Essentials: Understanding & Healing the Mind | Dr. Karl Deisseroth

Andrew Huberman 0:00 Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health and performance. And now, my conversation with Dr. Karl Deisseroth. Well, thanks for being here.

Karl Deisseroth 0:16 Thanks for having me.

Andrew Huberman 0:17 So for people that might not be so familiar with the fields of neuroscience, et cetera, what is the difference between neurology and psychiatry?

Karl Deisseroth 0:26 Psychiatry focuses on disorders where we can't see something that's physically wrong, where we don't have a measurable, where there's no blood test that makes the diagnosis, there's no brain scan that tells us this is schizophrenia, this is depression for an individual patient. And so psychiatry is, is much more mysterious and the only tools we have are words. Neurologists are, uh, fantastic physicians. They see the stroke on brain scans, they see the seizure and the pre-seizure activity with an EEG, uh, and they can measure and treat based on those measurables. In psychiatry, we have a harder job. We use words, we have rating scales for symptoms, we can measure depression and autism with rating scales, but those are words still and ultimately that's what psychiatry is built around. It's, it's an odd situation because we've got the most complex, beautiful, mysterious, incredibly engineered, uh, object in the universe and yet all we have are words to, to find our way in.

Andrew Huberman 1:36 So do you find that if a patient is very verbal or hyper-verbal that you have an easier time diagnosing them as opposed to somebody who's, um, more quiet and reserved or it's, I could imagine, the opposite might be true as well?

Karl Deisseroth 1:51 Well, it, because we only have words, you've put your finger on a key point. If they don't speak that much, in principle it's harder. The lack of speech can be a symptom. We can see that in depression, we can see that in the negative symptoms of schizophrenia, we can see that in autism. Sometimes by itself that is a symptom of reduced speech, but ultimately you do need something. You need, uh, some, some words to help guide you and that, in fact, and there's, there's challenges that I, I can tell you about where patients with depression who are so depressed they can't speak, that makes it a bit of a challenge to distinguish depression from some of the other reasons they might not be speaking. And this is, uh, sort of the art and the science of psychiatry.

Andrew Huberman 2:31 Do you think we will ever have a blood test for depression or schizophrenia or autism and would that be a good or a bad thing?

Karl Deisseroth 2:41 I think, uh, ultimately there will be quantitative tests. Uh, already efforts are being made to look at certain rhythms in the brain using external EEGs, uh, to look at brain waves effectively, but ultimately what's going on in the brain, in psychiatric diseases, physical, uh, and it's due to the circuits and the connections and the projections in the brain that are, um, not working as they would in a typical situation. And I- I do think we'll have those measurables at some point. Could it be abused or misused? Uh, certainly, but that's, I think, true for all of medicine.

Andrew Huberman 3:16 I want to know, and I'm sure there are several, but what do you see as the biggest challenge facing psychiatry and the treatment of mental illness today?

Karl Deisseroth 3:27 I think we have, uh, we're making progress on what the biggest challenge is, which I think there's still such a strong stigma for psychiatric disease that, uh, patients often don't come to us, um, and, uh, they feel that they should be able to handle this on their own. And that, that can slow treatment, it can lead to, you know, worsening symptoms. We know, for example, patients who have, uh, untreated anxiety issues, if you go for a year or more with a, a serious untreated anxiety issue, that can convert to depression. You can add another, uh, problem on top of the anxiety and so it would be, you know, why do people not come for treatment? They, they, they feel like this is something they should be able to master on their own, uh, which, which can be true but, uh, usually, uh, uh, some help is, is, is a good thing.

Andrew Huberman 4:20 That raises a, a question related to something I heard you say many years ago at a lecture which was that, um, this was a scientific lecture and you said, "You know, we don't know how other people feel. Most of the time, we don't even really know how we feel."

Karl Deisseroth 4:35 Yeah. (laughs)

Andrew Huberman 4:35 I mean, if you could elaborate on that a little bit and the, the, um, dearth of, of ways that we, we have to talk about feelings. I mean, there are so many words f- I don't know how many, but I'm guessing they're more than a dozen words to describe the state that I call sadness. But as far as I understand, we don't have any way of comparing that in a, in a real, objective sense. So how, as a psychiatrist when your job is to use words-

Karl Deisseroth 5:01 Mm-hmm.

Andrew Huberman 5:01 ... to diagnose, words of the patient to diagnose, do you maneuver around that and, and what is this landscape that we call feelings or emotions?

Karl Deisseroth 5:09 Yeah. This is, uh, really interesting. Uh, people, here we have a, there's a tension between the words that we've built up in the clinic that mean something to the, to the physicians and then there's the co- colloquial use of words that may not be the same. And so, that's the first level we have to sort out when someone says, "You know, I'm, I'm depressed," uh, what exactly do they mean by that? Uh, that may be different from, from what we're talking about in terms of depression. So part of psychiatry is to get beyond that word and to get into how they're actually feeling. Get, get rid of the, the jargon and get to real world examples of, of how they're feeling. So, you know, how do you, what, how much do you look forward into the future? How much, uh, hope do you have? How much planning are you doing for the future? So these, here now you're getting into actual things you can talk about that are unambiguous. If someone says, "Yeah, I, I can't even, I can't even think about tomorrow. I..."... I'm not... (laughs) I don't see how I'm gonna get to tomorrow. That- That's a nice, precise thing that, you know, it's- it's sad, it's tragic, but- but it's also, that means something, and we know what that means. That's the hopelessness symptom of depression. And- And that is what I try to do when I do a psychiatric interview. I try to get past the jargon and get to what's actually happening in a patient's life and- and in their mind. But as you say, ultimately, (laughs) you know, and this shows up across... I- I- I address this issue every day in my life, whether it's in the lab where we're- we're looking at animals, whether fish or mice or rats, and studying their behavior, or when I'm in, you know, a conversation with just a- a friend or a colleague, or when I'm talking to a patient. I never really know what's going on inside the mind of the other person. I get- I get some feedback and I get words, I get behaviors, I get actions, but I never really know.

Andrew Huberman 7:04 Are there any very good treatments for psychiatric disease? Meaning, are there currently any pills, potions, forms of communication that reliably work every time-

Karl Deisseroth 7:16 Yes.

Andrew Huberman 7:16 ... or work in most patients? And could you give a couple examples of great successes of psychiatry, if they exist?

Karl Deisseroth 7:22 Yes. In psychiatry, despite the depths of our... the mystery we struggle with, we... many of our treatments are actually... You know, we're- we're- We may be doing better than some other specialties in terms of actually causing, you know-

Andrew Huberman 7:34 Mm-hmm.

Karl Deisseroth 7:34 ... therapeutic benefit for patients. We do help patients. You know, the patients who suffer from... Uh, by the way, both medications and talk therapy have been shown to be extremely effective in many cases. Uh, for example, people with panic disorder. Cognitive behavioral therapy, just working with words, helping people identify the early signs of when they're starting to move toward a panic attack, what are the cognitions that are happening, you can train people to derail that and- and you can very potently treat panic disorder that way. There are many psychiatric medications that are very effective for, uh, the conditions that they're treating. Uh, antipsychotic medications, they have side effects, but, uh, boy, do they work. They really can clear up auditory hallucinations, the paranoia. And then, you know, this is a- a frustrating and yet heartening aspect of psychiatry, there are treatments like electroconvulsive- electroconvulsive therapy which is, uh, where, you know... It's extremely effective for depression. We have patients who nothing else works for them, where they can't tolerate medications, and, uh, you can administer under a very safe, controlled, uh, condition where the patient's body is not moving, they're put into a very safe, uh, uh, situation where the body doesn't move or seize. It's just an internal, uh, process that's triggered in the brain. This is an extraordinarily effective treatment for treatment-resistant depression. At the same time, I find it (laughs) , as- as- as heartening as it is to see patients respond to this with- with, uh, uh, who have severe depression, I'm also frustrated by it. Why- Why can't we do something more precise than- than this for these very severe cases? In all of these cases, though, in psychiatry, the- the- the frustrating thing is that we don't have the level of understanding that a cardiologist has in thinking about the heart. You know, the heart is, we now know, it's a pump. It's pumping blood. And so you can look at everything about how it's working or not working in terms of that frame. It's clearly a pump. We don't really have that level of, what- what is this circuit really there for in psychiatry?

Andrew Huberman 9:39 What are

Andrew Huberman 9:40 the pieces that are gonna be required to cure autism, cure Parkinson's, cure schizophrenia? I- I would imagine there are several elements and bins here. Um, understanding the- the natural biology, understanding what the activity patterns are, how to modify those. Maybe, um, you could just tell us what you think, uh, what is the- the bento box of the perfect cure?

Karl Deisseroth 10:05 Yeah. I think the first thing we need is understanding. What is the element in the brain that's analogous to the pumping heart? When we think about the symptoms of depression, that's maybe, you know, we think about motivation and dopamine neurons. And so then that turns our attention. As neuroscientists, we think, "Okay, let's think about the parts of the brain that are involved in dealing with merging complex data streams that are very high in bit rate that- that need to be fused together into a unitary concept." And that starts to guide us and maybe we can... And we know other animals are social in their own way, and we can study those animals. And so that, there's, that's how I think about it, there's hope for the future. Thinking about the symptoms as an engineer might, and trying to identify the circuits that are likely working, uh, to make this typical behavior happen, and that will help us understand how it becomes atypical.

Andrew Huberman 11:01 We need to know the circuits. We need to know the cells-

Karl Deisseroth 11:04 Yeah.

Andrew Huberman 11:04 ... in the various brain regions and- and portions of the body, and, uh, and how they connect to one another, and what the patterns of activity are under a normal, quote-unquote, healthy interaction.

Karl Deisseroth 11:15 Yeah.

Andrew Huberman 11:16 If we understand that, then it seems that the next step, which of course could be carried out in parallel, right? That-

Karl Deisseroth 11:24 Yeah.

Andrew Huberman 11:24 ... uh, that work can be done alongside work where various elements within those circuits are tweaked just right-

Karl Deisseroth 11:31 Right.

Andrew Huberman 11:31 ... like the tuning of a piano in the subtle way, or maybe even like the replacement of a whole set of keys if the piano is lacking keys, so to speak.

Karl Deisseroth 11:38 Right. Right.

Andrew Huberman 11:39 In 2015, there was this- this, uh, what I thought was a very nice article published in The New Yorker, um, describing your work and the current state of, um, your work in- in the laboratory, in the clinic, and an interaction with a patient. This was, as I recall, a woman who was severely depressed. And you reported in that article some of the discussion with this patient, and then in real time, increase the activation of the so-called vagus nerve, this 10th cranial nerve that extends out of the skull and innervates many of the- the viscera and- and body. What is the potential for channelrhodopsins or related...... types of algae engineering to be used to manipulate the vagus, because I believe in that instance it wasn't channelopsin stimulation-

Karl Deisseroth 12:26 Sure.

Andrew Huberman 12:26 ... it was electrical stimulation, right?

Karl Deisseroth 12:27 Yeah.

Andrew Huberman 12:27 Or to manipulate, for instance, a very small localized region of the brain. Let me phr- re- frame it a little bit differently in light of what we were talking about a couple minutes ago. M- my understanding is that if somebody has severe depression and they take any number of the available pharmaceutical agents that are out there, SSRIs, serotoninergic agents, increased dopamine, increased whatever, that sometimes they experience relief but there are often serious side effects. Sometimes they don't experience relief. But, as I understand it, channelopsins and their related technology in principle would allow you to turn on or off the specific regions of the brain that lead to the depressive symptoms, or maybe you turn up a happiness circuit, or an, or a, uh, a positive anticipation circuit. Where are we at now in terms of bringing this technology to the nervous system? And let's start with body and then move into the skull.

Karl Deisseroth 13:26 Yeah. So starting with the body is a good example because it, it, uh, highlights the opportunity and, and how far we have to go. So let's take this example of vagus nerve stimulation. So the vagus nerve, it's the 10th cranial nerve. It comes from the brain, it goes down, it innervates the heart, innervates the gut. By innervate I mean it sends little connections down to help, uh, guide what happens in these, these organs in the, in the, in the abdomen and, and chest. Uh, it also collects information back and, and there's information coming back from all those organs that go, also go through this vagus nerve, the 10th cranial nerve back to the brain. And so this is somewhat of a, of a, of a superhighway to the brain then, was the idea. And maybe the idea is maybe we could put a little cuff, a little electrical, uh, uh, device around the vagus nerve itself, so a way of getting into the brain without putting something physical into the brain.

Andrew Huberman 14:20 And why the vagus? I mean, it's there but, and it's accessible-

Karl Deisseroth 14:23 That's the reason. (laughs)

Andrew Huberman 14:24 Um, that's the reason?

Karl Deisseroth 14:24 That's the reason, yes.

Andrew Huberman 14:25 Really?

Karl Deisseroth 14:26 Yeah.

Andrew Huberman 14:26 You're not kidding.

Karl Deisseroth 14:27 I'm not kidding. It's-

Andrew Huberman 14:27 So stimulating the vagus to treat depression simply because it's accessible.

Karl Deisseroth 14:31 It started as, actually as a, as an epilepsy, uh, treatment, and it, it can help with epilepsy. But the vagus nerve lands on a particular spot on the brain called the solitary tract nucleus, which is just one synapse away from the serotonin, the dopamine, and the norepinephrine.

Andrew Huberman 14:47 So there's a link to chemical-

Karl Deisseroth 14:49 So-

Andrew Huberman 14:49 ... systems in the brain-

Karl Deisseroth 14:50 Yeah. Yeah.

Andrew Huberman 14:50 ... that make it a rational choice.

Karl Deisseroth 14:51 It, yes, it's not-

Andrew Huberman 14:52 Yeah.

Karl Deisseroth 14:52 ... it's not irrational.

Andrew Huberman 14:53 Mm-mm.

Karl Deisseroth 14:53 But I can tell you that even if that were not true, the same thing would've been tried. (laughs) You know, you know.

Andrew Huberman 14:58 (laughs) You guys would've done it anyway.

Karl Deisseroth 14:59 Because it's accessible, yeah.

Andrew Huberman 15:00 I see. How do you think it's working when it does work? Is it triggering the activation of, of neurons that release more serotonin or dopamine?

Karl Deisseroth 15:07 It could be, uh, but I would say we don't have evidence for, for that. Um, and so I, I, I, I just don't know. But, uh, what is clear is that it's dose limited, uh, in how high and strongly we can stimulate. And why? It's because it's an electrode and it's stimulating everything nearby. And when you turn on the vagus nerve stimulator, the voice, patient's voice becomes strangulated and hoarse, they can have trouble swallowing, they can have trouble speaking for sure, uh, even some trouble breathing, because everything in the neck, every electrically responsive cell and projection in the, in the neck is being affected by this electrode. And so you can go up just so far with the intensity and then you have to stop. So, you know, to, to your initial question, could a more precise stimulation method, uh, like optogenetics help in this setting? In principle it could, because that would, if you would target the light sensitivity to just the right kind of cell, let's say cell X that goes from point A to point B that you know causes symptom relief of a particular kind, then you're in business. You can have that be the only cell that's light sensitive, you're not gonna affect any of the other cells, the larynx and the pharynx and the projections passing through. So that's the hope, that's the opportunity. The problem is that we don't yet have that level of specific knowledge. We don't know, okay, it's the cell starting in point A and going to point B that relieves this particular symptom.

Andrew Huberman 16:31 We wanna fix this key on the piano.

Karl Deisseroth 16:33 Yeah.

Andrew Huberman 16:34 I'm imagining a little tiny, a blue light emitting, um, thing, object, that's a little bigger than a clump of cells, or maybe about the size of a clump of cells. So we're talking about a little tiny stamp-

Karl Deisseroth 16:48 Yeah.

Andrew Huberman 16:49 ... at each edge half a millimeter in size.

Karl Deisseroth 16:51 Yeah.

Andrew Huberman 16:51 I could imagine that being put under my skin-

Karl Deisseroth 16:53 Yeah.

Andrew Huberman 16:53 ... and then I would, what I, uh, hit an app on my phone and I'd say-

Karl Deisseroth 16:56 Yeah.

Andrew Huberman 16:57 ... I'd say, "Dr. Deisseroth, I'm not feeling great today. Can I increase the stimulation?" And you say, "Go for it." And then I ramp it up. Is that how it would go?

Karl Deisseroth 17:05 I mean, that's effectively what we already do with the vagus nerve stimulation. The, the doctor in this case ... And I, I have this in some of my patients in the clinic, I do vagus nerve stimulation. I talk to them, I say how are ... I, I go through the symptoms, I, I use the psychiatric interview to elicit their internal states, and then I have a radio frequency controller that I can dial in not-

Andrew Huberman 17:24 Right there in real time.

Karl Deisseroth 17:25 Right there in real time.

Andrew Huberman 17:25 You're holding the remote control-

Karl Deisseroth 17:27 Yeah.

Andrew Huberman 17:27 ... to the, essentially to their brain, although it's remote, remote control.

Karl Deisseroth 17:30 Yeah. Yeah.

Andrew Huberman 17:30 Yep. Yep.

Karl Deisseroth 17:30 Through a couple steps but yeah, yeah.

Andrew Huberman 17:31 Yeah.

Karl Deisseroth 17:32 And I can, I can turn up, I can turn up the frequency, I can turn up the intensity, uh, all with the radio frequency and, uh, uh, control. And then it's, it's reprogrammed or, uh, redosed, uh, and then the patient can, can then leave at this altered dose. In most patients I don't expect an immediate mood change. What I do is I increase the, the dose until, uh, uh, to, uh, next level up while asking the patient for side effects. "Can you still breathe okay? Can you still swallow okay?" And I can hear their voice as well, and, and I can get a sense-

Andrew Huberman 18:02 And you're looking at their face.

Karl Deisseroth 18:03 ... and I'm looking at their face.

Andrew Huberman 18:04 Yeah.

Karl Deisseroth 18:05 And so I can get a sense is there a, uh, am I in a, uh, still in a safe side effect, uh, regime. And I, and, and, and then, you know, I, I, I, I stop at a particular point that looks safe and then patient goes home, comes back a month later and I get the report on how things were over that month.

Andrew Huberman 18:22 That's very exciting.

Karl Deisseroth 18:23 Mm-hmm.

Andrew Huberman 18:24 What are your thoughts about, um, brain-machine interface? It's something that's been happening for a long time now. Devices, little probes that are gonna stimulate different patterns of activity and ensembles of neurons.

Karl Deisseroth 18:35 First of all, it's an a- it's an amazing, uh, scientific discovery approach. Uh, as you mentioned, we and others here at Stanford are using, uh, electrodes, collecting information from tens of thousands of neurons. Even separate from the Neuralink work, as you point out, many people have been doing this, uh, uh, in humans as well as in non-human primates. Um, and this is pretty, uh, powerful. It's important. This will let us, uh, understand what's going on in the brain, in, uh, s- in psychiatric disease and neurological disease, and will give us ideas for, for treatment. I see that as something that will be part of psychiatry, uh, in, in, in the long run. Already with deep brain stimulation, uh, approaches, we can help, uh, s- people with psychiatric disorders, and that's putting just a single electrode, not even a, a complex, you know, uh, closed loop system where you're both playing and, and getting information back. Even just a single stimulation electrode in the brain can help people with, uh, OCD, for example, uh, quite powerfully.

Andrew Huberman 19:37 One of the questions I get asked a lot is about, um, ADHD and, uh, attention deficit of various kinds. I have the, uh, hunch that, uh, one reason I get asked so often is that people are feeling really distracted and, and, uh, challenged in, um, funneling their attention and their behavior. But, uh... And there are a number of reasons for that, of course, but what is true ADHD and what does it look like? What can be done for it and, uh, what, if any, role for channelopsins or these downstream technologies that you're developing? Um, what do they, what do they offer for people that suffer from ADHD or have a family member that suffers from ADHD?

Karl Deisseroth 20:20 Yeah. This is, uh... It's a pretty interesting branch of, of psychiatry. There's no question that people have been helped by the, the treatments. Uh, there's, you know, active, you know, debate over, you know, uh, what fraction of people who have these symptoms, uh, can or should be, be, uh, treated.

Andrew Huberman 20:38 This is typically Adderall or stimulants of some kind.

Karl Deisseroth 20:41 Yeah. For example, stimulants.

Andrew Huberman 20:42 Yeah.

Karl Deisseroth 20:42 That's right. Um, so ADHD, it's... As, as its name suggests, it has, uh, symptoms of... Uh, it can have either a hyperactive, uh, state or an inattentive, uh, state, and, uh, those can be completely separate from each other. You could have a patient who, who, uh, effectively, uh, is, is not hyperactive at all, but can't, uh, remain focused on the, the what's going on around them, so

Andrew Huberman 21:06 So their body can be still, but their, their mind is darting around.

Karl Deisseroth 21:09 That's right. That's right.

Andrew Huberman 21:10 Or they can be very hyperactive with their body.

Karl Deisseroth 21:12 Yeah. Yeah. It happens both ways.

Andrew Huberman 21:13 So probably rarely is somebody hyperactive with their body, but their mind is still.

Karl Deisseroth 21:16 I, I notice... I have to think complex, abstract thoughts. I notice I have to be very still. So my body has to be almost completely unmoving for me to think very abstractly and, and deeply. Uh, other people are different. Some people, when they're running, they get their best thoughts. I can't even imagine that. My brain does not work that way at all. I have to be totally motionless (laughs) -

Andrew Huberman 21:35 I see.

Karl Deisseroth 21:35 ... which is kind of interesting.

Andrew Huberman 21:36 How do you go about that?

Karl Deisseroth 21:37 I, I, I sit, uh, much like this. You know, I, I, I try to have time e- in each day where I am, I'm literally, uh, sitting, uh, uh, almost in this, in this position, um, but, but without distraction and, and thinking. And, and so it's kind of a... It's almost meditative in some ways, except it's, it's not, uh, true meditation, but I am, I am thinking while not moving inten- intentionally.

Andrew Huberman 22:00 You're struc- you're trying to structure your thoughts-

Karl Deisseroth 22:02 Yeah.

Andrew Huberman 22:02 ... in that time.

Karl Deisseroth 22:03 Yeah. That's right.

Andrew Huberman 22:03 Interesting.

Karl Deisseroth 22:04 Yeah. So but everybody, as you say, is, is, is very different. And so with, with ADHD, you have... The key thing is we wanna make sure that this is present across different domains of life, so school and home, to show that it really is a pervasive pattern, uh, and not something specific to, oh, you know, the teacher or the, the home situation or something. And then you can help patients. It's interesting that, that ADHD is one of those disorders where people are trying to work on quantitative EEG-based diagnoses, and so there's some progress toward making a, a diagnosis with looking at particular externally detectable brainwave, uh, rhythms.

Andrew Huberman 22:43 So skullcap-

Karl Deisseroth 22:43 Yeah.

Andrew Huberman 22:43 ... with some electrodes that don't penetrate the skull?

Karl Deisseroth 22:45 That's right.

Andrew Huberman 22:46 And this can be done in an hour or two-hour session?

Karl Deisseroth 22:49 Yeah. That's right.

Andrew Huberman 22:49 Has to be done in a clinic, right? Yeah.

Karl Deisseroth 22:51 Yeah. In the clinic, right, you have to have the right recording apparatus and so on. But, but, but, uh, that's... In principle, uh, as you... Increasing confidence comes in exactly which measurements, uh, one could even imagine moving toward, you know, home tests, um, but we're not there yet.

Andrew Huberman 23:10 Amazing. I think, um, one of the reasons I get asked about it so much is a lot of people wonder if they have ADHD. Uh, do you think that some of the lifestyle factors that, um, inhabit us all these days could induce a subclinical or a clinical-like, um, ADHD? Meaning, if... I, I look at people's phone use, including my own, and I don't think of it like addiction. It looks to me and feels to me more like OCD. And I'll come clean here by saying when I was younger, when I was a kid, I had a grunting tic.

Karl Deisseroth 23:38 Mm-hmm.

Andrew Huberman 23:39 I used to hide it. I actually used to hide in the closet-

Karl Deisseroth 23:41 Mm-hmm.

Andrew Huberman 23:41 ... 'cause my dad would make me stop.

Karl Deisseroth 23:43 Mm-hmm.

Andrew Huberman 23:43 And I, I used to... I couldn't feel any relief of my mind until I (grunts) would do this.

Karl Deisseroth 23:48 Yeah.

Andrew Huberman 23:48 And actually, now, if I get very tired, if I've been pushing along hours, it'll come back.

Karl Deisseroth 23:52 Hmm. Interesting.

Andrew Huberman 23:53 I was not treated for it.

Karl Deisseroth 23:54 Mm-hmm.

Andrew Huberman 23:54 Um, but I will confess that I've had the experience of... I always liked sports where I involve a lot of impact. Fortunately, not football-

Karl Deisseroth 24:03 Yeah.

Andrew Huberman 24:03 ... because I went to a high school where the football team was terrible.

Karl Deisseroth 24:06 (laughs)

Andrew Huberman 24:06 Maybe that would have avoided more impact. But things like skateboarding, boxing-

Karl Deisseroth 24:09 Mm-hmm.

Andrew Huberman 24:10 ... they f- bring relief.

Karl Deisseroth 24:12 Mm-hmm.

Andrew Huberman 24:12 I feel clarity after a head hit, which I avoid-

Karl Deisseroth 24:15 (laughs)

Andrew Huberman 24:15 ... but, uh, but I used to say that's the only time I feel truly clear-

Karl Deisseroth 24:19 Mm-hmm.

Andrew Huberman 24:19 ... for a lo- And then eventually, it dissipated.

Karl Deisseroth 24:20 Oh, interesting.

Andrew Huberman 24:20 By about age 16, 17, it just disappeared.

Karl Deisseroth 24:23 Yeah.

Andrew Huberman 24:23 ANDREW HUBERMAN<|agent|><|en|> Um, so I have great, uh, empathy for those that feel like there's something contained in them that won't allow them to focus on what they wanna focus on. And these days, with the phone and, and all these, uh, email et cetera, I, I wonder and I empathize a bit when I hear people saying like, "I think I might have ADHD or ADD." Do you think it's possible that our behaviors and our interaction with the sensory world, w- which is really what phones and email really are, could induce ADD or reactivate it?

Karl Deisseroth 24:56 You know, I, uh, this is a great question. I, I think about it a lot. There's, you know... And, and you, you mentioned this, this, uh, tic-like behavior in, in yourself. It's very common that people who have tics have this building up of something that can only be relieved by executing the, the tic, which can be a motor movement or, or a vocalization or even a thought. And, uh, a- and it... People do, I think, these days, do have this... If they haven't checked their phone in a while, they do have a build-up, a build-up, a build-up, until they can, they can check it and relieve it. Um, and, and, and there's some similarities. You know, there is a little reward that comes with the, with the, the, the checking. Um, but the, the key question in all of psychiatry, what we do is, we, we don't diagnose something unless it's disrupting what we call social or occupational functioning, right? You could have any number of symptoms, but literally, every, every psychiatric diagnosis requires that it has to be disrupting someone's social or occupational functioning. And these days, you know, checking your phone is pretty adaptive. That pretty much helps your social and occupational functioning. And so we can't, we can't make... (laughs) We can't make it a, a psychiatric diagnosis.

Andrew Huberman 26:06 Interesting.

Karl Deisseroth 26:07 It's, uh, at least in the world of today.

Andrew Huberman 26:09 Uh-huh. I'd love

Andrew Huberman 26:10 your thoughts on, uh, psychedelic medicine, putting them into patients and seeing tremendous positive effects but also, um, tremendous examples of, um, induced psychiatric illness. In other words, many people lost their minds as a consequence of overuse of psychedelics. I'll probably lose a few, um, people out there, uh, but I do wanna talk about, w- what is the state of these compounds? And I realize it's a huge category of compounds, but LSD and psilocybin, as I understand, trigger activation of particular serotonin receptor mechanisms, may or may not lead to more widespread activation of the brain, more at, that one wouldn't see otherwise. But when you look at the clinical and experimental literature, w- what is your sort of top contour sense of how effective these tools are going to be for treating depression?

Karl Deisseroth 27:00 Well, you're, you're right to highlight both the opportunity and, and the peril that is there. Um, and of course, we wanna help patients and of course we want to, to explore anything that might, uh, be, be helpful and... But we wanna do it in a safe and, and rigorous way. But, uh, I, I do think we should explore these, these avenues. These are, um, agents that alter reality and alter the experience of reality, I should say, in, in relatively precise ways. They, they, they do have problems. They can be addictive. They can cause lasting change that is not desirable. Now, that said, uh, even w- as these medications ex- exist now, as you know, there's, uh, uh, an impulse to, to use them in very small doses and to use them as adjunctive, uh, treatments for, for th- therapy of, of various kinds. And I, I'm also supportive of that if done, you know, carefully and, and rigorously. Of course, there's risk, but there is risk with many other kinds of, of treatment. And I'm not sure that the risks, uh, for these, uh, medications, uh, vastly outweigh the risks that we normally tolerate in other branches of medicine.

Andrew Huberman 28:09 Why would they work? I mean, the, um... You know, l- let's say, uh, that indeed their main effect is to create more, uh, more connectivity, at least in, in the, in the moment, uh, between brain areas. So, psychedelics seem to be a, a trajectory, um, not off, too far off from the dream state where space and time are essentially not as rigid, and there is this element of synesthesia, blending of the senses-

Karl Deisseroth 28:40 Mm-hmm. Mm-hmm.

Andrew Huberman 28:40 ... um, you know, feeling colors and, um, hearing, uh, light and things of that sort. It... You hear these reports, anyway. Um, why would having that dreamlike experience somehow relieve depression long term?

Karl Deisseroth 28:58 Yeah.

Andrew Huberman 28:58 Is... Do we have any idea why that might be?

Karl Deisseroth 29:00 Yeah. I, uh... We have some ideas and no, no deep understanding. Uh, one way I, I think about the psychedelics is they, um, increase our willingness to... Or they increase the willingness of our brain to accept, uh, unlikely, uh, ways of constructing the world, unlikely hypotheses, as it were, as to what's going on. The brain, in particular our cortex, I think, is a hypothesis generation and testing machine. It's coming up with models about everything. It's got a, a lot of bits of data coming in and it's making models and updating the models and changing them, theories, hypotheses-

Andrew Huberman 29:38 Mm-hmm.

Karl Deisseroth 29:38 ... for what's going on. And some of those never reach our conscious mind. And this is something I talk about in Projections in the, in the book, uh, uh, quite a bit, is many of these are filtered out before they get to our, our conscious mind, and that's good. We, we, we... Think how distracted we'd be if we were constantly having to evaluate all these, you know, hypotheses about w- you know, what kinds of shapes or objects or processes were out there. And so a lot of this is, is handled, uh, uh, before it gets to consciousness. What the psychedelics seem to do is they change the, uh, threshold for us to become aware of these incomplete hypotheses or wrong hypotheses or, or concepts that might be noise, uh, but are just wrong and so are never allowed to get into our, our conscious mind.Now, uh, you know, that- that's pretty interesting and it goes wrong in psychiatric disorders. I think, uh, in, in schizophrenia that sometimes the paranoid, uh, uh, delusions that people have are examples of these, uh, poor models that escape into the conscious mind and become, uh, accepted as reality, and they never should have gotten out there. Now, how could something like this, in the right way, help with something like depression? Patients with depression often are, uh, are stuck. They, they can't, uh, uh, look into the future world of possibilities as effectively. There's... Everything seems, uh, hopeless. And what does that really mean? They s- they discount the value of their own action. They discount the value of the world at giving rise to a future that matters. Everything seems to run out like a river just running out into a desert and drying up. And what these agents may do that increase the, the, the flow through circuitry, if you will, the percolation of activity through circuitry, may, uh, end up doing for depression is increasing the, the, the escape of some, some tendrils of, of, of process, of, of forward progression through, through the world. Um, that's c- a concept. It's how I think about it.

Andrew Huberman 31:48 Mm-hmm.

Karl Deisseroth 31:48 There are ways we can make that rigorous. We, we can, indeed, identify in the brain by recording. We can see cells that represent steps along a path and, uh, look into the future, and we can rigorously define these cells and we can see if these are altered on psychedelics. And so that's one of the reasons that we're, uh, working with these agents in the laboratory to say, "Are... Is this really the case? Are, are these opening up new paths, uh, or, or representations of paths into the future?"

Andrew Huberman 32:18 Mm-hmm.

Andrew Huberman 32:19 MDMA, um, ecstasy is a unique compound in that it leads to big increases in brain levels of dopamine and serotonin simultaneously, and I realize that the neuromodulators like dopamine and serotonin often work in concert, not alone the way they're commonly described in the-

Karl Deisseroth 32:37 Sure.

Andrew Huberman 32:37 ... um, you know, the more general popular discussions. However, uh, it is a unique compound and it's different than the serotonergic compounds like LSD and psilocybin. And there are now data, um, still emerging that it might be and, and k- in some cases r- can be useful for the treatment of trauma, PTSD, and, and similar things. Why, why would that work? And do you th- and a larger question, perhaps an even more important question is, psychedelics, MDMA, LSD, all those compounds, they're t- in my mind there are two components. There's the experience you have while you're on them, and then there's the effect they have after. People are generating variations of these compounds that are non-hallucinatory variations, but how crucial do you think it is to have the, let's stay with MDMA, the experience of huge levels of dopamine, huge levels of serotonin, atypical levels of dopamine and serotonin released, having this highly abnormal experience in order to be normal again?

Karl Deisseroth 33:45 Yeah. I think the brain learns from those experiences. That's, that's the way I see it. And, and so for example, people on, who have taken MDMA, they will, as you say, they'll ha- they'll d- be the acute phase of being, you know, on th- the, the drug and experiencing the, this extreme connectedness with other people, for example. And then the, the drug, uh, wears off and, but the brain learned from that experience, and so what, what people will report is, "Yeah, I'm not, I'm not in that state, but I saw what was possible. You know, I saw... Yeah, you can... Th- there don't need to be barriers, or at least not as many barriers as, as I thought. I can connect with more people in a, uh, uh, in a way that's-"

Andrew Huberman 34:28 I see.

Karl Deisseroth 34:28 "... that is helpful." And so I think it, it, it's the learning-

Andrew Huberman 34:31 Mm-hmm.

Karl Deisseroth 34:31 ... that happens in that state that actually, uh, matters.

Andrew Huberman 34:35 And this, uh... As you described that, that sounds a lot like what I understand to be the hallmark feature of really good psychoanalysis, that the relationship between patient and therapist hopefully evolves to the point where, um, uh, these kinds of tests can be run within the context of that relationship and then exported-

Karl Deisseroth 34:52 Yeah.

Andrew Huberman 34:52 ... to other relations. Is that-

Karl Deisseroth 34:53 Exactly right, yeah.

Andrew Huberman 34:54 And th- and that probably, I'm assuming, is still the goal of really good psychiatry also.

Karl Deisseroth 34:59 It's a part of, uh, it, it sh-

Andrew Huberman 35:00 Intimacy really.

Karl Deisseroth 35:02 It, it should be, uh, whe- when we have time, I think all, all good psychiatrists try to achieve that, that level of, of-

Andrew Huberman 35:09 Mm-hmm.

Karl Deisseroth 35:09 ... of connection and learning, uh, try to help patients, um, create a new, a new model that is stable, that is learned, and that, that can, you know, uh, help instruct future behavior.

Andrew Huberman 35:21 One of the things that I, um, took from reading your book in addition to, uh, learning so much science and the future of psychiatry and brain science was, um, i- you know, amidst these ver- many, in many cases, very tragic cases and, and sadness and a lot of the, the, uh, the weight that that puts on the clinician, on you also, that there's a, that there's a s- central chord of, of optimism that where we're headed is, uh, not just, um, possible but very likely and, and better.

Karl Deisseroth 35:53 Yeah.

Andrew Huberman 35:54 And, um, you know, it... Are you an optimist? (laughs)

Karl Deisseroth 35:58 I am. And this, this is... By the way, this was a really interesting experience in writing Projections because I had a, a, a dual goal. I wanted it to be for everybody, literally everybody in the world who wants to, to, to, to, to read it, and yet at the same time I wanted to, uh, stay absolutely rigorously close to the, the science, what was actually known, um, eh, when I was speaking about science, when I was speaking about the, the neurobiology of the, of the brain or, or psychiatry. I wanted to......to not, uh, have any of my scientific colleagues think, "Oh, he's, uh, he's going too far. He's saying too much." And so I had these, these two goals which I kept in my mind the entire time and, and a lot of this... Trying to find exactly the right word. We talked about... Was on this path of staying excruciatingly rigorous in the science and yet letting people see the hope, the, the, the... Where things were. Have everybody see that we've come a long way, we have a long way to go, but, but the trajectory and the, the path is, is beautiful. And so that, that, that was the, the goal. I, I, I think, uh, you know, the, the... Of course that sounds almost impossible to, to (laughs) jointly satisfy those two, those two goals, but I, I kept that in my mind the whole way through. And, yes, I am optimistic. I... And I hope that it came through in the book.

Andrew Huberman 37:21 Well, it certainly did and at least from this colleague, um, uh, you, you did achieve both and, um, it's a wonderful... It's, it's a masterful book really and one that as a scientist and, um, somebody who is a br- a fellow brain explorer, uh, hits all the marks of, of rigor and is incredibly interesting and there's a ton of storytelling. Definitely, uh, check out the book. Um, there are other people in our community that, of course, are going to, uh, uh, be reaching out on your behalf, but it's, it's incredible that you juggle this enormous number of things. Um, perhaps even more important, however, is that it's all in service to this larger thing of relieving suffering. So thank you so much for your time today, for the book and the work (laughs) that went into the book. I can't even imagine.

Karl Deisseroth 38:10 (laughs)

Andrew Huberman 38:10 For the laboratory work and the development of channelopsins, Clarity and all the related technologies and, and for the clinical work you're doing and, and for sharing with us.

Karl Deisseroth 38:17 Well, thank you for, for all you're doing and reaching out. I, I, I, uh, I'm very impressed by it. It's important and, and, uh, it's, it's so valuable and thank you for taking the time and, and for all your gracious words about the book. Thank you. (instrumental music plays)