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A | Welcome to the Huberman Lab podcast, where. |
B | 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 Doctor Matthew Johnson. Doctor Johnson is a professor of psychiatry at Johns Hopkins School of Medicine, where... |
A | So I gave the waking up app. |
B | A try, and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain a... |
A | For those of you who don't know. |
B | Yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations, and there's excellent scientific data to show that yoga Nidra and something similar to it called non sleep deep rest, or NSDR, I can greatly restore levels of cognitive and physical energy, even with just ... |
A | 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. |
C | Likewise, big fan and happy to do this with you. |
A | 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 as a psychedelic? |
C | Nomenclature is a real challenge in this area of psychedelics. So starting with the word psychedelic, it just, if you're a pharmacologist. 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 | Does that come from? |
C | Salvia divinorum. It's a plant it became 20 years ago. It sort of popped onto the legal high scene and there's a long history of this predating the Internet going back to the stuff one gador in the back of high Times magazine and most of this stuff never worked. Smoke enough of anything, maybe you get a little bit ligh... |
A | So I get the impression that the psychedelic space is an enormous cloud of partially overlapping compounds, meaning some are impacting the serotonin system more than the dopamine system, others are impacting the dopamine system more than the serotonin system. Given that the definition of a psychedelic is that it profou... |
C | Yeah. |
A | That gets more complicated as you get into the emotional realm. But is it fair to say that psychedelics are impacting the space time analysis that the brain is performing and thereby creating hallucinations and thereby altering, you know, the blending of senses? Is it fair to say that I. |
C | Think it's fair to explore that area, and here's what I'm thinking. Clearly, there is a changed relationship, certainly at the right dose of orientation in space time. I think as a. I'm primarily a behaviorist, and in terms of human behavioral pharmacology, I always go to comparative pharmacology. Okay, what can we say... |
A | Proprioception, your balance, proprioception, versibular. |
C | And in many ways in those gross motorways, like, far worse. Of course, everything's dose dependent. But in the classic psychedelics, obviously, the benzodiazepines being very similar. Alcohol, same thing. You know, I'd want to dig in a little more in terms of, like, maybe there's something more specific we could say ab... |
A | Can you give us an example of a model? I know that when I throw a ball in the air, it falls down, not up. That's a prediction that I learned as a child. I did not come into the world with a brain that knew that relationship between objects and gravity. But one of the first things that a child learns is the relationship... |
C | 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. |
A | Right. So if he were to throw a ball, if your child were to throw a ball and it went up into the sky, that would be absolutely mind blowing. It would be for an adult too. |
C | It'd be a pretty psychedelic experience, probably. |
A | Right. And so there's a. There's a space, there's a rule there. You're saying there's a kind of a prediction. There's a rule that. That underlies a prediction, that when that rule is violated, all of a sudden the circuit, presumably for that prediction, it doesn't have a mind of its own, but somehow it creates a surpri... |
C | Or a recognition element and it's not filtered out. You know, and this might sound extreme, but there are these cases. It was overblown in sort of the propaganda, the late sixties, early seventies. But there are credible cases of people, I think it's very atypical of sounds like they really thought they could fly and j... |
A | Yeah. So they're violating these predictions. Yeah. The reason I ask it, the question the way I did is because given the enormous cloud of different substances and given the range of previous experiences that people show up to, a psychedelic experience with, I feel like the ability to extract some universal themes is u... |
C | 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, serotonin itself is not psychedelic, or else we'd be t... |
A | Because when I eat a bagel, I get serotonin release, right? |
C | Or turkey. |
A | There's tryptophan. My understanding of serotonin is that 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 the immediate experience, whereas the dopamine system really places us into an external view of what's out there in t... |
C | Yeah. Need to do something. I mean, that's consistent with my understanding and certainly not in terms of. I don't primarily identify as a neuroscientist. I definitely tell the viewers that we're far more in your domain here than mine. But in terms of how psychedelics and other drugs interface at the neuroscience level... |
A | Well, feel free to explain it. At the experiential level, I think there probably are some audience members that are interested in, is it the five h, two c? Is it the layer five neurons and cortex? That conversation we could hold, and that's an interesting conversation. But just in terms of the experience of serotonergi... |
C | And in terms of how they. And 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 ideas are. |
A | Please. |
C | You have this path, you know, as you know, like, 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 it question best addressed by the biology, the chemistry, or the physics? That's how I think ... |
A | But do people hallucinate on ketamine? |
C | Yes. Yes. And it's more dissociative. So someone is more likely to sort of be less behaviorally active. If they have a really high dose, they go into a k hole. And if they go in a really high dose, like, you get into subconscious. Yeah. |
A | Not an a hole, but a k hole. |
C | A k hole, yeah, it's very different, the k hole. And ketamine is interesting because people can take kind of bumps and kind of dance on it with the sort of an alcohol level strength of effect. And that's sort of the classic kind of raving, you know, use of it. But then those folks want to titrate their dose because if ... |
A | So that's like, why would somebody want to take a dissociative anesthetic? Like, to me, it's completely mysterious as to why someone will want to dissociate from their body. |
C | People claim that these NMDA antagonist psychedelics are extremely insightful in a very similar way to the experiences with the classic psychedelics. |
A | And ketamine is now legal for therapeutic users. |
C | Right, right. Spravato, the intranasal form marketed by Janssen, which is s ketamine. It's prescription. Yeah, it's prescription. |
A | So people are taking in the nasal spray and then are they undergoing talk therapy while they're doing this? |
C | Typically not. So this is very interesting. And there's so much work that needs to be done. It's not treated as psychedelic therapy. And by that psychedelic therapy, I mean you tell the person they're going to have an altered experience. You tell them to pay attention to that experience, that they might learn something... |
A | Walk us through this. So let's say I were to come to one of your clinical trials. Cause these are clinical trials, right at your lab at Hopkins. And would I need to be depressed or could I just be somebody who wanted to explore psychedelics? |
C | We've had studies for all of these and a number of other disorders. So healthy, normal studies, the code for not a problem to fix. But we're all here. That's what's amazing about psychedelics, though, because if you administer them under this model and you develop a relationship and give a high dose of psychedelic, you... |
A | So a variety of reasons. So maybe I'll just ask some very simple questions that will kind of step us through the process. So let's say I were to sign up for one of these trials 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 be pr... |
C | First there's screening, so it's kind of like a couple of days of both psychiatric, structured psychiatric interviews about your past and symptoms across the DSM, the psychiatric Bible to see if you might have various disorders that could disqualify you, like the main ones being the psychotic disorders, schizophrenia, ... |
A | I think it's so important for people to hear because the all arounders, you really can't predict how somebody is going to react internally. I want to just briefly touch on something because we left that topic, but it occurred to me that a lot of these effects of psychedelics and how they function, et cetera, is still v... |
C | So they receive pure psilocybin. So the mushroom, and there are many species the most. If people have taken mushrooms in the United States, it's most likely psilocybin cubensis. 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 thousand watt light like... |
A | Does it look like serotonin? Molecularly? |
C | Yes. Yes, yes. |
A | So if I looked at. If I were to show people the chemical structure of serotonin, chemical structure of psilocybin, it would look quite similar. |
C | Right. Right. |
A | And they're basically taking serotonin, a modified. |
C | Version of serotonin, which makes sense. But then again, this repeated theme of the chemistry doesn't always neatly line up because, like, mescaline looks more like dopamine than it does like serotonin. But yet at the receptor activation level, the pharmacology, neural pharmacological effect, those are similar, but, ye... |
A | 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 variety of effects from different compounds is, for instance, serotonin might affect a certain pathway... |
C | And there's a dose effect curve that's really interesting. Some of our early work with psilocybin in healthy normals looked at a true placebo plus four active doses, 510, 20, and 30 milligrams of psilocybin. Body weight adjusted so those milligrams per 70 body weight. We've recently published a paper in our newer trial... |
A | Yeah, well, brain size doesn't vary that much between individuals. |
C | Yeah. |
A | The end. This is a brain effect mostly, probably body as well. Okay, so the person ingests the powder. |
C | In a little pill. Yeah. And it does take 30 milligrams is a small. Fit it into a tiny little capsule and it'll take about a half hour, anywhere from 15 minutes to an hour to kick in. |
A | And you said whatever dose range was. |
C | Most of our studies are looking at where we want a psychedelic effect are in the 20 to 30 milligram range. Again, because we have adjusted by body weight, and the average american is over 70 kg, about 150 pounds. People, in fact, have gotten more like 40, 45 in a lot of cases, but it's still a small pill. The session d... |
A | You're doing therapy for people, it's not just about the experience. |
C | Right. And the experience itself is very much shaped by that container, by the environment and the degree to which one allows it to happen. Like one should let go of control. |
A | Yeah, let's talk about the letting go of control and then as we march through this hypothetical experience that does take place in your lab. But we're using a sort of generic case example, if you will. The letting go of control is an interesting feature, actually, because one of the common themes of good psychoanalysis... |
C | Yeah. |
A | Let's coarsely, space and time are altered in some way. Sense of self. For instance, I might be going to a strongly interoceptive mode where I'm focusing on 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'... |
C | Yeah. |
A | You're not worried whether or not your brain is going to explode. Even though a thought could feel enormous if I keep going like this, it almost sounds psychedelic, but that's the idea here. Or if I'm paying attention, for instance, to some somatic experience like the coursing of waves of heat through my body that I'm ... |
C | Is that especially these days. Yeah. Multitask. |
A | Multitask. And the more that we focus on one thing, the more bizarre that thing actually can appear to us. Right, right. I mean, even if it's the tip of your finger and you're not taking any psychedelics, you spend long enough looking at the tip of your finger, you will notice weird things. Right. |
C | I think of that as the classic psychedelic effect, or one classic effect and one I've used many times of this example of why people should necessarily, you know, these aren't. One should be judicious in putting themselves in these circumstances. Someone could be, you know, having a very strong psilocybin experience, an... |
A | Like, no, I'm so glad you brought this up. I mean, here I'm reflecting my bias as a vision scientist, but most people don't realize this, but if you look at something long enough, it eventually disappears. It doesn't actually disappear, but perceptually, it disappears. You have these little microsuccides that ensure th... |
C | Because I've had people there on the couch. I remember one lady said, this is probably 1314 years ago said, matt, tell me again, I can't die. I feel like my heart is gonna rip through my chest. I mean, she was feeling, and I should say, typically, cardiovascular response is modest. The pulse and blood pressure go up so... |
A | Are you monitoring this the whole time? We do, yeah, we do monitor a variety of devices. |
C | Yeah. So every half hour or so, we take their on protocol and we 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. The physician comes in, gives them a little ... |
A | I don't realize. |
C | Exactly. But people. That can be so compelling. And so one of the reasons. 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 wearing the eye shades. We don't call them blindfolds because that has a negative connotation, like being kidnap... |
A | And they're probably seeing a lot in there anyway, so blind isn't the appropriate. |
C | Right, right. I've never thought of it. These should be like inner sight shades. |
A | But when you close the eyes, the levels of activity in the retina actually are maintained. It's just spontaneous activity, and it seems. |
C | And I'd be curious about your thoughts on this, but the way I describe it is that the mind's eye, this kind of loose term we use, can be on rocket boosters. So a lot of times, for some people, like a compound like psilocybin, for some people, there's no perceptual effect. Like, if they're looking at this room, it would... |
A | We will definitely get to those. But the reason I kind of cringe and say, oh my when you talked about those is that knowing a little bit about the pharmacology of acetylcholine, the idea of manipulating that system to me sounds very uncomfortable because, like, the whole idea of witches and flying, there was a whole hi... |
C | Yeah. |
A | 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 o... |
C | How can the pen and the processing, your childhood trauma, both lead to. |
A | Right. |
C | Yeah. |
A | So what does this. I mean, at that level, it raises this question, like, first of all, how, why? I mean, or just what are your thoughts on that? |
C | So this is definitely in the. This is in the terrain we're figuring out, you know, so there's no educated speculation is the best I can provide, but I think the best, I think the common denominator are persisting changes in self representation. |
A | Okay, tell me more about self representation. |
C | That's the way one holds the sense of self, the fundamental relationship of a person in the world. I mentioned earlier that these experiences seem to alter the models we hold of reality. And I think that the self is the biggest model that I am, a thing that's separate from other things, and that's. I am defined by cert... |
A | High dose of mescaline? |
C | Yeah. Yeah. And that's, you know, that's a heroic dose for sure. And he's just going off on the cherry ness of the chair. Like, this chair is exuding the quality of being chair. |
A | This is this expansion of the perceptual bubble, a narrow percept that then grows within the confines of that narrow percept. So sense of self is a very interesting phenomenon. If we could dissect it a little bit, there's the somatic sense of self. So the ability to literally feel the self in this process we call inter... |
C | Right. And I think certainly more work needs to be done. This is the horizon. And I should credit Chris Letheby, a philosopher in Australia, who has a forthcoming book. It might be out right about now or soon, within the coming months. Psychedelics and philosophy. |
A | That's the title of the book. |
C | It might be psychedelic philosophy. It's really close. |
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