Adderall, Stimulants & Modafinil for ADHD: Short- & Long-Term Effects

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.080 | and I'm a professor of neurobiology and ophthalmology

00:00:13.060 | at Stanford School of Medicine.

00:00:14.960 | Today, we're discussing stimulants,

00:00:17.120 | in particular stimulants for the treatment of ADHD,

00:00:20.480 | or attention deficit hyperactivity disorder.

00:00:23.640 | As many of you know, there's tremendous interest

00:00:25.960 | in drugs like Adderall, Ritalin, Vyvanse,

00:00:29.640 | and other stimulants,

00:00:30.600 | as well as non-stimulant prescription drugs

00:00:33.080 | that have been shown to improve the symptoms of ADHD,

00:00:36.100 | such as modafinil, armodafinil, and guanfacine.

00:00:40.240 | Today, I'm going to discuss all of these compounds

00:00:42.560 | in the context of how they work

00:00:44.700 | to improve the symptoms of ADHD.

00:00:47.000 | I'm going to address common questions about these compounds,

00:00:49.840 | such as, are they just speed?

00:00:52.100 | Are they similar to meth or methamphetamine?

00:00:54.920 | I'll talk about their addictive potential,

00:00:57.280 | as well as their potential to cause psychotic symptoms,

00:01:00.380 | both in the short and long-term.

00:01:02.320 | And of course, I will talk about the scientific literature

00:01:04.520 | surrounding the most frequently asked question

00:01:07.120 | about these compounds,

00:01:08.380 | which is, what are the long-term consequences

00:01:10.980 | of taking any of them in childhood or in adulthood?

00:01:14.520 | Now, today's discussion centers

00:01:15.760 | around the use of these compounds,

00:01:17.640 | both for childhood and for adult ADHD.

00:01:21.620 | But of course, I'd be remiss if I didn't acknowledge

00:01:24.160 | that there are a tremendous number of people

00:01:26.880 | that use these prescription drugs without a prescription

00:01:30.440 | in order to improve their ability to focus

00:01:32.880 | and indeed also use them recreationally.

00:01:35.500 | In fact, some surveys reveal that as high as 80%

00:01:39.080 | of college-age young adults have used one or several

00:01:43.020 | of prescription drugs, such as Adderall, Ritalin, Vyvanse,

00:01:46.400 | or similar, at some point,

00:01:48.560 | and are doing so without a prescription.

00:01:50.440 | So they are either obtaining those drugs

00:01:52.400 | from those that do have prescriptions for them, for ADHD,

00:01:56.020 | or they are obtaining them through black market sources,

00:01:58.520 | which of course carries an additional and very serious risk

00:02:02.140 | related to the so-called fentanyl crisis

00:02:04.280 | that is as high as 75% of black market drugs nowadays

00:02:08.680 | of various kinds, but certainly including the sorts of drugs

00:02:11.680 | we're going to talk about today

00:02:13.080 | are contaminated with fentanyl

00:02:14.840 | and therefore are very deadly.

00:02:17.280 | So today I'm going to describe

00:02:18.760 | what these various drugs really are,

00:02:20.840 | how they work at the level of neurons and brain networks,

00:02:23.720 | and how they change those brain networks

00:02:26.140 | in ways that really can allow people with ADHD

00:02:29.300 | to be able to focus better.

00:02:31.120 | I will answer the common question,

00:02:32.820 | which is why is it that giving children speed,

00:02:35.880 | because indeed several, not all,

00:02:38.180 | but several of the compounds I'm going to discuss are speed.

00:02:40.640 | They are amphetamine.

00:02:41.640 | Why would that cause a reduction in hyperactivity

00:02:45.780 | if speed is a stimulant?

00:02:46.980 | So I'll answer that question for you.

00:02:49.100 | And I will also answer questions that are commonly asked,

00:02:51.820 | such as how these drugs impact things like sleep,

00:02:55.420 | hormone health, reproductive health,

00:02:58.040 | as well as what is their impact on height.

00:03:01.060 | Indeed, it was one prominent hypothesis

00:03:03.600 | that these ADHD meds could actually restrict

00:03:05.820 | the height of children.

00:03:06.700 | I'll tell you whether or not that's actually true or not.

00:03:09.480 | And I'll discuss the data surrounding

00:03:10.900 | whether or not these drugs predispose people

00:03:13.180 | to becoming addicts to other substances,

00:03:15.940 | even if people cease or continue taking the stimulants

00:03:19.300 | that can help them in the clinical sense for ADHD.

00:03:22.460 | Before we begin, I'd like to emphasize that this podcast

00:03:24.860 | is separate from my teaching and research roles at Stanford.

00:03:27.460 | It is, however, part of my desire and effort

00:03:29.500 | to bring zero cost to consumer information about science

00:03:31.980 | and science-related tools to the general public.

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00:07:22.980 | Let's talk about treatments for ADHD

00:07:25.080 | and why stimulant treatments in particular

00:07:27.740 | can be so effective.

00:07:30.220 | First of all, it's long been known

00:07:32.020 | that there are specific brain networks

00:07:33.620 | involved in what we call attention.

00:07:35.980 | Now, attention is not one thing, actually.

00:07:39.340 | It involves several different cognitive operations,

00:07:42.140 | including the suppression of noise,

00:07:44.420 | that is turning down the background chatter in our heads

00:07:48.260 | and turning down our attending to things outside us

00:07:51.620 | like noises or visual cues

00:07:54.240 | that are not relevant to what we want to do.

00:07:56.820 | And it also involves ramping up or attending or focusing

00:08:01.820 | on particular things that are happening

00:08:04.560 | either in our immediate environment or in our head or both.

00:08:08.620 | So if that all sounds rather complex, indeed it is.

00:08:11.020 | It involves several different networks

00:08:12.820 | operating in parallel.

00:08:14.620 | But what we know for sure,

00:08:16.140 | based on a lot of clinical and scientific laboratory data,

00:08:19.980 | is that the so-called prefrontal cortex,

00:08:22.740 | the region of neural real estate in your brain

00:08:25.220 | just behind your forehead,

00:08:26.940 | is critically important for orchestrating

00:08:30.380 | which neural circuits are going to be more or less active

00:08:34.320 | at a given moment

00:08:35.620 | in order to bring about what we call focus or attention

00:08:40.060 | or task switching or our ability indeed to multitask

00:08:44.120 | because we can actually multitask to some extent.

00:08:46.500 | In fact, if you were to look at somebody

00:08:48.800 | and focus on perhaps the expression on their face,

00:08:52.180 | you could do that while also attending to a conversation

00:08:54.620 | that's happening nearby.

00:08:55.960 | It's energetically demanding, it's hard to do,

00:08:58.320 | but we can do that.

00:08:59.520 | That's actually referred to as covert attention.

00:09:01.460 | You're covertly paying attention to something else.

00:09:03.660 | And then you can switch that attention

00:09:05.240 | back to just one thing or one small collection of things.

00:09:08.880 | The point being that attention is a powerful resource.

00:09:11.780 | It's what allows us to navigate through life

00:09:14.260 | with efficiency and to be adaptive in our behaviors.

00:09:17.460 | It's what allows us to learn and to build relationships

00:09:20.040 | and have successful school careers

00:09:22.280 | and professional careers and so on.

00:09:25.060 | But it is indeed expensive.

00:09:26.560 | It takes metabolic resources, just at rest.

00:09:29.980 | If you were to think about essentially nothing or whatever

00:09:32.960 | just pops into your mind with no dedicated effort

00:09:35.620 | toward paying attention to anything,

00:09:37.600 | your brain would consume about 25%

00:09:40.220 | of your daily caloric needs.

00:09:42.340 | And then when you lump on top of that,

00:09:44.760 | your need or your attempts to focus on things,

00:09:48.280 | to pay attention to specific things,

00:09:50.360 | it should come as no surprise

00:09:51.920 | as to why that often can make us feel tired

00:09:54.020 | as if we've been working really hard

00:09:55.640 | and we've been running a quote unquote mental marathon

00:09:57.680 | when trying to learn and attend to things.

00:09:59.400 | It's hard work for the brain and yet we can pay attention

00:10:02.080 | because of that very precious real estate

00:10:04.680 | just behind our foreheads, the prefrontal cortex.

00:10:07.580 | Now in people, both children and adults that have ADHD,

00:10:12.580 | their prefrontal cortex is not necessarily deficient

00:10:16.200 | in any specific way, except that it is not as good

00:10:20.360 | at orchestrating the activity of other brain networks

00:10:23.440 | operating in parallel with it.

00:10:25.480 | What do I mean by that?

00:10:26.440 | Well, if we take a step back and say,

00:10:27.920 | what is the prefrontal cortex really doing?

00:10:30.320 | The prefrontal cortex has this amazing ability

00:10:33.120 | through what's called top-down inhibition

00:10:35.920 | to quiet other brain areas.

00:10:37.720 | So for instance, if you are feeling agitated

00:10:41.200 | but you need to sit still, your ability to sit still,

00:10:44.480 | even if it takes a bit of work,

00:10:46.280 | is coordinated by your prefrontal cortex

00:10:48.560 | sending inhibitory suppressive electrical signals

00:10:52.000 | to the networks of your brain

00:10:53.180 | that are trying to generate physical action.

00:10:55.820 | In addition to that, if you are in a conversation,

00:10:58.320 | that's either a difficult one or a boring one,

00:11:01.080 | or you are tempted to interrupt

00:11:02.800 | and you are actively holding back your desire to walk away

00:11:06.520 | or to yawn or to blurt something out,

00:11:10.140 | it's your prefrontal cortex

00:11:11.500 | that is controlling that active suppression.

00:11:14.140 | So in many ways, you can just think of the prefrontal cortex

00:11:17.620 | as an orchestra conductor that is essentially saying,

00:11:21.900 | shh, or not right now, be quiet, this is not the time,

00:11:27.100 | to many different brain networks all at once.

00:11:30.700 | Now, in addition to that,

00:11:32.260 | your prefrontal cortex is coordinating

00:11:34.760 | with other brain networks

00:11:36.440 | that are involved in generating what's called salience

00:11:39.480 | or attention to particular signals.

00:11:41.720 | So the prefrontal cortex in many ways

00:11:43.440 | is like a teacher or an orchestra conductor.

00:11:46.280 | It can point to, in the neurochemical sense, that is,

00:11:49.680 | point to a given brain structure and say,

00:11:52.720 | you, I'd like to hear more from you right now.

00:11:54.560 | Yes, you, the student in the back, speak up.

00:11:57.300 | And a moment later, point to a collection of small students

00:12:00.600 | chattering in the back,

00:12:01.680 | again, I'm presenting all this by analogy,

00:12:03.960 | and say, hey, hey, hey, you guys, quiet down right now.

00:12:07.080 | So-and-so is going to come up to the front of the room

00:12:09.340 | and help us work through this particular math problem.

00:12:12.200 | So when we hear that the prefrontal cortex

00:12:13.960 | exerts what's called executive function,

00:12:16.900 | what that refers to is the prefrontal cortex's ability

00:12:19.840 | to quiet the activity of particular neural circuits

00:12:23.420 | and to enhance or increase the salience

00:12:26.300 | of other neural circuits that are involved

00:12:28.520 | in creating our spotlight of attention.

00:12:30.800 | And what we know for sure,

00:12:32.160 | based on many, many brain imaging studies,

00:12:35.480 | is that ADHD is not necessarily a deficit

00:12:39.200 | in prefrontal cortical function,

00:12:41.520 | but rather the prefrontal cortex's ability

00:12:44.160 | to communicate with other brain areas in the proper ways.

00:12:47.600 | And so what results in the brain of a person,

00:12:50.680 | either young or old with ADHD,

00:12:52.840 | is that a lot of the background chatter

00:12:55.360 | becomes very, very loud.

00:12:56.680 | So for instance, we have a brain network

00:12:58.720 | called the default mode network.

00:13:00.180 | This is a fascinating brain network.

00:13:01.780 | This is the brain network that is active

00:13:03.840 | when you just sort of sit in place

00:13:05.620 | and don't think about much,

00:13:06.720 | and then you start having ideas

00:13:08.260 | about what you might do next week.

00:13:10.300 | It tends to be very autobiographical,

00:13:12.080 | so you might remember an experience from the past.

00:13:14.820 | You might think about some of your desires,

00:13:16.640 | some of your dislikes.

00:13:18.440 | This default mode network, as it's called,

00:13:20.800 | is also involved in our imagination,

00:13:22.720 | in our spooling together of different experiences

00:13:25.400 | that we've had.

00:13:26.800 | It doesn't tend to be the thing

00:13:28.000 | that's really focused on anything external in particular

00:13:31.760 | all at once.

00:13:33.420 | The default mode network is always active,

00:13:36.520 | but it's when we start to attend to something,

00:13:39.260 | especially things external to us,

00:13:40.920 | like something written on a page or a conversation

00:13:43.700 | or something that we really need to learn,

00:13:45.440 | something we need to pay attention to,

00:13:47.520 | that the activity of the default mode network

00:13:50.040 | is suppressed somewhat,

00:13:51.720 | and that suppression occurs not just by accident,

00:13:55.520 | but because the prefrontal cortex

00:13:56.760 | is actively suppressing it.

00:13:59.040 | In kids and adults with ADHD,

00:14:01.900 | the default mode network is often still active

00:14:05.000 | at a very robust level,

00:14:06.240 | even while we're trying to attend to things,

00:14:08.120 | and that's why someone with ADHD will sit down

00:14:11.500 | and try and do some focused work,

00:14:13.300 | and they'll start thinking about something they want

00:14:16.200 | or something they dislike.

00:14:17.800 | Their internal state will start to distract them,

00:14:20.400 | and of course, there are other networks in the brain.

00:14:22.840 | There's actually what's called a true salience network.

00:14:26.200 | There's the dorsal attention network.

00:14:27.640 | There are a bunch of different networks and brain areas,

00:14:30.040 | but again, when thinking about ADHD,

00:14:32.840 | and especially when thinking about how the drugs

00:14:35.400 | that we're going to talk about today

00:14:36.680 | work to alleviate the symptoms of ADHD,

00:14:39.860 | and in thinking about why so many people use

00:14:42.560 | or even abuse these drugs for sake of learning

00:14:46.360 | or recreationally, we might say,

00:14:50.040 | you start to realize that everything centers back

00:14:52.720 | to the prefrontal cortex and the prefrontal cortex's ability

00:14:56.080 | to actively suppress and actively enhance the activity

00:14:59.160 | of these multiple brain networks,

00:15:00.960 | including default mode network, salience network,

00:15:03.400 | dorsal attention network, et cetera.

00:15:06.040 | So rather than overwhelm you with a bunch of names

00:15:08.480 | of brain areas and brain networks,

00:15:10.360 | today I'd really like our discussion to focus on first

00:15:13.400 | what the various drugs that are used to treat ADHD are,

00:15:17.320 | that is, how do they work at the level of neurons?

00:15:20.240 | Second, how they create a certain set of conditions

00:15:25.220 | that allow the prefrontal cortex to be a better conductor.

00:15:28.660 | Third, how that can be leveraged during development

00:15:31.520 | to actually teach the prefrontal cortex of a young child

00:15:34.920 | to learn to be a better conductor,

00:15:36.780 | because that's really the hallmark of the use of these drugs

00:15:39.580 | is to try and enhance the activity of particular circuits

00:15:42.620 | to create a sort of learning so that the prefrontal cortex

00:15:45.560 | is much more efficient at doing its job of conducting.

00:15:49.040 | And then fourth, we're going to talk about

00:15:51.200 | the various things that I think most people out there

00:15:54.080 | ask about when they hear about drugs

00:15:55.920 | like Adderall, Vyvanse, and Ritalin, et cetera,

00:15:58.440 | which is, you know, are they addictive?

00:16:00.760 | Why are they addictive?

00:16:02.100 | Can one use them briefly or even from time to time

00:16:05.460 | and still be okay?

00:16:06.640 | What if I use them as a child

00:16:08.080 | and I don't want to be on them anymore?

00:16:09.440 | Should I put my child on these drugs, et cetera?

00:16:12.780 | It is, I believe, only by understanding the biology

00:16:15.840 | of how these drugs work

00:16:17.780 | and their potential both to improve brain function,

00:16:20.820 | but also some of the dangers associated with these drugs

00:16:23.780 | that one can really answer those questions for themselves

00:16:26.660 | or for their children.

00:16:27.820 | Okay, so let's start with a very basic but critical question,

00:16:31.100 | which is why in the world would amphetamines, speed,

00:16:36.100 | or other stimulants improve the symptoms of ADHD?

00:16:41.140 | That's so critical to answer because if you think about it,

00:16:44.280 | the prefrontal cortex needs to coordinate the actions

00:16:47.100 | of these other circuits.

00:16:48.820 | And so just increasing the amount of activity

00:16:51.320 | in prefrontal cortex, you can imagine,

00:16:53.020 | would create a state of hyper-focus perhaps,

00:16:55.860 | but actually that's not the case.

00:16:57.100 | If you just were to ramp up the activity

00:16:59.440 | of prefrontal cortex, what you would find

00:17:01.840 | is that somebody would become even less efficient

00:17:05.820 | at paying attention to what they wanted to.

00:17:07.860 | Rather, they would pay attention to whatever was presented

00:17:10.220 | in front of them with laser focus.

00:17:11.720 | They would lock on to essentially anything.

00:17:14.000 | And that's not good.

00:17:15.120 | One of the key things about prefrontal cortex

00:17:16.980 | is that it needs to be flexible.

00:17:19.000 | It needs to be able to pay attention to this.

00:17:21.100 | Then it needs to be able to pay attention to that.

00:17:23.000 | Then it needs to go back to paying attention

00:17:24.680 | to the thing it was paying attention to previously

00:17:27.060 | and so on and so forth.

00:17:28.620 | Life, that is an effective, adaptive life, a good life,

00:17:32.740 | consists of self-directing one's attention

00:17:35.980 | most all of the time.

00:17:37.820 | So why would stimulants do that?

00:17:40.780 | Well, almost all, not all,

00:17:43.860 | but almost all of the drugs used to treat ADHD

00:17:47.060 | fall under the category of stimulants

00:17:49.180 | or what are called sympathomimetics.

00:17:51.740 | Sympathomimetic refers to the fact

00:17:54.140 | that we naturally have a component of our nervous system

00:17:58.220 | called the autonomic nervous system.

00:18:00.480 | The autonomic nervous system has two major components.

00:18:03.500 | One is called the sympathetic arm

00:18:05.660 | of the autonomic nervous system.

00:18:07.220 | Has nothing to do with sympathy,

00:18:08.420 | has everything to do with ramping up

00:18:10.440 | our level of attention and arousal.

00:18:13.060 | It is the so-called fight or flight

00:18:15.540 | aspect of our nervous system,

00:18:16.940 | or rather it mediates fight or flight,

00:18:19.220 | but it mediates a bunch of other things too,

00:18:21.540 | including sexual arousal, including excitement and focus

00:18:25.500 | about something that we want to learn

00:18:27.480 | or somebody that we want to learn more about

00:18:30.020 | or remembering a phone number

00:18:31.920 | or anything that puts us into a state of alertness and focus.

00:18:37.020 | The other arm of the autonomic nervous system

00:18:39.380 | is the so-called parasympathetic arm

00:18:41.400 | of the autonomic nervous system.

00:18:42.560 | And that's often referred to as the so-called

00:18:44.500 | rest and digest component of our nervous system.

00:18:47.740 | And yes, it controls rest.

00:18:49.580 | Indeed, it puts us into sleep.

00:18:51.340 | And yes, it's involved in digestion,

00:18:54.520 | but it's involved in a bunch of other things as well,

00:18:57.320 | including sexual arousal, including rates of digestion,

00:19:00.860 | including salivation, including all sorts of things

00:19:05.040 | that don't just have to do with resting and digesting.

00:19:08.100 | The way to think about the autonomic nervous system

00:19:09.700 | is it's a sort of seesaw.

00:19:11.080 | So it's always at a balance someplace

00:19:13.860 | between either predominantly sympathetic

00:19:17.080 | or predominantly parasympathetic,

00:19:19.100 | but both the parasympathetic and the sympathetic arms

00:19:21.860 | of the autonomic nervous system

00:19:23.040 | are always active all the time.

00:19:25.340 | It's not as if one is completely active

00:19:27.060 | and the other is shut off.

00:19:27.900 | Even in sleep, your sympathetic nervous system

00:19:29.940 | is not completely turned off.

00:19:31.060 | And even during a panic attack,

00:19:33.100 | your parasympathetic nervous system is not completely

00:19:35.620 | turned off.

00:19:36.460 | Drugs to treat ADHD,

00:19:40.520 | which fall under the category of stimulants,

00:19:42.900 | are sympathomimetics because they trigger the release

00:19:46.900 | of neurochemicals and the activation of components

00:19:50.340 | of our nervous system that very much resemble

00:19:53.860 | the activation of the so-called sympathetic nervous system,

00:19:56.740 | the one that makes us more alert and more aroused.

00:19:59.560 | So that's why they're called sympathomimetics.

00:20:01.580 | And the word stimulant refers to a general category

00:20:05.620 | of drugs that are sympathomimetics.

00:20:08.460 | Now, the most commonly discussed sympathomimetic

00:20:12.300 | is one that fortunately is not prescribed for ADHD,

00:20:17.060 | and that's methamphetamine.

00:20:18.540 | These days, we hear a lot about meth.

00:20:20.980 | Meth, which is methylated amphetamine,

00:20:23.840 | is an extremely potent sympathomimetic,

00:20:27.280 | and it has tremendous abuse potential.

00:20:31.180 | Believe it or not, meth or methamphetamine

00:20:34.640 | is actually available as a prescription drug,

00:20:37.640 | but it is used very rarely because of its high abuse

00:20:40.700 | potential and all the terrible things that it can do

00:20:44.520 | in terms of cardiovascular health,

00:20:46.260 | in terms of oral health, right?

00:20:48.240 | There's this stereotype that meth users

00:20:50.280 | have very degraded teeth, and indeed they do.

00:20:52.860 | There's a reason for that related

00:20:54.100 | to how meth impacts the brain and body.

00:20:56.260 | I'm going to talk a little bit about methamphetamine

00:20:58.060 | a little bit later,

00:20:59.260 | but let's just place methamphetamine high on the shelf

00:21:03.260 | as the most potent sympathomimetic that's out there,

00:21:08.260 | because even though it's not often prescribed for ADHD,

00:21:12.980 | there are a class of compounds very similar to it

00:21:15.760 | that have a very similar pattern of action

00:21:18.740 | that is not quite as potent,

00:21:20.540 | but that leverages the same underlying mechanisms,

00:21:23.440 | and they are very commonly prescribed for ADHD,

00:21:26.700 | namely Adderall and Vyvanse.

00:21:29.460 | So first let's talk about Adderall and what Adderall is.

00:21:32.980 | Adderall is a combination

00:21:34.520 | of what are called amphetamine salts.

00:21:37.140 | Amphetamine salts refers to the fact

00:21:38.940 | that there are two major forms of amphetamine.

00:21:41.600 | There's a D amphetamine or dexer amphetamine

00:21:44.820 | and levoenfetamine or L amphetamine.

00:21:47.220 | So I'll refer to these as D and L amphetamine.

00:21:50.340 | And for you chemistry-minded folks out there,

00:21:52.580 | the D and the L also refer to the fact

00:21:55.200 | that there is a L left-handed version of the molecule,

00:21:58.880 | and there's a D or right-handed version of the molecule.

00:22:02.500 | This is only important to understand

00:22:05.460 | insofar as you know that the D and the L forms

00:22:08.720 | of the molecule look very similar,

00:22:10.760 | but they're mirror images of one another,

00:22:13.200 | and yet they can have very different actions

00:22:15.780 | in the brain and body.

00:22:17.160 | So Adderall is a three to one ratio

00:22:20.240 | of D amphetamine to L amphetamine.

00:22:23.660 | You should know that L amphetamine tends to be less potent

00:22:28.100 | in increasing certain neurochemicals in the brain,

00:22:30.400 | I'll talk about which neurochemicals they are in a moment,

00:22:33.660 | than is D amphetamine.

00:22:34.920 | So D amphetamine is potent stuff,

00:22:36.780 | not as potent as methamphetamine, but very potent stuff.

00:22:40.420 | L amphetamine, a little bit less potent.

00:22:43.260 | L amphetamine tends to be the amphetamine

00:22:46.120 | that increases blood pressure and heart rate,

00:22:48.660 | what we call peripheral effects,

00:22:51.220 | because it happens in the periphery,

00:22:52.560 | outside the central nervous system.

00:22:54.800 | Peripheral effects like increased heart rate,

00:22:57.200 | increased blood pressure, sweating, et cetera,

00:23:01.540 | are mostly activated by L amphetamine,

00:23:04.000 | whereas D amphetamine tends to work mainly

00:23:06.880 | on receptors in the brain,

00:23:08.080 | and therefore have effects mainly restricted to the brain.

00:23:11.520 | Now, what are these effects that I've been referring to?

00:23:15.020 | The major effect of Adderall

00:23:17.320 | and other sympathomimetic stimulants

00:23:20.000 | is to increase the activity of two neurochemicals.

00:23:23.940 | The first of those neurochemicals is dopamine,

00:23:26.640 | and the other of those neurochemicals is norepinephrine.

00:23:29.980 | First off, I want to be clear that when I say norepinephrine,

00:23:33.280 | I could just as easily say noradrenaline,

00:23:35.660 | because those are the exact same thing.

00:23:37.680 | And forgive me, even though I wasn't the one

00:23:40.240 | to name the same thing, two different things,

00:23:43.220 | I'll try and stay with norepinephrine,

00:23:45.600 | but I may say noradrenaline, they are the same thing.

00:23:48.160 | There's a whole story as to how they got named,

00:23:50.760 | two different things, but it's the same thing.

00:23:53.060 | The major effect of Adderall

00:23:55.640 | and other sympathomimetic stimulants

00:23:58.080 | is to increase the transmission

00:24:01.200 | of dopamine and norepinephrine.

00:24:03.980 | So what is dopamine and what is norepinephrine?

00:24:06.380 | Well, both dopamine and norepinephrine

00:24:08.120 | are what are called neuromodulators.

00:24:09.960 | That is, they have the ability to increase or decrease

00:24:13.600 | the firing patterns, the electrical activity

00:24:16.720 | of particular brain circuits.

00:24:18.500 | Both dopamine and norepinephrine have separate roles

00:24:23.680 | in creating certain states within our brain and body,

00:24:27.020 | but they like to collaborate,

00:24:29.120 | meaning they tend to be released at similar locations

00:24:31.780 | in the brain in order to deliver us

00:24:34.300 | to a particular state of mind and or body.

00:24:38.320 | So if we were to take a look at just dopamine,

00:24:41.060 | we would find that dopamine is released

00:24:43.320 | at sites within the brain

00:24:45.160 | and increases the activity of brain networks

00:24:48.120 | that for the most part lead to increases

00:24:50.200 | in motivation, pursuit, and to some extent, mood.

00:24:54.340 | If we were to look at norepinephrine

00:24:57.040 | and where it's released in the brain,

00:24:58.680 | it tends to be released at many, not all,

00:25:00.940 | but many of the same sites where dopamine is released.

00:25:04.120 | And the main function of norepinephrine

00:25:06.960 | is to increase the activity of neural networks

00:25:09.780 | that are involved in attention and focus

00:25:12.540 | to particular things in our environment.

00:25:15.040 | Okay, so think of dopamine and norepinephrine

00:25:17.700 | as collaborators because indeed they are.

00:25:20.680 | And actually they're very neurochemically similar as well.

00:25:24.160 | It actually just takes one chemical conversion

00:25:27.520 | to turn dopamine into norepinephrine.

00:25:29.820 | So they are very similar.

00:25:31.040 | They're like close cousins that work together

00:25:33.040 | to help us achieve a common goal

00:25:35.160 | that involves increased motivation, focus, and alertness.

00:25:39.560 | So when we talk about attention in ADHD,

00:25:42.440 | or we talk about quieting the hyperactivity

00:25:45.000 | or impulsivity of ADHD,

00:25:47.160 | one of the reasons why drugs that are effective

00:25:49.560 | in treating ADHD are so effective

00:25:51.900 | is because they increase motivation, focus, and alertness,

00:25:55.760 | and they tend to do that

00:25:56.760 | at very focal locations in the brain.

00:25:58.980 | It's worth taking a couple of minutes

00:26:00.220 | to think about how sympathomimetics, such as Adderall,

00:26:03.000 | actually increase dopamine and norepinephrine.

00:26:05.920 | They do so by affecting a couple of specific operations

00:26:09.820 | at the so-called synapse.

00:26:11.000 | What are synapses?

00:26:11.840 | Synapses are the communication points between neurons.

00:26:14.400 | They're actually the spaces between neurons,

00:26:17.000 | but that's where a lot of the action is

00:26:18.540 | when neurons, as we say, are stimulating the next neuron

00:26:22.080 | or activating the next neuron or inhibiting the next neuron.

00:26:25.040 | The word neuron just simply refers to nerve cell.

00:26:27.920 | And so what nerve cells have is they have a cell body

00:26:31.000 | that contains their DNA and a bunch of other stuff.

00:26:33.580 | They have a long wire-like process,

00:26:36.280 | which is referred to as an axon.

00:26:38.000 | And at the end of that axon,

00:26:39.660 | there are a bunch of proteins in there

00:26:41.000 | that do really interesting things.

00:26:43.120 | So for instance, there are proteins

00:26:44.640 | down at the end of the axon

00:26:46.080 | that package neurotransmitter into little spherical things

00:26:48.840 | that we call vesicles.

00:26:50.520 | Those vesicles can fuse with the end of the axon

00:26:54.040 | and vomit the contents, those neurotransmitters,

00:26:57.640 | into the synaptic cleft,

00:26:58.920 | into that little space between neurons.

00:27:01.160 | And then if enough of those neurotransmitters

00:27:04.360 | bind to receptors on what's called the postsynaptic side,

00:27:07.040 | which just simply means the neuron on the other side,

00:27:09.620 | well, then the next neuron will become active.

00:27:12.640 | And then the signal will propagate

00:27:14.840 | from one neuron to the next.

00:27:16.740 | Now, I just described that whole process pretty quickly.

00:27:18.960 | And I like to think pretty simply,

00:27:21.080 | but it actually involves a lot of different protein bits

00:27:24.720 | and some pretty complex machinery

00:27:26.480 | in order to make that happen.

00:27:27.880 | I don't want to overcomplicate our conversation,

00:27:30.800 | but what I will tell you is that down in the synapse,

00:27:33.800 | in the presynaptic terminal,

00:27:36.040 | the neuron that is going to release neurotransmitter,

00:27:38.860 | there are what are called transporters,

00:27:40.420 | which sit there and suck up or suck back up

00:27:45.020 | some of the neurotransmitter that's been released.

00:27:47.520 | There are dopamine transporters

00:27:50.020 | and there are norepinephrine

00:27:51.740 | or noradrenergic transporters down in the synapse.

00:27:54.800 | What Adderall does and what other sympathomimetics do

00:28:00.580 | is to inhibit or disrupt the action of those transporters.

00:28:04.580 | And the net consequence of that

00:28:06.180 | is that when dopamine and norepinephrine

00:28:08.700 | are released into the synapse,

00:28:10.220 | more of it is allowed to stick around

00:28:12.780 | and to bind to receptors on the postsynaptic cell

00:28:15.280 | than would be the case if Adderall or the other stimulant

00:28:19.500 | were not present in the system.

00:28:21.260 | So one way that Adderall increases dopamine

00:28:23.400 | and norepinephrine is by disrupting the activity

00:28:26.260 | of these presynaptic transporters

00:28:28.460 | for dopamine and norepinephrine.

00:28:30.820 | The other way that Adderall increases

00:28:32.900 | dopamine and norepinephrine

00:28:34.900 | is that it disrupts the activity

00:28:37.020 | of a different piece of machinery in the presynaptic neuron,

00:28:40.780 | which is called a VMAT,

00:28:42.320 | the vesicle monoamine transporter two,

00:28:45.380 | if you really want to get specific.

00:28:47.020 | You don't have to remember these names,

00:28:48.240 | but what these VMATs do is actually really cool.

00:28:51.340 | What they do is they actually take whatever transmitter

00:28:54.600 | has been brought back up into the cell by transporters

00:28:57.500 | and they package it into those vesicles

00:29:01.040 | that are then going to be released.

00:29:04.780 | By disrupting the transporters that vacuum back up

00:29:08.660 | some of the dopamine or norepinephrine that's been released,

00:29:12.980 | and by also disrupting the packaging

00:29:16.260 | of dopamine and norepinephrine into vesicles themselves,

00:29:20.360 | what ends up happening is that there's a buildup

00:29:22.740 | of a lot more dopamine and norepinephrine

00:29:24.900 | in the presynaptic terminal,

00:29:26.560 | so that when an electrical signal travels down the neuron,

00:29:29.820 | now the total amount of dopamine and norepinephrine

00:29:33.460 | that's released is increased, okay?

00:29:35.940 | So what's happening when you take Adderall

00:29:38.340 | is that you're getting more out of the dopamine

00:29:41.580 | and norepinephrine that you're releasing,

00:29:43.300 | and you're releasing more dopamine

00:29:45.100 | and norepinephrine altogether.

00:29:47.700 | And there's a third mechanism

00:29:48.860 | by which Adderall increases the amount of dopamine

00:29:51.140 | and norepinephrine present in synapses,

00:29:53.740 | and therefore can act on other neurons.

00:29:56.380 | And that has to do with disruption of the entire network

00:29:59.780 | between these different proteins.

00:30:02.180 | I'm not going to go into that in any detail

00:30:03.800 | because it gets somewhat complicated

00:30:05.140 | in terms of the cell biology and some of the biochemistry

00:30:08.140 | down at the tips of these axons,

00:30:09.940 | but suffice to say that Adderall

00:30:12.700 | is such an effective sympathomimetic,

00:30:15.820 | that is, it can increase dopamine to such a great extent,

00:30:20.180 | especially compared to other treatments for ADHD,

00:30:23.840 | because of its ability to increase dopamine release

00:30:27.140 | and transmission, and therefore action,

00:30:29.860 | as well as noradrenergic release and transmission and action

00:30:34.140 | down there in the synapse.

00:30:35.700 | And it's worth pointing out

00:30:36.980 | that most of the effect of Adderall

00:30:39.800 | is in increasing dopamine as opposed to norepinephrine.

00:30:42.980 | It does increase norepinephrine, but its major effects,

00:30:46.740 | or we should say the major effects

00:30:48.260 | that have made it such an attractive drug to so many people,

00:30:51.940 | both for the treatment of ADHD

00:30:53.540 | and for people to take recreationally or off prescription

00:30:57.480 | or for sake of studying or work

00:30:58.980 | simply because they want to focus more and longer,

00:31:01.620 | is because of its ability to increase dopamine

00:31:04.260 | to such a great extent.

00:31:05.920 | I'd like to take a quick break

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00:32:20.280 | Now, a bit earlier, I mentioned that L-amphetamine,

00:32:22.860 | levoanphetamine, is present in Adderall,

00:32:25.320 | but at 1/4 the amount of D-amphetamine.

00:32:29.520 | Okay, so there's a little bit of L-amphetamine

00:32:31.180 | and a lot of D-amphetamine in Adderall.

00:32:33.540 | Many of you are probably familiar with Vyvanse.

00:32:35.900 | Vyvanse is a commercial name

00:32:37.820 | for what many people think is extended-release Adderall,

00:32:40.920 | but actually, Vyvanse is not extended-release Adderall.

00:32:44.480 | Vyvanse is a drug in which the pharmaceutical industry

00:32:48.900 | has taken one component of Adderall,

00:32:51.480 | just the D-amphetamine component,

00:32:54.220 | and attached to it an amino acid called lysine.

00:32:57.940 | Now, the amino acid lysine is a big amino acid,

00:33:01.240 | and the attaching of lysine to D-amphetamine,

00:33:05.360 | what we call Vyvanse, makes it what's called a prodrug.

00:33:07.980 | It actually can't have any effect on its own.

00:33:10.740 | But when one takes Vyvanse and it's broken down in the gut,

00:33:14.420 | but to a greater extent, actually, in the bloodstream,

00:33:17.420 | the lysines are cleaved off slowly over time.

00:33:20.700 | And as a consequence, Vyvanse is basically timed-release

00:33:24.400 | D-amphetamine.

00:33:25.940 | Okay, this is important because I think a lot of people

00:33:28.100 | think that Adderall, which, again,

00:33:30.640 | is D-amphetamine and L-amphetamine,

00:33:33.120 | and those two things operate quite a bit differently

00:33:35.500 | at the level of norepinephrine and epinephrine

00:33:37.820 | and cardiac versus brain effects.

00:33:40.260 | A lot of people think Vyvanse is just slow-release Adderall,

00:33:43.360 | but it is not.

00:33:44.440 | What Vyvanse is is it's D-amphetamine only,

00:33:47.740 | but in time-release form.

00:33:49.300 | And Vyvanse was actually developed as a way

00:33:52.080 | to try and get around or rather prevent

00:33:54.820 | some of the abuse potential of Adderall

00:33:57.640 | and other drugs that contain D-amphetamine.

00:34:00.940 | D-amphetamine stands for dextro-amphetamine.

00:34:04.220 | And in the '70s and '80s,

00:34:06.980 | there were a fair amount of movies

00:34:09.220 | and there was a lot of trafficking

00:34:10.740 | and there was a lot of criminal activity

00:34:12.360 | related to what was called dexedrine.

00:34:14.700 | Dexedrine is pure D-amphetamine.

00:34:17.180 | So if we're going to be very direct,

00:34:19.960 | if I were going to just frame these things

00:34:21.860 | in the context of their neurochemistry,

00:34:24.120 | what I can tell you is that Vyvanse

00:34:27.060 | is time-release dexedrine.

00:34:29.500 | Okay, it's not time-release Adderall.

00:34:31.500 | Now, just because there were movies

00:34:32.900 | and reports of criminal activity related to dexedrine,

00:34:36.400 | that doesn't necessarily mean that dexedrine

00:34:37.920 | is not an effective and useful pharmaceutical.

00:34:40.980 | In fact, Vyvanse, which is time-release dexedrine,

00:34:43.580 | has proved to be very effective in the treatment of ADHD

00:34:46.380 | for a lot of people.

00:34:47.940 | And the reason for that is this time-release

00:34:51.260 | does indeed prevent abuse in the sense that

00:34:54.220 | despite people's many attempts, from what I hear,

00:34:57.280 | to increase the rate of entry of the D-amphetamine

00:35:01.260 | into their system by either snorting it

00:35:04.140 | or, God forbid, even injecting it and things of that sort,

00:35:07.280 | the attaching of that lysine to D-amphetamine

00:35:09.900 | really does slow the absorption.

00:35:11.540 | So when somebody takes Vyvanse,

00:35:13.140 | and hopefully people are taking it responsibly,

00:35:16.020 | when they take Vyvanse, what they're really getting

00:35:18.420 | is a slow trickle of D-amphetamine into their system

00:35:21.740 | and therefore a slow, long-lasting increase

00:35:24.840 | in dopamine and norepinephrine.

00:35:26.380 | And indeed, that's what happens.

00:35:27.500 | The effects of Vyvanse can extend over anywhere

00:35:30.500 | from 12 to 16, sometimes even 18 hours,

00:35:33.220 | depending on how quickly somebody metabolizes it.

00:35:35.460 | And I should say that there's no way to predict

00:35:38.180 | how quickly one will metabolize any of these drugs

00:35:41.240 | except by trying them.

00:35:42.320 | That's one of the sort of downsides

00:35:43.940 | of the state of things these days.

00:35:45.500 | There's no blood test or enzymatic test

00:35:47.480 | that will tell you whether or not

00:35:48.660 | you're going to be a fast metabolizer or a slow metabolizer.

00:35:51.140 | And that's why people just have to sort through

00:35:53.180 | different dosages, which we'll talk about in a little bit.

00:35:55.500 | They have to sort through

00:35:56.340 | different types of sympathomimetics, you know?

00:35:58.260 | Some people try Adderall, and they find that, you know,

00:36:00.780 | the quick time course of Adderall,

00:36:02.100 | or at least quick for them of about six to eight hours,

00:36:04.700 | is just too fast, and then it wears off

00:36:06.820 | and they get into a slump in the afternoon.

00:36:08.460 | Other people will find that one Adderall taken at 6 a.m.

00:36:11.540 | will have them going all day long and into the night,

00:36:13.960 | and it's just too much stimulation,

00:36:15.520 | and they need to come way, way down in dose,

00:36:17.660 | or they need to think about

00:36:18.680 | other sympathomimetics for ADHD.

00:36:20.580 | And we'll talk about what some of those other options are

00:36:22.900 | in a little bit as well.

00:36:24.280 | So the important thing to understand

00:36:25.500 | is that Adderall is really two drugs, DNL amphetamine.

00:36:28.300 | Vyvanse is D-amphetamine, which is also called Dexedrine,

00:36:32.380 | but with this time-released aspect

00:36:34.820 | created by lumping a lysine on there.

00:36:36.980 | And you may notice that I haven't mentioned

00:36:39.580 | one of the major drugs used to treat ADHD,

00:36:43.840 | and that's Ritalin, or what's sometimes also called concerta,

00:36:48.380 | depending on, again, the time-release forms, et cetera.

00:36:51.700 | Ritalin was very commonly prescribed

00:36:53.560 | for the treatment of ADHD early in the days

00:36:56.280 | of using sympathomimetics in order to treat ADHD.

00:37:00.100 | So for instance, I went to college in the early '90s.

00:37:03.800 | So I started college in '93, and I graduated in '98.

00:37:07.500 | It was one year in there as a,

00:37:08.900 | let's call it a transition year.

00:37:10.620 | I can recall hearing that Ritalin was being prescribed

00:37:13.760 | for ADHD in kids, and I, like many other people,

00:37:17.380 | were wondering, what are the long-term consequences

00:37:19.740 | of this going to be?

00:37:20.980 | I also, like many other people, was very perplexed

00:37:23.460 | as to why a stimulant, sympathomimetic like Ritalin,

00:37:27.140 | was being prescribed for hyperactive kids.

00:37:30.300 | That will become clear in a moment,

00:37:31.740 | but we don't hear so much about Ritalin nowadays,

00:37:36.100 | and I think that's because Adderall and Vyvanse

00:37:39.060 | and things like them have become so popular

00:37:41.160 | for the treatment of ADHD.

00:37:43.300 | It's worth noting that Ritalin is not actually amphetamine.

00:37:47.840 | Ritalin is what's called methylphenidate,

00:37:50.180 | and methylphenidate works in a lot of ways

00:37:53.080 | that are similar to the way that Adderall and Vyvanse work,

00:37:57.460 | but there are certain ways in which it's different.

00:38:00.460 | Now, Ritalin, methylphenidate,

00:38:01.980 | does increase dopamine transmission at synapses,

00:38:04.600 | and it does so also by inhibiting the function

00:38:07.980 | of that presynaptic dopamine transporter

00:38:10.380 | that would otherwise suck more dopamine back up

00:38:13.560 | into the presynaptic cell.

00:38:14.920 | Methylphenidate, Ritalin, also disrupts the activity

00:38:19.720 | of the noradrenergic transporter,

00:38:22.020 | leading to net increases

00:38:24.860 | in the amount of norepinephrine at the synapse,

00:38:28.180 | but it is not as much a potent inhibitor

00:38:31.660 | of the noradrenergic transporter,

00:38:33.620 | and therefore most of the effect of methylphenidate

00:38:36.040 | is to increase dopamine at synapses.

00:38:39.300 | A lot of people don't realize this.

00:38:40.360 | A lot of people think that Ritalin

00:38:41.860 | is just very short-acting Adderall, and that's not the case.

00:38:45.360 | It is true that Ritalin, at least in its standard form,

00:38:49.260 | tends to have a pretty short half-life,

00:38:51.100 | and therefore its effects basically kick in

00:38:54.260 | about 20 to 40 minutes after taking it,

00:38:57.500 | sometimes a little bit sooner, sometimes a little later,

00:38:59.500 | and they last about four to six hours,

00:39:02.360 | as opposed to the six to eight hours typical of Adderall,

00:39:06.300 | but Ritalin is not short-acting Adderall.

00:39:09.460 | Ritalin is mainly increasing dopamine,

00:39:11.900 | and to some extent, norepinephrine at synapses,

00:39:14.720 | whereas Adderall and Vyvanse are increasing

00:39:17.900 | both dopamine and norepinephrine to a much greater extent,

00:39:22.020 | and for those of you that are interested

00:39:23.140 | in the underlying cell biological reason for that,

00:39:25.920 | it has something to do with Ritalin's

00:39:27.980 | relatively lower affinity for the noradrenergic transporter,

00:39:31.540 | but it's also because, remember,

00:39:32.620 | I listed off three mechanisms by which Adderall

00:39:35.900 | and by extension, Vyvanse, increased dopamine

00:39:38.900 | and norepinephrine transmission, right?

00:39:40.260 | Disruption of the transporter, disruption of the VMAT2,

00:39:43.500 | as well as a disruption of the whole kind of complex

00:39:45.860 | of communication between those proteins.

00:39:47.980 | Well, Ritalin is really only tapping into the drug's ability

00:39:51.640 | to disrupt the dopamine and noradrenergic transporter,

00:39:55.580 | so it's three mechanisms of increasing dopamine

00:39:58.380 | and norepinephrine for Adderall and Vyvanse,

00:40:01.400 | and by extension, Dexedrine,

00:40:03.300 | and it's only one mechanism for Ritalin

00:40:06.660 | to increase dopamine and norepinephrine,

00:40:08.580 | and therein, mostly dopamine.

00:40:10.920 | So if we take a step back for a moment from all these drugs

00:40:13.580 | and all this cell biology of neurons and so forth,

00:40:17.300 | and we go back to the brain networks involved in attention,

00:40:20.240 | remember the orchestra model or the teacher model

00:40:22.580 | where the prefrontal cortex really sits in top seat

00:40:25.820 | in terms of coordinating the actions,

00:40:27.420 | both the shh, the quieting, and the yes, please speak

00:40:31.020 | actions of the brain, really bringing about what we think of

00:40:34.020 | as focused attention and task switching,

00:40:36.060 | all the stuff that goes along with learning

00:40:37.900 | and focus and cognition.

00:40:40.860 | Well, what we know is that dopamine and norepinephrine,

00:40:45.340 | which are differentially increased by these different drugs

00:40:48.620 | that we've been talking about,

00:40:50.580 | also differentially impact the various aspects

00:40:54.420 | of executive function of the prefrontal cortex,

00:40:57.240 | increasing our attention for specific things.

00:40:59.980 | And while there is a lot of nuance in the literature

00:41:02.580 | about this, we can safely say a couple of things.

00:41:05.300 | First of all, increasing dopamine at particular synapses

00:41:10.300 | and networks in the brain can serve

00:41:12.820 | as what's called noise reduction.

00:41:14.900 | It can help further enhance the quieting

00:41:17.980 | of all that background stuff.

00:41:20.100 | That background stuff can be attention to things

00:41:21.900 | in your environment like noises or visual cues.

00:41:25.320 | It could be some internal narrative

00:41:27.860 | that you had about yesterday

00:41:29.060 | or something that somebody said about you

00:41:30.700 | or something that somebody you like

00:41:33.980 | would like to say about you

00:41:35.140 | or whatever it might be that's happening in your head

00:41:37.820 | that's distracting you,

00:41:39.260 | as well as your representation of your internal bodily state,

00:41:43.380 | what we call interoception.

00:41:44.860 | This is a really important aspect of attention

00:41:47.540 | that we don't often hear about,

00:41:48.960 | which is that we have the ability to attend to things

00:41:51.260 | outside of us, which is called exteroception,

00:41:53.740 | as well as an ability to attend to things inside of us,

00:41:57.340 | which include things like thoughts,

00:41:58.940 | but also includes, you know, for instance,

00:42:00.740 | how empty or full our gut feels,

00:42:03.540 | whether or not we're comfortable in our chair.

00:42:05.420 | You know, and when we think about the practice of focus

00:42:07.780 | and learning or focusing as a verb,

00:42:10.240 | it involves often forcing ourselves to sit still.

00:42:14.820 | It often involves us suppressing the fact

00:42:17.940 | that our foot is a little bit cramped

00:42:19.600 | or that we might need to use the restroom for, you know,

00:42:22.620 | we might want to delay that for 10, 15 minutes,

00:42:24.820 | even though it might be fairly urgent.

00:42:26.580 | All these sorts of things are central

00:42:29.580 | to our ability to attend and focus.

00:42:32.140 | And so dopamine,

00:42:33.860 | while it does many different things in the brain,

00:42:36.220 | many, many different things,

00:42:37.580 | one of its main functions in the context

00:42:40.140 | of all this prefrontal cortex and attention stuff

00:42:43.700 | is to quiet the amount of noise.

00:42:46.340 | That is, it helps the prefrontal cortex

00:42:49.020 | suppress the signals that would otherwise distract us

00:42:53.100 | into thinking about, oh yeah, I'm kind of thirsty right now,

00:42:55.380 | or I need to use the restroom,

00:42:56.500 | or I really want to make this call,

00:42:57.420 | or I really want to pick up my phone.

00:42:59.580 | All of that stuff, all of that suppression,

00:43:01.740 | that shh, that quieting down of all the background chatter

00:43:05.660 | related to things external and internal to us in our head

00:43:08.660 | and our body is greatly facilitated

00:43:11.660 | by having more dopamine present in the synapses

00:43:14.640 | that allow for what we call noise reduction.

00:43:17.780 | Now, in parallel to that is norepinephrine.

00:43:20.420 | Norepinephrine is released from multiple sites

00:43:22.860 | in the brain and body,

00:43:23.840 | but within the brain, there's one major site of neurons

00:43:28.000 | that manufacture norepinephrine,

00:43:29.660 | and the name of that site is locus coeruleus.

00:43:32.560 | It sits in the back of the brain.

00:43:34.760 | It's actually a relatively small collection of neurons,

00:43:37.020 | but they are very, very powerful.

00:43:38.920 | They extend their little axons, their wires,

00:43:41.820 | to multiple locations in the brain,

00:43:44.500 | and they release norepinephrine at those locations.

00:43:47.800 | So think of them sort of as a sprinkler system

00:43:50.600 | that originates from one very focal location,

00:43:53.720 | but that can sprinkle norepinephrine

00:43:56.340 | at multiple locations in the brain.

00:43:58.420 | And the amazing thing about locus coeruleus

00:44:01.780 | and that sprinkler system is that indeed

00:44:03.940 | the sprinkler system can be pretty widespread

00:44:06.100 | where everywhere there's a sprinkler head,

00:44:08.760 | somebody's getting norepinephrine,

00:44:10.420 | but it also can fairly focally release norepinephrine

00:44:13.900 | at particular sites.

00:44:15.100 | So while in the context of today's discussion,

00:44:17.300 | dopamine is acting largely to impart noise reduction,

00:44:22.380 | norepinephrine has the ability to boost signals at synapses,

00:44:27.380 | to increase the amplitude

00:44:29.560 | and frequency of communication between neurons.

00:44:32.020 | And in that way, in the context of today's discussion,

00:44:35.060 | norepinephrine, when released at the particular synapses

00:44:39.100 | in the particular brain networks

00:44:40.540 | that are related to attention and learning,

00:44:42.680 | is largely serving to increase signal.

00:44:45.600 | So what we have in the context of a drug

00:44:47.700 | like Adderall or Vyvanse,

00:44:49.520 | or to some extent methylphenidate,

00:44:51.140 | Ritalin does this as well,

00:44:52.740 | is an increase in dopamine and norepinephrine

00:44:55.700 | that is leading to two things,

00:44:57.380 | both a reduction in noise, a quieting of the circuitry

00:45:00.660 | that we don't want to hear so much from,

00:45:03.260 | and an increase in the signal of the networks

00:45:06.920 | that we do want to pay attention to.

00:45:08.860 | And the net effect of that noise reduction

00:45:11.020 | and signal amplification is what the engineers refer to as

00:45:14.860 | increased signal to noise.

00:45:16.820 | And the consequence of that is a heightened subjective sense

00:45:21.100 | or ability to decide what we want to focus on,

00:45:24.600 | sit down or stand there, and just focus on it.

00:45:28.140 | So the way that we've been discussing drugs to treat ADHD

00:45:30.980 | and their ability to increase dopamine and norepinephrine,

00:45:34.340 | and thereby to reduce the amount of noise, so to speak,

00:45:38.220 | in the brain, and to increase the amount of signal

00:45:40.940 | related to things that we want to attend to,

00:45:43.740 | all presumes that the amount of dopamine

00:45:46.980 | and the amount of norepinephrine that's being increased

00:45:50.000 | is perfect for what we want to accomplish,

00:45:53.140 | which is increased focus

00:45:54.340 | and reduced hyperactivity and impulsivity.

00:45:57.120 | But of course, in the real world, that's not always the case

00:45:59.240 | depending on the dosage of the drug,

00:46:00.760 | one sensitivity to the drug,

00:46:02.760 | even what stage of development across the lifespan

00:46:06.200 | a person is at, things can really go haywire pretty fast.

00:46:10.580 | And what I'm referring to when I say haywire is,

00:46:14.300 | if you think about dopamine and its ability to reduce noise,

00:46:17.600 | well, dopamine does a bunch of other things as well.

00:46:20.060 | And in fact, we know that if dopamine is increased too much

00:46:24.100 | in the brain of somebody that has ADHD

00:46:25.820 | or somebody that doesn't have ADHD,

00:46:28.040 | people can become euphoric, people can become manic,

00:46:30.940 | people can even become psychotic.

00:46:32.580 | Likewise, if norepinephrine is increased too much,

00:46:36.020 | people won't just become alert,

00:46:37.580 | they will become very anxious, have panic attacks,

00:46:40.640 | and depending on the drug they're taking,

00:46:42.440 | they may even experience very serious peripheral symptoms,

00:46:45.900 | meaning elevated heart rate and sweating

00:46:48.600 | that is super uncomfortable and on and on.

00:46:51.320 | So everything I've been discussing up until now is true,

00:46:54.400 | but I want to make it clear that it's true in the context

00:46:57.080 | of appropriately dosed prescribed drug for a given condition

00:47:02.080 | which leads us to the next question,

00:47:04.480 | which is why would it be that giving these drugs

00:47:07.400 | which are in fact stimulants,

00:47:09.380 | why would that calm a kid down?

00:47:11.040 | Why would that calm an adult with ADHD down?

00:47:13.720 | And the answer to that is not completely straightforward

00:47:16.900 | and it is worth pointing out that not everyone with ADHD

00:47:21.040 | has impulsivity and hyperactivity

00:47:23.600 | and therefore an inability to focus.

00:47:25.880 | Some kids and adults with ADHD do have challenges

00:47:29.540 | with impulsivity and hyperactivity, some do not.

00:47:32.420 | Some just have challenges with focus.

00:47:34.900 | And I did an entire episode about ADHD

00:47:37.080 | and we are going to have an expert guest on this podcast

00:47:39.420 | who specializes in the treatment of ADHD

00:47:41.460 | to talk about some of these issues further.

00:47:43.680 | But I just want to remind everybody

00:47:45.680 | that as in the general population,

00:47:48.560 | children and adults with ADHD are capable

00:47:52.060 | of very concentrated periods of focus.

00:47:55.780 | The pattern however, tends to be that children and adults

00:47:58.960 | with ADHD have a harder time getting into that state of focus

00:48:02.960 | and perhaps most importantly, they have a very hard time

00:48:06.240 | getting into a forced state of focus

00:48:08.760 | for things that they don't enjoy doing.

00:48:11.160 | I'm sure many of you are also thinking,

00:48:12.920 | wait, I don't like to do certain things

00:48:14.700 | and it's harder to focus on those things

00:48:16.280 | than on the things I like.

00:48:17.360 | Of course, does that mean I have ADHD?

00:48:19.420 | And the answer is not necessarily so.

00:48:21.540 | Kids and adults with ADHD exhibit an extreme variation

00:48:27.040 | in their ability to focus such that if there's something

00:48:29.720 | they really, really like doing, they can indeed focus.

00:48:32.960 | However, for many, many other activities

00:48:35.680 | that are required in order to develop,

00:48:38.880 | I guess we'll just call it normal life advancement.

00:48:41.280 | So sitting still, listening to conversations

00:48:43.360 | that we may or may not be particularly interested in,

00:48:46.800 | that's where the challenge has come about.

00:48:48.720 | So the point is that these brain networks

00:48:50.760 | and these neuromodulators like dopamine and norepinephrine

00:48:53.200 | that we've been talking about in fairly straightforward

00:48:55.560 | terms as it relates to a drug's ability

00:48:58.700 | to increase their transmission and therefore

00:49:01.320 | an improved ability to focus presumes two things.

00:49:03.660 | It presumes that the dosing is right,

00:49:05.700 | that is that the levels of increases

00:49:07.800 | in these neuromodulators is just right.

00:49:10.040 | And I also just want to acknowledge that ADHD is,

00:49:12.680 | first of all, not an inability to focus at all.

00:49:16.040 | It is immense challenges in focusing

00:49:18.760 | on lots of different things as required

00:49:22.140 | for normal life progression.

00:49:24.040 | And it's also the case that there is no one specific pattern

00:49:28.120 | of ADHD that applies to everyone with ADHD.

00:49:30.720 | Some people, both kids and adults,

00:49:33.180 | will exhibit the hyperactivity, but not the impulsivity,

00:49:36.040 | although those two things tend to go hand in hand.

00:49:38.200 | Some people will have a challenge in focus

00:49:40.100 | without hyperactivity, impulsivity, and so forth.

00:49:42.560 | And all of this just really speaks

00:49:44.060 | to the complexity of ADHD, and yet,

00:49:46.740 | and yet we can confidently say that there are more drugs

00:49:50.560 | to treat ADHD than any other psychiatric condition.

00:49:53.980 | We've talked about a few of those now,

00:49:55.240 | but among those, Adderall, Vyvanse, Ritalin,

00:49:58.680 | also called methylphenidate, there are time-release versions.

00:50:02.020 | There are different variations

00:50:04.200 | on those time-release versions.

00:50:05.920 | There's even straight Dexedrine, which is prescribed

00:50:09.280 | for ADHD in some cases, and on and on.

00:50:12.340 | And you might also find it interesting to know

00:50:14.140 | that that very large kit of drugs, all of which,

00:50:17.040 | at least the ones we've talked about so far,

00:50:18.400 | are sympathomimetics, are stimulants,

00:50:20.800 | are more effective at treating ADHD

00:50:26.020 | than are any other collection of drugs

00:50:27.940 | for treating other psychiatric disorders.

00:50:30.080 | So what all of that diversity of symptomology and ADHD,

00:50:33.320 | as well as differences in sensitivity to drugs

00:50:36.960 | and individual variation, what all of that speaks to

00:50:39.200 | is that the large kit of drugs that's out there

00:50:42.800 | is designed to be assessed with the careful consult

00:50:46.040 | of a very qualified psychiatrist

00:50:48.120 | in order to allow the child or adult

00:50:50.080 | to arrive at the specific drug and the specific dosage

00:50:53.640 | that's ideal for their particular pattern of ADHD.

00:50:58.080 | And that issue actually gives rise to the answer

00:51:00.840 | to that now somewhat age-old question

00:51:03.280 | as to why giving stimulants to a kid that is hyperactive

00:51:06.440 | would calm them down.

00:51:07.440 | And the answer is that the hyperactivity, impulsivity,

00:51:11.000 | and focus issues present in ADHD in children and adults

00:51:15.880 | are the consequence not necessarily of deficient activity

00:51:20.680 | of neural circuits in the prefrontal cortex,

00:51:23.480 | or deficient activity of the default mode network,

00:51:26.920 | or deficient activity of the salience network, et cetera.

00:51:30.420 | What appears to be the case

00:51:31.640 | based on a lot of high quality neuroimaging data

00:51:35.000 | is that the brains of children and adults with ADHD

00:51:38.720 | have all of these networks functioning,

00:51:41.580 | but those networks are actually hyper-connected.

00:51:44.920 | That is, they tend to be co-active

00:51:47.160 | at times when ordinarily,

00:51:49.400 | meaning in kids and adults without ADHD,

00:51:52.260 | they would not be co-active.

00:51:54.860 | So that's an important point

00:51:56.320 | because it's easy to get the impression

00:51:58.920 | that ADHD is just a deficiency in dopamine and norepinephrine,

00:52:03.080 | and that's simply not the case.

00:52:04.420 | If you recall, dopamine and norepinephrine

00:52:06.780 | are neuromodulators.

00:52:08.200 | They modulate the activity of other neural circuits,

00:52:11.040 | and they can both increase and decrease activity

00:52:13.960 | within those circuits.

00:52:15.040 | So you don't necessarily want to think about dopamine

00:52:17.080 | and norepinephrine just as molecules

00:52:19.560 | that increase neural activity.

00:52:21.640 | And you certainly don't want to think about ADHD

00:52:23.560 | as just a deficiency in dopamine

00:52:25.700 | or deficiency in norepinephrine.

00:52:27.900 | The way these drugs work

00:52:29.440 | when they are used effectively to treat ADHD

00:52:32.220 | is to tune the amount of dopamine and norepinephrine

00:52:34.620 | that are present in particular brain networks

00:52:37.500 | in order to allow the person to arrive

00:52:39.660 | at just the right balance between the activation

00:52:42.340 | of these different neural circuits,

00:52:44.020 | causing them largely to be less synchronous in their firing.

00:52:48.420 | So this takes us back to this question

00:52:50.820 | of why giving stimulants to a kid would calm them down.

00:52:53.940 | It's not so much that you're giving a stimulant to a kid

00:52:57.240 | to place them into a state of calm.

00:52:59.480 | I think that's a common misconception.

00:53:01.400 | Rather, by increasing dopamine and norepinephrine,

00:53:04.280 | these drugs, yes, increase levels

00:53:06.660 | of overall autonomic arousal.

00:53:08.160 | They are, after all, sympathomimetics.

00:53:11.040 | But more importantly to the treatment of ADHD symptoms,

00:53:15.260 | you are activating the prefrontal cortex

00:53:17.720 | in a way that allows it to be more of a coordinator,

00:53:20.420 | of that orchestra conductor,

00:53:22.080 | or if you prefer the analogy to a teacher in the classroom,

00:53:24.760 | to ramp up the activity of certain neural circuits

00:53:27.820 | in a given moment and quiet down the activity

00:53:30.640 | of other neural circuits such that the default mode network

00:53:33.500 | can still perform its incredible actions.

00:53:35.260 | After all, the default mode network is involved

00:53:37.480 | not just in self-referencing and kind of daydreaming,

00:53:40.200 | but also creativity and imagination.

00:53:42.880 | That's been well described in the literature,

00:53:45.940 | as well as the salience network and these other networks

00:53:49.000 | that are designed to drop us

00:53:50.440 | into very narrow trenches of attention.

00:53:52.940 | These drugs for the treatment of ADHD are indeed stimulants,

00:53:57.040 | but the goal of prescribing these drugs

00:53:59.180 | to a child or adult with ADHD is to adjust dosage, timing,

00:54:04.180 | and the duration over which somebody takes it

00:54:06.920 | in their lifespan in order to allow those neural circuits

00:54:10.300 | to work in the proper way,

00:54:12.300 | meaning for the conductor to activate the instruments

00:54:15.640 | in that little symphony or band in the appropriate order

00:54:18.640 | in order to arrive at the right music

00:54:20.760 | as opposed to all the instruments playing at once,

00:54:22.840 | which would just be complete noise.

00:54:24.560 | Or again, if you prefer the classroom teaching analogy

00:54:27.820 | for the teacher to call on one student

00:54:29.520 | while the others are quiet

00:54:30.600 | and then to call on a different student,

00:54:31.960 | have one student return to their seats

00:54:33.280 | to have the students work in small groups.

00:54:34.940 | Again, all of this by analogy,

00:54:37.320 | the point being that dopamine and norepinephrine

00:54:40.640 | are all allowing these networks to be activated

00:54:43.220 | to the precisely correct levels

00:54:45.800 | and in the precisely correct sequence.

00:54:48.320 | Now, the other key aspect of drugs like Adderall,

00:54:51.400 | 5-ants, Ritalin, and similar to treat ADHD

00:54:55.600 | has everything to do with these neuromodulators,

00:54:58.040 | dopamine and norepinephrine,

00:54:59.800 | but it has to do with their other incredible feature

00:55:03.280 | besides just their ability to reduce noise

00:55:05.800 | and increase signal within these brain networks.

00:55:09.120 | And that incredibly important feature

00:55:11.540 | is what we call neuroplasticity

00:55:13.480 | or the brain and nervous system's ability to change

00:55:15.720 | in response to experience.

00:55:17.680 | I've done entire episodes of the Huberman Lab Podcast

00:55:20.140 | on neuroplasticity, what it is and how to access it

00:55:23.440 | at different stages of development and in adulthood.

00:55:26.960 | By the way, you can find those episodes at HubermanLab.com

00:55:29.700 | by simply searching plasticity in the search function.

00:55:32.640 | But the important thing to understand about plasticity

00:55:35.800 | in the context of today's discussion

00:55:38.080 | is that while there are many different ways

00:55:40.580 | to induce neuroplasticity,

00:55:43.200 | almost all of them, almost all of them

00:55:45.840 | involve strongly activating certain brain networks.

00:55:50.840 | And in that case, also strong or elevated release

00:55:56.220 | of certain neuromodulators.

00:55:58.360 | Now we've talked about dopamine and norepinephrine.

00:56:01.640 | They are but two of many neuromodulators.

00:56:04.860 | Others include serotonin, acetylcholine,

00:56:07.360 | and each of the neuromodulators does different things

00:56:10.140 | at different synapses in the brain.

00:56:11.900 | And there's some global statements

00:56:13.220 | that can be made about each of them.

00:56:14.640 | We made some of those earlier,

00:56:15.900 | like dopamine is broadly involved in motivation,

00:56:19.040 | craving and pursuit, and norepinephrine in signal detection

00:56:22.660 | and drawing a focus or salience

00:56:25.160 | to something in our environment

00:56:26.520 | or in our body or inner experience.

00:56:30.160 | Serotonin does other things.

00:56:31.300 | Acetylcholine does other things.

00:56:32.920 | But what's really important to understand

00:56:35.260 | is that any time there is a dramatic elevation

00:56:40.120 | in dopamine and norepinephrine relative to baseline,

00:56:44.040 | relative to what was happening

00:56:45.920 | with dopamine and norepinephrine just prior to that,

00:56:49.060 | that has a tendency to promote neuroplasticity

00:56:53.040 | at particular synapses.

00:56:55.000 | So here's where it's appropriate to remind everybody

00:56:58.100 | that neuromodulators are different than neurotransmitters.

00:57:01.120 | Neurotransmitters are chemicals

00:57:02.640 | that just like dopamine and norepinephrine

00:57:04.480 | are released between neurons,

00:57:05.760 | and they are what actually contribute

00:57:07.920 | to the electrical signals going up or down

00:57:09.880 | between different neurons.

00:57:10.840 | And again, dopamine and norepinephrine modulate

00:57:14.320 | that activity, causing a given amount of neurotransmitter

00:57:17.600 | to have an even greater effect, for instance.

00:57:21.480 | So when we hear about dopamine and norepinephrine

00:57:24.500 | and we hear about motivation or focus, et cetera,

00:57:27.920 | that's all fine and good.

00:57:29.400 | But it's also important to remember

00:57:30.860 | that when dopamine and norepinephrine are increased,

00:57:34.000 | there is a higher probability of strengthening connections

00:57:37.880 | where dopamine and norepinephrine are increased.

00:57:40.100 | And what that means is that later,

00:57:42.840 | even if levels of dopamine and norepinephrine

00:57:45.280 | are not increased, if they go back to baseline,

00:57:49.080 | it's often the case that if in our prior history

00:57:53.280 | or the history of a given set of neurons in our brain,

00:57:56.640 | there was more dopamine or norepinephrine around,

00:58:00.360 | it's very likely that the connections

00:58:02.500 | where that took place are strengthened

00:58:04.380 | and therefore more easily activated.

00:58:06.540 | And this takes us back to the really original purpose

00:58:10.560 | of prescribing these sympathomimetic stimulants

00:58:13.100 | to children with ADHD during development.

00:58:15.800 | It was, yes, designed to try and help them focus,

00:58:19.740 | to reduce their hyperactivity and help them focus.

00:58:22.820 | But it was also designed to help the brain networks

00:58:26.120 | that are responsible for focus to undergo neuroplasticity,

00:58:29.420 | that is, for the synapses involved to strengthen

00:58:32.400 | so that those networks could function more efficiently

00:58:35.240 | later on, even after cessation of the drug.

00:58:38.340 | This is an absolutely crucial point

00:58:40.460 | that I think is not often discussed

00:58:43.000 | when people, for instance, say,

00:58:44.860 | "Should I put my kid on ADHD meds

00:58:47.980 | "or should I take my kid off of ADHD meds

00:58:50.520 | "as they transition from adolescence

00:58:52.940 | "to their later teen years and into college?"

00:58:55.580 | I mean, after all, no child or parent,

00:58:58.300 | or adult for that matter,

00:58:59.620 | wants to achieve a bunch of benefits with a drug

00:59:02.040 | and then lose those benefits later.

00:59:05.060 | Nor does any parent or child want to take a drug

00:59:09.620 | that they don't need to take

00:59:11.380 | when they could access other routes

00:59:13.340 | to improving the neural circuitry

00:59:15.480 | or the function of some health system in the body,

00:59:17.640 | because I don't think anyone really wants

00:59:19.740 | to medicate their kids unless they have to.

00:59:21.740 | I would hope not.

00:59:22.740 | And I don't think any kid wants to be medicated

00:59:24.560 | unless they absolutely need to be medicated.

00:59:26.740 | So increasing dopamine and norepinephrine with these drugs,

00:59:29.300 | like Adderall, Vyvanse, Ritalin, and similar,

00:59:33.180 | is causing several things.

00:59:34.660 | And some of those things actually provide

00:59:37.780 | some general answers as to whether or not parents

00:59:40.660 | should put their kids on these compounds in the first place.

00:59:44.000 | Obviously, they're going to do that

00:59:46.200 | under the careful consult of a qualified psychiatrist,

00:59:49.060 | I would hope, and only under those circumstances,

00:59:51.860 | but also whether or not the child

00:59:53.220 | should stay on those drugs over time.

00:59:55.620 | And here's what we do know for sure.

00:59:58.080 | I did a vast search within the literature

01:00:01.220 | in order to arrive at what is very clear,

01:00:04.460 | which is that children with ADHD, true ADHD,

01:00:09.180 | who are diagnosed with ADHD and are treated

01:00:12.800 | with appropriate doses of drugs like Adderall,

01:00:16.520 | Ritalin, or Vyvanse,

01:00:18.220 | fare far better both in childhood and later in life

01:00:24.300 | when it comes to performance in school,

01:00:27.540 | performance in terms of focusing on anything,

01:00:30.060 | and in terms of general outcomes.

01:00:32.060 | So for instance, a lot of people have wondered

01:00:34.940 | and worried about whether or not treatment

01:00:37.420 | with these drugs early in life will set up a predisposition

01:00:40.840 | for illicit drug abuse

01:00:42.200 | or craving an addictive potential later.

01:00:44.820 | And it is very clear from the studies that have emerged

01:00:48.100 | over the last really 15 years,

01:00:50.540 | but mainly within the last five years,

01:00:53.260 | 'cause that's when most of the data have arrived,

01:00:55.580 | that children with ADHD who are not treated correctly,

01:01:00.640 | both with drugs and behavioral treatments,

01:01:02.660 | because really the combination of drugs

01:01:04.160 | and behavioral treatments is the optimal situation.

01:01:07.840 | So kids with ADHD who are not treated

01:01:11.320 | with drugs and behavioral treatments

01:01:13.820 | to deal with their ADHD have a much higher tendency

01:01:18.180 | towards illicit drug use and addictive drug potential

01:01:22.120 | in their adulthood, okay?

01:01:23.680 | So there is a real danger

01:01:25.380 | to not treating ADHD during childhood.

01:01:28.100 | And the reverse is also true,

01:01:29.620 | which is that children with ADHD

01:01:32.100 | who take prescription drugs that are sympathomimetics,

01:01:36.020 | so yes, as you've heard, they are speed,

01:01:38.820 | amphetamine is speed,

01:01:40.420 | although I should say if they take methylphenidate,

01:01:42.940 | Ritalin or Concerta or something of that sort,

01:01:45.440 | that's not amphetamine.

01:01:47.100 | Nonetheless, it's a stimulant,

01:01:48.540 | it's a sympathomimetic also.

01:01:51.120 | These are kids that are taking these drugs

01:01:52.480 | during development and therefore levels of dopamine,

01:01:55.200 | levels of norepinephrine are being increased

01:01:57.000 | in their brain and body.

01:01:59.000 | And you might say, well,

01:02:00.320 | wouldn't that lead to a craving

01:02:01.800 | for these things later in life?

01:02:03.240 | And that does not appear to be the case.

01:02:05.160 | In fact, there's some very nice neuroimaging studies,

01:02:08.200 | mainly positron emission tomography studies

01:02:10.320 | that I'll provide a link to in the show note captions

01:02:12.360 | that show the early treatment with these drugs

01:02:15.020 | actually leads to combinations

01:02:18.240 | of increased dopamine transmission

01:02:20.320 | in the forebrain later in life at a lower level

01:02:23.920 | or a lower threshold, I should say,

01:02:26.360 | in a way that essentially says there's normalization

01:02:29.660 | of the circuits across time

01:02:31.240 | by the application of these drugs early in life.

01:02:33.560 | Again, in the case of children that have diagnosed ADHD,

01:02:38.300 | I in no way, shape or form want to imply

01:02:40.040 | that all children should be treated with these drugs.

01:02:42.480 | That is quite clearly not going to be a good idea.

01:02:46.280 | So all of this really speaks to the critical importance

01:02:48.800 | of getting an accurate diagnosis of ADHD.

01:02:52.640 | Diagnostic criteria include many things in children.

01:02:55.960 | There are multiple, there are more than nine

01:02:58.640 | diagnostic criteria for each of the categories

01:03:01.360 | relating to impulsivity, hyperactivity, and so on.

01:03:04.080 | So a well-qualified psychiatrist will do several things.

01:03:07.740 | They will, first of all,

01:03:08.620 | do a careful diagnostic evaluation of a child.

01:03:12.720 | And in addition, one would hope that they would think about

01:03:15.660 | prescribing both appropriate pharmacologic treatments

01:03:18.740 | for ADHD, but also be aware of and prescribe

01:03:22.240 | the various other types of prescriptions,

01:03:24.680 | meaning behavioral prescriptions.

01:03:26.120 | So there are clearly certain learning tools

01:03:30.140 | and things that kids can do

01:03:31.920 | in order to improve their ability to focus

01:03:34.120 | and to be less impulsive

01:03:35.880 | that combine especially well with drug treatments,

01:03:38.500 | as well as new advancements in the realm of nutrition

01:03:41.920 | and supplementation that are constantly coming online.

01:03:44.280 | And the best psychiatrists are going to be tuned in

01:03:46.400 | to all of those aspects of treatment for ADHD,

01:03:48.800 | not just prescription drugs, but also behavioral treatments,

01:03:51.600 | also nutritional guidelines, also supplementation,

01:03:55.720 | and also updating each and all of those things

01:03:58.680 | as a child matures from each stage

01:04:01.200 | of development to the next.

01:04:03.240 | I'd like to take a quick break

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01:05:12.740 | Now, the other common question is,

01:05:14.320 | if a child has been treated

01:05:15.720 | with these ADHD meds during development,

01:05:18.040 | do they need to continue on those drugs indefinitely?

01:05:21.240 | And the short answer to this is it depends,

01:05:25.260 | and that can be a somewhat frustrating answer, I realize,

01:05:28.760 | but the good news is it's something that can be assessed

01:05:32.200 | in a fairly straightforward way.

01:05:34.620 | Let's recall that the use of these drugs to treat ADHD

01:05:37.220 | is designed to accomplish two things.

01:05:39.400 | It's designed to improve the function

01:05:42.360 | of those neural circuits that allow a child to focus,

01:05:47.160 | and it's also designed to increase the strength

01:05:50.120 | of those circuits to effectively teach the circuits

01:05:53.080 | how to learn what focus is.

01:05:55.440 | In other words, these drugs are designed,

01:05:58.040 | in some cases, to be used and then withdrawn later

01:06:01.800 | because the circuits that they helped build up

01:06:04.520 | are functioning well.

01:06:05.720 | In some cases, however, the circuits that underlie focus

01:06:09.280 | are not going to be able to function at the level required

01:06:12.640 | for normal healthy life progression

01:06:14.980 | unless there's continued application of the drug.

01:06:17.940 | So how would this work in the real world context?

01:06:20.700 | Well, I think any child or adolescent

01:06:24.620 | or person younger than 25 that's taken these drugs

01:06:27.740 | has no doubt achieved some level of neuroplasticity

01:06:32.340 | of the neural circuits related to all the things

01:06:34.780 | we call focus, and I want to be very clear.

01:06:37.540 | There is no single brain area or set of brain circuits

01:06:40.420 | for what I'm referring to as focus

01:06:42.900 | because after all, focus involves task switching,

01:06:45.420 | focus involves all sorts of different cognitive operations

01:06:48.800 | depending on what we're focusing on, right?

01:06:51.880 | Focusing on a sport is basically a practice

01:06:55.080 | of directing one's attention in different locations

01:06:58.020 | at different moments.

01:06:58.860 | Focusing on studying is an entirely different pattern

01:07:02.260 | of focus altogether, but the point being,

01:07:05.560 | if a person 25 years or younger takes a drug

01:07:08.660 | that increases dopamine and norepinephrine

01:07:10.880 | and assuming that things are working,

01:07:13.520 | meaning the dose is right,

01:07:15.560 | they're achieving better ability to focus, et cetera,

01:07:18.400 | those circuits are going to get stronger,

01:07:20.560 | and it seems entirely reasonable.

01:07:21.900 | In fact, it was supported by the psychiatrist

01:07:24.800 | that I spoke to prior to this episode

01:07:27.420 | that people who have been on ADHD meds

01:07:30.300 | for any point of time prior to 25

01:07:32.720 | talk to their psychiatrist

01:07:34.300 | about what tapering off those drugs

01:07:37.400 | in order to examine whether or not

01:07:39.640 | they still need those drugs would look like.

01:07:42.200 | Now, I mentioned the word taper

01:07:43.880 | because there is a withdrawal potential

01:07:46.560 | of simply stopping these drugs very quickly

01:07:49.560 | because they do ramp up dopamine and norepinephrine.

01:07:53.160 | Even though they increase plasticity of the neural circuits

01:07:55.600 | for focus and mood and motivation,

01:07:58.160 | if one very abruptly ceases taking any of these drugs,

01:08:02.720 | it does not feel good.

01:08:03.960 | That drop in dopamine that one inevitably experiences

01:08:08.040 | is almost always associated with lethargy,

01:08:11.000 | with depressed mood,

01:08:12.680 | with feeling not good in a number of ways,

01:08:14.660 | and of course, challenges in focus.

01:08:16.200 | So anytime one is going to go off one of these drugs

01:08:19.080 | or sample what it is to even reduce dosage,

01:08:21.360 | that has to be done in close communication

01:08:24.520 | with a board-certified psychiatrist.

01:08:26.800 | At the same time, it was made very clear to me

01:08:28.720 | from ADHD expert psychiatrist

01:08:31.840 | that reductions in dosage over time

01:08:35.080 | often are optimal for a patient, okay?

01:08:38.480 | And this gets to the whole issue of dosage generally.

01:08:41.360 | You know, I spend a good amount of time

01:08:43.300 | talking to somebody who prescribes these drugs,

01:08:45.680 | both to children and adults, about dosage ranges.

01:08:48.840 | And I don't want to spend too much time on this

01:08:51.480 | from the perspective of how much one should take.

01:08:54.060 | In fact, I don't want anyone to think

01:08:55.680 | that what I'm about to say

01:08:56.920 | should dictate what they should take specifically

01:08:59.600 | because that's something that really has to be worked out

01:09:01.520 | on an individual basis.

01:09:03.220 | But it is worth noting that if you look at the studies

01:09:06.200 | on Adderall and methylphenidate,

01:09:08.860 | what you'll see is a pretty broad range in those studies.

01:09:13.600 | And that's because some of the studies used people

01:09:17.100 | that were already taking these drugs

01:09:19.720 | and asked them to participate in neuroimaging studies.

01:09:22.760 | Other studies actually put people on these drugs

01:09:25.340 | for the very first time or adjusted their dosage.

01:09:28.100 | And so you'll see a tremendous range

01:09:30.640 | of drug doses explored.

01:09:31.980 | For instance, you will see anywhere

01:09:34.560 | from 10 to 40 milligrams of Adderall per day.

01:09:38.120 | You'll see anywhere from 10 to 60 milligrams

01:09:41.740 | of Ritalin per day.

01:09:43.200 | And here we could easily be talking about studies

01:09:45.520 | on children or adults.

01:09:46.780 | With respect to Vyvanse,

01:09:49.280 | you'll see that the dosages tend to be much higher.

01:09:51.880 | In part, that's because Vyvanse has, if you recall,

01:09:55.480 | it's that lysine, which is a big molecule

01:09:57.520 | stuck on d-amphetamine, which is a smaller molecule.

01:10:00.120 | And so the dosages of Vyvanse tend to be

01:10:02.320 | in the hundreds of milligram ranges,

01:10:04.420 | but most of that hundred milligrams of Vyvanse

01:10:07.860 | is not going to be the d-amphetamine.

01:10:09.620 | It's going to be the lysine, which doesn't do anything

01:10:11.940 | in the context of treating the brain.

01:10:13.580 | It's just there to control the slow release.

01:10:16.220 | So it's thought that a hundred milligrams of Vyvanse

01:10:18.840 | translates to roughly nine milligrams of Adderall

01:10:21.180 | and on and on.

01:10:22.020 | And actually it's pretty hard to translate

01:10:23.640 | between dosages of different drugs in any direct way.

01:10:26.120 | And in speaking with a psychiatrist expert in ADHD

01:10:29.540 | in preparation for this episode,

01:10:31.000 | he made very clear that it is extremely,

01:10:34.560 | extremely difficult to predict how a child or adult

01:10:38.500 | will react to a given dosage of any of these drugs.

01:10:41.900 | So much so in fact that he anecdotally reported to me

01:10:45.540 | that one of his patients is a male, 300 pounds,

01:10:49.260 | diagnosed with ADHD and who achieves tremendous relief

01:10:53.040 | from just 2.5 milligrams of Adderall per day.

01:10:57.320 | And at the same time, he has two patients,

01:10:59.940 | both of whom are sisters, so they're genetically related,

01:11:02.840 | who are in the 120 to 140 pound range

01:11:07.840 | who did not respond well at all

01:11:10.800 | for the treatment of their ADHD

01:11:12.800 | until their dosages were very, very high.

01:11:15.520 | And if I tell you these dosages,

01:11:16.840 | I just want to warn you in advance,

01:11:18.060 | I'm not suggesting anyone explore these dosages

01:11:21.160 | without of course the approval of their psychiatrist.

01:11:24.380 | Turns out that neither of these two young women responded

01:11:28.000 | at all to ADHD medication until they achieved dosages

01:11:31.620 | in the range of 180 in the case of one sister

01:11:34.900 | and 240 milligrams in the case of the other sister per day,

01:11:39.380 | which is an astronomically high dose on the face of it.

01:11:42.580 | But this physician, again,

01:11:43.980 | board certified physician expert in ADHD,

01:11:47.020 | verified for me that indeed neither of them

01:11:49.460 | experienced any discomfort or side effects

01:11:51.860 | that led them to not want to take the drug.

01:11:54.740 | But of course, that amount of Adderall

01:11:57.200 | could send somebody else into an absolute psychotic fit,

01:12:00.820 | could potentially even cause cardiac arrest.

01:12:03.680 | I mean, it's remarkable the ranges of Adderall

01:12:07.100 | that are used effectively in children and adults.

01:12:10.260 | And this is true for a lot of the other sympathomimetics

01:12:12.640 | used to treat ADHD.

01:12:14.300 | And of course, a good psychiatrist will always assess dosage

01:12:18.240 | as it relates to positive benefits, relief of symptoms.

01:12:22.480 | So relief of impulsivity, relief of hyperactivity,

01:12:26.380 | improvements in ability to focus.

01:12:28.880 | And of course, they are going to consider side effects,

01:12:31.980 | any uncomfortable adverse effects

01:12:34.260 | that come from taking the drug at a given dosage

01:12:37.120 | or taking the drug at all.

01:12:38.580 | Now, of course, this all begs the question

01:12:40.060 | of why such tremendous variation is this

01:12:43.480 | due to genetic differences in the amount of dopamine

01:12:45.620 | or norepinephrine that people make.

01:12:47.640 | It appears that the major underlying factor

01:12:50.980 | for why people require such vastly different dosages

01:12:53.980 | of these sympathomimetics for the relief of ADHD

01:12:57.160 | has to do with the different enzymes

01:12:59.420 | or levels of enzymes that people make

01:13:01.360 | which metabolize these drugs, both in the brain and body.

01:13:04.660 | And unfortunately, there is no simple blood test

01:13:07.780 | or saliva test or test of any kind

01:13:09.940 | that can predict how someone will respond to these drugs.

01:13:12.620 | So the most logical and safe way to assess dosage

01:13:16.860 | is to start with the lowest possible effective dose

01:13:20.500 | and to increase only as necessary

01:13:23.020 | in order to achieve the positive benefits

01:13:25.080 | while of course paying attention

01:13:26.380 | to any side effects that might arise.

01:13:28.400 | A question that comes up from time to time

01:13:30.160 | when discussing the long-term effects

01:13:32.260 | of drugs like Adderall, Ritalin, and Vyvanse

01:13:35.500 | is whether or not they can negatively impact height

01:13:38.820 | or growth or development in some other way.

01:13:41.980 | This is a logical question to ask

01:13:43.780 | because after all, these drugs are effectively

01:13:47.000 | mimicking stress in the body.

01:13:48.660 | And most everyone has heard by now

01:13:50.960 | that while stress can help us in the short term,

01:13:53.800 | it helps us deploy immune molecules

01:13:55.740 | to protect us against infection,

01:13:57.340 | it sharpens our visual focus

01:13:59.260 | and our ability to respond to things for survival,

01:14:02.300 | chronically elevating our stress over long periods of time,

01:14:05.760 | we know reduces the effectiveness of our immune system

01:14:09.140 | and can actually cause certain forms of brain degeneration.

01:14:12.220 | And while there aren't a lot of longitudinal studies

01:14:15.140 | on the heights of kids with ADHD,

01:14:17.860 | and of course we never can tell

01:14:20.060 | how tall someone would have grown to be

01:14:23.140 | if they were treated with a drug

01:14:24.420 | because we don't have a perfect control experiment

01:14:27.020 | even in the case of identical twin experiments

01:14:29.060 | and therein there aren't that many of those examples

01:14:32.140 | where one twin was treated for ADHD

01:14:34.660 | and the other wasn't, et cetera.

01:14:36.500 | But here's what we know.

01:14:37.860 | It does not appear that treatment

01:14:40.260 | with sympathomimetics during development

01:14:42.220 | provided the dosages are kept in the appropriate ranges

01:14:45.540 | is going to limit overall height.

01:14:48.780 | In fact, if you look at the data,

01:14:51.000 | it appears that children with ADHD

01:14:54.060 | who are treated with ADHD meds

01:14:55.740 | actually arrive at slightly higher BMIs, body mass indexes,

01:15:00.420 | compared to age-matched peers.

01:15:03.340 | Now, of course, body mass index

01:15:05.380 | doesn't necessarily correlate with height, right?

01:15:07.980 | Someone could not achieve a full height

01:15:09.700 | but could be heavier, either through bone or fat or muscle

01:15:13.340 | or combination of all three.

01:15:15.100 | But what we know is that the appropriate use

01:15:17.080 | of ADHD meds during development

01:15:18.900 | is not stunting development in any kind of overall way.

01:15:22.840 | It's not preventing maturation of the body

01:15:25.340 | in ways that are leading to reduced weight

01:15:27.860 | or somehow impaired growth overall.

01:15:30.460 | With that said, long-term elevations

01:15:32.900 | of sympathetic nervous system activity does carry some risk.

01:15:35.980 | And one of the primary risks that people have wondered about

01:15:39.860 | is cardiovascular risk.

01:15:41.500 | And this makes perfect sense, right?

01:15:42.860 | When you increase the activity

01:15:44.160 | of the sympathetic nervous system,

01:15:45.180 | you increase blood pressure, you increase heart rate,

01:15:48.140 | you increase, in some cases, peripheral sweating,

01:15:51.060 | you know, all the things that we associate with stress.

01:15:53.420 | So you can imagine that a child or adult with ADHD

01:15:55.960 | that takes these sympathomimetics every day,

01:15:59.020 | even if the dosage is kept in a range

01:16:01.040 | that doesn't allow them to experience

01:16:02.840 | any immediate untoward side effects,

01:16:05.340 | so they're not feeling miserable,

01:16:06.500 | they're just feeling like they can focus better.

01:16:08.720 | But one always wonders what's going on under the hood,

01:16:11.700 | so to speak.

01:16:13.260 | There is, as far as I know,

01:16:15.160 | one major study that's addressed this,

01:16:17.380 | and the conclusions of that study were a little bit hard

01:16:21.940 | to put into a single category.

01:16:24.540 | It did point to a subtle increase in cardiovascular risk,

01:16:29.040 | but the results did not point to anything so dramatic

01:16:33.140 | that the authors of the study warned against

01:16:36.000 | taking these drugs or encouraging people

01:16:37.720 | to cease taking these drugs,

01:16:39.200 | again, provided they're being prescribed

01:16:41.260 | by a board-certified physician for ADHD

01:16:43.780 | and at the appropriate dosage for that person.

01:16:46.820 | That said, I think this all, again,

01:16:49.220 | speaks to the importance of arriving

01:16:51.500 | at minimal effective dosage.

01:16:53.500 | And it stands to reason that if you're somebody

01:16:55.540 | who's taking ADHD meds,

01:16:57.220 | or if your child is taking ADHD meds,

01:17:00.140 | that one would want to do all the other things

01:17:02.540 | that they could do in order to try

01:17:04.140 | and improve cardiovascular health,

01:17:05.940 | or at least not put it at additional risk.

01:17:07.860 | So those are going to be the obvious things

01:17:09.580 | like avoiding smoking or vaping nicotine.

01:17:13.420 | Regular exercise is going to be encouraged,

01:17:16.580 | and things of that sort.

01:17:18.340 | And that dovetails into a bunch of other questions

01:17:20.300 | that are often asked any time the topic of Adderall

01:17:23.500 | or Ritalin comes up, which is, what about alcohol?

01:17:27.500 | You know, is drinking alcohol at the same time

01:17:29.940 | or at different times even going to be problematic

01:17:34.180 | if one is taking these drugs?

01:17:36.100 | Is taking benzodiazepines going to be a problem,

01:17:38.540 | et cetera, et cetera?

01:17:40.280 | There's a very straightforward answer to this,

01:17:41.820 | which is it's very clear that alcohol,

01:17:44.620 | certainly in children, but also in adults,

01:17:48.380 | is best not consumed.

01:17:50.860 | I did an entire episode about alcohol,

01:17:53.340 | which got into this and the data for this.

01:17:55.620 | If you've heard that having some alcohol,

01:17:57.540 | in particular red wine, is better for you than no alcohol,

01:17:59.740 | that is simply not true.

01:18:01.540 | Sorry, it's not true.

01:18:02.980 | Most adults who are not alcoholics

01:18:04.740 | can probably have up to two, that's right,

01:18:07.900 | two drinks per week and still be on the safe side of health,

01:18:11.500 | although zero is better than two.

01:18:13.460 | And once you get past two,

01:18:14.660 | you start seeing effects on various systems,

01:18:16.860 | including increased cancer risk,

01:18:19.260 | especially brain neuron loss and degeneration risk.

01:18:23.680 | I covered all of those data in the episode on alcohol

01:18:25.920 | that you can find at hubermanlab.com.

01:18:28.880 | Combining alcohol with sympathomimetics,

01:18:31.720 | even though they reside in very different pathways

01:18:34.040 | within the brain, in fact,

01:18:35.380 | the sympathomimetics are driving up

01:18:38.080 | sympathetic nervous system activity,

01:18:40.320 | whereas alcohol is actually doing the opposite,

01:18:42.320 | it's depressing it, and yet all the data point to the fact

01:18:45.860 | that combining alcohol with sympathomimetics,

01:18:48.920 | such as Vyvanse, Adderall, Ritalin,

01:18:51.500 | or any kind of amphetamine is going to be more detrimental

01:18:55.900 | to the brain and body than simply taking those drugs

01:18:58.940 | on their own.

01:18:59.840 | Put differently and more directly,

01:19:01.800 | if you are taking any of the drugs

01:19:03.880 | that we've been talking about to treat ADHD,

01:19:06.400 | or if you just happen to be taking them for whatever reason,

01:19:09.580 | you are going to want to avoid drinking alcohol at any time,

01:19:13.720 | and you're going to want to avoid benzodiazepines and similar

01:19:17.160 | unless they've been prescribed to you by your physician.

01:19:20.620 | In advance of this episode,

01:19:21.820 | I put a call out on social media for questions

01:19:24.220 | about Adderall, et cetera,

01:19:26.420 | and I got a lot of questions

01:19:28.480 | about whether or not there are impacts of these drugs

01:19:30.900 | on the hormone systems of the body,

01:19:33.420 | and if they impact the reproductive system in particular.

01:19:37.020 | I also got questions about whether or not these drugs

01:19:39.240 | impact sexual behavior or libido or anything of that sort.

01:19:44.240 | In reviewing the literature,

01:19:45.680 | what I can tell you is that there are very few studies,

01:19:48.920 | unfortunately, of the long-term effects of these drugs

01:19:51.800 | on the endocrine or hormone systems of the body,

01:19:55.300 | but we do know a few things for sure.

01:19:57.040 | First of all, when you increase the activity

01:19:58.800 | of the sympathetic nervous system for long periods of time,

01:20:01.520 | you are very likely increasing levels of cortisol.

01:20:04.840 | Cortisol is a quote-unquote stress hormone,

01:20:07.220 | but cortisol also plays some really important

01:20:09.420 | positive roles in your body.

01:20:10.780 | In fact, if you want cortisol released,

01:20:12.740 | especially early in the day,

01:20:14.440 | you don't want cortisol released so much late in the day.

01:20:17.560 | This actually relates back to timing

01:20:19.740 | and schedules of taking drugs.

01:20:21.080 | This is something, again, that needs to be worked out

01:20:23.220 | with your psychiatrist or your child's psychiatrist.

01:20:26.940 | But one of the reasons why there are so many different drugs

01:20:29.840 | for the treatment of ADHD is that each and all of them

01:20:33.040 | has a different time course of action.

01:20:35.120 | So Ritalin is very short-lived, which might sound bad

01:20:37.440 | because then you have to take it multiple times

01:20:38.960 | throughout the day.

01:20:40.020 | But if you think about from the perspective of sleep

01:20:42.220 | and the importance of having low cortisol at night

01:20:45.000 | and these drugs increase cortisol

01:20:46.600 | and the importance of getting sleep,

01:20:47.760 | because after all, sleep is the foundation

01:20:50.520 | of mental health, physical health,

01:20:51.640 | and performance in kids and adults.

01:20:53.480 | It's responsible for growth.

01:20:54.640 | It's when neuroplasticity happens.

01:20:56.160 | It's just so vitally important.

01:20:57.780 | A lot of the drugs that we've been talking about

01:21:00.520 | can severely limit one's ability to fall and stay asleep.

01:21:03.680 | And so a short-acting drug like Ritalin

01:21:05.760 | is actually attractive from the perspective

01:21:07.920 | of being able to take it in the morning

01:21:09.800 | and still get to sleep at night,

01:21:11.040 | or taking it in the morning and in the afternoon,

01:21:13.080 | and maybe even again in the evening,

01:21:14.600 | depending on the person,

01:21:16.440 | and then still being able to fall asleep at night.

01:21:19.400 | Whereas long duration release of D-amfetamine,

01:21:22.720 | which is what you get when you take Vyvanse,

01:21:25.720 | for some people is going to inhibit their sleep.

01:21:27.940 | They'll get a nice, steady rise and improvement in focus

01:21:31.660 | and reduction in hyperactivity,

01:21:33.000 | but they might have a lot of trouble

01:21:35.220 | falling asleep at night.

01:21:36.680 | And Adderall, having a somewhat intermediate

01:21:38.940 | time course of action between Ritalin,

01:21:40.440 | which is short-lived, and Vyvanse, which is very long-lived,

01:21:43.960 | perhaps is going to be the best solution for somebody else,

01:21:47.100 | where they can take it early in the day,

01:21:48.400 | perhaps at a low dose, maybe again later in the day,

01:21:50.880 | low dose, and then still fall asleep at night.

01:21:53.240 | But I've spoken to people,

01:21:54.680 | and I spoke to this clinician expert in ADHD

01:21:58.200 | who told me that some people will take

01:21:59.400 | as little as 2.5 milligrams of Adderall at 6 a.m.

01:22:04.400 | and have a hard time falling asleep

01:22:06.400 | later that night at 11 p.m.

01:22:08.220 | So again, vastly different sensitivities to these drugs,

01:22:11.820 | leading to vastly different requirements

01:22:14.740 | of dosage and timing of intake

01:22:16.520 | and which particular drug somebody might choose to

01:22:19.640 | or choose not to take.

01:22:21.400 | So how does that relate to hormones

01:22:23.160 | and sex and reproduction?

01:22:24.580 | Well, cortisol itself is a hormone.

01:22:27.360 | It can act as a bit of a hormone

01:22:29.500 | and a neurotransmitter in the brain,

01:22:32.200 | but for the most part,

01:22:33.560 | it's acting as a hormone in the brain and body,

01:22:36.600 | and it does a number of things.

01:22:38.060 | First of all, it can enhance your levels

01:22:40.260 | of focus and alertness.

01:22:41.680 | It can activate your immune system.

01:22:43.520 | I know the immunologists out there just cringe

01:22:45.400 | when I say activate the immune system.

01:22:47.000 | Your immune system is always doing various things,

01:22:49.880 | so it's always active,

01:22:50.740 | just as your nervous system is always active,

01:22:52.880 | but it can, to be specific,

01:22:55.760 | it can amplify or mobilize the release

01:22:59.360 | of anti-inflammatory molecules in your brain and body

01:23:02.280 | to combat different types of bacterial,

01:23:04.040 | viral, and fungal infections.

01:23:05.680 | It's doing an enormous number of positive things.

01:23:08.160 | It's also involved in setting mood.

01:23:10.240 | It has interactions with thyroid hormone pathways.

01:23:13.380 | I've done entire episodes about cortisol

01:23:15.420 | and cortisol regulation.

01:23:17.320 | To paint all of that with a very broad brush

01:23:20.620 | and briefly now,

01:23:22.180 | it's advantageous to have your cortisol release high

01:23:24.740 | in the early part of the day

01:23:26.100 | and to taper off toward the end of the day.

01:23:27.860 | In fact, late day elevations in cortisol

01:23:31.900 | are a strong correlate of depressive symptoms.

01:23:33.900 | This was demonstrated by my colleagues,

01:23:35.420 | David Spiegel and Robert Sapolsky

01:23:37.300 | at Stanford School of Medicine,

01:23:39.620 | but that is not to say that cortisol is bad.

01:23:42.060 | It's to say that the timing of cortisol release is key.

01:23:45.540 | So do these sympathomimetic drugs

01:23:49.660 | disrupt the endocrine system?

01:23:51.180 | Well, they can.

01:23:52.060 | If you are very awake and very alert,

01:23:54.060 | regardless of whether or not

01:23:55.200 | you're taking your sympathomimetic treatment for ADHD

01:23:58.040 | early in the day or late in the day,

01:23:59.940 | you are very likely experiencing elevations in cortisol

01:24:03.100 | late in the day.

01:24:04.200 | So it is important,

01:24:05.600 | even for those of you that like to study

01:24:07.600 | and need to focus in the evening and nighttime hours,

01:24:10.340 | that you try and limit your levels of overall alertness

01:24:13.260 | and certainly stress late in the day,

01:24:15.560 | because doing that day after day after day

01:24:18.060 | for several weeks or months or years

01:24:20.060 | can indeed disrupt other hormones in the endocrine system.

01:24:22.940 | And again, that's because cortisol

01:24:24.380 | is interacting with thyroid hormone

01:24:25.940 | and testosterone and estrogen.

01:24:27.780 | In fact, cortisol in many ways competes with

01:24:32.700 | or can out-compete for the production of testosterone

01:24:36.540 | and other so-called steroid hormones.

01:24:38.580 | Remember, cortisol itself is a corticosteroid hormone.

01:24:42.940 | So when we hear the word steroids,

01:24:44.200 | oftentimes people just think about athletes

01:24:45.880 | and steroid abuse in sports,

01:24:47.440 | but steroid hormones includes

01:24:48.980 | a lot of different types of hormones which are good for us.

01:24:51.180 | Our endogenous steroid hormones are vital

01:24:53.420 | for all sorts of things, vitality, reproduction, et cetera.

01:24:56.780 | And the way this works in general terms

01:25:00.060 | is that the cholesterol molecule

01:25:01.900 | is used to create testosterone and cortisol and estrogen.

01:25:07.780 | If we make too much cortisol,

01:25:09.960 | we in many ways are reducing

01:25:12.380 | the total amount of testosterone that we make

01:25:14.460 | or that is active.

01:25:15.460 | It's not exactly that straightforward,

01:25:18.300 | but we can make that statement with confidence.

01:25:21.940 | For instance, if you spike your cortisol

01:25:24.780 | just briefly during the day

01:25:25.900 | 'cause you have some sort of stressful event,

01:25:27.680 | that's not going to inhibit your testosterone.

01:25:29.580 | In fact, it probably is going to boost

01:25:31.100 | your testosterone levels somewhat.

01:25:32.860 | However, if your cortisol levels are chronically elevated,

01:25:36.080 | yes, indeed, it's likely that you're going to suppress

01:25:38.960 | your total and/or free unbound forms of testosterone.

01:25:42.460 | And downstream to that, you will experience effects

01:25:46.160 | such as reductions in libido,

01:25:47.640 | reductions in muscle and bone mass,

01:25:50.860 | reductions in all sorts of aspects

01:25:52.720 | of testosterone-related psychology and bodily biology.

01:25:57.120 | This is true for both males and females.

01:25:58.880 | And the same thing could be said for estrogen.

01:26:01.160 | Now, what's impossible for us to say

01:26:02.580 | is whether or not taking a given treatment for ADHD

01:26:05.280 | is going to, for instance, prevent a woman from ovulating.

01:26:08.080 | That could happen through chronic elevations in cortisol,

01:26:11.360 | but there's no direct link,

01:26:13.180 | meaning there are no studies, at least that I'm aware of,

01:26:15.680 | showing that people that take Adderall

01:26:17.580 | have irregular ovulatory cycles

01:26:20.740 | or that they cease menstruating entirely.

01:26:22.860 | I don't think there's any evidence for that whatsoever,

01:26:24.960 | nor is there any evidence that people that take Adderall

01:26:27.540 | or other sympathomimetics for the treatment of ADHD

01:26:30.340 | have lower overall testosterone.

01:26:32.780 | In fact, you can imagine all sorts of instances

01:26:34.540 | in which the opposite was true,

01:26:36.320 | that a child or young adult or adult who has ADHD

01:26:40.240 | but then goes on these meds to improve their symptoms

01:26:43.400 | is now focusing and achieving more in life.

01:26:45.400 | We know that happiness can impact dopamine and vice versa

01:26:48.960 | and testosterone levels and productivity itself

01:26:52.080 | and reaching our goals can feed back on the hormone system.

01:26:54.740 | So anytime there's a discussion about hormones

01:26:57.240 | or a study that shows that doing X or not doing Y

01:27:00.560 | impacts hormone levels of a given type,

01:27:02.720 | we have to be very careful to make sure

01:27:05.160 | that we're talking about causality

01:27:06.840 | because all of these hormones

01:27:08.180 | are in a very intricate crosstalk with one another.

01:27:11.640 | We can, however, make a very general statement,

01:27:14.020 | which is that when you are in states of stress

01:27:17.140 | for long periods of time,

01:27:18.700 | that is not a favorable condition for your immune system,

01:27:22.420 | your hormone system, or frankly,

01:27:24.360 | any other system in the brain and body.

01:27:26.560 | So the treatment of ADHD with these drugs

01:27:28.960 | should never be done at the expense

01:27:30.640 | of these other critical biological systems.

01:27:33.320 | Another common question and concern is whether or not kids,

01:27:37.160 | and I suppose for that matter,

01:27:38.360 | adults that take medication for ADHD

01:27:41.920 | are basically being predisposed to psychosis

01:27:45.520 | and/or other forms of addiction.

01:27:47.600 | And earlier we talked a bit about the risk for addiction

01:27:50.380 | and the take-home message there is very clear

01:27:52.400 | that kids and adults that are treated for ADHD appropriately,

01:27:57.360 | so with the appropriate dosage of the appropriate drugs

01:28:00.240 | under the supervision of a board-certified

01:28:02.400 | qualified psychiatrist, are at less risk

01:28:05.480 | for forming addictions to other substances in adulthood

01:28:10.480 | or other substances generally.

01:28:13.040 | I think a lot of people also wonder whether or not

01:28:15.080 | those kids and those adults that take these ADHD meds

01:28:18.800 | become addicted to the medications themselves.

01:28:21.760 | That's a bit of a tricky issue to resolve.

01:28:24.400 | Anytime one stops taking a drug or even tapers off a drug

01:28:28.200 | that's used to treat something where they feel better

01:28:31.160 | on the drug, they're going to experience two sets of effects

01:28:34.720 | and these two sets of effects are often confounded

01:28:37.020 | with one another.

01:28:37.860 | One is the withdrawal effects,

01:28:40.120 | so the effects of removing the drug

01:28:41.880 | that makes somebody feel less good than baseline.

01:28:44.840 | So for instance, a kid that takes ADHD meds

01:28:48.620 | until their late teens or early 20s

01:28:50.660 | decides they're going to taper off, they do that,

01:28:53.520 | and they're feeling lousy during the taper

01:28:55.860 | or when they reduce their dosage to zero,

01:28:57.880 | they're foggy brain, they can't focus,

01:29:02.020 | they feel a little bit depressed mood.

01:29:04.480 | It's unclear whether or not those are withdrawal symptoms

01:29:08.000 | or whether or not those are the consequence

01:29:09.940 | of not having the systems in their brain activated

01:29:13.520 | the way that those systems were activated before.

01:29:16.080 | I realize that for some of you

01:29:17.080 | that might seem like the same thing,

01:29:18.560 | but that's not necessarily the same thing.

01:29:20.400 | And probably the best analogy would be

01:29:22.680 | something along the lines of a hangover, right?

01:29:25.180 | If somebody drinks too much on a given night,

01:29:27.720 | the next morning they have a hangover,

01:29:29.400 | the hangover makes them feel lousy.

01:29:31.640 | It is actually a withdrawal from alcohol effect.

01:29:34.560 | But then when they recover from the hangover,

01:29:37.340 | they realize that their sober state feels pretty good.

01:29:40.720 | It doesn't obviously feel the same as being on alcohol,

01:29:43.400 | but that sober state is not a state of withdrawal, okay?

01:29:47.480 | If we were to look at removal

01:29:49.760 | or tapering off of ADHD meds,

01:29:52.280 | there's going to be a period of withdrawal symptoms,

01:29:54.880 | but then the real question is how does somebody feel

01:29:57.120 | after they get through those withdrawal symptoms?

01:29:59.240 | So that's an important issue to highlight.

01:30:01.120 | Now, in terms of psychosis,

01:30:02.360 | this is a very interesting and very important literature.

01:30:05.280 | First of all, any amphetamine,

01:30:07.520 | whether or not it's D-amphetamine, L-amphetamine,

01:30:09.960 | and also methylphenidate for that matter,

01:30:11.960 | Ritalin, can induce psychosis.

01:30:15.300 | Now, there are a number of different factors

01:30:17.240 | that are going to predispose somebody to psychosis.

01:30:20.080 | Having a first relative who's had psychotic episodes,

01:30:22.640 | either schizophrenic episodes or bipolar episodes

01:30:25.840 | is certainly a strong predisposition.

01:30:29.280 | Of course, if an individual themselves

01:30:30.920 | have had psychotic episodes,

01:30:33.220 | that's the strongest predisposition that one can imagine.

01:30:37.160 | So having a first relative with schizophrenia

01:30:39.760 | or with bipolar depression,

01:30:41.680 | or it's sometimes called bipolar disorder,

01:30:43.320 | sometimes it's also just called bipolar these days,

01:30:46.840 | is going to be a strong predisposition

01:30:49.500 | for psychotic episodes made much greater

01:30:53.440 | anytime one takes a sympathomimetic drug,

01:30:55.940 | such as amphetamine, but also methylphenidate, Ritalin,

01:30:59.240 | is going to increase that likelihood of psychotic episodes.

01:31:03.320 | Then comes the question of,

01:31:04.660 | if somebody has a psychotic episode

01:31:06.520 | as the consequence of taking any of these drugs,

01:31:09.920 | whether or not it's been prescribed for ADHD or not,

01:31:12.780 | will those psychotic symptoms go away

01:31:15.080 | after the person stops taking the drug?

01:31:17.520 | There appears to be a divide in the literature,

01:31:19.840 | or rather a divide according to drug,

01:31:22.120 | such that people that take Ritalin, methylphenidate,

01:31:24.840 | and have a psychotic episode, often, not always,

01:31:27.880 | but most often if they stop taking methylphenidate,

01:31:32.160 | the psychotic episode will cease.

01:31:34.920 | Not always the case, but most often times it will cease.

01:31:37.800 | Whereas in individuals who have a predisposition to psychosis

01:31:42.100 | or even if they're not aware

01:31:43.240 | of a predisposition to psychosis and they take Adderall,

01:31:46.640 | which as you recall is a combination of D and L-amphetamine,

01:31:50.520 | they can have psychotic episodes

01:31:52.580 | that sometimes are very long lasting

01:31:54.560 | even after the cessation of the drug.

01:31:57.160 | And while that might sound kind of shocking

01:31:59.480 | and really scary, and indeed it is scary,

01:32:01.680 | it perhaps shouldn't shock us that much

01:32:04.820 | because if you recall, D-amphetamine,

01:32:07.360 | which there's a lot of in Adderall,

01:32:09.980 | it's a very potent way of increasing dopamine.

01:32:13.320 | And anytime you potently increase dopamine

01:32:15.840 | in a person who has a predisposition to psychotic episodes,

01:32:19.480 | you are shifting the whole system

01:32:21.300 | toward a greater propensity for psychosis.

01:32:24.840 | This would also be the appropriate time

01:32:26.220 | to talk about meth, methamphetamine.

01:32:29.120 | Again, methamphetamine is considered an illicit drug,

01:32:32.360 | a drug of abuse.

01:32:33.640 | It is responsible for a lot of the misfortune

01:32:36.960 | and tragedy that you see on the streets of major cities

01:32:40.480 | and even outside of major cities and rural areas.

01:32:43.600 | It has all sorts of negative effects on health,

01:32:46.640 | including oral health, cardiovascular health.

01:32:49.960 | It is neurotoxic to serotonergic neurons,

01:32:53.260 | so it kills serotonin neurons, that is absolutely clear.

01:32:56.520 | It kills dopaminergic neurons, that is absolutely clear.

01:33:00.460 | One of the ways that methamphetamine

01:33:01.760 | creates so many of the problems that it does,

01:33:04.200 | getting effects on the body,

01:33:06.040 | abuse potential, addictive potential,

01:33:08.760 | the fact that methamphetamine can spark psychosis

01:33:12.440 | in those that have a predisposition to psychosis,

01:33:14.480 | but also that it can create psychosis

01:33:17.000 | in individuals who have no predisposition to psychosis.

01:33:20.920 | All of this points to methamphetamine

01:33:22.440 | just being a terrible drug all around.

01:33:25.120 | And yet, if you recall back to the beginning of the episode,

01:33:27.300 | there is one form of prescription methamphetamine,

01:33:30.460 | but its uses are extremely narrow,

01:33:33.080 | and it's probably best left out of this conversation

01:33:36.020 | because its uses are so, so narrow in the clinical sense.

01:33:39.880 | I managed to talk to one expert.

01:33:41.360 | This is a board-certified psychiatrist

01:33:42.980 | who's expert in ADHD, who is also very familiar

01:33:46.280 | with the psychosis symptoms induced by methamphetamine

01:33:50.840 | and by various ADHD drugs

01:33:53.060 | and people who have the predisposition.

01:33:55.060 | They made it very clear that any of the sympathomimetic

01:33:57.780 | ADHD drugs that are of the amphetamine variety,

01:34:01.760 | so that would be Adderall and extended-release Adderall,

01:34:06.480 | that would be pure Dexedrine,

01:34:08.340 | or any variants that include amphetamine

01:34:11.160 | are going to have higher likelihood of inducing psychosis

01:34:15.140 | in people that have a predisposition to psychosis.

01:34:18.240 | And yet, they did assure me

01:34:20.080 | that at appropriately prescribed and safe dosages,

01:34:24.260 | that the total incidence of psychosis

01:34:26.540 | in people that take those drugs is still fairly low

01:34:30.020 | and not that much greater than in the general population,

01:34:33.240 | although there is an increased risk, it's not that severe.

01:34:37.000 | And they also highlighted the fact

01:34:38.480 | that methylphenidate Ritalin carries a lower potential

01:34:41.520 | for inducing psychosis, not zero,

01:34:44.560 | but a lower level of inducing psychosis.

01:34:46.960 | Then for the amphetamine-type sympathomimetics,

01:34:49.780 | now one exception is Vyvanse,

01:34:51.640 | that long-release d-amphetamine that we talked about earlier.

01:34:54.960 | There does seem to be something protective

01:34:56.920 | about that long-duration release of d-amphetamine

01:34:59.360 | that occurs with Vyvanse,

01:35:01.080 | which is not to say that there's zero abuse

01:35:03.880 | or addictive potential with Vyvanse.

01:35:07.120 | I was told by this same individual

01:35:09.080 | that indeed they've had knowledge of patients

01:35:12.880 | trying to increase the rate of absorption of Vyvanse

01:35:16.280 | and release of Vyvanse, or technically of the d-amphetamine,

01:35:19.880 | in order to get more of a high from Vyvanse

01:35:22.560 | as opposed to just the extended release.

01:35:24.580 | But they did assure me, however,

01:35:26.200 | that Vyvanse seems to be associated

01:35:27.600 | with fewer psychotic episodes

01:35:29.040 | and less abuse and addictive potential overall,

01:35:31.920 | which again is not to say that it's a perfectly safe drug,

01:35:34.860 | but really this just highlights the fact

01:35:36.480 | that the kinetics or the time course

01:35:38.840 | of dopamine and norepinephrine release

01:35:40.640 | that's caused by a given drug

01:35:42.200 | is going to correlate very strongly

01:35:43.920 | with its abuse potential and addictive potential

01:35:46.280 | and its potential to induce psychotic episodes.

01:35:48.720 | And this is where the discussion about meth

01:35:50.400 | becomes especially relevant.

01:35:51.840 | One of the reasons why meth is so dangerous

01:35:54.220 | in terms of its addictive potential

01:35:56.400 | and its potential to induce psychotic episodes

01:35:58.920 | is first of all, how much dopamine it releases,

01:36:02.160 | again, five times more than any of the other drugs

01:36:04.240 | that we've been talking about,

01:36:05.260 | but also how fast that peak comes on.

01:36:08.080 | It's a very fast onset.

01:36:09.660 | And that's true whether or not people are snorting it,

01:36:11.680 | whether or not they're taking it orally,

01:36:12.880 | or especially if they inject it intravenously.

01:36:15.760 | But meth, because it increases dopamine so fast

01:36:19.600 | and to such a great degree,

01:36:21.000 | and then the peak in dopamine comes down very fast as well,

01:36:25.440 | and it drops below the baseline levels of dopamine

01:36:28.600 | that were present initially,

01:36:30.120 | that's one of the reasons why methamphetamine

01:36:31.920 | is so dangerous in terms of addiction

01:36:33.960 | and in terms of psychotic episodes.

01:36:36.020 | Now, this gets back to a bunch of issues

01:36:38.120 | we've talked about before on the Huberman Lab Podcast

01:36:40.300 | about dopamine kinetics.

01:36:41.700 | And I've done two episodes on dopamine

01:36:43.360 | that I'll refer you to.

01:36:44.200 | One is called "Dopamine Motivation and Drive,"

01:36:46.020 | which is all about dopamine and regulating dopamine.

01:36:48.420 | And the other one is about optimizing dopamine.

01:36:50.920 | It's more of a toolkit focused episode,

01:36:52.700 | both of those you can find at HubermanLab.com.

01:36:54.680 | But the general takeaway that's relevant

01:36:56.700 | for what we're talking about now is that with dopamine,

01:36:59.180 | it's not just about the absolute levels of dopamine

01:37:01.740 | that are reached, but how long lasting

01:37:04.240 | those increases in dopamine are.

01:37:06.380 | So with Vyvanse, even though Vyvanse is D-amphetamine,

01:37:11.220 | it's fairly potent, not as potent as meth,

01:37:14.020 | but fairly potent at increasing dopamine and norepinephrine,

01:37:17.760 | it's a long extended release in dopamine and norepinephrine,

01:37:21.340 | which reduces its overall abuse potential

01:37:23.660 | because it doesn't tend to create that immediate euphoria

01:37:26.780 | and high and then crash below baseline.

01:37:30.920 | A lot of you will hear that it increases dopamine a lot

01:37:33.300 | and then stays up as translating to,

01:37:36.440 | okay, well then you're just euphoric for 16 hours,

01:37:38.940 | but that's not the case.

01:37:40.180 | When it comes to dopamine,

01:37:41.820 | it's an issue of how high that peak is

01:37:44.540 | and whether or not that peak is stable

01:37:46.220 | or whether or not it comes down again.

01:37:48.100 | And when it comes to psychotic episodes

01:37:50.300 | or addictive potential, it seems that any drug or behavior

01:37:54.080 | that increases dopamine very quickly

01:37:55.920 | and then brings dopamine down very quickly

01:37:59.340 | is what sets the high potential for addiction and abuse

01:38:02.980 | and for inducing psychotic episodes.

01:38:04.860 | So that's why I'm talking about these two things in parallel.

01:38:07.720 | And now it should be very clear why Vyvanse

01:38:10.960 | doesn't have so much addictive and abuse potential

01:38:13.620 | and has at least lower potential

01:38:16.060 | for inducing psychotic episodes.

01:38:17.580 | And it should also be clear to you

01:38:19.300 | that for people who do not have ADHD as a child

01:38:25.700 | or for people that do not have ADHD in adulthood,

01:38:29.660 | if they were to take any, truly any of the compounds

01:38:33.080 | that we're talking about thus far,

01:38:35.220 | methylphenidate, Ritalin, Adderall, Vyvanse,

01:38:39.080 | Dexedrine, and certainly methamphetamine,

01:38:41.780 | what we observe from neuroimaging studies

01:38:44.000 | is that these people get enormous increases in dopamine.

01:38:47.800 | They're not familiar with these drugs,

01:38:49.220 | so the increases in dopamine are just cosmic for them.

01:38:53.060 | They experience a lot of euphoria.

01:38:55.420 | Even if the dosages are low,

01:38:56.940 | the euphoria is associated

01:38:58.460 | with a very heightened degree of focus

01:39:00.700 | they've never really felt before.

01:39:02.020 | Here, what I'm talking about is a lot of the recreational

01:39:04.560 | and off-prescription use of Adderall and things like it.

01:39:08.060 | And what we know is that that sets in motion

01:39:11.660 | both a potential for abuse and addiction

01:39:14.860 | to that feeling and substance,

01:39:17.200 | as well as a higher potential

01:39:19.420 | for psychotic episodes down the road, okay?

01:39:22.120 | So put differently, children who have ADHD

01:39:25.520 | and are prescribed any of these drugs,

01:39:28.520 | or adults who have ADHD

01:39:31.000 | and are prescribed any of these drugs,

01:39:32.640 | who take them for some period of time,

01:39:34.820 | are actually at lesser risk to all of the issues

01:39:39.240 | related to having chronically elevated

01:39:41.860 | and greatly elevated dopamine

01:39:43.920 | as a kind of first-time event or as a rare event,

01:39:46.920 | whereas anyone who takes these drugs without a prescription

01:39:50.760 | and decides, okay, I want to focus more,

01:39:52.660 | or I'm going to use this to stay up for a couple of days,

01:39:55.460 | in other words, using it recreationally

01:39:57.740 | or using it for, quote unquote, performance enhancement,

01:40:00.460 | is at far greater risk for addiction to these substances

01:40:04.260 | because of the amplitude and the time course of dopamine

01:40:08.220 | that results when one takes these drugs

01:40:10.220 | just out of the blue.

01:40:11.860 | And so for that reason,

01:40:13.360 | I really want to caution everybody

01:40:15.440 | against using any of the compounds

01:40:17.500 | that I've discussed thus far,

01:40:19.260 | unless it's been prescribed to you by a physician

01:40:21.820 | for the specific purpose of ADHD.

01:40:25.100 | Now I'm sure someone out there is screaming from the back,

01:40:27.420 | wait, if a kid takes these drugs

01:40:30.520 | because they're prescribed them for ADHD

01:40:32.720 | the very first time they take them,

01:40:34.140 | they're going to have a huge amplitude dopamine response.

01:40:37.940 | Or if an adult goes in and talks to their psychiatrist

01:40:41.640 | and says, you know, I'm having issues with focusing

01:40:43.740 | and they're prescribed one of these meds for ADHD

01:40:46.060 | and they take it,

01:40:46.900 | they're going to have a huge amplitude dopamine response.

01:40:49.460 | Isn't that going to set in motion all the same things

01:40:52.020 | that somebody who is using these drugs recreationally

01:40:54.740 | would have?

01:40:55.580 | And indeed, that's one of the reasons

01:40:57.740 | why a lot of psychiatrists will start with a very low dosage

01:41:01.220 | or the lowest possible dosage

01:41:03.460 | to see how somebody responds to that low dosage.

01:41:06.540 | And then over time might or might not increase that dosage.

01:41:10.140 | In fact, they might even bring it down further

01:41:11.860 | depending on how sensitive somebody is to the drug.

01:41:14.260 | But equally important is the fact that

01:41:17.420 | it is the repeated taking of that drug

01:41:20.340 | by the child with ADHD or by the adult with ADHD

01:41:23.820 | that actually leads to lesser and lesser peaks

01:41:27.080 | in dopamine each time,

01:41:28.740 | which is not to say that the person

01:41:30.580 | becomes entirely desensitized to the effects of the drug,

01:41:33.740 | but rather that the system equilibrates

01:41:35.920 | through what's called homeostatic plasticity.

01:41:37.900 | It's sometimes referred to broadly as habituation to a drug,

01:41:41.300 | but there are systems in the brain and body

01:41:43.980 | that regulate the connections between neurons

01:41:46.340 | so that if dopamine and norepinephrine

01:41:48.500 | are elevated above baseline levels for a while,

01:41:52.080 | the system normalizes so that instead

01:41:55.800 | the connections between neurons become stronger

01:41:58.420 | and there isn't the critical requirement

01:42:00.440 | for all that increase in dopamine and norepinephrine.

01:42:03.040 | I realize that might sound a little bit technical,

01:42:04.680 | but basically what I'm saying is

01:42:06.060 | the response that somebody has to taking a drug

01:42:08.360 | for the first time is far and away different

01:42:11.560 | than the response to a drug that somebody has

01:42:14.060 | if they are taking the same drug day after day after day.

01:42:18.020 | This gets to another issue,

01:42:19.260 | which is not discussed that often these days,

01:42:21.600 | but that is really important.

01:42:22.840 | If you go back to the original clinical literature

01:42:24.760 | on these sympathomimetics,

01:42:26.800 | what you'll find is that the original use

01:42:30.000 | of these sympathomimetics to treat childhood ADHD

01:42:32.980 | suggested that children not take these drugs

01:42:36.400 | every single day.

01:42:37.440 | Now, I'm not recommending that kids take drug holidays

01:42:40.640 | because I'm not a clinician,

01:42:41.960 | I'm not promoting any specific dose or dosing regimen,

01:42:46.200 | but in speaking again to a psychiatrist expert in ADHD,

01:42:50.600 | who by the way is going to be a guest on this podcast

01:42:52.680 | in the not too distant future,

01:42:54.560 | what he told me was that many of these drugs

01:42:56.880 | were designed to be taken during the school week

01:42:59.440 | for children with weekends off

01:43:01.900 | or during the school year with weekends off,

01:43:04.300 | but then also with vacations during the summer holidays.

01:43:07.640 | And that these days rarely, if ever,

01:43:10.480 | is that the pattern of intake that these kids are following.

01:43:14.920 | And why that is has interesting sociological

01:43:18.160 | and financial explanations.

01:43:20.640 | I'm not alluding to any kind of conspiracy here,

01:43:22.620 | but this is an aspect of the dosing with these drugs

01:43:25.880 | that has fallen away in recent years,

01:43:28.720 | but I think is really interesting.

01:43:30.040 | And it's something that actually was supported

01:43:32.480 | for the treatment of adult ADHD as well.

01:43:35.200 | Again, there is a very different biological

01:43:39.520 | and neuroplastic response to taking a drug once

01:43:43.000 | versus taking a drug for say five days

01:43:46.040 | and then taking weekends off

01:43:47.280 | to taking a drug over and over again every single day

01:43:51.080 | for a pattern of years.

01:43:52.540 | And when exploring the literature

01:43:54.600 | in preparation for this episode,

01:43:56.320 | I confess it was a bit dizzying to find answers

01:43:59.120 | to what are the long-term effects of taking Adderall

01:44:01.540 | or what are the long-term effects

01:44:02.780 | of taking Vyvanse, et cetera.

01:44:04.700 | In fact, most of the literature on the long-term effects

01:44:07.380 | of taking drugs to treat ADHD

01:44:09.700 | has focused on methylphenidate on Ritalin.

01:44:11.840 | There are studies on Vyvanse and Adderall,

01:44:14.060 | and actually those were the studies

01:44:15.980 | that I will link in the show note captions primarily,

01:44:19.760 | 'cause that's where most of the interest is these days.

01:44:22.140 | The reason why so many of the studies have focused

01:44:26.200 | on methylphenidate on Ritalin is largely

01:44:29.000 | because that was one of the first drugs used to treat ADHD.

01:44:32.060 | So in terms of addressing long-term effects

01:44:34.860 | of kids treated with ADHD meds,

01:44:37.260 | those kids are now adults

01:44:39.480 | and therefore can be neuroimaged and assessed.

01:44:42.040 | Whereas a lot of kids that have been prescribed Adderall

01:44:44.640 | or Vyvanse or similar have not yet made it to stages of life

01:44:48.720 | in which we can answer that question directly.

01:44:50.500 | There are a few studies and I've made it clear

01:44:52.880 | to include those studies in my description of results today.

01:44:55.680 | In particular, the results I talked about earlier

01:44:58.120 | where there's an improvement in executive function

01:45:01.840 | in kids that have taken ADHD meds

01:45:04.320 | or adults that have taken ADHD meds

01:45:06.520 | for a longer period of time, anywhere from months to years,

01:45:10.460 | those studies did include both Adderall and Vyvanse

01:45:13.740 | and methylphenidate, and again, I'll link to those studies.

01:45:16.480 | But by and large, most of what we know

01:45:18.000 | about the long-term effects of any of these drugs

01:45:20.480 | has to do primarily with studies of methylphenidate.

01:45:23.880 | I'd like to spend a little bit of time

01:45:25.320 | talking about some compounds

01:45:26.880 | that are not considered amphetamines at all,

01:45:30.360 | but that are now being used to treat ADHD

01:45:33.160 | both in children and adults more frequently.

01:45:36.000 | The major drug in this category

01:45:37.520 | of non-amphetamine treatments for ADHD is modafinil,

01:45:41.980 | which is also called by its commercial name, Provagil.

01:45:45.940 | There's a variant on this, which is armodafinil,

01:45:48.280 | which goes by the brand name Nuvagil.

01:45:50.380 | The major difference between modafinil and armodafinil,

01:45:54.480 | aside from having a slight chemical difference,

01:45:57.040 | is that modafinil was released first,

01:45:59.940 | armodafinil is the second in the generation of these drugs,

01:46:03.620 | and modafinil tends to be very expensive.

01:46:06.860 | That's one of the reasons

01:46:07.800 | why it's prohibitive for some people to take.

01:46:09.380 | It can be as expensive as $25 a pill or more,

01:46:12.240 | so more than $1,000 per month.

01:46:14.720 | And armodafinil tends to be far, far less expensive.

01:46:18.940 | I've talked to a couple experts

01:46:20.220 | about whether or not there are any genuine differences

01:46:22.680 | between these two drugs, and they report no,

01:46:26.920 | although consumers of these drugs, for whatever reason,

01:46:30.600 | whether or not it's placebo or not,

01:46:32.660 | report yes, there is a difference.

01:46:34.400 | When I say placebo, I in no way mean

01:46:36.800 | that these drugs are just acting as placebo,

01:46:38.600 | I just mean that people tend to get very attached

01:46:41.480 | to certain drugs and whether or not the brand name

01:46:43.760 | or the generic version works better for them.

01:46:45.880 | There's all sorts of lore about this.

01:46:48.180 | In fact, there are a lot of people out there

01:46:50.720 | who strongly feel that brand name Adderall

01:46:54.620 | works better than generic Adderall for them.

01:46:58.880 | There are a lot of people out there

01:46:59.960 | who say the same thing about Vyvanse.

01:47:01.640 | There are a lot of people out there

01:47:02.480 | who say the same thing about Ritalin and all sorts of drugs.

01:47:04.500 | Whether or not that's true or not is unclear.

01:47:07.720 | It is clear that generic versions of drugs can use binders

01:47:11.880 | and other things that are in the pill or capsule

01:47:14.820 | that are different than what the brand name pillar capsule

01:47:17.220 | uses as binders to hold the drug together,

01:47:19.280 | and that can impact rates of release and metabolism, et cetera.

01:47:22.940 | But a lot of this is just lore.

01:47:24.640 | In fact, I went into the literature

01:47:26.040 | to try and find any real concrete support

01:47:29.420 | for the idea that generic Adderall is less potent

01:47:33.280 | or less effective than brand name Adderall.

01:47:35.720 | And despite the tens of thousands of people

01:47:38.260 | who will say to the contrary,

01:47:40.520 | I could not find any peer-reviewed published data about that.

01:47:43.840 | So who knows?

01:47:44.680 | Maybe it's a belief effect as it's called.

01:47:46.880 | Maybe there's a real difference there.

01:47:48.600 | Nowadays, modafinil and armodafinil

01:47:50.440 | are prescribed for a huge range

01:47:52.920 | of daytime sleepiness issues.

01:47:55.080 | And we were talking about narcolepsy,

01:47:57.940 | but there are also people who suffer

01:47:59.300 | from daytime sleepiness related to dementia,

01:48:02.260 | daytime sleepiness related to post-surgery anesthesia.

01:48:06.780 | So there's this thing where people have surgery

01:48:09.420 | and then they come out of surgery

01:48:11.100 | and they feel better for a few days,

01:48:12.580 | but then they find that they aren't recovering

01:48:14.240 | their normal levels of wakefulness.

01:48:15.820 | So it's prescribed sometimes to try and get people back

01:48:17.900 | into a normal state of wakefulness.

01:48:19.880 | It's been prescribed for traumatic head injury after stroke.

01:48:23.180 | Again, all of these prescribed uses

01:48:25.660 | have to be carried out by a certified physician.

01:48:29.120 | You really don't want to start cowboying

01:48:31.520 | the use of modafinil or armodafinil

01:48:33.420 | or any other prescription drug for that matter.

01:48:36.360 | I must say that in discussing all these different drugs

01:48:38.660 | during today's episode,

01:48:40.160 | I have zero knowledge of any of these drugs

01:48:43.940 | from a firsthand experience, except for armodafinil.

01:48:47.120 | Back in 2017, I was prescribed a very, very low dose

01:48:50.820 | of armodafinil for jet lag,

01:48:53.260 | for daytime sleepiness issues, really,

01:48:55.540 | when I was traveling overseas to give a talk.

01:48:58.100 | So armodafinil was given to me in a 25 milligram tablet.

01:49:02.960 | It was advised to me that I take a half

01:49:06.120 | or even a quarter of that.

01:49:07.140 | So I started with a quarter.

01:49:08.620 | I am a believer in minimal effective dose.

01:49:11.140 | I'm also somebody who's fairly hypersensitive

01:49:13.900 | to most medication.

01:49:14.980 | So I took what I measured out to be five to seven milligrams

01:49:19.480 | of armodafinil, and what I experienced was pretty profound.

01:49:23.960 | Certainly it relieved any daytime sleepiness.

01:49:26.860 | In fact, it made me feel extremely alert

01:49:29.400 | for a period of about four to six hours.

01:49:32.020 | I can't say it was the most comfortable state,

01:49:34.440 | although I did not feel as if I had a racing heart

01:49:37.340 | or anything of that sort.

01:49:38.480 | I basically felt as if I was in a narrow tunnel of attention

01:49:41.900 | for that entire period.

01:49:43.920 | One thing I did not like about the experience

01:49:46.020 | is that it was a very hard experience to come down from.

01:49:49.020 | There was no crash, but I found that that high arousal state

01:49:52.500 | didn't taper off for many hours later.

01:49:54.900 | Even though it was most heightened for four hours,

01:49:57.340 | I would say anywhere from eight to 12 hours later,

01:49:59.620 | I still felt like I was blinking once

01:50:01.820 | every four minutes or so.

01:50:03.020 | And I've certainly been accused on this podcast

01:50:05.280 | and at other times of blinking too seldom.

01:50:07.980 | To my knowledge, I don't have ADHD.

01:50:10.180 | I've never been prescribed ADHD meds.

01:50:12.120 | I've never been tested for ADHD.

01:50:14.760 | I don't think I have ADHD.

01:50:16.220 | And yet taking R-modafinil certainly increased my levels

01:50:20.480 | of attention, but at least by that one experience,

01:50:23.780 | it's not something that I would want to repeat again.

01:50:25.900 | I certainly would not want to be in that state

01:50:28.160 | for learning new material.

01:50:29.300 | When I sit down to research a podcast

01:50:31.120 | or research papers in my lab or forage for information

01:50:34.340 | or learn from people or books or lectures or podcasts,

01:50:37.560 | I want to be in a state of alertness but calm

01:50:40.180 | where I can really consider the ideas,

01:50:41.940 | where I can script things out by hand.

01:50:43.580 | I'm a big believer in writing things out by hand

01:50:45.180 | to remember them later, drawing little diagrams.

01:50:47.500 | I would not want to be in the state

01:50:49.460 | that even that very low dose of R-modafinil put me in

01:50:52.900 | in order to learn.

01:50:54.020 | And I should mention that both modafinil and R-modafinil

01:50:56.540 | are associated with a good number of side effects

01:50:59.540 | if they don't agree with you or if the dosage is too high.

01:51:02.340 | Things like decreased appetite,

01:51:03.920 | people can get a runny nose, headache.

01:51:06.300 | There's this instance of skin rashes.

01:51:09.460 | In fact, one of the reasons why modafinil and R-modafinil

01:51:13.100 | aren't more broadly prescribed

01:51:14.540 | is that there's a very rare skin condition

01:51:17.340 | in which people who have taken certain drugs,

01:51:20.820 | not just modafinil or R-modafinil,

01:51:23.260 | have developed these very severe burn-type blisters.

01:51:27.100 | And in some cases, this can be fatal.

01:51:28.980 | This is, again, very rare.

01:51:30.900 | And it was observed in at least one patient

01:51:34.120 | who took modafinil as part of a trial

01:51:37.020 | for modafinil as a treatment for ADHD.

01:51:38.880 | It's called Stevens-Johnson syndrome.

01:51:40.540 | Please, if you are squeamish to images of skin abrasions

01:51:44.060 | and lesions and things of that sort,

01:51:45.900 | please don't look it up on the internet

01:51:47.420 | unless you're able to handle that and maybe not at all.

01:51:50.460 | But the point here is that one of the reasons

01:51:54.440 | that modafinil and R-modafinil

01:51:56.060 | are not more widely prescribed for ADHD

01:51:58.360 | and that it's still only prescribed off-label

01:52:00.620 | is that Stevens-Johnson syndrome

01:52:04.280 | was flagged as kind of a potential risk,

01:52:07.180 | although the ADHD specialists that I spoke to

01:52:11.300 | are somewhat frustrated with that

01:52:12.840 | because they insist that the frequency of this syndrome

01:52:16.620 | that causes the skin rash that's sometimes fatal

01:52:19.160 | is no more frequent in those that took modafinil

01:52:21.480 | in this trial than with other drugs that have been approved.

01:52:24.540 | So this gets into all sorts of issues

01:52:26.420 | around what drugs make it to approval and which ones don't.

01:52:29.180 | And as we know, modafinil and R-modafinil

01:52:31.580 | are already being prescribed

01:52:33.280 | in the general population for other things.

01:52:35.420 | This was dealing specifically with the question

01:52:37.620 | of whether or not it should be prescribed in kids with ADHD.

01:52:40.840 | And certainly I am a proponent of exerting extreme caution

01:52:45.840 | when thinking about which drugs should be approved

01:52:48.740 | for the treatment of anybody, but especially kids.

01:52:51.540 | And to round out our discussion of drugs

01:52:54.880 | used for the treatment of ADHD that fall into,

01:52:58.020 | let's call it the atypical category, right?

01:53:00.100 | The typical category being Adderall, Vyvanse,

01:53:03.040 | methylphenidate, and things of that variety.

01:53:06.220 | The less typical would be modafinil, R-modafinil,

01:53:09.940 | purpirin, wellbutrin, and so forth.

01:53:13.020 | The last in this category of atypical is guanfacine.

01:53:17.440 | Guanfacine is an interesting compound.

01:53:19.700 | It's a compound that was developed to lower blood pressure,

01:53:22.560 | and indeed it does lower blood pressure.

01:53:24.620 | And it is an alpha-2A agonist,

01:53:28.160 | alpha-2A being a receptor for norepinephrine.

01:53:33.160 | So guanfacine is a non-stimulant medication to treat ADHD,

01:53:37.660 | and it's also used to treat some other conditions as well

01:53:40.540 | that is only working on the noradrenergic system.

01:53:44.560 | It is not tapping into the dopamine system.

01:53:47.220 | But all the other stuff that we talked about

01:53:49.500 | is really ramping up dopamine and norepinephrine.

01:53:53.860 | Guanfacine is only increasing norepinephrine,

01:53:56.180 | and it's doing so by what we say agonizing or stimulating

01:54:00.700 | one particular aspect of the noradrenergic system,

01:54:03.180 | and that's the alpha-2A system.

01:54:04.940 | What's interesting about guanfacine

01:54:08.060 | is that it has a bunch of pathways that it activates

01:54:10.860 | that feed back onto the autonomic nervous system

01:54:14.980 | to dampen down the activation

01:54:17.900 | of the sympathetic nervous system.

01:54:19.300 | So whereas most of what we talked about today

01:54:21.340 | are sympathomimetics, they tend to make us more ramped up,

01:54:24.300 | more aroused and alert.

01:54:26.100 | Guanfacine is doing the opposite.

01:54:27.620 | And as a consequence, it's not prescribed that often

01:54:30.940 | because a lot of times when people take guanfacine,

01:54:33.340 | it either has no effect on ADHD symptoms,

01:54:36.620 | or it tends to make people feel very sleepy.

01:54:38.740 | However, there's a small subset of individuals,

01:54:41.500 | probably about 5% to 10% of people that try it,

01:54:44.280 | including kids, that do get some significant relief

01:54:48.260 | from their ADHD symptoms,

01:54:50.180 | and they seem to tolerate guanfacine better

01:54:52.420 | than they're tolerating some of the other drugs

01:54:54.100 | that we've talked about up until now.

01:54:55.900 | The way guanfacine works is also really interesting.

01:54:58.880 | You're now familiar with the locus coeruleus,

01:55:00.760 | this packet, or we call it a nucleus of neurons

01:55:04.060 | in the back of the brain that release norepinephrine

01:55:05.940 | at other sites in the brain.

01:55:07.140 | And they're going to be those alpha 2A receptors

01:55:10.140 | that guanfacine works on and stimulates

01:55:13.020 | lots of different places in the brain

01:55:14.600 | related to increasing salience

01:55:16.560 | and relevance of particular stimuli that we see

01:55:19.740 | and that we need to attend to.

01:55:21.400 | It appears that guanfacine can activate

01:55:24.360 | the prefrontal cortical networks

01:55:27.060 | in ways that are above their normal baseline.

01:55:29.760 | So that's good.

01:55:30.600 | So improvements in executive function,

01:55:32.000 | that orchestra or teacher-like function

01:55:33.620 | we talked about before,

01:55:34.960 | and can increase the efficacy of that output

01:55:38.260 | from locus coeruleus.

01:55:39.900 | And what that seems to do is increase the coordinated firing

01:55:43.620 | of locus coeruleus neurons with prefrontal cortex.

01:55:46.120 | So in many ways, it's acting like a fine tuning

01:55:49.080 | of that orchestra conductor operation

01:55:51.740 | that is so valuable in teaching these brain circuits

01:55:55.040 | during childhood of how to attend to one thing

01:55:57.300 | and ignore everything else.

01:55:58.980 | So this is one reason why guanfacine is now approved

01:56:01.420 | not just for adults with ADHD,

01:56:02.940 | but is primarily used in kids aged six to 17 years old

01:56:07.940 | for the treatment of ADHD.

01:56:09.980 | Again, with the hope that these kids can take the drug

01:56:12.880 | and these circuits can learn how to focus

01:56:15.160 | and how to attend to certain things

01:56:17.860 | and limit impulsivity and hyperactivity,

01:56:20.700 | and then perhaps come off the drugs.

01:56:22.440 | Although sometimes, again,

01:56:23.520 | people have to stay on them indefinitely.

01:56:26.200 | The other thing about guanfacine

01:56:27.280 | is that because it lowers blood pressure

01:56:29.340 | and it has this effect of kind of dampening down

01:56:31.680 | overall sympathetic arousal,

01:56:33.300 | sometimes it is prescribed in conjunction

01:56:35.660 | with other ADHD meds.

01:56:37.300 | So yes, there are kids out there and adults out there

01:56:39.860 | who are taking Adderall and guanfacine,

01:56:42.620 | or they're taking Vyvanse and guanfacine,

01:56:44.540 | and this is where it starts to get into drug cocktails

01:56:47.220 | and a bunch of other things that gets everybody

01:56:49.980 | a little bit uncomfortable, I think,

01:56:51.460 | because the idea of taking one drug

01:56:53.220 | to dampen down the side effects of another drug

01:56:55.140 | and to offset things and compensate

01:56:57.780 | is getting towards what's called polypharmacology.

01:57:00.940 | And I think it's understandable

01:57:02.880 | that people be concerned about that.

01:57:04.220 | And yet, again, in viewing this

01:57:06.840 | with some of the experts on ADHD,

01:57:08.820 | there do seem to be a certain category

01:57:11.100 | of children out there and adults

01:57:12.340 | who really struggle with the standard ADHD meds.

01:57:15.640 | And in that case, guanfacine has provided

01:57:18.260 | a certain number of these individuals tremendous relief.

01:57:21.080 | One note about guanfacine, in no way, shape, or form,

01:57:24.100 | am I encouraging anyone

01:57:25.140 | who's not prescribed guanfacine to take it,

01:57:27.500 | but should you know someone

01:57:29.000 | who's taking guanfacine off-label

01:57:30.740 | in order to improve their focus

01:57:32.580 | or enhance any aspect of their biology or psychology,

01:57:37.180 | please let them know that it has a profound effect

01:57:39.400 | on lowering the tolerance for alcohol,

01:57:41.140 | such that even small amounts of alcohol

01:57:43.580 | can lead to really serious problems

01:57:45.460 | and even potentially death.

01:57:46.920 | So that's a very serious warning with guanfacine.

01:57:50.980 | So today we discussed a lot of different compounds

01:57:53.180 | for the treatment of ADHD,

01:57:54.600 | and it now should become clear

01:57:56.420 | what the general themes of those compounds is.

01:57:59.540 | The general theme is that they tend to increase

01:58:02.460 | overall levels of arousal and wakefulness,

01:58:05.080 | which leads to decreased levels

01:58:07.360 | of hyperactivity, impulsivity, and focus.

01:58:10.360 | And on the face of it, that might seem counterintuitive,

01:58:12.720 | raise arousal to reduce hyperactivity and impulsivity.

01:58:16.100 | Indeed, that's the case because these compounds,

01:58:18.580 | because they act on neuromodulator systems

01:58:21.620 | like dopamine and norepinephrine

01:58:23.880 | are effective in creating neuroplasticity.

01:58:26.140 | They change the strength of the connections

01:58:28.020 | in the neural circuits of the brain

01:58:29.620 | that lead to states of heightened focus

01:58:32.100 | and reduced impulsivity and reduced hyperactivity.

01:58:35.460 | So we talked about the different mechanisms

01:58:37.060 | by which the different medications

01:58:38.560 | for ADHD accomplish this,

01:58:40.640 | both the typical sort like methylphenidate

01:58:43.120 | and Adderall and Vyvanse,

01:58:44.740 | and some of the atypical compounds

01:58:46.660 | that are now being used in addition,

01:58:48.540 | such as modafinil or modafidil,

01:58:51.080 | guanfacine, and wellbutrin.

01:58:53.240 | And where possible, I tried to highlight

01:58:55.100 | both the short and long-term effects

01:58:57.460 | of these various compounds.

01:58:59.380 | And I tried to address some of the major concerns

01:59:02.160 | about these compounds,

01:59:03.320 | most notably the question of

01:59:04.740 | why are we putting so many kids on amphetamine

01:59:07.720 | and what is the long-term consequence of that?

01:59:10.100 | And throughout today's episode,

01:59:11.160 | I tried to highlight both the immediate

01:59:13.000 | and long-term benefits,

01:59:14.100 | but also the immediate and long-term risks

01:59:16.480 | that can exist with these compounds.

01:59:18.300 | Certainly when taken without a prescription,

01:59:20.800 | recreationally, there is a real risk

01:59:23.180 | for abuse and addiction,

01:59:25.980 | as well as even a risk for psychotic episodes,

01:59:29.220 | but also the risks that accompany

01:59:30.660 | long-term use of these drugs in people with ADHD.

01:59:33.900 | And yet it is also clear

01:59:35.380 | that not treating the symptoms of ADHD

01:59:38.220 | carries significant risk as well.

01:59:40.340 | And what's very clear from the scientific

01:59:41.900 | and clinical literature,

01:59:43.060 | and is covered in a significant amount of detail

01:59:45.680 | in the episode that I did about ADHD,

01:59:48.380 | which you can find at hubermanlab.com,

01:59:50.760 | is that combinations of drug treatments

01:59:53.220 | and behavioral protocols seem to surpass

01:59:55.860 | either drug treatments or behavioral protocols alone,

01:59:59.780 | speaking to the tremendous importance

02:00:01.960 | of combining multiple methodologies when treating ADHD

02:00:05.580 | and working with a board-certified psychiatrist

02:00:07.580 | who really understands ADHD

02:00:09.460 | and is really up to date

02:00:10.900 | on all the latest scientific and clinical literature.

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02:01:56.320 | Thank you for joining me for today's discussion,

02:01:58.700 | all about pharmaceutical interventions

02:02:00.540 | for the treatment of ADHD.

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Adderall, Stimulants & Modafinil for ADHD: Short- & Long-Term Effects | Huberman Lab Podcast

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