Essentials_ Psychedelics for Treating Mental Disorders _ Dr. Matthew Johnson

Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now, my 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 here to learn from you. Likewise, big fan and happy to do this with you. Very well, thank you. My first question is a very basic one, which is what qualifies a substance to as a psychedelic? Nomenclature is a real challenge in this area of psychedelics. So starting with the word psychedelic, 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 compound, it spans several classes of compounds. But overall, so it's really more of a cultural term, or it does have a relationship to drug effects, but it's at a very high level. So all of the so-called psychedelics across these distinct classes that I can talk more about, the way I put it is they all had the ability to profoundly alter one sense of reality. And that can mean many things. Part of that is profoundly altering the sense of self acutely. So when someone's on the psychedelic, so the different classes that can be the specific pharmacological classes that can be called a psychedelic are one that 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. I think there was a little bit tendency to stay away from psychedelics at 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, psilocybin, which is in so-called magic mushrooms. It's in over 200 species that we know so far of mushrooms, dimethyltriptamine or DMT, which is in dozens and dozens of plants, mescaline, which is in the peyote, cacti and some other cacti, like sand, Pedro. And even amongst these classic psychedelics, there are two structural classes. That's the chemistry. There's the triptamine-based compounds like psilocybin and DMT. And then there's the phenethylamine-based compounds. So these are the basic two to basically building blocks that you're starting from, either a triptamine structure or a phenethylamine structure. But that's just the chemistry that all of the, what's more important, or at least 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 agnist or partial agnist at the serotonin two-way receptor, so subtype of serotonin receptor. Then you have these other classes of compounds that you could call psychedelic. Big one would be the NMDA antagonist. So this would include ketamine, PCP, and dexamethorapin, something I've done some research with, which folks might recognize from like robo-tripping, guzzling, like, you know, colser. A large overlap in the types of subjective effects that you get from those compounds compared to the two-way agnist, classic psychedelics. But then you have another big one of MDMA, which really stands in a class by itself. So it's been called an entactogen and-- What does that mean? It means, like, touching within. It's sort of that lutes the idea that it can really put someone in touch with their emotions. It's also been called an entactogen, meaning it can afford empathy. So I get the impression that the psychedelic space is a enormous cloud of partially overlapping compounds. Meaning summary 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 profoundly alters sense of self, at least that's included as a partial definition. I think of these as psychedelics as profoundly altering models. You know, we're all-- we're prediction machines. And that's large-- so much of that is top down. And psychedelics have a good way of, you know, loosely speaking, dissolving those models. Can you give us an example of like a model? Like I know that when I throw a ball in the air, it falls down, not up. This might sound extreme, but there are these cases. It was overblown in sort of the propaganda the late 60s, early 70s. But there are credible cases of people. I think it's very atypical of sounds like they really thought they could fly. And, you know, jump out of a window. Now, far more people every year fall-- I mean, who knows, you know, 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 cases. There was one research volunteer in our studies that she 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-- reviewing the video, it looked like she really thought that she was going to go through that painting. So she was the other dimension. Yeah, so the violating these predictions. 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 useful, especially for people who haven't done them before, right, who might not have an understanding of what their effects are like, can we just briefly touch on the serotonin system? So, compounds like LSD, my surgeic acid diethylmide, and psilocybin. My understanding is that they primarily target the serotonin system. How do they do that at a 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 model challenges, challenging pre-existing models and researches? 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. What do we think is going on in a general sense? 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 for oncology. There's some things about post-receptor signaling pathways, in other words, just fitting into the receptor. Clearly, you know, serotonin itself is not psychedelic. You know, or else we'd be tripping all of us all the time. Because when I eat a bagel, I get serotonin release, right? Uh-huh. I mean, there's-- And we're trying to do that. Right. My understanding of serotonin is that in very broad strokes, that 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 the world and what's possible. Yeah. Need to do something. I mean, that's consistent with my understanding, and I'll certainly not-- in terms of-- I don't primarily identify as a neuroscientist, definitely tell the, you know, the viewers that were far more neurodomain here than mine, but in terms of how psychedelics and other drugs, you know, interface at the neuroscience level. Well, feel free to explain it at the experiential level. Yeah. I mean, it doesn't have-- let's say I were to come to one of your clinical trials, because these are clinical trials, right? And in your-- at your lab at Hopkins. Yeah. And would I need to be depressed, or could I just be somebody who wanted to explore psychedelics? 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 psychedelics, you can be healthy, normal, without a diagnosable issue. But man, we're all human, and the issues seem to come to the surface. Sure. But we've done work with smoking cessation, so people trying to quit tobacco and haven't been successful. So a variety of reasons. So maybe I'll just ask some very simple questions that would 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 would show up, you said I would do several hours in advance of getting to know the team that would be present during this psychedelic journey. 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, and we're also including bipolar, so the manic side of bipolar. So after that's in also cardiovascular screening, heart disease. After that screening, then the preparation where you get, you're both, you develop a therapeutic rapport with the people who are going to be in the room with you, your guides. 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. 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. I think it's so important for people to hear because you really can't predict how somebody is going to react internally. Let's say that somebody passes all the prerequisites, and it's the day. Yeah, comes the day that they're going to have this experience. Are they eating mushrooms like you hear about or are they taking it in capsule form and how do they get it into their body? So they receive pure psilocybin. Most of our studies are looking at where we want a psychedelic effect or in the 20 to 30 milligram range. The session day itself is not full of, for most of our studies is not full of tasks. I really want to look at the therapeutic response. Obviously, if it's a therapeutic study, we want it to be a meaningful experience. And research has found not surprisingly that you get a less meaningful experience when you're in an FMRI or when you're doing a lot of cognitive tasks. 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, is to have that preparation so the person feels very comfortable with their guides. Ultimately, what I tell people is like any emotional response, it's all welcome. I mean, you could be crying like a baby hysterically. That's what you should be doing if that's what you feel like. I mean, you're doing therapy for people. It's not just about the experience. Right. And the experience itself is very much shaped by that container, by the environment. And there's a great which one allows it to happen. Like, one should let go of control. The letting go of control is an interesting feature, actually, because one of the common themes of good psychoanalysis 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 oneself. 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 aspects to psychedelics is that normally the social pressure, but also just our internal pressure from our own brain is pay attention to many things at once, not just one. Especially these days. Yeah, multi-task. Yeah, multi-task. 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 a long enough looking at the tip of your finger. You will notice very weird things, right? I think it has the classic psychedelic effect or one classic effect. And one of you's many times of this example of why people should necessarily, you know, these aren't these. One should be judicious in putting themselves in these circumstances. Someone could be, you know, having a very strong psilocybin experience and they're trying to navigate their way in Manhattan, cross in the street. And they might be staring into the hand and real, 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. I think of the simplest form of, well, we know that the simplest form of learning is habituation. Simply keep applying stimuli and there's less response. This is what organisms do. This is what we have to do. And it's like there's this habituation component that like-- Dis habituation. Yes. Like we wouldn't be able to get through life if we wouldn't be able to cross that street if we were like, this is a miracle. It sounds like on psychedelics, one of the primary goals therapeutically is to really drill into one of these perceptual bubbles and expand that bubble. And the safety, it seems, is the safety, it's sort of like a permission to do that without worrying that something's going to happen. Right. Because, you know, I've had people there on the couch. Yeah, I remember one lady said, this is probably 13, 14 years ago, said, Matt, tell me again, I can't die. I feel like my heart is going to 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. 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 him a little nitric glycerin under the tongue, and, 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. But, yeah, but someone can feel that, I got it, I'm going to die. Like, I have never felt my heart beat like this before. So, there's an expansion of a particular fairly narrow percept. It could be sound, can be an emotion, could be sadness, could be a historical event or a fear of the future. And you've mentioned before that there's something to be learned in that experience. Yeah. There's something about going into that experience in an undeterred way that allows somebody to bring something back into more standard reality. Yeah. 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. That raises all sorts of interesting questions. And this is not a philosophy discussion. We're talking about biology and psychology here. What are your thoughts on that? This is in the terrain we're figuring out, you know, so there's no educated speculations the best I can provide, but I think the best, I think the common denominator are persisting changes in self-representation. Okay. Tell me more about self-representation. That's the way one holds the sense of self, the relate, 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 at the self is the biggest model 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'm a smoker that's having a hard time quitting or I'm a depressed person that you know, these myself as a failure and all of these things, those are models too. And this expansion of the perceptual bubble, a narrow, 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 into this process we call interoception. And then there's the title of the self, the I am blank. And I know as you said that several times, it's intriguing to me how one defines themselves internally, not just to other people, but how one psychologically and by default in defines themselves, I think is very powerful like 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 so interesting that letting go and going into this perceptual bubble, which is facilitated by obviously a really wonderful team of therapists, but also the serotonergic agent, allows us to potentially reshape the perception of self. That's a tremendous feat of neuroplasticity. I think there's something about this change in sense of self. It seems to be something on the identity level, both with I think of 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 real, there seems to be when it really works this change in how people view themselves like smoking 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 failed a bunch of times. I remember one participant during the session, but he held on to this afterwards said, God, it's like, I can really just decide, like flicking off a bite, I can decide not to smoke. And it's I call these duh experiences with psychedelics because people often like in the cancer, say 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 supplant for the, I'm not getting outside, 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, so it sounds, when it comes out of their mouths, any folks will say this is part of the ineffability of a psychedelic experience, folks say, 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, that seems to be at times fundamentally like supercharged from a psychedelic experience. This idea, like, I'm just going to 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. It's just, yeah, it's like, and you can actually, in one of these states, having 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, 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 altered, you know, very consistent with the understanding of the way memory works. So the whole idea of people can actually, in a few hours, have such a profound experience that they decide to make these changes in who they are, and it sticks. It's fascinating by this idea that a somatic and a perceptual experience, but a real experience of the sort that you're describing, is what allows us to reshape our neural circuitry, and to feel differently about ourselves. And I know there's been really tremendous success in many individuals of alleviating depression, treating trauma with these different compounds. If we could, I'd like to just ask about some of the more dopaminergic compounds, in particular, MDMA. And my understanding is that MDMA leads to very robust increases in both dopamine and serotonin simultaneously. Why would it be that having this 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? Speculating, but it may be that MDMA for a broader number of people is better 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 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 typically you'll hear something like, I didn't know it was going to be like this. No matter how hard you try to prepare them, that like, this is like, get me off this. - You're trying to call us to your psilocybin. Yeah, yeah, and just this 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. I can't have a toe hold on anything, even that I exist as an entity, and that can be really, I think frankly, experientially, that's kind of the gateway to both the transcendental mystical experiences, the sense of unity with all things, which we know our data suggests is related to long-term positive outcomes. Wait, I want to make sure I understand, so you're saying the bad trip can be related to the transcendental experience? - Right, I think those are both speculating, but you have to pass through this sort of like, you know, reality shattering, including your sense of self, and one can handle that in one of two ways. You can either completely surrender to it, or you can try to hang on, and if you try to hang on, it's going to be more like a bad trip. So again, I wish there was more, and hopefully there will be more experimentation. There's a lot going on here in the black box in terms of the operant behavior of how you are, you know, within yourself choosing to handle like letting go, you know, and eventually we'll be able to see this in real time with brain imaging. Ah, they are surrendering to the psychedelic experience. Here they are trying to hold on, but we're not there yet. But I think it's a good clinical observation, seems pretty clear that something like that is going on. There has been an attempt at creating this movement toward openness about psychedelics and their positive effects. This has happened before. The difference is that now there are people like you inside the walls of the university or publishing peer reviewed studies and things of that sort. The question is to me, you know, what are the, what are the valuable exports, right? And where does the extreme lie? I mean, clearly there's a, there's a problem with tinkering with reality through pharmacology. And there's a benefit it sounds like to tinkering with a reality through pharmacology. And for the average person, right, or for kids that are hearing this, kids that are in their teens, right? What are the, I want to talk about what are the dangers of psychedelics? There's something you don't hear a lot about these days. And it's not because I'm anti-psychidoc at all, but what are the dangers? Yeah, so these can be profoundly destabilizing experiences and ones that, you know, ideally are, are had in a safe container, you know, sort of where, where someone, you know, what are the relevant dangers and what can we do to mitigate those? So there's two biggies. One, and I've already mentioned, it's people with very severe psychiatric illness, not, not depression, not anxiety. I'm talking about psychotic disorders like schizophrenia or mania as part of bipolar disorder. The far more likely danger is the bad trip. Anyone can have this, the most psychologically healthy person in the world, probably. Jack the dose high enough, and especially in a less than an ideal environment, you can have a bad trip. You even get it in an ideal environment like ours at a high dose of around 30 milligrams of psilocybin, after, you know, the best preparation we can provide about a third of people will say essentially at some point they have a bad trip. At some point within the entire journey. Right. Now they could have one of the most beautiful experiences that they're like sometimes like a couple minutes later, but at some point they had a sense of strong anxiety, fear, losing their mind, feeling trapped, something like that. I definitely want to ask you about microdose versus standard or macrodosing psilocybin. I'm micro cynical, if you will, about this term microdose. Is there any clinical evidence or peer-reviewed published evidence that it works, quote-unquote, to make people feel better about anything? The claims are, in their number of them, there's two general ones. One is sort of acting in place of the ADHD treating drugs, so the psychometer stimulants are like a better version of Adderall. The other claims are essentially a better version of the traditional antidepressants, a better version of Prozac. None of the peer-reviewed studies that have much credibility, none of them have shown a benefit. The handful of studies that have done that have shown they've ranged from finding no effect whatsoever to just a little bit of impairment, like impairing someone's ability to do time estimation and production tasks. You want an accurate sense of time, at least if you're navigating in the real world. It's different if you're on the couch on a heroic dose for therapeutic reasons where you're safe, but if you're crossing the street, if you're in your work life, which is the way people are claiming to use that to help some be a better CEO, like you want an accurate sense of time. So if anything, the data suggests that it makes it a little bit less accurate and there's evidence that someone feels a little bit impaired and they feel a little bit high. So in terms of, you know, you call that abuse liability in research. So far, no studies have shown an increase in creativity, enhancement of any form of cognition or a sustained improvement in mood. Now, no studies have actually looked at the system of microdosing that the aficionados are claiming. And folks like Paul Stamets and others, they'll have particular formulas. They're like, you need to take it one day and then take so many days off and take it every four days. They really say you need to be on it for a while, like a few weeks in, you may start to notice through this pattern of using it and you're feeling the benefits on those off days, like the three or two days in between your active doses. So those are the claims. Again, we don't know that there's any truth to that working, but studies have not been done to model that. So that's a big caveat. My bet is, and this is totally based on anecdotes, that I think there is probably a reality to the antidepressant effects. I find that more intriguing, because of the suffering with depression. Even if it's a, it wouldn't be as interesting as I think what we're doing with high dose psilocybin or psychedelics to treat depression. It would be, if this is developed in this reality, it would be more like a better, you know, perhaps a better SSRI, a better pro-ZAC, which are similar. Instead of being more tools than fewer tools in the toolbox. And it shouldn't be that surprise, like even before the, as going back to the tricyclics and the MAO inhibitors going back to the 50s, like augmenting extracellular serotonin in one way or another. For many people leads to a reduction in depressive symptoms. It wouldn't be that crazy for chronically stimulating a subtype of serotonin receptor that you have an antidepressant effect. So I think, if I put my bets on it, that there's, if there's anything real, it is in that category. Although I'm very open to, like, maybe there is something to the creativity to the improved cognition, which covers many domains in and of itself. But my greatest hopes are on the antidepressant effects. That said, in the big picture, I think all of the most interesting thing about psychedelics are the heroic doses. I mean, the idea you can give something, one, two, three times, and you see improvements in depression, months later, and in addiction, you know, over a year later, and with these, you know, people dealing with potentially terminal illness. I mean, it's, I mean, I'm interested in big effects. I want to make sure that I ask you about the other really important mission that you're involved in with respect to psychedelics, which is not about depression per se, but is about neurological, neurologic injury or head injury. You know, we always think sports, but there are many people who make a living in a way that is over time is detrimental to the brain. What do you think is the potential for these compounds, particular psilocybin, but other compounds as well, for the treatment and possible, even reversal of neurological injuries? There are anecdotes of people saying that that psychedelics have helped heal their brain. You know, they've been in one of these situations, like in sports, a sport where there's repetitive head impact, and they're claiming that, you know, using psychedelics has actually improved their cognitive function, for example, improved their memory. If you take these anecdotes and you combine it way across orders of analysis to the rodent research from several labs, like David Olson, Brian Roth, these folks that have shown different forms of neuroplasticity unfolding. Those effects may be at play in the psychiatric treatments that we're dealing with. We don't know that. It seems like a decent guess, and we're going to be figuring out whether that's the case. But another potential that that sets up is that maybe that's what's going on with these claims of improvements from neurological issues, that there's actually, you know, a repair of the brain from injuries underlying, you know, things that, you know, situations where those repetitive head impact. Perhaps there's a potential for helping folks recover from stroke and disorders like that. It is more exploratory. But what I'm hoping to do is some work with retired athletes who have been exposed, but by the nature of their sport, for example, in an A athletes in the UFC, who have been exposed to repetitive head impacts, like a lot of sports, a lot of, you know, sports exposed people to and who are retired from the sport and are suffering from, say, depression, which can, in part, result from those types of that history of head impact. See if we can fix the depression, but then also as a cherry on top in a more exploratory aim, see if we can have evidence of improvement in cognitive function and associate like using MRI, see if it affects great matter over time, these types of things to see if they're actually some evidence of this improved. Like this more direct repair of the brain, but again, it is very sort of like we've got some rodent data. We've got some human anecdotes. We will acknowledge its early days and we look forward to seeing the data. I appreciate how cautious you are. Intentative you are. You're not trying any conclusions. Thank you so much for your time, for your knowledge and I think you put it best earlier for holding the candle in a very dark time and then now there's light.