribed off-label is that Steven Johnson syndrome was flagged as kind of a potential risk. Although the ADHD specialist that I spoke to are somewhat frustrated with that because they insist that the frequency of this,
Syndrome that causes the skin rash
that sometimes fatal is no more frequent in those that took modafinil in this trial than with other drugs that have been
approved. So this gets into all sorts of issues around what drugs make it to approval and which ones don't. And we do mode often on our modafinil are already being prescribed in the general population for other things, this was dealing specifically with the question of whether or not should be prescribed in kids with ADHD and certainly. I am a proponent of exerting Extreme Caution.
Caution when thinking about which drugs should be approved for the treatment of anybody, but especially kids and to round out our discussion of drugs used for the treatment of ADHD that fall into. Let's call it the atypical category, right? The typical category being Adderall Vyvanse, methylphenidate and things of that variety, the less typical would be modafinil are modafinil proprietor and Wellbutrin and so forth. The last in this category of a typical
Is guanfacine guanfacine is an interesting compound. It's a compound
that was developed to lower blood pressure
and indeed, it does lower blood pressure,
and it is an alpha 2, a Agonist Alpha 2, a being a receptor for norepinephrine. So guanfacine is a non stimulant medication to treat ADHD, and it's also used to treat some other conditions as well. That is only working on the nor adrenergic system. It is not tapping into.
To the dopamine system. But all the other stuff that we talked about is really ramping up, dopamine and norepinephrine. Guanfacine is only increasing norepinephrine and it's doing so by what we say agonizing or stimulating one particular aspect of the nor adrenergic system and that's the alpha to a system. What's interesting about guanfacine is that it has a bunch of Pathways that it activates that feedback on to the autonomic nervous system to dampen down.
Own the activation of the sympathetic nervous system. So whereas most of what we talked about today are sympathy memetics, they tend to make us more ramped up more
aroused and alert guanfacine is doing the opposite. And as a consequence it's not prescribed that
often because a lot of times when people take guanfacine it either has no
effect on ADHD symptoms or
tends to make people feel very sleepy. However there is a small subset of individuals
about 5 to 10% of people that try it, including kids that
That do get some significant relief from their ADHD
symptoms and they seem to tolerate guanfacine better than they're tolerating. Some of the other drugs that we've talked about up. Until now, the way guanfacine works is also really interesting. You're now familiar with the locus coeruleus, this packet, or we call it, a nucleus of neurons in the back of the brain, that release norepinephrine at other sites in the brain and they're going to be those Alpha 2, a receptors that guanfacine works on and stimulates lots of different places in the brain related to increasing sales.
Lance and relevance of particular stimuli that we see and that we need to attend to it appears that guanfacine can activate the prefrontal cortical networks in ways that are above their normal Baseline. So that's
good. So improvements in executive function that Orchestra our teacher like function, we talked about before
and can increase the efficacy of that output from Locus coeruleus and what that seems to do is increase the coordinated firing of locus coeruleus neurons with prefrontal.
Tex. So, in many ways it's acting like a fine tuning
of that, Orchestra conductor operation, that is so valuable in teaching these brain circuits during childhood of how to attend to one thing and ignore everything else. So this is one reason why guanfacine is now approved not just for adults with
ADHD, but is primarily used in kids aged 6 to 17 years old for the treatment of ADHD. Again, with the hope that these kids can take the drug. And these circuits can learn how to focus and how to
Attend to certain things and limit impulsivity and
hyperactivity and then, perhaps come off the drugs. Although sometimes again, people have to stay on them indefinitely. The other thing about guanfacine is that because it lowers blood pressure and it has this effect of kind of dampening down overall sympathetic arousal. Sometimes it is prescribed in conjunction with other ADHD meds. So yes, there are kids out there and adults out there who are taking Adderall and guanfacine where they're taking Vyvanse and guanfacine and this is where it starts to get into.
Drug cocktails and a bunch of other things that get everybody a little bit uncomfortable. I think, because the idea of taking one drug to dampen down the side effects of another drug and to offset things and compensate, you know, is getting towards what's called poly pharmacology. And, you know, I think it's understandable that people be concerned about that. And yet again in reviewing this with some of the experts on ADHD. There, do seem to be a certain category of children out there in adults who really struggle with the standard ADHD meds and
That case guanfacine has provided a certain number of these individuals tremendous relief.
One note about guanfacine
in no way shape or form. Am I encouraging anyone who's not prescribed guanfacine to take it? But should you know someone who's taking guanfacine off label in order to improve their focus or enhance any aspect of their biology or psychology, please let them know that it has a profound effect on lowering the tolerance for alcohol. Such that even small amounts of alcohol can lead to really serious problems and even
actually death. So that's a very serious warning with guanfacine. So today we discussed a lot of different compounds for the treatment of ADHD and announce should become clear what the general themes of those compounds is the general theme is that they tend to increase overall levels of arousal and wakefulness which leads to decreased levels of hyperactivity impulsivity and focus. And on the face of it, that might seem counterintuitive raise arousal to reduce hyperactivity and impulsivity.
That's the case because these compounds
because they act on neuromodulator
systems like dopamine and norepinephrine are effective in creating neuroplasticity, they change the strength of the connections in the neural circuits of the brain that lead to states of heightened, focus and reduced impulsivity and reduce hyperactivity. So we talked about the different mechanisms by which the different medications for ADHD accomplish this. Both the
typical sort like methylphenidate and Adderall, and Vyvanse. And some of the a
typical
compounds that are now being used in addition such as modafinil are modafinil guanfacine and Wellbutrin and where possible? I tried to highlight
both the short and long-term effects of these various compounds. And I tried to address some of the major concerns about these compounds. Most notably the question of why are we putting so many kids on amphetamine and what is the long-term consequence of that? And throughout today's episode, I tried to highlight both the immediate and long-term benefits, but also the immediate and long-term.
That can exist with these compounds.
Certainly when taken without a prescription recreationally, there is a real risk for
abuse and addiction as well as even a risk for psychotic episodes. But also the risk that a company long-term use of these drugs in people with ADHD and yet it is also clear that not treating the symptoms of ADHD carry significant risk as well. And what's very clear from the scientific and clinical literature and is covered in a significant amount of detail in the
The episode that I did about ADHD, which you can find at huberman. Lab.com is that combinations of drug treatments and behavioral. Protocols seem to surpass either drug treatments or behavioral protocols alone. Speaking to the tremendous importance of combining multiple methodologies when treating ADHD and working with a board-certified psychiatrist who really understands ADHD and it's really up to date on all the latest scientific and clinical literature if you're learning from and or enjoying this podcast.
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