Psychedelics for Treating Mental Disorders | Dr. Matthew Johnson

Andrew Huberman 0:00 (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.

Andrew Huberman 2:10 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. It has the vitamins I need, the minerals I need, and the probiotics are important to me, because there is now so much data about the importance of the so-called gut microbiome, maintaining healthy gut bacteria, and the ways in which those gut bacteria impact things like inflammation and keeping inflammation down in the brain and body, as well as supporting things like quality mood, endocrine function, metabolic function, just so many factors. The great thing about Athletic Greens is that it also tastes very good. I mix mine with water, a little bit of lemon juice, and as I mentioned, I drink that once or twice a day. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman, and if you do that, you'll get the Athletic Greens plus you'll get five free travel packs. The travel packs make it very easy to mix up Athletic Greens when you're on the road, in the car, on the plane, et cetera. And you'll get a year's supply of vitamin D3 K2. There's now a lot of evidence that vitamin D3 and K2 are important for various aspects of metabolic health, cardiac health, and so forth. So, once again, that's athleticgreens.com/huberman to get Athletic Greens, the five free travel packs, and your year's supply of vitamin D3 and K2. Today's podcast is also brought to us by InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done, and now with the advent of quality DNA tests, you can get a lot of information about your genetics and how that also impacts your immediate and long-term health. The reason I'm such a fan of getting blood work done is that it is really the only way to understand what's going on in your system at a level that can really inform your decisions about your immediate and long-term health. The problem with a lot of blood and DNA tests, however, is that you get numbers back about your hormones and your metabolic factors, et cetera, but you don't know what to do with that information. With InsideTracker, they have a very easy to use dashboard that gives you that information, and then gives you some suggestions and directives about things you could change about your nutrition, about your exercise, and other lifestyle factors that can help you move those numbers in the direction that's best for you and for your health. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 25% off any of InsideTracker's plans. Just use the code Huberman at checkout. Today's podcast is also brought to us by Belcampo. Belcampo is a regenerative farm in Northern California that raises organic, grass-fed, and finished certified humane meats. I eat meat about once a day. In general, my lunch or my breakfast consists of some meat, and that meat has to be a very high quality, and generally I'll eat some vegetable as well. And then I tend to eat pastas and rice and things of that sort later in the day or in the evening in order to facilitate the transition to sleep. So, I'm eating meat about once a day, and I always insist that the meat that I eat be of the very highest quality, and that the animals were raised and maintained humanely. While conventionally raised animals are confined to feedlots and eat a diet of inflammatory grains, Belcampo's animals graze on open pastures and seasonal grasses, resulting in meat that's higher in nutrients and healthy fats. In addition, they raise their animals in a way that's not just better for our health, but also has a positive impact on the environment.They practice regenerative agriculture, which means the meat is climate positive and carbon negative, so you can feel good about what you're eating at the environmental level and for sake of your health. You can order Belcampo's sustainably raised meats to be delivered to you by using my code Huberman at belcampo.com/huberman and entering my code Huberman to get 20% off your first time order. I'm partial to the ribeyes or the New York steaks, so on one day, I might have a ribeye, the next day I might have a New York steak. I also really like the meatballs. I'm a particular fan of the meatballs. So again, that's belcampo.com/huberman and enter the code Huberman at checkout to get 20% off your order. And now, my

Andrew Huberman 6:40 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-

Dr. Matthew Johnson 6:50 Likewise. Big fan, and happy to do this with you.

Andrew Huberman 6:53 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?

Dr. Matthew Johnson 7:06 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-

Andrew Huberman 10:48 Where does that come from?

Dr. Matthew Johnson 10:49 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-

Andrew Huberman 11:57 What does that mean?

Dr. Matthew Johnson 11:58 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-

Andrew Huberman 13:31 Dumping more serotonin. Yeah.

Dr. Matthew Johnson 13:32 ... dumping more serotonin-

Andrew Huberman 13:33 Yeah.

Dr. Matthew Johnson 13:33 ... flooding-

Andrew Huberman 13:34 Yeah.

Dr. Matthew Johnson 13:34 ... the synapse.

Andrew Huberman 13:36 So I get the impression that the s- psychedelic space is a enormous cloud of partially overlapping compounds-

Dr. Matthew Johnson 13:43 Right.

Andrew Huberman 13:43 ... 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-

Dr. Matthew Johnson 14:02 Mm-hmm.

Andrew Huberman 14:03 ... can we break that down into a couple of subcategories? So for instance, um, hallucinating,

Andrew Huberman 14:09 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-

Dr. Matthew Johnson 14:22 Yeah.

Andrew Huberman 14:22 ... 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.

Dr. Matthew Johnson 14:50 Right.

Andrew Huberman 14:50 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.

Dr. Matthew Johnson 15:01 Mm-hmm.

Andrew Huberman 15:01 And then you get a rate and a, you know, speed and all that kind of stuff, right?

Dr. Matthew Johnson 15:04 Yeah.

Andrew Huberman 15:05 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?

Dr. Matthew Johnson 15:28 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.

Andrew Huberman 16:05 And proprioception, your balance-

Dr. Matthew Johnson 16:06 Proprioception.

Andrew Huberman 16:07 ... vestibular, yep.

Dr. Matthew Johnson 16:07 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-

Andrew Huberman 17:13 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-

Dr. Matthew Johnson 17:30 Yes.

Andrew Huberman 17:30 ... between objects and gravity, but one of the first things that a child learns is the relationship between objects and gravity and their trajectories.

Dr. Matthew Johnson 17:40 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)

Andrew Huberman 17:48 Right.

Dr. Matthew Johnson 17:48 Like, oh-

Andrew Huberman 17:48 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.

Dr. Matthew Johnson 17:57 Yeah.

Andrew Huberman 17:57 It would be for an adult too.

Dr. Matthew Johnson 17:58 It'd be a pretty psychedelic-

Andrew Huberman 17:59 Right.

Dr. Matthew Johnson 17:59 ... experience probably. (laughs)

Andrew Huberman 18:01 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-

Dr. Matthew Johnson 18:07 Right.

Andrew Huberman 18:07 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-

Dr. Matthew Johnson 18:16 Yeah. It's, it's not-

Andrew Huberman 18:16 I mean, it doesn't have a mind of its own, but somehow it, it creates a surprise element or a, or a-

Dr. Matthew Johnson 18:21 Yeah.

Andrew Huberman 18:21 ... a recognition element.

Dr. Matthew Johnson 18:22 And it's not filtered out, you know. Uh, that... And this might sound extreme, but there are these cases, it was over- overblown in sort of the propaganda of the late '60s, early '70s, but there are credible cases of people, and it's very atypical, of sounds like they really thought they could fly, and, you know, jump out of a, a, a, a, of a window. Now, far more people every year (laughs) fall, j- I mean, who knows, you know?

Andrew Huberman 18:52 Sure.

Dr. Matthew Johnson 18:52 They, they, they, they fall and die out of, you know, from height because they're drunk, you know? So this is extremely rare. But, you know, there are some like pretty convincing, um, cases. There was one research volunteer in our studies, uh, that, uh, it, she l- looked like she was, in one of our studies, like she was trying to dive through a painting on the wall. She was fine, but she, (laughs) reviewing the video, it looked like she really thought that she was gonna go through that painting, and who knows? (laughs)

Andrew Huberman 19:26 Right. So, so she would-

Dr. Matthew Johnson 19:27 You know what I mean? Into the other dimension.

Andrew Huberman 19:28 Yeah.

Dr. Matthew Johnson 19:28 Yeah.

Narrator 19:28 Mm-hmm.

Andrew Huberman 19:28 So they're violating these predictions. Um, yeah, I, the reason I ask it, the, the question the way I did, is because, um, given the enormous cloud of different substances, and given the range of previous experiences that people show up to a psychedelic experience with, uh, I feel like the ability to extract some universal themes is, is useful.

Dr. Matthew Johnson 19:50 Mm-hmm.

Andrew Huberman 19:50 Especially for people who haven't done them before, right?

Dr. Matthew Johnson 19:52 Yeah.

Andrew Huberman 19:52 Who might j- uh, not have an understanding of what their effects are like.

Andrew Huberman 19:56 Can, uh, we just briefly touch on the serotonin system-

Dr. Matthew Johnson 20:01 Mm-hmm.

Andrew Huberman 20:01 ... 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-

Dr. Matthew Johnson 20:28 Yeah.

Andrew Huberman 20:28 ... will be active, in a, in a-

Dr. Matthew Johnson 20:29 Mm-hmm.

Andrew Huberman 20:30 ... 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?

Dr. Matthew Johnson 21:05 Yeah.

Andrew Huberman 21:05 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.

Dr. Matthew Johnson 21:12 Yeah.

Andrew Huberman 21:14 W- w- uh, what do we think is going on at- in a general sense?

Dr. Matthew Johnson 21:17 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.

Andrew Huberman 21:38 'Cause when I eat a bagel, I get serotonin release, right?

Dr. Matthew Johnson 21:41 Uh-huh.

Andrew Huberman 21:41 I mean, there's... Uh, or turkey-

Dr. Matthew Johnson 21:43 And it's very different than LSD.

Andrew Huberman 21:43 I mean, there's tryptophan and... Right.

Dr. Matthew Johnson 21:44 Mm-hmm.

Andrew Huberman 21:45 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-

Dr. Matthew Johnson 21:56 Right.

Andrew Huberman 21:56 ... 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.

Dr. Matthew Johnson 22:06 Yeah.

Andrew Huberman 22:07 Is that fair to say?

Dr. Matthew Johnson 22:07 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-

Andrew Huberman 22:28 Well, feel free to, to explain it at the experiential level.

Dr. Matthew Johnson 22:31 Yeah.

Andrew Huberman 22:31 I mean, it doesn't have...

Dr. Matthew Johnson 22:32 Well-

Andrew Huberman 22:32 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?

Dr. Matthew Johnson 22:38 Yeah.

Andrew Huberman 22:39 Th- that conversation we could hold, and that's an interesting conversation. But just in terms of the experience of serotonergic versus dopaminergic-

Dr. Matthew Johnson 22:47 Right.

Andrew Huberman 22:47 ... drugs-

Dr. Matthew Johnson 22:48 Yeah.

Andrew Huberman 22:49 ... they, they do seem to create distinct classes of experience. So I think that's, that's a, a appropriate-

Dr. Matthew Johnson 22:56 Right.

Andrew Huberman 22:56 ... level for us to discuss them.

Dr. Matthew Johnson 22:58 And in terms of how they... And I'd, I'd like to explore the biology a little bit here, and tell you like sort of what's known and what some of the i- ideas are.

Andrew Huberman 23:05 Mm-hmm. Please.

Dr. Matthew Johnson 23:05 Um, y- you have this pat- you know, as, as you know, like, you know, these are levels of analysis, and it's not which one is going on. It's almost like, for the particular question, which level of analysis is most appropriate? Is it... You know, is a question best addressed by the biology, the, the, the chemistry, or the, or the physics? Th- that's how I think of like receptor level, post-receptor signaling downstream effects on other, uh, other neurotransmitters, and then, um, you know, activation level effects, and then, um, coordination of activation. So you've got the, clearly the, with the classic psychedelics, the 2A, um, activation. We, we do know that there are downstream effects in terms of, uh, in- increasing glutamate transmission, so this is likely a commonality

Dr. Matthew Johnson 23:50 why... You know, ketamine is very psychedelic in a slightly different way, but-

Andrew Huberman 23:54 Do people hallucinate on ketamine?

Dr. Matthew Johnson 23:56 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.

Andrew Huberman 24:09 That's why it's called a K-hole?

Dr. Matthew Johnson 24:09 Yeah, a K-hole.

Andrew Huberman 24:09 Not an A-hole, but a K-hole.

Dr. Matthew Johnson 24:10 A K-hole. (laughs) Yeah.

Andrew Huberman 24:12 Right.

Dr. Matthew Johnson 24:12 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-

Andrew Huberman 24:44 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.

Dr. Matthew Johnson 24:53 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-

Andrew Huberman 25:05 And ketamine is now legal for therapeutic use, correct?

Dr. Matthew Johnson 25:07 Right, right, Spravato, the- the- the- the intranasal form, um, marketed by Janssen, which is esketamine. It's one of the-

Andrew Huberman 25:16 It's prescription.

Dr. Matthew Johnson 25:16 Yeah, it's prescription, and, um-

Andrew Huberman 25:18 So people are taking in the nasal spray.

Dr. Matthew Johnson 25:20 Yeah.

Andrew Huberman 25:21 And then are they undergoing talk therapy while they're doing this?

Dr. Matthew Johnson 25:24 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-

Andrew Huberman 25:49 Spravato is?

Dr. Matthew Johnson 25:49 Is esketamine.

Andrew Huberman 25:51 Okay.

Dr. Matthew Johnson 25:51 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.

Andrew Huberman 27:34 Right.

Dr. Matthew Johnson 27:34 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-

Andrew Huberman 27:54 So what would that look like?

Dr. Matthew Johnson 27:55 Um, really just like our- our psilocybin th- uh, you know, sessions, which I know I haven't

Dr. Matthew Johnson 28:00 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.

Andrew Huberman 28:08 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?

Dr. Matthew Johnson 28:15 Mm-hmm.

Andrew Huberman 28:16 In- in your- at your lab at Hopkins.

Dr. Matthew Johnson 28:17 Yeah.

Andrew Huberman 28:18 And, uh, would I need to be depressed, or could I just be somebody who wanted to explore psychedelics?

Dr. Matthew Johnson 28:22 It, we've had studies for all of these-

Andrew Huberman 28:25 Okay.

Dr. Matthew Johnson 28:25 ... and- and- and a number of other disorders.

Andrew Huberman 28:27 Okay.

Dr. Matthew Johnson 28:27 So healthy/normal studies-

Andrew Huberman 28:28 Okay.

Dr. Matthew Johnson 28:28 ... 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.

Andrew Huberman 28:46 Sure. Yeah, I agree.

Dr. Matthew Johnson 28:47 So but we've done work with, uh, smoking cessation, so people trying to quit tobacco, and haven't been successful.

Andrew Huberman 28:52 So a variety of reasons. So-

Dr. Matthew Johnson 28:54 Right.

Andrew Huberman 28:54 ... 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-

Dr. Matthew Johnson 29:07 Mm-hmm.

Andrew Huberman 29:07 ... th- that would be present during this psychedelic journey.

Dr. Matthew Johnson 29:11 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.

Andrew Huberman 29:34 Right.

Dr. Matthew Johnson 29:34 So the manic side of- of bipolar.

Andrew Huberman 29:36 Mm-hmm.

Dr. Matthew Johnson 29:36 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-

Andrew Huberman 30:00 Mm-hmm.

Dr. Matthew Johnson 30:01 ... 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.

Andrew Huberman 30:29 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.

Dr. Matthew Johnson 30:38 Right.

Andrew Huberman 30:39 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-

Dr. Matthew Johnson 31:15 Mm-hmm.

Andrew Huberman 31:15 ... um, and th- and it's the day.

Dr. Matthew Johnson 31:18 Yeah.

Andrew Huberman 31:19 It comes, comes the day that they're going to have, uh, this experience. Are they, uh, eating mushrooms like, uh, you hear about, or are they taking it in capsule form, and how- what sorts of doses are you prescribing? Is there a dose response curve?

Dr. Matthew Johnson 31:34 Yeah. Mm-hmm.

Andrew Huberman 31:35 Um, and then s- uh, secondary to that, I'd like to talk about microdose versus macrodose.

Dr. Matthew Johnson 31:39 Mm-hmm.

Andrew Huberman 31:40 So how do they get the stuff into- how do people, uh, receive it, and how do they get it into their body?

Dr. Matthew Johnson 31:46 So they receive pure psilocybin. So the mushroom, and there are many species, the most pri- people who have taken mushrooms in the United States, it's p- it's most likely psy- psil- psilocybe cubensis. Uh, they're easy to grow. They grow in cow patties. It's easy for anybody to grow them in their closet. It doesn't take a- a thousand-watt light like cannabis. It takes like a little, you know, 10-watt light bulb in a Tupperware bin. So those are what- those are the types of mushrooms that people typically take. We're not administering those. Psilocybin is the compound. You could draw a molecule, psilocybin, again, based on the tryptamine structure. Like, that's a single molecular entity, so it's a white powder.

Andrew Huberman 32:26 Does it look like serotonin, molecularly?

Dr. Matthew Johnson 32:28 Yes, yes, yes-

Andrew Huberman 32:30 Okay.

Dr. Matthew Johnson 32:30 ... which is a tryptamine structure, yeah.

Andrew Huberman 32:30 So if I- so if I looked at- if I were to show people the chemical structure of serotonin and the chemical structure of psilocybin, it would look quite similar?

Dr. Matthew Johnson 32:36 Right, right, and there's a-

Andrew Huberman 32:37 So they're basically taking serotonin?

Dr. Matthew Johnson 32:40 It- e- a modified version of serotonin, which makes sense. But th- then, again, this repeated theme of the chemistry doesn't always neatly-

Andrew Huberman 32:49 Sure.

Dr. Matthew Johnson 32:49 ... line up, because like mesculin looks more, uh, like, uh, like dopamine than it does like serotonin, but yet, it- at the receptor activation level, the pharmacolog- neural pharmalogical effect, it's- those are similar. But- but yeah. I mean, and what it does at the receptor is an alternate- it's- it's- it's hitting the same switch, but then having an alternate response at the receptor, um, level.

Andrew Huberman 33:13 Yeah, so for people that don't necessarily understand the relationship between what we call ligand, the thing that parks in the receptor, and the receptor is the parking spot, one of the reasons that you can get such a- a variety of effects from different compounds is, for instance, serotonin might affect a certain pathway at a particular rate, and, uh, psilocybin might trigger activation of different components of that pathway at different rates, and so you can get vastly different experiences from two things that look chemically similar.

Dr. Matthew Johnson 33:42 Right.

Andrew Huberman 33:42 This is also a good, um, (smacks lips) uh, reason why people shouldn't just assume that they can cowboy their own chemistry, right? That what you see on paper and what you can mix up in a vial is often vastly different, uh, than what you predict.

Dr. Matthew Johnson 33:58 Right. Right. And there's a dose-effect curve that's really interesting. Some of our early work with psilocybin, um, in healthy normals, um, looked at, uh, a true placebo plus four active doses, five, 10, 20, and 30 milligrams of psilocybin. Body weight adjusted, so you know-

Andrew Huberman 34:15 Sure.

Dr. Matthew Johnson 34:15 ... those milligrams per 70 kilograms of body weight. We've recently published a paper in our newer trials where we're dropping the body weight adjustment, 'cause our- going across hundreds of volunteers, we've kind of figured out that, that you shouldn't really be- you don't need to be adjusting by body weight.

Andrew Huberman 34:32 Interesting.

Dr. Matthew Johnson 34:32 So, so yeah.

Andrew Huberman 34:33 Well, brain size doesn't vary that much between individuals.

Dr. Matthew Johnson 34:37 Yeah, yeah.

Andrew Huberman 34:38 And you know, the end, this is a brain effect-

Dr. Matthew Johnson 34:42 Yeah.

Andrew Huberman 34:42 ... mostly. Probably body as well. Um, okay, so the person ingests the, the-

Dr. Matthew Johnson 34:47 Yeah.

Andrew Huberman 34:47 ... powder or capsule-

Dr. Matthew Johnson 34:48 In a little pill.

Andrew Huberman 34:49 Okay.

Dr. Matthew Johnson 34:49 Yeah, and it doesn't take-

Andrew Huberman 34:50 And how long is it?

Dr. Matthew Johnson 34:51 30 milligrams is a small. You could fit it into a tiny, little capsule.

Andrew Huberman 34:55 Mm-hmm.

Dr. Matthew Johnson 34:55 And, and it'll take about a half hour, well, anywhere from 15 minutes to an hour to kick in. On average, about a hou-

Andrew Huberman 35:00 And you said the dose range was?

Dr. Matthew Johnson 35:02 Um, most of our studies, uh, are looking at where we, we want a psychedelic effect are in the 20 to 30 milligram range. Um, again, because we have adjusted by body weight, and the average American is over 70 kilograms, about 150 pounds, like s- people, and in fact, have gotten more like, you know, 40, 45, in a lot of cases. But, um, it's still a small pill. Um, they're, eh, eh, the session day itself is not full of- for most of our studies, is not full of tasks. We really wanna look at the therapeutic response. Obviously, if it's a therapeutic study, we want it to be a meaningful experience, and, uh, research has found, not surprisingly, that you get a less meaningful experience when you're in an fMRI-

Andrew Huberman 35:48 Right.

Dr. Matthew Johnson 35:48 ... or when you're doing a lot of cognitive tasks. Um, we've done some research on, on, you know, of, of, of that type for sure, and plenty of colleagues have, but when you're in a therapeutic study, or if you're trying to understand the therapeutic effects, you, you have to recognize there is this, this, this trade-off of, of what you can do. So our typical therapeutic model, which again, isn't just limited necessarily to the therapeutic studies where we're trying to treat a specific disorder, um, i- i- is, is to, you know, have that preparation so y- the person feels very comfortable with their guides. Um, uh, I mean, ult- ultimately, what I tell people is like, "Be"...any emotional response, it's all welcome. I mean, y- you could, you could be crying like a baby hysterically, like that's what you should be doing if that's what you feel like. And so, in a lot of ways, sometimes people with psychedelic experience, uh, on their own, it can be harder to train them in this model. Because in the real world, people with psychedelic experience, a lot of times the rule is, you know, hold your shit. So a, a, a, you know, several friends go to a party, they split a bag of mushrooms, it's like, you know, there's a social pressure, for good reason, not to be the guy, you know, in the corner o- of the room where everyone's trying to just have a good time and relax, like, crying about your mother. Your other friends are, they're having an experience too, and you're being a drama king, and blah, blah, blah. And so like, yeah, compose yourself. Hold your impude.

Andrew Huberman 37:12 Right. You're doing th- I mean, you're doing therapy for people. This is, it's not just about the experience.

Dr. Matthew Johnson 37:17 Right. And the experience itself is very much shaped by, by that, that container, by the environment-

Andrew Huberman 37:23 That's true.

Dr. Matthew Johnson 37:23 ...and, and the degree to which one allows it to happen. Like, one should let go of control. Like-

Andrew Huberman 37:29 Yeah, let's talk about

Andrew Huberman 37:30 the, the letting go of control, and then as we march through this, um, hypothetical experience, that does take place in your lab-

Dr. Matthew Johnson 37:37 Mm-hmm.

Andrew Huberman 37:38 ...but so we're using a sort of generic case example-

Dr. Matthew Johnson 37:41 Mm-hmm.

Andrew Huberman 37:41 ...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-

Dr. Matthew Johnson 38:11 Mm-hmm.

Andrew Huberman 38:11 ...if you spend a little time with that statement it, it actually pans out.

Dr. Matthew Johnson 38:14 Mm-hmm.

Andrew Huberman 38:15 So the psychedelic experience is one in which chemically you're under a new, new set of conditions, right?

Dr. Matthew Johnson 38:25 Yeah.

Andrew Huberman 38:25 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.

Dr. Matthew Johnson 38:50 Yeah.

Andrew Huberman 38:50 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.

Dr. Matthew Johnson 39:06 Yeah.

Andrew Huberman 39:07 You're not worried whether or not your, um, brain is gonna explode even though a thought could feel enormous.

Dr. Matthew Johnson 39:12 Mm-hmm.

Andrew Huberman 39:13 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-

Dr. Matthew Johnson 39:26 Mm-hmm.

Andrew Huberman 39:26 ...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.

Dr. Matthew Johnson 39:57 Mm-hmm.

Andrew Huberman 39:57 Not just one. Is that, is-

Dr. Matthew Johnson 39:59 Especially these days. You gotta multitask.

Andrew Huberman 40:01 Exactly. Right.

Dr. Matthew Johnson 40:01 Yeah.

Andrew Huberman 40:02 Multitask. And the more that we focus on one thing, the more bizarre that thing actually can appear to us, right?

Dr. Matthew Johnson 40:08 Right. (laughs)

Andrew Huberman 40:08 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-

Dr. Matthew Johnson 40:14 Yeah, that's weird.

Andrew Huberman 40:14 ...some very weird things.

Dr. Matthew Johnson 40:16 Yeah.

Andrew Huberman 40:16 Right?

Dr. Matthew Johnson 40:16 That's, I think of that as the classic psychedelic effect that, or, or one classic effect and one I've used many times of this example of why people shouldn't necessarily, you know, uh... These aren't, these, eh, one should be judicious in putting themselves in these circumstances. Someone could be, you know, having a, a very strong psilocybin experience, and they're trying to navigate their way in Manhattan-

Andrew Huberman 40:43 Right.

Dr. Matthew Johnson 40:43 ...crossing the street, and they might be staring into their hand and reali- like that's... Their hand is the most amazing miracle. Like, the entire universe has essentially conspired to come to this one point to make this absolutely breathtaking... It's almost like I think of the simplest form of, of, of, well, we know the simplest form of learning is habituation, simply keep applying stimuli and there's less response. Like, this is what organisms do, this is what we have to do, and it's like there's this dishabituation component that like-

Andrew Huberman 41:11 Dishabituation?

Dr. Matthew Johnson 41:12 Yes.

Andrew Huberman 41:13 Yeah.

Dr. Matthew Johnson 41:13 Like, we wouldn't be able to get through life if, we wouldn't be able to cross that street if we were like, "Ho- like, th- this is a miracle." Like, you know? (laughs)

Andrew Huberman 41:21 Well, I'm so glad you... No, I'm so glad you brought this up. I mean, here I'm reflecting my biases of vision scientists, but most people don't realize this, but if you look at something long enough it eventually disappears to e- per se it doesn't actually disappear, but perceptually it disappears. You have these little microsaccades that ensure that it doesn't-

Dr. Matthew Johnson 41:35 Right.

Andrew Huberman 41:36 ...but most of us don't look at any one thing for very long.

Dr. Matthew Johnson 41:39 Right.

Andrew Huberman 41:39 The, the brain's default is to perceptually jump around like crazy-

Dr. Matthew Johnson 41:44 Yeah.

Andrew Huberman 41:44 ...with the visual system, with the auditory system. We all, ADD, (laughs) people talk about ADD a lot, is sort of baked into our underlying networks at some level, and then we ha- we can force attention. But it sounds like on psychedelics the, one of the primary goals therapeutically is to really drill into one of these perceptual bubbles and expand that bubble, and the safety-

Dr. Matthew Johnson 42:05 Yeah.

Andrew Huberman 42:06 ...it seems is the safety, it's sort of like a permission to, to do that without worrying that something's gonna happen.

Dr. Matthew Johnson 42:14 Right. Because, you know, I've had people there on the couch, um, yeah. I remember one lady said, this is probably, uh, 13, 14 years ago, said, "Matt, tell me again I can't die. Like, I feel like my heart is gonna rip through my chest." I mean, she was feeling her a- and, and I should say-... typically, cardiovascular response is, is modest. The, the, uh, pulse and blood pressure go up somewhat. It can be dangerous for people if they're at severe heart risk, and we do, uh-

Andrew Huberman 42:41 Are you monitoring this the whole time?

Dr. Matthew Johnson 42:42 We do. Yeah, we do monitoring.

Andrew Huberman 42:43 So they're plugged into a variety of devices every day.

Dr. Matthew Johnson 42:45 Yeah. So every half hour or so, we, we take... They're on protocol. And we, you know, space it out a little further, further into the time course. But we take their blood pressure and their pulse. And if it goes over a certain level, we have a protocol. And we've had to do this only a few times. But the physician comes in, gives them a little nitroglycerin under the tongue, uh, and, uh, you know, knocks the blood pressure down a little bit. Doesn't affect the experience. So we have it all in place, even though they'd probably be fine out of an abundance of caution.

Andrew Huberman 43:09 Sure.

Dr. Matthew Johnson 43:10 Um, but, but yeah, but someone can feel that, "My god, I'm gonna die. Like, I, I have never felt my heart beat like this (laughs) before." And, like, the experience of the breath can be just, you know, absolutely fantastic. And to... The, the sort of... And the breath is obviously interesting, because it's this auto- automatic, you know, control, but it could, and also be voluntary. So people could get into a sense of like, "My god, what if I for- what if I..." (laughs) It sounds silly, like a stoner movie.

Andrew Huberman 43:40 What if I forget to breathe?

Dr. Matthew Johnson 43:40 Exactly. (laughs)

Andrew Huberman 43:41 Yeah.

Dr. Matthew Johnson 43:42 But people could... That can be so compelling. And so one other reason, to get back to one of your questions, it's like, what do we do to kind of allow them to go further into these bubbles? It's like, one is bl- is wearing the eye shades.

Andrew Huberman 43:55 Mm-hmm.

Dr. Matthew Johnson 43:56 We don't call them, um, blindfolds, 'cause that has a negative connotation, (laughs) like being kidnapped.

Andrew Huberman 44:00 Well, and they're probably seeing a lot in there anyway, so blind isn't the appropriate word for it.

Dr. Matthew Johnson 44:04 Right, right. That's, I've never thought of it. These should be like inner sight shades. Uh-

Andrew Huberman 44:09 Mm-hmm.

Dr. Matthew Johnson 44:09 But when-

Andrew Huberman 44:09 But when you close the

Andrew Huberman 44:10 eyes, the, the levels of activity in the retina actually are maintained. It's spont- it's just spontaneous activity.

Dr. Matthew Johnson 44:16 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.

Andrew Huberman 44:59 Yeah. Yeah.

Dr. Matthew Johnson 44:59 Those are the, those are the true hallucinations, where you thought you were having a conversation with someone who was never there.

Andrew Huberman 45:04 Right.

Dr. Matthew Johnson 45:05 You know?

Andrew Huberman 45:05 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.

Dr. Matthew Johnson 45:36 Yeah.

Andrew Huberman 45:36 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-

Dr. Matthew Johnson 45:54 Yeah.

Andrew Huberman 45:54 ... could be an emotion, could be sadness, could be a historical event, or a fear of the future.

Dr. Matthew Johnson 46:00 Yes.

Andrew Huberman 46:01 And you've mentioned before that there's something to be learned in that experience.

Dr. Matthew Johnson 46:06 Yeah.

Andrew Huberman 46:06 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.

Dr. Matthew Johnson 46:20 Yeah.

Andrew Huberman 46:22 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-

Dr. Matthew Johnson 46:54 Yeah.

Andrew Huberman 46:54 ... that raises all sorts of interesting questions. And this is not a, a philosophy discussion. We're talking about biology and psychology here.

Dr. Matthew Johnson 47:01 Yeah.

Andrew Huberman 47:02 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.

Dr. Matthew Johnson 47:12 (laughs)

Andrew Huberman 47:12 But I could feel real love-

Dr. Matthew Johnson 47:14 Yeah.

Andrew Huberman 47:14 ... for the pen.

Dr. Matthew Johnson 47:15 Yeah.

Andrew Huberman 47:16 Right? That's not an unreasonable thing to expect on a psy- in a psychedelic journey.

Dr. Matthew Johnson 47:19 Right, right.

Andrew Huberman 47:20 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.

Dr. Matthew Johnson 47:33 Yeah.

Andrew Huberman 47:34 And yet the export from that, those two ver- vastly different experiences, is one of feeling a better relationship to the world and to oneself.

Dr. Matthew Johnson 47:43 Right.

Andrew Huberman 47:44 So what does this tell us about-

Dr. Matthew Johnson 47:44 Like, how can the pen-

Andrew Huberman 47:45 Right.

Dr. Matthew Johnson 47:45 ... and the processing your childhood trauma both lead to-

Andrew Huberman 47:49 Right.

Dr. Matthew Johnson 47:49 Yeah. So-

Andrew Huberman 47:50 So what does this m- I mean, at, at that level-

Dr. Matthew Johnson 47:53 Yeah.

Andrew Huberman 47:53 ... it raises this question. Like, h- first of all, how, why? I mean, or just, what are your thoughts on that?

Dr. Matthew Johnson 48:00 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.

Andrew Huberman 48:20 Okay.

Dr. Matthew Johnson 48:21 And-

Andrew Huberman 48:21 Tell me more about self-representation.

Dr. Matthew Johnson 48:23 That's, uh, the way one holds th- the sense of self.

Andrew Huberman 48:27 Mm-hmm.

Dr. Matthew Johnson 48:27 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-

Andrew Huberman 48:39 Mm-hmm.

Dr. Matthew Johnson 48:39 ... 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.

Andrew Huberman 49:04 Mm-hmm.

Dr. Matthew Johnson 49:04 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-

Andrew Huberman 49:32 Mm-hmm.

Dr. Matthew Johnson 49:32 ... 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.

Andrew Huberman 49:47 Mm-hmm. Mm-hmm.

Dr. Matthew Johnson 49:48 And you used the pen, but I think it sounds so similar to Aldous Huxley's classic description-

Andrew Huberman 49:52 Mm-hmm.

Dr. Matthew Johnson 49:53 ... in The Doors of Perception of the chair and the drapes. Like, he took, um, 500 milligrams of mescaline. He was just like-

Andrew Huberman 50:00 Is that a high dose of mescaline?

Dr. Matthew Johnson 50:01 Yeah. Yeah. And, and that's, uh, and, you know, that's a heroic dose, for sure.

Andrew Huberman 50:06 Mm-hmm.

Dr. Matthew Johnson 50:06 And he just going off on the chair-iness of the chair, like, this chair is exuding the quality of being a chair.

Andrew Huberman 50:12 Mm-hmm.

Dr. Matthew Johnson 50:13 And, and like-

Andrew Huberman 50:13 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.

Dr. Matthew Johnson 50:23 Yeah.

Andrew Huberman 50:23 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.

Dr. Matthew Johnson 50:41 Yeah.

Andrew Huberman 50:41 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.

Dr. Matthew Johnson 51:17 Mm-hmm.

Andrew Huberman 51:17 And it, uh, uh, the first pass, it al- it sounded to me a little bit like, you know, kind of like internet psychology type thing-

Dr. Matthew Johnson 51:24 Mm-hmm.

Andrew Huberman 51:25 ... like, oh, The Secret or something s- which frankly I'm just not particularly-

Dr. Matthew Johnson 51:28 Okay, a little new age-y.

Andrew Huberman 51:28 I'm, yeah, you know, so if you, you kind of like, the whole fake it till you make it, like, I, I don't actually subscribe to any of that.

Dr. Matthew Johnson 51:34 Uh-huh.

Andrew Huberman 51:34 But in dissecting that a little bit further with him, I c- I came to realize that, um, that th- these words, "I am," are very powerful. I don't think you reprogram your brain just by saying them, but how one defines themselves internally, not just to other people-

Dr. Matthew Johnson 51:51 Mm-hmm.

Andrew Huberman 51:51 ... but how one psychologically and by default in- uh, defines themselves I think is a very powerful-

Dr. Matthew Johnson 51:57 Mm-hmm.

Andrew Huberman 51:58 Like, um, and depressed people, as well as happy people, seem to define themselves in terms of these categories of emotional states. So I think it's, it, it's so interesting that letting go and going into this perceptual bubble, which is facilitated by, obviously, a really wonderful team of, of therapists, but also this serotonergic agent-

Dr. Matthew Johnson 52:17 Yeah.

Andrew Huberman 52:17 ... allows us to, um, potentially reshape the perception of self. That's, that's a tremendous feat of neuroplasticity.

Dr. Matthew Johnson 52:26 Right. And I think m- certainly more work needs to be done. You know, this is the, the, the horizon, and I, and I should credit, uh, Chris Lethaby, a philosopher, um, in Australia, who, um, has a forthcoming book. It might be out right about now or, or soon, within the coming months, uh, uh, Psychedelics and Philosophy, um-

Andrew Huberman 52:47 That's the title of the book?

Dr. Matthew Johnson 52:48 ... that it's, is it might be Psychedelic Philosophy.

Andrew Huberman 52:51 Okay.

Dr. Matthew Johnson 52:51 It's really close.

Andrew Huberman 52:51 Chris, Chris Lethaby. Uh, we'll, we'll put a link to it.

Dr. Matthew Johnson 52:53 Right. And, and, and so his conclusion in this, it's a really great book, and he really plays with the idea. It's like psychedelic experiences come along with a lot of supernatural stuff, uh, experience. It can certainly go along with that, but the idea is like can it- can these experiences, and including those therapeutic effects, be explained from a naturalist point of, of view? And, and his conclusion is that the changes in self-representation may be the commonality. Now, that could go along with plant spirits, and the Buddha, and chakras, and whatever your model, you know, system, and Jesus, all of that, but it could also, uh, be completely devoid of any supernatural, any religious. Um, and we do in fact see all, you know, all of these v- varieties. So I, I, I think there's something about this change in, in sense of self. There is- it seems to be something on the identity level, both with, I think of the, the work we did with cancer patients who had substantial depression and anxiety because of their cancer, and also our work with people trying to quit cigarette smoking. I mean, there's this w- real, there seems to be when it really works, this change in how people view themselves.

Andrew Huberman 54:06 Mm-hmm.

Dr. Matthew Johnson 54:06 Like with smoking-

Andrew Huberman 54:07 Mm-hmm.

Dr. Matthew Johnson 54:09 ... like, really stepping out of this model like, "I'm a smoker. It's tough to quit smoking cigarettes. I can't do it. I've failed a bunch of times." I remember one participant during the session, but he held onto this afterwards, said, "My God, it's like I can really just decide, like flicking off a bu- I can decide not to smoke." And it's- I call these duh experiences with psychedelics, 'cause people often, like in the cancer study you say-... I'm causing most of my own suffering. Like, I can, I can follow my appointments, I can do everything, but I can still plan for the vaca- I'm not getting outside, ah, ah, you know, in the sunshine, I'm not playing with my grandkids. I'm choosing to do that. And it's like, they told themselves that before, and the smoker has told themselves a million times, "I can ch-" And it, so it sounds, when it comes out of their mouths, and your folks will say, this is part of the ineffability of a psychedelic experience. Folks are like, "I know this sounds like bullshit, and this sounds like... But, my god, I could just decide." Like, they're feeling this gravity of agency. And, which I think is interesting, 'cause regardless of the, the, the, the, you know, debates on the reality of free will, I think the philosophy of that, whether there's- it's ultimately free w- free will, like pure agency, if that exists, which I'm skeptical of, or just the idea that, clearly, we have a sense of agency. There's something there, whether it's the sense of agency even, that is, the human being has, and that seems to be, at times, fundamentally, like, supercharged from a psychedelic experience. This idea, like, I'm just gonna make a decision. Like, normally, like you tell a depressed person, like, "Don't, don't think of yourself that way. You're not a failure. Look at all the-"

Andrew Huberman 55:51 They can't do it.

Dr. Matthew Johnson 55:51 It's just, yeah, it's like-

Andrew Huberman 55:53 Right. Well-

Dr. Matthew Johnson 55:53 And, but, you can actually, in one of these states, have an experience where you realize, like, my god. Just like using MDMA to treat PTSD, and we're going to be starting work with psilocybin to treat PTSD, someone could really reprocess their trauma in a way that, like, has lasting effects, and clearly, there's probably something, you know, reconsolidation of those memories, they are, they are, they are altered, you know, very consistent with what the, our understanding of the way memory works. So, the whole idea people can actually, in a, in a few hours, have a, such a profound experience that they, they decide to make these changes in who they are, and it sticks.

Andrew Huberman 56:32 Mm-hmm.

Dr. Matthew Johnson 56:32 There seems to be something like that.

Andrew Huberman 56:34 Right. And that's profound. I mean, I, I think a, a few moments ago, I was, I, I made some semi-disparaging statements about things like The Secret and affirmations, and, and the reason I, I do that with, with a, with a nod to the fact that the people in, uh, who are putting those ideas forward are, are well-intentioned people, is that the neural networks of the brain put language last. We, we tell stories, you know, and stories are very powerful, but I think one of the, uh, most cruel aspects of the whole self-help, uh, literature and pop- popular psychology is this idea that everything you say, your brain and body hear it. That's actually a very, uh, unkind or even cruel thing for people who are depressed or anxious to hear, because if they hear that and believe that, and I want to be clear, I don't think it's true, that they think that... It's very hard to control thoughts. It's very hard to control thoughts. So if somebody, um, says, "You know, I can't," and then somebody says, "Well, no, every time you say you can't, your brain hears that, and it reinforces it," that's a very, a treacherous place to live. Um, and language is powerful, but neural networks, the brain, and the networks that underlie emotionality and perception and sense of self, they don't change in response to language. They change in response to experience.

Dr. Matthew Johnson 57:58 Yeah.

Andrew Huberman 57:59 And it just, fundamentally, you need, there are some prerequisites. You need certain neuromodulators present, like serotonin or dopamine. You need them to be at sufficient levels. You don't need a drug necessarily to do it. You could, uh, you know, you give a kid a kitten or a puppy, their first kitten or puppy, and the levels of dopamine and serotonin, I've never measured them, but we can be pretty sure that they are higher than baseline.

Dr. Matthew Johnson 58:21 (laughs) Uh-huh.

Andrew Huberman 58:21 And that experience will reshape them, right?

Dr. Matthew Johnson 58:24 Yeah.

Andrew Huberman 58:24 Uh, likewise with an adult in a certain circumstances. So I think... I, I'm fascinated by this idea that a, a somatic and a perceptual experience, but a real experience of the sort that you're describing-

Dr. Matthew Johnson 58:39 Yeah.

Andrew Huberman 58:39 ... is what allows us to reshape our neural circuitry and to feel differently about ourselves. And, uh, I know there's been, um, really tremendous success in many individuals of alleviating depression-

Dr. Matthew Johnson 58:52 Mm-hmm.

Andrew Huberman 58:52 ... of treating trauma with these different compounds. I want to

Andrew Huberman 58:56 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.

Dr. Matthew Johnson 59:16 Mm-hmm.

Andrew Huberman 59:16 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-

Dr. Matthew Johnson 59:26 Mm-hmm.

Andrew Huberman 59:26 ... 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-

Dr. Matthew Johnson 59:38 Right.

Andrew Huberman 59:38 ... like writing on the chalkboard.

Dr. Matthew Johnson 59:40 (laughs) Yeah.

Andrew Huberman 59:40 Right? Didn't work for him, doesn't work for this other stuff too.

Dr. Matthew Johnson 59:43 Uh-huh.

Andrew Huberman 59:43 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-

Dr. Matthew Johnson 59:49 Yeah.

Andrew Huberman 59:49 ... 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.

Dr. Matthew Johnson 59:57 Right.

Andrew Huberman 59:57 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.

Dr. Matthew Johnson 1:00:18 Right.

Andrew Huberman 1:00:18 What do you, what do you do to guide people through the, um, out, out the tunnel, as they exit the tunnel?

Dr. Matthew Johnson 1:00:25 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-

Andrew Huberman 1:00:53 What's the follow-up in your studies? Are they, are they writing or talking as they're doing it?

Dr. Matthew Johnson 1:00:56 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."

Andrew Huberman 1:02:55 Mm-hmm.

Dr. Matthew Johnson 1:02:55 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-

Andrew Huberman 1:03:12 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?

Dr. Matthew Johnson 1:03:18 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-"

Andrew Huberman 1:04:08 Do you also tell them not to start any relationships?

Dr. Matthew Johnson 1:04:13 I don't remember that ever coming up.

Andrew Huberman 1:04:15 Interesting. (laughs)

Dr. Matthew Johnson 1:04:16 But, but if it, but if it-

Andrew Huberman 1:04:16 No. (laughs) I mean, it's, I'm not joking. I was just wondering, you know, it seemed, but-

Dr. Matthew Johnson 1:04:19 Yeah.

Andrew Huberman 1:04:19 ... makes sense why you would want-

Dr. Matthew Johnson 1:04:20 Like, if they're dating, and they're thinking like, "Oh, I, uh, might be time to take it to the next another level. Should I ask this girl to marry me?" If it did come up, I would say there too, "Um, why don't you sit on that a week or two?"

Andrew Huberman 1:04:30 Yeah, don't get a puppy.

Dr. Matthew Johnson 1:04:31 "And let your sober mind"-

Andrew Huberman 1:04:32 Don't, don't get a puppy. Certainly don't get four puppies-

Dr. Matthew Johnson 1:04:34 (laughs) .

Andrew Huberman 1:04:34 ... until you're...

Andrew Huberman 1:04:36 I have a question about, um, flashbacks.

Dr. Matthew Johnson 1:04:40 Uh-huh.

Andrew Huberman 1:04:40 You know, one of, one of the kind of, uh, things you hear is, you know, flashbacks, and that-

Dr. Matthew Johnson 1:04:45 Yeah.

Andrew Huberman 1:04:45 ... 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?

Dr. Matthew Johnson 1:05:02 No evidence for that, so probably complete nonsense. The-

Andrew Huberman 1:05:06 Flashbacks are nonsense, or the storage in body fat is complete nonsense?

Dr. Matthew Johnson 1:05:09 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.

Andrew Huberman 1:05:41 Mm.

Dr. Matthew Johnson 1:05:41 They'll see some trails, like-

Andrew Huberman 1:05:43 Mm-hmm.

Dr. Matthew Johnson 1:05:43 ... 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?

Andrew Huberman 1:06:38 Right.

Dr. Matthew Johnson 1:06:38 You know? Like, is you're drinking during it, and you're taking-

Andrew Huberman 1:06:39 Did you take what you thought you took?

Dr. Matthew Johnson 1:06:41 Yeah. What's the dose? Is, what's-

Andrew Huberman 1:06:42 Yeah.

Dr. Matthew Johnson 1:06:42 ... 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-

Andrew Huberman 1:07:10 What is HPPD?

Dr. Matthew Johnson 1:07:11 Oh, hallucinogen-

Andrew Huberman 1:07:12 What is it? What is it?

Dr. Matthew Johnson 1:07:12 ... persisting perceptual disorder-

Andrew Huberman 1:07:14 Okay.

Dr. Matthew Johnson 1:07:14 ... who have never taken a psychedelic. So it's often prompted by, um, alcohol-

Andrew Huberman 1:07:20 Yeah.

Dr. Matthew Johnson 1:07:21 ... benzodiazepines-

Andrew Huberman 1:07:22 Yeah.

Dr. Matthew Johnson 1:07:22 ... cannabis-

Andrew Huberman 1:07:24 Yeah.

Dr. Matthew Johnson 1:07:24 ... even tobacco.

Andrew Huberman 1:07:25 Mm-hmm.

Dr. Matthew Johnson 1:07:25 And, and I believe in one individual, n- no lifetime history of any... It wasn't preceded by any of those, uh, you know, substance, um, uses. So I think it's... I think of it like the precipitation/exacerbation of psychotic disorders. We... It seems pretty clear through observation that some people with, with either predisposition or active psychotic disease, that this can destabilize them.

Andrew Huberman 1:07:51 Yeah.

Dr. Matthew Johnson 1:07:51 A psychedelic, the same way that a life experience can destabilize those-

Andrew Huberman 1:07:55 Sure.

Dr. Matthew Johnson 1:07:55 ... person more easily. I think of it like that there's probably some pretty rare neurological susceptibility. We have tended, going... This goes back to the '80s. You know, clinical practice, it ended up in the DSM, focused on hallucinogen, because I, I relate it to the psychology of xenophobia. It's always the weird other thing that gets the attribution. You don't attribute to the thing.

Andrew Huberman 1:08:18 Mm-hmm.

Dr. Matthew Johnson 1:08:18 Like, "Oh, yeah, did you smoke cigarettes? Did you drink?" It's like, "Well, yeah, but I see lots of people drinking and not ending up with this."

Andrew Huberman 1:08:25 Mm-hmm.

Dr. Matthew Johnson 1:08:25 Like, you take a, a crazy, like, drug, and you can get pe- people to believe all sorts of crazy stuff. The biggest example of that is the, the cathinone derivatives, so-called bath salts. And if you remember several years back-

Andrew Huberman 1:08:38 Oh, yeah, what was the deal with that?

Dr. Matthew Johnson 1:08:39 ... the guy in Florida that, that ate the other guy's face. There was a homeless guy that, like, literally ate part of someone's face off, like, yeah, it's one of the craziest-

Andrew Huberman 1:08:48 While the person was alive?

Dr. Matthew Johnson 1:08:49 While the person was alive. And all it took was one sheriff's deputy to say, "Well, I don't know, but I bet it was some of that bath salt stuff, stuff that's been going on." The only thing-

Andrew Huberman 1:08:59 What, what was the, was-

Dr. Matthew Johnson 1:09:00 And the only thing in his system-

Andrew Huberman 1:09:01 Well, maybe we could set the record straight for people. What, what was this? Why would he say bath salts, and was it bath salts? And-

Dr. Matthew Johnson 1:09:08 It wasn't. And, and so the only thing in his tox was cannabis, which we all know. Typically, people don't eat people's faces off after they get stepped on.

Andrew Huberman 1:09:17 No. Makes you hungrier, but not that hungry.

Dr. Matthew Johnson 1:09:19 (laughs) Yeah, right.

Andrew Huberman 1:09:20 Yeah.

Dr. Matthew Johnson 1:09:20 Right. So it's just an example of the xenophobia. Like, today, if you get on Google Images and look up, you know, bath salts, one of the most common i- images you'll see is this poor guy's face being eaten off. So we're just so ready to latch on, just like the people of another culture that we don't know. But it's, it's, it's very easy to assign attribution to a class that you're very unfamiliar with. So I think they, the psychedelics, got that attribution with this very rare neurological susceptibility the way that alcohol didn't. So I think it's not specific to psychedelics, but we don't really know. We need... But we'd, we'd look at it in our research, have never seen an example of it. But flashbacks can mean a number of other things. I think the most common thing people experience is what we call state-dependent learning. It's, it's, it's, it's returning yourself to a similar context can bring back the same thoughts and emotions as the experience. So, you know, someone used to smell mushrooms a week ago. Now, they do something like they smoke some cannabis or they, uh, or they're, they take a warm bath, um, or they're simply, like, relaxed, and it seems to come out of the blue. And all of a sudden, these, or, or they follow a, a thought trail that takes them, that reminds them of their... And they find themselves in that same experience again. I think that's more state-dependent learning. It's not the distressing component that is in, and it's n- typically not perceptual. And then another class are just sort of, um, perceptual anomalies within a day or two following the experience, which is not HPPD. Most people have, you know, joked that this is a free trip. Like, you might see a few trails or halos the day afterwards. It doesn't last longer than that, and it's, doesn't screw you up. It's kind of fun, like, "Oh, yeah, I'm still seeing some trail-" most people will say. So it could mean any of those things.

Andrew Huberman 1:11:15 Got it.

Dr. Matthew Johnson 1:11:15 So flashback is, yeah, confusing.

Andrew Huberman 1:11:17 Interesting. No, I appreciate you, you clarifying that. I mean, one very common misconception about neuroplasticity is that it's an event. And it's not an event, it's a process, and we have no understanding of the duration of that process. However, the experience of any drug or any life experience, right, even if it's, uh, trauma, or a wonderful experience, or a psychedelic experience, doesn't matter, sets in motion a series of dominoes that fall. And it's the falling of those dominoes that we call neuroplasticity. I mean, the, the reshaping of neural circuits could take years.

Dr. Matthew Johnson 1:11:54 Mm-hmm.

Andrew Huberman 1:11:54 We don't know. It's the, uh, the trigger, and then there's the actual change. And so I think that some of what you described could be literally the reordering of circuitry that, in some individuals, might extend longer than others. Um, and there is one phenomenon

Andrew Huberman 1:12:10 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-

Dr. Matthew Johnson 1:12:28 Yeah, so it's DMT, the active-

Andrew Huberman 1:12:28 The DMT system, right. Excuse me.

Dr. Matthew Johnson 1:12:30 ... yeah, it's orally, uh, it's MAO inhibitors-

Andrew Huberman 1:12:32 That's right, of course, of course, yeah.

Dr. Matthew Johnson 1:12:32 ... that allow the DMT to be orally.

Andrew Huberman 1:12:34 Right, I should have-

Dr. Matthew Johnson 1:12:34 Mm-hmm.

Andrew Huberman 1:12:34 ... 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-

Dr. Matthew Johnson 1:13:18 Uh-huh.

Andrew Huberman 1:13:18 ... and I was like, "It's really hot here." And I could actually create, like, a cooling of, uh, perce- cooled perception.

Dr. Matthew Johnson 1:13:24 Yeah.

Andrew Huberman 1:13:24 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-

Dr. Matthew Johnson 1:13:33 (laughs)

Andrew Huberman 1:13:33 ... 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-

Dr. Matthew Johnson 1:13:59 Uh-huh.

Andrew Huberman 1:13:59 ... 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-

Dr. Matthew Johnson 1:14:26 Uh-huh.

Andrew Huberman 1:14:26 ... experience immense pleasure from it. It's not really sexual pleasure, but it's this kind of deep core of the body-

Dr. Matthew Johnson 1:14:32 Yeah.

Andrew Huberman 1:14:32 ... that it's the autonomic nervous system down the core of the spine.

Dr. Matthew Johnson 1:14:34 Probably what a certain number of people would call kundalini, which is another one-

Andrew Huberman 1:14:38 Right, and it-

Dr. Matthew Johnson 1:14:39 ... scientifically who, yeah.

Andrew Huberman 1:14:40 That's right.

Dr. Matthew Johnson 1:14:40 Yeah.

Andrew Huberman 1:14:40 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.

Dr. Matthew Johnson 1:14:50 Ah.

Andrew Huberman 1:14:51 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-

Dr. Matthew Johnson 1:15:01 Wow.

Andrew Huberman 1:15:01 ... neurologic phenomenon.

Dr. Matthew Johnson 1:15:02 Have any studies been done?

Andrew Huberman 1:15:03 Yeah.

Dr. Matthew Johnson 1:15:03 I would imagine that person might actually like, would they duck?

Andrew Huberman 1:15:07 Oh, what-

Dr. Matthew Johnson 1:15:07 If there, like that would be an interesting experiment, like-

Andrew Huberman 1:15:09 That'd be kind of thing my lab would want to get into.

Dr. Matthew Johnson 1:15:10 ... where they could-

Andrew Huberman 1:15:11 That's right.

Dr. Matthew Johnson 1:15:11 Yeah, their body could clear, but their-

Andrew Huberman 1:15:13 Right, right.

Dr. Matthew Johnson 1:15:13 ... projection-

Andrew Huberman 1:15:14 Yeah.

Dr. Matthew Johnson 1:15:14 ... wouldn't. Uh (laughs) ...

Andrew Huberman 1:15:15 Yeah, the sense of self, I mean, there's a, there's a well-known phenomenon. It, it's very, uh, in a few individuals, very sad, where people actually, uh, avidly seek out amputation of their limbs because their limbs, they feel, don't belong to their body.

Dr. Matthew Johnson 1:15:27 Oh, yeah.

Andrew Huberman 1:15:28 This is a very sad, and, uh, unfortunately, very rare, but also very sad condition. Anyway, I think the, the, the core of this conversation that we're, we're drilling into is this notion of, of, of reordering the self. And it's, and it's a relief to me to know that flashbacks are not something that is, uh, kind of, um, uh, forgive the term (laughs) , baked in to the, uh, to the psychedelic experience. And I suppose that's a good segue to ask about

Andrew Huberman 1:15:54 other sorts of drugs. I, uh, having said baked in, the temptation is to go to, um, marijuana or cannabis.

Dr. Matthew Johnson 1:16:00 Yeah (laughs) .

Andrew Huberman 1:16:00 But, but if we, if we could, I'd like to just ask about some of the more dopaminergic compounds.

Dr. Matthew Johnson 1:16:06 Uh-huh.

Andrew Huberman 1:16:06 In particular, MDMA.

Dr. Matthew Johnson 1:16:08 Yeah.

Andrew Huberman 1:16:09 My understanding is that MDMA is a purely synthe- synthetic compound, that you're not going to find MDMA in nature.

Dr. Matthew Johnson 1:16:17 So far.

Andrew Huberman 1:16:18 So far.

Dr. Matthew Johnson 1:16:18 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) -

Andrew Huberman 1:16:27 Yeah, actually the-

Dr. Matthew Johnson 1:16:27 ... inside America.

Andrew Huberman 1:16:28 Yeah.

Dr. Matthew Johnson 1:16:28 So who knows? A plant out there-

Andrew Huberman 1:16:29 Right.

Dr. Matthew Johnson 1:16:29 ... might be making MDMA.

Andrew Huberman 1:16:31 Right, right.

Dr. Matthew Johnson 1:16:31 But as far as we know now, no.

Andrew Huberman 1:16:33 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.

Dr. Matthew Johnson 1:16:50 Mm-hmm.

Andrew Huberman 1:16:50 Which from an, from a neural network's perspective, is a very unusual situation.

Dr. Matthew Johnson 1:16:56 Mm-hmm.

Andrew Huberman 1:16:57 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-

Dr. Matthew Johnson 1:17:11 Yeah.

Andrew Huberman 1:17:11 ... kind of neurochemical states.

Dr. Matthew Johnson 1:17:13 Yeah.

Andrew Huberman 1:17:13 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.

Dr. Matthew Johnson 1:17:38 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-

Andrew Huberman 1:18:12 Mm-hmm.

Dr. Matthew Johnson 1:18:12 ... 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-

Andrew Huberman 1:18:20 Well, I, I should have said, it, it seems like MDMA is being used, clinically anyway, mainly for trauma.

Dr. Matthew Johnson 1:18:27 Right.

Andrew Huberman 1:18:27 Not just for depression, so.

Dr. Matthew Johnson 1:18:30 Although, part of it we really don't know. Um, it may be that MDMA is great for depression and some of these other, and it may be that, and I'm going to be looking at this soon, that psilocybin is great for treating PTSD. A lot of underground therapists, um, say that, underground psychedelic therapists. So we don't really know yet which-

Andrew Huberman 1:18:47 What do you mean by underground? Oh, because they're doing it-

Dr. Matthew Johnson 1:18:49 People doing illegal...

Andrew Huberman 1:18:50 Yeah.

Dr. Matthew Johnson 1:18:50 You know, but the, more like, you know, a professional therapist would, it's just illegal. Um, and this is a kind of a growing, um, thing. Um, so we don't really know which. It, it, speculating, but it may be that MDMA, for a broader number of people, is better for, for trauma, because the chances of having an extremely challenging experience, what I call the bad trip, like really freaking out, is much lower with MDMA. People can have bad trips, but they're of a different nature. It's not-

Andrew Huberman 1:19:26 Well, what is? You could... Tell us.

Dr. Matthew Johnson 1:19:26 It's not sort of like freaking out, because all of reality is sort of shattering, and it's less of this... It can take so many forms with the classic psychedelics, but like, typically, you'll, you'll hear something like, "I didn't know it was going to be like this," no matter how hard you tried to prepare them, that like, this...... is, like, get me off this ride.

Andrew Huberman 1:19:49 You're talking about LSD or psilocybin?

Dr. Matthew Johnson 1:19:50 LSD, psilocybin, ayahuasca.

Andrew Huberman 1:19:52 Bad trip.

Dr. Matthew Johnson 1:19:52 Yeah. Yeah. A- and just the sense of, like, "I'm going insane. This is so far beyond anything I've ever experienced, and it's scaring the shit out of me."

Andrew Huberman 1:20:03 How often does that happen?

Dr. Matthew Johnson 1:20:03 "I- I- I don't have a toehold on anything-"

Andrew Huberman 1:20:05 Yeah.

Dr. Matthew Johnson 1:20:06 "... even that I exist as a- as- as- as an entity." And that can be really... I think, frankly, experientially, that's kind of the gateway to both the transcendental mystical experiences,