Psychedelics for Treating Mental Disorders | Dr. Matthew Johnson

1. 0:00 – 2:10

   Introducing Dr. Matthew Johnson

   1. AHAndrew Huberman0:00

      (uptempo music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, I have the pleasure of introducing Dr. Matthew Johnson. Dr. Johnson is a professor of psychiatry at Johns Hopkins School of Medicine, where he also directs the Center for Psychedelic and Consciousness Research. As many of you know, there's extreme excitement about the use of psychedelics for the treatment of various disorders of the mind. Dr. Johnson's laboratory is among the premier laboratories in the world understanding how these compounds work, how things like psilocybin and LSD and related compounds allow neural circuitry in the brain to be shaped and change, such that people can combat diseases like depression, or trauma, or other disorders of the mind that cause tremendous suffering. Dr. Johnson is also an expert in understanding how different types of drugs impact different types of human behaviors, such as sexual behavior, risk-taking, and crime. Dr. Johnson and his work have also been featured prominently in the popular press, such as articles in the New York Times, in Michael Pollan's book, How To Change Your Mind, and in a feature in 60 Minutes about psychedelics and the new emerging science of psychedelic therapies for treating mental disorders. During the course of today's conversation, Dr. Johnson and I talk about psychedelics at the level of what's called microdosing, whether or not it is useful for the treatment of any mental disorders. We also talk about more typical macrodosing, what those macrodosages entail, and he walks us through what an experiment of a patient taking psychedelics for the treatment of depression looks like in his laboratory from start to finish. The conversation was an absolutely fascinating one for me to partake in. I learned so much about the past, present, and future of psychedelic treatments and compounds. And indeed, I hope to have Dr. Johnson on this podcast again in the not too distant future, so that we can talk about other compounds that powerfully impact the mind and human behavior, and perhaps can also be used to treat various diseases.

2. 2:10 – 6:40

   Supporting Sponsors

   1. AHAndrew Huberman2:10

      Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Athletic Greens. Athletic Greens is an all-in-one vitamin mineral probiotic drink. I've been taking Athletic Greens since 2012, and so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and the reason I still take Athletic Greens once or twice a day, every day, is because it covers my foundational nutritional needs. 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3. 6:40 – 14:09

   ‘Psychedelics’ Defined

   1. AHAndrew Huberman6:40

      conversation with Dr. Matthew Johnson. Well, Matthew, I've been looking forward to this for a long time. I'm a huge fan of your scientific work, and I'm eager to learn from you. So-

   2. MJDr. Matthew Johnson6:50

      Likewise. Big fan, and happy to do this with you.

   3. AHAndrew Huberman6:53

      All right. Well, thank you. My first question is a very basic one, which is, what is a psychedelic? We hear this term all the time, but what qualifies a substance to, as a psychedelic?

   4. MJDr. Matthew Johnson7:06

      Nomenclature is a real challenge in this area of psychedelics. So starting with the word psychedelic, it just, if, if you're a pharmacologist, it's, it's not very satisfying, because that term really spans different pharmacological classes. In other words, if you're really concerned about receptor effects and the basic effects of a compound, it spans several com- classes of compounds. But overall, so it's really more of a, a cultural term, or a... It does have a relationship to drug effects, but it's at the, at, at a very high level. So all of the so-called psychedelics across these distinct, uh, classes that I can talk more about, um, the way I put it is, they all have the ability to profoundly alter one's sense of reality, and that can mean many things. Part of that is profoundly altering the sense of self, um, acutely, so when someone's on the psychedelic. Um, so the different classes that can be the specific pharmacological classes that can be called a psychedelic are, one, the, what are called the classic psychedelics. So in the literature, you'll see that term. And hallucinogen and psychedelic are all, have traditionally been used synonymously. Um, I think there was a little of a tendency to stay away from psychedelic 'cause of the baggage, but there's been a return to that in the last several years. But the classic psychedelics or classic hallucinogens are things like LSD, um, psilocybin, which is in so-called magic mushrooms. It's in over 200 species that we know of so far of mushrooms. Uh, dimethyltryptamine, or DMT, which is in dozens and dozens of, of, of plants. Um, mescaline, which is in the peyote cacti and some other cacti like San Pedro. And even amongst these classic psychedelics, um, there are two structural, structural classes. So that's the chemistry. There's the tryptamine-based compounds like psilocybin and DMT, and then there's the phenethylamine-based compounds. These are the basic, two of the basic, the building blocks that, that you're starting from, either a tryptamine structure or a phenethylamine structure. But that's just the chemistry. The, all of the... What's more important, or at least to, to someone like me, are the receptor effects, and then ultimately, that's going to have a relationship to the behavioral and subjective effects. So all of these classic psychedelics serve as agonists or partial agonists at the serotonin 2A receptor, so a subtype of serotonin receptor. Then you have these other classes of, of, of, that you, compounds that you could call a psychedelic. Another bi- big one would be the NMDA antagonist, so this would include ketamine, PCP, and dextromethorphan, something I've done some research with, which folks might recognize from, like, robo tripping, guzzling, like, you know, uh, cough syrup. Um, which is something kind of, like, high school kids are known to do when they can't get a hold of real drugs, that type of thing. So, um, a, a large overlap in the types of subjective effects that you get from those compounds compared to the 2A agonist classic psychedelics. Um, but then you have... And, and by the way, this description, this framework I'm describing, not everyone will agree. Some people will say, "No, psychedelic only means classic psychedelic." So there's different opinions here. But you have, gosh, Salvinorin A, which is a kappa opioid agonist, which, again-

   5. AHAndrew Huberman10:48

      Where does that come from?

   6. MJDr. Matthew Johnson10:49

      Salvia divinorum. It's a plant that became 20 years ago, it sort of popped onto the legal high scene. And there's a, you know, long history of this. Pre-dating the internet, going back to, like, the stuff one could order in the back of High Times Magazine, and, and most of this stuff, like, never worked, you know? (laughs) Where it's like, smoke enough of anything, maybe you get a little bit lightheaded. But this is one of those things that popped around 20 years ago when it quickly got the reputation of, like, "Holy shit, this stuff actually works," (laughs) and works really strongly. In these smoked extracts particularly, people have these reality-altering experiences on par with smoked DMT, the classic psychedelic. So often... And, uh, we did the first blinded controlled human research with Salvinorin A, so lots of entity contact, so feeling that you, in the experience of one is actually interacting with autonomous beings, that type of thing. And then you have a, another big one I probably should've mentioned even before the, you know, Salvinorin A, um, but you have MDMA, which really stands in a class by itself. So it's been called an entactogen, and, and, uh-

   7. AHAndrew Huberman11:57

      What does that mean?

   8. MJDr. Matthew Johnson11:58

      Um, it means, like, uh, uh, touching within.It sort of alludes the idea that it can really put someone in touch with their emotions. Um, it's also been called an empathogen, meaning it can, it can afford empathy. Um, but I think entactogen's probably the... That's the, the term that I, I tend to focus on. And I know I'm not telling you anything you don't know, but the, for the, for the, um, viewers, the, the, the primary mechanism of MDMA is serotonin release, and to a degree other monoamine release, dopamine, serotonin. And so structurally, that's also in the phenethylamine class, which contains mescaline, the classic psychedelic, um, but also amphetamine, so just, you know, like Adderall is, is, is in that phenethylamine class. And so this is another example where chemistry doesn't dictate. I mean, you can tweak a molecule. It might have that same basic structure, but now you've profoundly changed the way it interacts with the receptors. So, you know, MDMA does not, uh, you know, exert its actions by, um, I like to say, by, by, by, you know, mimicking the baseball entering the glove- the post, uh, uh, synaptic receptor side, you know, acting as an agonist, so mimicking the, the, the, the endogenous neurotransmitter, serotonin, like the classic psychedelics do. MDMA works on the pitcher side of just basically throwing out more of the natural, the, the endogenous-

   9. AHAndrew Huberman13:31

      Dumping more serotonin. Yeah.

   10. MJDr. Matthew Johnson13:32

       ... dumping more serotonin-

   11. AHAndrew Huberman13:33

       Yeah.

   12. MJDr. Matthew Johnson13:33

       ... flooding-

   13. AHAndrew Huberman13:34

       Yeah.

   14. MJDr. Matthew Johnson13:34

       ... the synapse.

   15. AHAndrew Huberman13:36

       So I get the impression that the s- psychedelic space is a enormous cloud of partially overlapping compounds-

   16. MJDr. Matthew Johnson13:43

       Right.

   17. AHAndrew Huberman13:43

       ... uh, meaning some are impacting the serotonin system more than the dopamine system. Others are impacting the dopamine system more the, than the serotonin system. Given that the definition of a psychedelic is that it profoundly alters sense of self, at least that's included as a partial definition-

   18. MJDr. Matthew Johnson14:02

       Mm-hmm.

   19. AHAndrew Huberman14:03

       ... can we break that down into a couple of subcategories? So for instance, um, hallucinating,

4. 14:09 – 19:56

   Hallucinations, Synesthesia, Altered Space-Time Perception

   1. AHAndrew Huberman14:09

      a- either auditory or visual, um, synesthesia, perceptual blending, the sense that, um, you know, you can hear colors, uh, and see sounds, for instance, a common, um, report of people-

   2. MJDr. Matthew Johnson14:22

      Yeah.

   3. AHAndrew Huberman14:22

      ... that take psychedelics, uh, in sufficiently high doses. So hallucinating, synesthesia, and then in terms of sense of self, you know, as a neuroscientist, I think, okay, what does it mean to alter a sense of reality? Really, what the brain does, uh, in a very coarse way, um, is to try and figure out what's happening in space, physical space, and that physical space could be within us or outside us, and what's happening in time.

   4. MJDr. Matthew Johnson14:50

      Right.

   5. AHAndrew Huberman14:50

      And, um, as a vision scientist, the simplest explanation is when I move my hand from one location to another location, it's measuring the space, the location of my hand in space over time.

   6. MJDr. Matthew Johnson15:01

      Mm-hmm.

   7. AHAndrew Huberman15:01

      And then you get a rate and a, you know, speed and all that kind of stuff, right?

   8. MJDr. Matthew Johnson15:04

      Yeah.

   9. AHAndrew Huberman15:05

      That gets more complicated as you get into the emotional, um, realm. But is it fair to say that psychedelics are impacting the spacetime analysis that the brain is performing and thereby creating hallucinations and thereby altering s- you know, the blending of senses? Is it fair to say that?

   10. MJDr. Matthew Johnson15:28

       I think it's, it's fair to explore that area, and here, here's what I'm thinking. The, the... Clearly, there is a changed relationship, certainly at the right dose, of orientation in spacetime. I think as a, as a, a... You know, I'm primarily a, a behaviorist, and in terms of pharmac- human behavioral pharmacology, I'm, I, I always go to comparative pharmacology, okay? What can we say that isn't truly unique about the classic psychode- or psychedelics in general? So with that description, I'm thinking, okay, alcohol can really screw up your, you know, time-space, uh, orientation.

   11. AHAndrew Huberman16:05

       And proprioception, your balance-

   12. MJDr. Matthew Johnson16:06

       Proprioception.

   13. AHAndrew Huberman16:07

       ... vestibular, yep.

   14. MJDr. Matthew Johnson16:07

       You know, and in many ways, and, and cert- in those gross motor ways, like, far worse. You know, of course, everything's dose-dependent, but in the classic psychedelics, you know, obviously the benzodiazepines, being very similar to alcohol, same thing. So, you know, I'd wanna, you know, dig in a little more in terms of, like, maybe there's something more specific we could say about that relationship to time and space that the, the psychedelics are tinkering with. But u- I'm not sure. It's an interesting hypothesis, the, the idea that that's a mediator, that, uh, that that's something, that there's something fundamental about changing that, the representation in time and s- and space. Um, there might be something to that. Uh, I mean, I think o- of these as, as psychedelics as profoundly altering models, you know? You know, we're all, you know, we're prediction machines, and that's lar- So much of that is, is top-down, and, uh, a- and, and psychedelics have a good way of, you know, loosely speaking, dissolving those models. And, and one of th- th- the reality-

   15. AHAndrew Huberman17:13

       Can you give us an example of one of, like a model? Like a, like I know that when, um, I throw a ball in the air, it falls down, not up. That's a, that's a prediction that I learned as a child. Uh, I, I did not come into the world with a brain that, um, knew that relationship-

   16. MJDr. Matthew Johnson17:30

       Yes.

   17. AHAndrew Huberman17:30

       ... between objects and gravity, but one of the first things that a child learns is the relationship between objects and gravity and their trajectories.

   18. MJDr. Matthew Johnson17:40

       Yeah, and with a four-year-old, I mean, I saw that at earlier ages, like, that experimentation of like, "Oh, yeah, that's what happens," you know? (laughs)

   19. AHAndrew Huberman17:48

       Right.

   20. MJDr. Matthew Johnson17:48

       Like, oh-

   21. AHAndrew Huberman17:48

       So if, if a, if he were to throw a ba- If your, uh, child were to throw a ball, and it went up into the sky, that would be absolutely m- mind-blowing.

   22. MJDr. Matthew Johnson17:57

       Yeah.

   23. AHAndrew Huberman17:57

       It would be for an adult too.

   24. MJDr. Matthew Johnson17:58

       It'd be a pretty psychedelic-

   25. AHAndrew Huberman17:59

       Right.

   26. MJDr. Matthew Johnson17:59

       ... experience probably. (laughs)

   27. AHAndrew Huberman18:01

       Right. Right. And so there's a, there's a spa- there's a rule there, you're saying. There's a kind of a, a, a prediction ba-

   28. MJDr. Matthew Johnson18:07

       Right.

   29. AHAndrew Huberman18:07

       There's a rule that, that underlies the prediction that when that-... rule is violated, all of a sudden the circuit presumably for that prediction go like-

   30. MJDr. Matthew Johnson18:16

       Yeah. It's, it's not-
5. 19:56 – 23:50

   Serotonin & Dopamine

   1. AHAndrew Huberman19:56

      Can, uh, we just briefly touch on the serotonin system-

   2. MJDr. Matthew Johnson20:01

      Mm-hmm.

   3. AHAndrew Huberman20:01

      ... and the dopamine system? I, I want to acknowledge that, as you already know, that there are many neuromodulator systems in the body, op- and, you know, the opioid systems, cannabinoid systems. But there's something so profound about the serotonin system and the dopamine system, because the way I define a neuromodulator is, it's a modulator. It changes the way that other circuits behave. In essentially, it up- it increases the probability that certain circuits will be active, and decreases the probability that other circuits-

   4. MJDr. Matthew Johnson20:28

      Yeah.

   5. AHAndrew Huberman20:28

      ... will be active, in a, in a-

   6. MJDr. Matthew Johnson20:29

      Mm-hmm.

   7. AHAndrew Huberman20:30

      ... in a general sense. So compounds like LSD, lysergic acid diethylamide, and psilocybin, my understanding is that they primarily target the serotonin system. How do they do that at a kind of general level, and why would increasing the activity of a particular serotonin receptor or batch of serotonin receptors lead to these profoundly different experiences that we're calling, um, m- model challenges, challenging preexisting models and predictions?

   8. MJDr. Matthew Johnson21:05

      Yeah.

   9. AHAndrew Huberman21:05

      I mean, at the end of the day, it's a chemical, and these receptors are scattered around the brain with billions of other receptors.

   10. MJDr. Matthew Johnson21:12

       Yeah.

   11. AHAndrew Huberman21:14

       W- w- uh, what do we think is going on at- in a general sense?

   12. MJDr. Matthew Johnson21:17

       Yeah, yeah. And this is really the area of active exploration, and we don't have great answers. We know a good amount about the receptor level pharmacology, some things about post-receptor signaling pathways. In other words, just fitting into the receptor. Clearly, you know, serotonin itself is not psychedelic, (laughs) you know, or else we'd be tripping, all of us all the time.

   13. AHAndrew Huberman21:38

       'Cause when I eat a bagel, I get serotonin release, right?

   14. MJDr. Matthew Johnson21:41

       Uh-huh.

   15. AHAndrew Huberman21:41

       I mean, there's... Uh, or turkey-

   16. MJDr. Matthew Johnson21:43

       And it's very different than LSD.

   17. AHAndrew Huberman21:43

       I mean, there's tryptophan and... Right.

   18. MJDr. Matthew Johnson21:44

       Mm-hmm.

   19. AHAndrew Huberman21:45

       My understanding of serotonin is, is that in j- in very broad strokes, that it, it generally leads to a state of being fairly... It pushes the mind and body towards a state of contentment within-

   20. MJDr. Matthew Johnson21:56

       Right.

   21. AHAndrew Huberman21:56

       ... the immediate experience. Whereas the dopamine system really places us into an external view of what's out there in the world, and what's possible.

   22. MJDr. Matthew Johnson22:06

       Yeah.

   23. AHAndrew Huberman22:07

       Is that fair to say?

   24. MJDr. Matthew Johnson22:07

       Need to do something. I mean, that's consistent with my u- understanding. And, uh, and, and, and certainly not in terms of, I don't primarily identify as a, a neuroscientist. I'll definitely tell the, you know, the viewers that we're h- far more in your domai- domain here than mine. But in terms of how psychedelics and other drugs, you know, interface at the, at the neuroscience level-

   25. AHAndrew Huberman22:28

       Well, feel free to, to explain it at the experiential level.

   26. MJDr. Matthew Johnson22:31

       Yeah.

   27. AHAndrew Huberman22:31

       I mean, it doesn't have...

   28. MJDr. Matthew Johnson22:32

       Well-

   29. AHAndrew Huberman22:32

       I, I think prob- there probably are some audience members that are interested in, is it the 5-H2C? Is it the layer five neurons and cortex?

   30. MJDr. Matthew Johnson22:38

       Yeah.
6. 23:50 – 28:00

   Ketamine & Glutamate

   1. MJDr. Matthew Johnson23:50

      why... You know, ketamine is very psychedelic in a slightly different way, but-

   2. AHAndrew Huberman23:54

      Do people hallucinate on ketamine?

   3. MJDr. Matthew Johnson23:56

      Yes, yes, and it's more dissociative, so someone is more likely to sort of, uh, be less behaviorally active. If they have a really high dose, they go into a K-hole. And, uh, and if they go in a really high dose, like you get in surgery, they're just unconscious.

   4. AHAndrew Huberman24:09

      That's why it's called a K-hole?

   5. MJDr. Matthew Johnson24:09

      Yeah, a K-hole.

   6. AHAndrew Huberman24:09

      Not an A-hole, but a K-hole.

   7. MJDr. Matthew Johnson24:10

      A K-hole. (laughs) Yeah.

   8. AHAndrew Huberman24:12

      Right.

   9. MJDr. Matthew Johnson24:12

      It's very different. Um-... the K hole in ketamine's interesting, 'cause people can take kinda bumps and kinda dance on it with the sort of an alcohol-level strength of e- effect. Um, and that's sort of the classic kind of raving, you know, use of it, but then those folks wanna titrate their dose, because, uh, if they do more of, like, a line, you get up to, like, 75, 100 milligrams. Then you're talking about, um, you know, if you're on the dance floor, you're on the- on the floor, and your friends are trying to make sure people aren't stepping on you. So (laughs) that's like the K hole or something you can't-

   10. AHAndrew Huberman24:44

       Yeah, why would somebody want to take a dissociative anesthetic? It, like, to me, it's completely mysterious as to why someone would want to dissociate from their body.

   11. MJDr. Matthew Johnson24:53

       People claim that these- these- the in- these NMDA antagonist psychedelics are extremely insightful, you know, in a very similar way to the experiences with the classic psychedelics. So and it-

   12. AHAndrew Huberman25:05

       And ketamine is now legal for therapeutic use, correct?

   13. MJDr. Matthew Johnson25:07

       Right, right, Spravato, the- the- the- the intranasal form, um, marketed by Janssen, which is esketamine. It's one of the-

   14. AHAndrew Huberman25:16

       It's prescription.

   15. MJDr. Matthew Johnson25:16

       Yeah, it's prescription, and, um-

   16. AHAndrew Huberman25:18

       So people are taking in the nasal spray.

   17. MJDr. Matthew Johnson25:20

       Yeah.

   18. AHAndrew Huberman25:21

       And then are they undergoing talk therapy while they're doing this?

   19. MJDr. Matthew Johnson25:24

       Typically not. So it's, it- this is very interesting, and there's so much work that needs to be done. Um, it's not treated as psychedelic therapy, and by that, psychedelic therapy, I mean you tell the person they're gonna have an altered experience. You tell them to pay attention to that experience, that they might learn something from that experience, and afterwards, you discuss that experience. With Spravato, you know, the model is-

   20. AHAndrew Huberman25:49

       Spravato is?

   21. MJDr. Matthew Johnson25:49

       Is esketamine.

   22. AHAndrew Huberman25:51

       Okay.

   23. MJDr. Matthew Johnson25:51

       It's the- the, yeah, the- the spray form of ketamine that's- it's been FDA approved for treatment-resistant depression. But it's, you'll f- you'll probably feel different. Ignore that. That's a side effect. (laughs) That's an adverse effect. Um, just ignore it. Um, we don't think that has anything to do with the way it works. Um, but just get this thing. It's a- it's a direct, you know, sort of chemotherapeutic effect in a sense. It's- it's a- it's not facilitating a learning process. Now, there's older work. There was a guy, Kripitsky, in Russia, that did extensive work with higher doses of ketamine. I should say Spravato at the prescribed doses isn't very psy- it's a pretty low dose. It's in the s- mild psychedelic range, but it's not very strong. But this older work that happened in the '90s and early 2000s in- in Russia, um, they were using very high doses and treating it like a psychedelic, you know, treating it as if it was a psychedelic therapy. In other words, telling people, "You're gonna have this experience. It's gonna, you know, we're hoping you learn something from it. We're gonna help you through it. We're gonna d- discuss it afterwards." And they found incredibly high rates of success in some pretty well-controlled trials for both heroin addiction and alcohol a- a- a- addiction. So I think a whole lot of work needs to be done now, and you see it, some of the ketamine clinics that are using ketamine off-label, a lot of them are treating it like psychedelic therapy. There's r- essentially no research at this point on that. Do you get better results? Um, straight-up use of Spravato, there's some good variability, but its antidepressant effects last about a week. Um, but they kick in immediately. Now, a week is a long time for, like, most- most psychiatric drugs. Like, you'd take it every day.

   24. AHAndrew Huberman27:34

       Right.

   25. MJDr. Matthew Johnson27:34

       You know, so that's amazing, but it's still just a week. We're seeing effects y- a year or more later with- with s- with psilocybin and- and- and some of the classic psychedelics. That could be a pharmacological difference, or it could be that they get a lot more mileage out of ketamine if they treated it like psychedelic therapy, and so that's some- some work that needs-

   26. AHAndrew Huberman27:54

       So what would that look like?

   27. MJDr. Matthew Johnson27:55

       Um, really just like our- our psilocybin th- uh, you know, sessions, which I know I haven't

7. 28:00 – 37:30

   An Example Psychedelic Experiment

   1. MJDr. Matthew Johnson28:00

      described, but briefly, you have anywhere from four to eight hours of preparation, getting to know the people who are gonna be the guides or the therapists in the room with the person.

   2. AHAndrew Huberman28:08

      Yeah, maybe you could walk us through this. Um, so let's say I were to come to one of your clinical trials, 'cause these are clinical trials, right?

   3. MJDr. Matthew Johnson28:15

      Mm-hmm.

   4. AHAndrew Huberman28:16

      In- in your- at your lab at Hopkins.

   5. MJDr. Matthew Johnson28:17

      Yeah.

   6. AHAndrew Huberman28:18

      And, uh, would I need to be depressed, or could I just be somebody who wanted to explore psychedelics?

   7. MJDr. Matthew Johnson28:22

      It, we've had studies for all of these-

   8. AHAndrew Huberman28:25

      Okay.

   9. MJDr. Matthew Johnson28:25

      ... and- and- and a number of other disorders.

   10. AHAndrew Huberman28:27

       Okay.

   11. MJDr. Matthew Johnson28:27

       So healthy/normal studies-

   12. AHAndrew Huberman28:28

       Okay.

   13. MJDr. Matthew Johnson28:28

       ... the- the code for not a problem to fix, but we're all hu- that's what's amazing about s- psychedelics, though, because you, if you administer them under this model, and you develop a relationship, and give a high dose of psychedelic, you could be a healthy/normal without a- a diagnosable issue. But man, we're all human, and the issues seem to come to the surface.

   14. AHAndrew Huberman28:46

       Sure. Yeah, I agree.

   15. MJDr. Matthew Johnson28:47

       So but we've done work with, uh, smoking cessation, so people trying to quit tobacco, and haven't been successful.

   16. AHAndrew Huberman28:52

       So a variety of reasons. So-

   17. MJDr. Matthew Johnson28:54

       Right.

   18. AHAndrew Huberman28:54

       ... um, maybe I'll just ask some very simple questions that- that would kind of step us through the process. So let's say I were to sign up for one of these trials, and- and I qualified for one of these trials. I'd show up. You said I would do several hours in advance of getting to know the team that would-

   19. MJDr. Matthew Johnson29:07

       Mm-hmm.

   20. AHAndrew Huberman29:07

       ... th- that would be present during this psychedelic journey.

   21. MJDr. Matthew Johnson29:11

       Right. First, there's screening. So it's kind of like a- a couple a days of both psychiatric, like, str- structured in- psychiatric interviews about your whole, you- your- your past, and symptoms across the- the- the DSM, the psychiatric bible, to see if you might have various disorders that- that could, um, disqualify you. Like, the- the main ones being the psychotic disorders, schizophrenia, and we're also including, um, bipolar.

   22. AHAndrew Huberman29:34

       Right.

   23. MJDr. Matthew Johnson29:34

       So the manic side of- of bipolar.

   24. AHAndrew Huberman29:36

       Mm-hmm.

   25. MJDr. Matthew Johnson29:36

       So- so after that's, and also cardiovascular screening, heart disease, after that screening, then the preparation, where you get, you're both, you get, you develop a therapeutic rapport with the people who are gonna be in the room with you, your guides. Um, but you're also then didactically sort of explained about what the psychedelic could be like. And that's kind of a laundry list, because they're more known by their variability-

   26. AHAndrew Huberman30:00

       Mm-hmm.

   27. MJDr. Matthew Johnson30:01

       ... than, you know, it's gonna ha- it's not like cocaine. Like, you're gonna feel stimulated. You're gonna feel like, you know, you can do any, it's like, you know, or alcohol. You're gon- probably gonna feel more relaxed. It's like, I call 'em uppers, downers, and all-arounders, and the psychedelics are all-arounders. It's like, yeah, you could be-... you could have the most beautiful experience of your life, or the most terrifying experience of your life. So it's this kind of laundry list of like the things that could happen, so there's no surprises.

   28. AHAndrew Huberman30:29

       Mm-hmm. I think that's so important for people to hear, because, um, the all-arounders, they- the- you really can't predict how somebody is going to react internally.

   29. MJDr. Matthew Johnson30:38

       Right.

   30. AHAndrew Huberman30:39

       Um, I, I wanna just briefly touch on something, uh, because we, we left that topic, but, um, it occurred to me that a lot of these effects of psychedelics and how they function, et cetera, is still very mysterious, but then I recalled to mind that how most prescription antidepressants work is also very mysterious. They increase serotonin, or dopamine, or epinephrine, et cetera, but why they take weeks on end- you know, several weeks to kick in, et cetera, is also mysterious. But going back to the, the, the experience of, of coming to your laboratory. Okay. So the- let's say that somebody passes all the prerequisites-
8. 37:30 – 44:10

   ‘Letting Go’ with Psychedelics

   1. AHAndrew Huberman37:30

      the, the letting go of control, and then as we march through this, um, hypothetical experience, that does take place in your lab-

   2. MJDr. Matthew Johnson37:37

      Mm-hmm.

   3. AHAndrew Huberman37:38

      ...but so we're using a sort of generic case example-

   4. MJDr. Matthew Johnson37:41

      Mm-hmm.

   5. AHAndrew Huberman37:41

      ...if you will. Um, the letting go of control is an interesting feature actually, because, uh, one of the common themes of, of good psychoanalysis is, or psychotherapy of any kind, is that there's a trust built between the patient and the analyst, and that relationship becomes a template for trust more generally, and trust in one's self. It's actually the, the end goal of good psychoanalysis is that the patient actually... One of the end goals is that they develop an empathy for themselves, which almost sounds like an oxymoron, but-

   6. MJDr. Matthew Johnson38:11

      Mm-hmm.

   7. AHAndrew Huberman38:11

      ...if you spend a little time with that statement it, it actually pans out.

   8. MJDr. Matthew Johnson38:14

      Mm-hmm.

   9. AHAndrew Huberman38:15

      So the psychedelic experience is one in which chemically you're under a new, new set of conditions, right?

   10. MJDr. Matthew Johnson38:25

       Yeah.

   11. AHAndrew Huberman38:25

       Let's coarsely, space and time are, are altered in some way, sense of self. Uh, uh, for instance, I might be going to a strongly interoceptive mode where I'm focusing on my, everything within the confines of my skin, whereas normally, we're sort of interacting in space, and pens, and conversation, and I'm sort of, if I had, occasionally I'll pay attention to my breathing, but I'm sort of dilating my, and contracting my focus for different things all the time.

   12. MJDr. Matthew Johnson38:50

       Yeah.

   13. AHAndrew Huberman38:50

       The letting go of control, it seems to me, could be sort of the expansion of one perceptual bubble to the point where you're not actually worried that that perceptual bubble is gonna pop or that... Meaning you're not worried about what people think of you.

   14. MJDr. Matthew Johnson39:06

       Yeah.

   15. AHAndrew Huberman39:07

       You're not worried whether or not your, um, brain is gonna explode even though a thought could feel enormous.

   16. MJDr. Matthew Johnson39:12

       Mm-hmm.

   17. AHAndrew Huberman39:13

       Um, if I keep going like this it'll almost sound psychedelic, but that's the idea here. Um, or if I'm paying attention, for instance, to some somatic experience like, um, the, the coursing of waves of heat through my body-

   18. MJDr. Matthew Johnson39:26

       Mm-hmm.

   19. AHAndrew Huberman39:26

       ...that I'm not suddenly saying, w- w- you know, "Is that weird?" I'm actually just going deeper and deeper into it. So it's essentially expanding a perceptual phenomenon. How do you convince people to go further and further down that path? What do you think allows them to do that? Because I think that, that to me is one of the more unusual, uh, aspects to psychedelics, is that normally the, the social pressure, but also just our internal pressure from our own brain, is pay attention to many things at once.

   20. MJDr. Matthew Johnson39:57

       Mm-hmm.

   21. AHAndrew Huberman39:57

       Not just one. Is that, is-

   22. MJDr. Matthew Johnson39:59

       Especially these days. You gotta multitask.

   23. AHAndrew Huberman40:01

       Exactly. Right.

   24. MJDr. Matthew Johnson40:01

       Yeah.

   25. AHAndrew Huberman40:02

       Multitask. And the more that we focus on one thing, the more bizarre that thing actually can appear to us, right?

   26. MJDr. Matthew Johnson40:08

       Right. (laughs)

   27. AHAndrew Huberman40:08

       I mean, even if it's the tip of your finger and you're not taking any psychedelics, you spend a- long enough looking at the tip of your finger, you will notice-

   28. MJDr. Matthew Johnson40:14

       Yeah, that's weird.

   29. AHAndrew Huberman40:14

       ...some very weird things.

   30. MJDr. Matthew Johnson40:16

       Yeah.
9. 44:10 – 48:00

   Our Mind’s Eye

   1. AHAndrew Huberman44:10

      eyes, the, the levels of activity in the retina actually are maintained. It's spont- it's just spontaneous activity.

   2. MJDr. Matthew Johnson44:16

      And it seems, and I'd be curious about your thoughts on this, I mean, uh, but the way I describe it is that the, you know, the mind's eye, you know, this kind of loose term we use, can be on rocket boosters. So a lot of times, for some people, like a compound like psilocibin, for some people, there's no perceptual effect. Like, if they're looking at this room, it would pre- pretty much look the same. Sometimes folks are like, "Yeah, things seem a little bit brighter." Now some people will say, "Oh my god, there's waves. That wall is waving, and these curtains are..." You know? On these compounds, people don't typically see pink elephants. You do actually get that in another class I didn't mention, the, the anticholinergics, uh, sort of like atropine and scopolamine, those drugs.

   3. AHAndrew Huberman44:59

      Yeah. Yeah.

   4. MJDr. Matthew Johnson44:59

      Those are the, those are the true hallucinations, where you thought you were having a conversation with someone who was never there.

   5. AHAndrew Huberman45:04

      Right.

   6. MJDr. Matthew Johnson45:05

      You know?

   7. AHAndrew Huberman45:05

      Those are the... Um, well, we will definitely get to those. But when, the reason I kind of cringe and said, "Oh my," when you talked about those, is that, um, knowing a little bit about the pharmacology of acetylcholine, the, the idea of manipulating that system, to me, sounds very uncomfortable. Because, uh, like, the whole idea of, of, well, witches and flying, there was a whole history there, you know, hundreds of years ago, so-called witches taking these agents, and then f- thinking they were flying around on broomsticks and things of that sort.

   8. MJDr. Matthew Johnson45:36

      Yeah.

   9. AHAndrew Huberman45:36

      And, and there's a lot of mythology around the broomsticks. It's complicated. But, but that sounds very unpleasant. One thing I, I, about the, the serotonergic, let's just, uh, for, with psilocybin, um, so there's a per- an expansion of a particular fairly narrow percept. It could be sound-

   10. MJDr. Matthew Johnson45:54

       Yeah.

   11. AHAndrew Huberman45:54

       ... could be an emotion, could be sadness, could be a historical event, or a fear of the future.

   12. MJDr. Matthew Johnson46:00

       Yes.

   13. AHAndrew Huberman46:01

       And you've mentioned before that there's something to be learned in that experience.

   14. MJDr. Matthew Johnson46:06

       Yeah.

   15. AHAndrew Huberman46:06

       There's something about going into that experience in a, in an un- um, in an, in an undeterred way that allows somebody to bring something back into more standard reality.

   16. MJDr. Matthew Johnson46:20

       Yeah.

   17. AHAndrew Huberman46:22

       Given the huge variety of experiences that people have on psychedelics, given the huge variety of humans that are out there, but what are now very clear therapeutic effects in the realm of depression, what do you think is the value of going into this fairly restricted perceptual bubble, what we are calling letting go, or giving up control? Because if the experiences are many, but the value of what one exports from that experience is kind of similar across individuals-

   18. MJDr. Matthew Johnson46:54

       Yeah.

   19. AHAndrew Huberman46:54

       ... that raises all sorts of interesting questions. And this is not a, a philosophy discussion. We're talking about biology and psychology here.

   20. MJDr. Matthew Johnson47:01

       Yeah.

   21. AHAndrew Huberman47:02

       So let's say I decide that I'm gonna focus on the tip of my pen. I mean, in a psychedelic state, I could fall in love with this pen. I do happen to like these Pilot V5s and V7s very much.

   22. MJDr. Matthew Johnson47:12

       (laughs)

   23. AHAndrew Huberman47:12

       But I could feel real love-

   24. MJDr. Matthew Johnson47:14

       Yeah.

   25. AHAndrew Huberman47:14

       ... for the pen.

   26. MJDr. Matthew Johnson47:15

       Yeah.

   27. AHAndrew Huberman47:16

       Right? That's not an unreasonable thing to expect on a psy- in a psychedelic journey.

   28. MJDr. Matthew Johnson47:19

       Right, right.

   29. AHAndrew Huberman47:20

       And, and in the context of your laboratory model, which I think is a great one, that experience would be just as valid as me going into the experience of some of the deep friction that I might have with a family member over my entire lifespan.

   30. MJDr. Matthew Johnson47:33

       Yeah.
10. 48:00 – 58:56

    Redefining Your Sense of Self

    1. AHAndrew Huberman48:00

    2. MJDr. Matthew Johnson48:00

       So this is definitely in the, this is in the terrain we're figuring out, you know? So there's no... The educated speculation is the best I can provide. But I, uh, I think the best, the, the, the, the mo- I think the common denominator are persisting changes in self-representation.

    3. AHAndrew Huberman48:20

       Okay.

    4. MJDr. Matthew Johnson48:21

       And-

    5. AHAndrew Huberman48:21

       Tell me more about self-representation.

    6. MJDr. Matthew Johnson48:23

       That's, uh, the way one holds th- the sense of self.

    7. AHAndrew Huberman48:27

       Mm-hmm.

    8. MJDr. Matthew Johnson48:27

       The rela- the fundamental relationship of a person in the world. I mentioned earlier that-... these experience seems to alter the models we hold of reality. And I think of the self as the biggest model-

    9. AHAndrew Huberman48:39

       Mm-hmm.

    10. MJDr. Matthew Johnson48:39

        ... that I am a thing that's separate from other things, and that's... I am defined by certain... I have a certain personality, and I, I'm a smoker that's having a hard time quitting, or I'm a depressed person that, you know, views myself as a failure, and all of these things. Those are models too. And, and I think, I think that change in self-repre- representation may be an endpoint for these different experiences.

    11. AHAndrew Huberman49:04

        Mm-hmm.

    12. MJDr. Matthew Johnson49:04

        I mean, maybe the falling in love with the pen, the whole idea that you're... especially in contemplation afterwards, and obviously I'm speculating here, but the whole idea that you could have such a, a deep connection with this random, obviously random aspect of, of the universe, could potentially lead to this, uh, you know, transformed understanding of the self, and, like, the pen may be a proxy for the, the miracle of reality, i- in-

    13. AHAndrew Huberman49:32

        Mm-hmm.

    14. MJDr. Matthew Johnson49:32

        ... a way that relies nothing on, uh, uh, on no supernatural thinking, you know? You could be a hard atheist and take this, you know, ultimately, "Oh my God," like that, just like the pen, this is, you know, th- this is amazing, the fact that we exist, and so y- there could be an extrapolation chair.

    15. AHAndrew Huberman49:47

        Mm-hmm. Mm-hmm.

    16. MJDr. Matthew Johnson49:48

        And you used the pen, but I think it sounds so similar to Aldous Huxley's classic description-

    17. AHAndrew Huberman49:52

        Mm-hmm.

    18. MJDr. Matthew Johnson49:53

        ... in The Doors of Perception of the chair and the drapes. Like, he took, um, 500 milligrams of mescaline. He was just like-

    19. AHAndrew Huberman50:00

        Is that a high dose of mescaline?

    20. MJDr. Matthew Johnson50:01

        Yeah. Yeah. And, and that's, uh, and, you know, that's a heroic dose, for sure.

    21. AHAndrew Huberman50:06

        Mm-hmm.

    22. MJDr. Matthew Johnson50:06

        And he just going off on the chair-iness of the chair, like, this chair is exuding the quality of being a chair.

    23. AHAndrew Huberman50:12

        Mm-hmm.

    24. MJDr. Matthew Johnson50:13

        And, and like-

    25. AHAndrew Huberman50:13

        So this is this expansion of the perceptual bubble, a narrow, a narrow, uh, percept that then grows within the confines of that narrow percept.

    26. MJDr. Matthew Johnson50:23

        Yeah.

    27. AHAndrew Huberman50:23

        The y- so sense of self is a very interesting, uh, phenomenon, and if we could dissect it a little bit, um, there's the somatic sense of self, so the ability to literally feel the self, uh, inter- this process we call interoception, and then there's the, the, the title of the self, the I am blank.

    28. MJDr. Matthew Johnson50:41

        Yeah.

    29. AHAndrew Huberman50:41

        And I noticed you said that several times, and it's intriguing to me. I have a, a good friend at- I don't think I, I, uh, can or should mention his name, but he had a very long and successful career in, um, within one of the more elite teams in- within the SEAL teams, and he, um, he's a fairly philosophical guy. Um, also very practical guy. Uh, but he has said many times, um, to me that, "The most powerful words in any language are 'I am'," because whatever follows that tends, if you repeat it enough, tends to have this, uh, kind of feedback effect on the, on how you are in the world.

    30. MJDr. Matthew Johnson51:17

        Mm-hmm.
11. 58:56 – 1:04:36

    Exporting Psychedelic Learnings to Daily Life

    1. AHAndrew Huberman58:56

       step from the, the experience under the effects of the psychedelic. So the person there with your team, they go into this expanded perceptual bubble. If, if things go well, they're able to do that to a really deep degree. Maybe it's the tr- the relived trauma. Maybe it's the beauty of the, their ability to connect to things in the world.

    2. MJDr. Matthew Johnson59:16

       Mm-hmm.

    3. AHAndrew Huberman59:16

       And I want to talk about the transition out of that state, and then the export into life, because this is really where the power of psychedelics seems to be in the therapeutic sense-

    4. MJDr. Matthew Johnson59:26

       Mm-hmm.

    5. AHAndrew Huberman59:26

       ... is the ability to learn, truly learn from that experience so that the learning becomes the default, that one doesn't have to remind themselves, "Oh, I am..." You know, they don't have to do an affirmation. "I am a happy person. I am a hap-" You know, I always think of Bart Simpson-

    6. MJDr. Matthew Johnson59:38

       Right.

    7. AHAndrew Huberman59:38

       ... like writing on the chalkboard.

    8. MJDr. Matthew Johnson59:40

       (laughs) Yeah.

    9. AHAndrew Huberman59:40

       Right? Didn't work for him, doesn't work for this other stuff too.

    10. MJDr. Matthew Johnson59:43

        Uh-huh.

    11. AHAndrew Huberman59:43

        But, so as they transition out of this state, I know that there's a kind of a heightened, there's a, a so-called peak-

    12. MJDr. Matthew Johnson59:49

        Yeah.

    13. AHAndrew Huberman59:49

        ... where everything seems to be kind of cascading in at such a level that, um, the person just, they can't really turn it off at that point.

    14. MJDr. Matthew Johnson59:57

        Right.

    15. AHAndrew Huberman59:57

        It would be challenging. Um, and then they start to exit the effects of the drug. Are those transition zones, are those valuable, much like is the transition between a dream and the waking state valuable? Because you're in a sort of mishmash of altered reality and new reality.

    16. MJDr. Matthew Johnson1:00:18

        Right.

    17. AHAndrew Huberman1:00:18

        What do you, what do you do to guide people through the, um, out, out the tunnel, as they exit the tunnel?

    18. MJDr. Matthew Johnson1:00:25

        Yeah. And I have to say, like, this is where we need more experimentation. Um, really, the clinical model goes back to literally the nine- late 1950s, and there's been virtually no experimentation on, let's say, you know, randomized people to-... we're gonna talk more during the latter half of the, of the session versus not, versus we have them, you know, write an essay after their session versus not, versus we have this amount of integration, uh, uh, discussion-

    19. AHAndrew Huberman1:00:53

        What's the follow-up in your studies? Are they, are they writing or talking as they're doing it?

    20. MJDr. Matthew Johnson1:00:56

        So, and it's called, you know, very loosey-goosey, you know, term, integration, but w- for us means, um, as they're coming back from the experience, so sort of five, six hours in. You know, so this is the afternoon. They've been dosed around nine o'clock, so this is like four o'clock or so. Just some initial, "Tell us about the experience. Do you wanna..." Not unpacking it totally, but just kind of initially just have a little bit of discussion before they go home, so there's a little bit of that. But then, that night, their homework is to write something. So it could be, you know, a few bullet points, it could be, you know, 20 pages. I mean, w- we get everything, you know, in that range. Um, but, you know, try not to be self-critical. It's not great at, like, this is just to process, and for a point of discussion the next day. So they write something, they come in the next day for a, a, a one to two hour, depending on the study, integration session. Basically, just discu- "Let's discuss your experience," and depending on what study it's in, like, what, you know, what might that mean for... You're dealing with cancer, what might that mean for y- your smoking, um, you know, or becoming a non-smoker? So y- you encourage them to simply take it seriously, and I think this, again, is sort of one of the points that could be the antithesis of what some just kind of social users, um, use. I mean, this was written about by, um, Huston, uh, Smith, the scholar of religion, in terms of these mystical experiences that can happen from psychedelics, and how a lot of times, the attribution to a drug effect is dismissed, like the ne- even the, if one has this, you know, this sense of being one with the universe, and it totally, like, shakes their soul, so to speak. You know, but the next day, their friends are like, "Oh, dude. You were screwed up. Too much acid for you. Woo!" You know? Like, "Man, next time, you needed to have a few more beers to, like, bring that down." You know, like, this sort of, like, you know, social, you know, reinforcement for dismissing the experience. "Oh, God, you were talking out of your head, man."

    21. AHAndrew Huberman1:02:55

        Mm-hmm.

    22. MJDr. Matthew Johnson1:02:55

        Like, you know, even if it's, you know, good-natured, but it's this dismissal. It's not like, you know, what you want to do, you know, is, like, "Tell me more about that. You know, you were crying at one point, like, and talking about your mom. Let's talk about that. What was that like? Do you remember that?" Like-

    23. AHAndrew Huberman1:03:12

        So are you doing that follow-up, or they're encouraged to do that in their own life with the various people in their life?

    24. MJDr. Matthew Johnson1:03:18

        Both. So we do that explicitly in, in the follow-up where we have these discussions, and I, t- depending on what the situation is, um, y- you might encourage the person to kind of follow up. It's, it's really, th- the basics of it is, is supportive, um, therapy. It's non-structured. It's, you know, use all the, you know, reflective listening, and the sort of the humanistic psychology th- you know, unconditional positive regard for the person. But, but, you know, I, I think i- if, you know, if someone f- feels inclined to, you know, apologize to their, to their, you know, to, to their sibling about something, it's like, "Yeah, go ahead and call them up." When it, with, if it's something big like a relationship change, I'd be like, "Sit on that two weeks. Don't make any big, don't end any (laughs) relationship. Don't quit your job. Don't make any big-"

    25. AHAndrew Huberman1:04:08

        Do you also tell them not to start any relationships?

    26. MJDr. Matthew Johnson1:04:13

        I don't remember that ever coming up.

    27. AHAndrew Huberman1:04:15

        Interesting. (laughs)

    28. MJDr. Matthew Johnson1:04:16

        But, but if it, but if it-

    29. AHAndrew Huberman1:04:16

        No. (laughs) I mean, it's, I'm not joking. I was just wondering, you know, it seemed, but-

    30. MJDr. Matthew Johnson1:04:19

        Yeah.
12. 1:04:36 – 1:12:10

    Flashbacks

    1. AHAndrew Huberman1:04:36

       I have a question about, um, flashbacks.

    2. MJDr. Matthew Johnson1:04:40

       Uh-huh.

    3. AHAndrew Huberman1:04:40

       You know, one of, one of the kind of, uh, things you hear is, you know, flashbacks, and that-

    4. MJDr. Matthew Johnson1:04:45

       Yeah.

    5. AHAndrew Huberman1:04:45

       ... uh, that people... Do people get flashbacks, and if so, what is the basis of flashbacks? The, um, the on-the-street, uh, lore about this is that somehow some of the compound gets stored in body fat tissues and then released later. Like, uh, uh, is that complete nonsense?

    6. MJDr. Matthew Johnson1:05:02

       No evidence for that, so probably complete nonsense. The-

    7. AHAndrew Huberman1:05:06

       Flashbacks are nonsense, or the storage in body fat is complete nonsense?

    8. MJDr. Matthew Johnson1:05:09

       The storage and body fat. So to answer whether flashbacks are complete nonsense, we have to define it. So I really think these are multiple constructs that are going. It's not the same thing that fall under that term. There is s- a phenomenon that, that appears real, that's called hallucinogen persisting perceptual disorder. It's in the DSM. A certain number of people, a very small number of people, uh, you know, percentage-wise, who have used psychedelics we will have these persisting perceptual disorders, like they'll see halos around things.

    9. AHAndrew Huberman1:05:41

       Mm.

    10. MJDr. Matthew Johnson1:05:41

        They'll see some trails, like-

    11. AHAndrew Huberman1:05:43

        Mm-hmm.

    12. MJDr. Matthew Johnson1:05:43

        ... you know, like the after images following a- an object in motion. Um, uh, eh, they'll see distortions in color. And it'll be, like anything else that's a, uh, a disorder in the DSM, it has to be clinically distressing, and it has to be persisting over some, uh, number of o- of months, and, and so very rare, very mysterious. Some of the keys to that are, amazingly, it's never been seen in the thousands of participants, either from the older era, from the late '50s to the early '70s, of people in psychedelic studies with LSD, psilocybin, mescalin, and it's never been seen in the modern era again, now with thousands of participants at a number of centers like ours, um, throughout the world. So it seems to be something that is, for some reason, happening in illicit use. So that, that brings in, okay, is there polypharmacology?

    13. AHAndrew Huberman1:06:38

        Right.

    14. MJDr. Matthew Johnson1:06:38

        You know? Like, is you're drinking during it, and you're taking-

    15. AHAndrew Huberman1:06:39

        Did you take what you thought you took?

    16. MJDr. Matthew Johnson1:06:41

        Yeah. What's the dose? Is, what's-

    17. AHAndrew Huberman1:06:42

        Yeah.

    18. MJDr. Matthew Johnson1:06:42

        ... the purity? But then also, what I think is actually even more so than that, what's likely going on, is some sort of very rare neurological susceptibility. There is one paper that, um, i- is a case series of individuals reporting these symptoms, and they didn't limit it to the, to just people who had had-... um, hallucinogen history. And the amazing thing about this is that, uh, a number of people seem to have straight up HPPD diagnosis-

    19. AHAndrew Huberman1:07:10

        What is HPPD?

    20. MJDr. Matthew Johnson1:07:11

        Oh, hallucinogen-

    21. AHAndrew Huberman1:07:12

        What is it? What is it?

    22. MJDr. Matthew Johnson1:07:12

        ... persisting perceptual disorder-

    23. AHAndrew Huberman1:07:14

        Okay.

    24. MJDr. Matthew Johnson1:07:14

        ... who have never taken a psychedelic. So it's often prompted by, um, alcohol-

    25. AHAndrew Huberman1:07:20

        Yeah.

    26. MJDr. Matthew Johnson1:07:21

        ... benzodiazepines-

    27. AHAndrew Huberman1:07:22

        Yeah.

    28. MJDr. Matthew Johnson1:07:22

        ... cannabis-

    29. AHAndrew Huberman1:07:24

        Yeah.

    30. MJDr. Matthew Johnson1:07:24

        ... even tobacco.
13. 1:12:10 – 1:15:54

    Ayahuasca, & ASMR, Kundalini Breathing

    1. AHAndrew Huberman1:12:10

       that, uh, I've been told, uh, people experience, and I'm wondering whether or not any of you, the patients you've worked with or, um, people in your trials have, have reported this. Um, I, I've never done ayahuasca, um, which I'm assuming has some overlap with the serotonin system, probably hits a variety of systems-

    2. MJDr. Matthew Johnson1:12:28

       Yeah, so it's DMT, the active-

    3. AHAndrew Huberman1:12:28

       The DMT system, right. Excuse me.

    4. MJDr. Matthew Johnson1:12:30

       ... yeah, it's orally, uh, it's MAO inhibitors-

    5. AHAndrew Huberman1:12:32

       That's right, of course, of course, yeah.

    6. MJDr. Matthew Johnson1:12:32

       ... that allow the DMT to be orally.

    7. AHAndrew Huberman1:12:34

       Right, I should have-

    8. MJDr. Matthew Johnson1:12:34

       Mm-hmm.

    9. AHAndrew Huberman1:12:34

       ... I should have, um, recalled that, absolutely. Well, I've never done it, but a number of people I know that have done ayahuasca, um, as well as people I know who have done MDMA, report an increased sense of what, uh, is sometimes called ASMR, these autonomic sensory meridian reflexes, which is... And it's interesting, a lot of people, um, have these naturally, and they hide these. These are... It's actually, uh, something that many people keep hidden to themselves. Um, I'll just ask you if you can do it. So, um, some people are able to pass a, like a shiver down their spine or up their spine consciously, you know? Like, you can kind of... I, I'm able to actually pass a shiver up my spine. I actually learned how to do this when I was a kid on a hot day. I was standing on a field in sports camp-

    10. MJDr. Matthew Johnson1:13:18

        Uh-huh.

    11. AHAndrew Huberman1:13:18

        ... and I was like, "It's really hot here." And I could actually create, like, a cooling of, uh, perce- cooled perception.

    12. MJDr. Matthew Johnson1:13:24

        Yeah.

    13. AHAndrew Huberman1:13:24

        Some people... I told someone this once, and then it, this led to a discussion of, "Oh, I can do it, but I always hid that from people 'cause it's actually somewhat pleasurable." And this is a well-known phenome-

    14. MJDr. Matthew Johnson1:13:33

        (laughs)

    15. AHAndrew Huberman1:13:33

        ... phenomenon, ASMR. And some people I know who have taken MDMA therapeutically or ayahuasca-... um, will report that they, um, feel great relief from this. They can generate these autonomic reflexes through their body more readily, probably, I'm guessing, because they were able to tune into a kind of deeper sense of somatic self. Now, on the internet, ASMR, if you look it up, it's a little bit like the bath salt thing-

    16. MJDr. Matthew Johnson1:13:59

        Uh-huh.

    17. AHAndrew Huberman1:13:59

        ... but in the other direction. Like, there are people that pay, uh, let me, let's just say their account's on YouTube that have many, many millions of viewers of, um, people that will whisper to them about... Like, for instance, there's a, a, people that will go listen to, uh, it seems to be women in particular, whispering about, like, car mechanics or something, or about, or scratching. So they're, certain sounds will do this, whispering, tapping, finger-tapping. And people-

    18. MJDr. Matthew Johnson1:14:26

        Uh-huh.

    19. AHAndrew Huberman1:14:26

        ... experience immense pleasure from it. It's not really sexual pleasure, but it's this kind of deep core of the body-

    20. MJDr. Matthew Johnson1:14:32

        Yeah.

    21. AHAndrew Huberman1:14:32

        ... that it's the autonomic nervous system down the core of the spine.

    22. MJDr. Matthew Johnson1:14:34

        Probably what a certain number of people would call kundalini, which is another one-

    23. AHAndrew Huberman1:14:38

        Right, and it-

    24. MJDr. Matthew Johnson1:14:39

        ... scientifically who, yeah.

    25. AHAndrew Huberman1:14:40

        That's right.

    26. MJDr. Matthew Johnson1:14:40

        Yeah.

    27. AHAndrew Huberman1:14:40

        And people who do long-duration kundalini breathing sessions, many of them will report later feeling as if they, their perception of self is outside of their head.

    28. MJDr. Matthew Johnson1:14:50

        Ah.

    29. AHAndrew Huberman1:14:51

        That they're ru- that they're literally wa- it's, um, very uncomfortable for them, that they feel like they're walking around with their sense of self extended beyond the body. And this is a neurol- this is a clinically described-

    30. MJDr. Matthew Johnson1:15:01

        Wow.
14. 1:15:54 – 1:26:00

    MDMA, DMT

    1. AHAndrew Huberman1:15:54

       other sorts of drugs. I, uh, having said baked in, the temptation is to go to, um, marijuana or cannabis.

    2. MJDr. Matthew Johnson1:16:00

       Yeah (laughs) .

    3. AHAndrew Huberman1:16:00

       But, but if we, if we could, I'd like to just ask about some of the more dopaminergic compounds.

    4. MJDr. Matthew Johnson1:16:06

       Uh-huh.

    5. AHAndrew Huberman1:16:06

       In particular, MDMA.

    6. MJDr. Matthew Johnson1:16:08

       Yeah.

    7. AHAndrew Huberman1:16:09

       My understanding is that MDMA is a purely synthe- synthetic compound, that you're not going to find MDMA in nature.

    8. MJDr. Matthew Johnson1:16:17

       So far.

    9. AHAndrew Huberman1:16:18

       So far.

    10. MJDr. Matthew Johnson1:16:18

        There are cer- DMT was first synthesized in the lab, and then we thought it didn't exist in nature, and then, like, uh, Richard Schultz found it, like, everywhere (laughs) -

    11. AHAndrew Huberman1:16:27

        Yeah, actually the-

    12. MJDr. Matthew Johnson1:16:27

        ... inside America.

    13. AHAndrew Huberman1:16:28

        Yeah.

    14. MJDr. Matthew Johnson1:16:28

        So who knows? A plant out there-

    15. AHAndrew Huberman1:16:29

        Right.

    16. MJDr. Matthew Johnson1:16:29

        ... might be making MDMA.

    17. AHAndrew Huberman1:16:31

        Right, right.

    18. MJDr. Matthew Johnson1:16:31

        But as far as we know now, no.

    19. AHAndrew Huberman1:16:33

        Right. And we'll talk about DMT and its sources within the body. But MDMA, um, could exist in, uh, elsewhere, uh, but has been synthesized. And my understanding is that MDMA leads to very robust increases in both dopamine and serotonin simultaneously.

    20. MJDr. Matthew Johnson1:16:50

        Mm-hmm.

    21. AHAndrew Huberman1:16:50

        Which from an, from a neural network's perspective, is a very unusual situation.

    22. MJDr. Matthew Johnson1:16:56

        Mm-hmm.

    23. AHAndrew Huberman1:16:57

        Right? Normally, because dopamine puts us in this exteroceptive, looking outside ourselves, seeking things in the world beyond the skin, our own skin, and dopami- excuse me, serotonin tends to focus us inward. Those are almost mutually exclusive-

    24. MJDr. Matthew Johnson1:17:11

        Yeah.

    25. AHAndrew Huberman1:17:11

        ... kind of neurochemical states.

    26. MJDr. Matthew Johnson1:17:13

        Yeah.

    27. AHAndrew Huberman1:17:13

        Although, they're always at different levels. So why would it be that having this, uh, increased dopamine and increased serotonin would provide an experience that is beneficial, and how do you, to the extent that you can describe it, how do you think that experience differs from the sorts of experiences that people have on psilocybin or more serotonergic agents? Just broadly speaking.

    28. MJDr. Matthew Johnson1:17:38

        Yeah, yeah. In terms of that, that bal- in terms of the, the, the effects generally on serotonin and dopamine, um, I can only, you know, speculate, you know. Like, sort of, is that dopaminergic component necessary for, let's say, we know that the a- amygdala is less reactive during, you know, under acute effects, and that may play a role in, um, uh, there, there's less sort of, uh, control from the, from the amygdala, in terms of, like, one's experience of memory. So it may be part of the sort of reprocessing-

    29. AHAndrew Huberman1:18:12

        Mm-hmm.

    30. MJDr. Matthew Johnson1:18:12

        ... um, this reconsolidation of these memories in a different way, where the amygdala's not like going crazy, saying, "Freak out," like, you know, fight or flight. Um-

Episode duration: 2:52:04