How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks

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 we are discussing psilocybin. Psilocybin is a psychedelic, meaning it modifies the psyche and in doing so it changes our level of consciousness. Psychedelics such as psilocybin change the way that we perceive the outside world and our internal world, our mind, memories, our thoughts, our feelings, et cetera, not just while one is under the influence of psilocybin, but it can also fundamentally change all of those things afterwards, and for a very long period of time afterwards as well. Which is one of the reasons why there's growing excitement about the application of psilocybin and other psychedelics for the treatment of various mental health issues such as depression, alcohol abuse disorder and addictions of various kinds, as well as things like OCD and eating disorders. Today we will discuss psilocybin. Toxic. Talking about what it is, in fact, you may be surprised to learn that psilocybin basically is serotonin. Now, for those of you that are familiar with psilocybin and serotonin, you might think, wait, that's not true. But in fact, psilocybin's main effect is to mimic serotonin, but it does it in a very specific way because it activates a subset of serotonin receptors in a very strong fashion, leading to neuroplasticity at the level of the neural circuits, that is the brain areas and connections that serve things like memory and perception. So if any of that is confusing at this point, I promise to make it all clear in just a few minutes. Psilocybin is one of many psychedelics. Of course, there are things like LSD, DMT, 5, MEO, DMT, even MDMA, while not considered a classic psychedelic, is considered a psychedelic in the general sense. Today's episode is going to focus on psilocybin in particular. I will tell you all what psilocybin is, how it works at the molecular and cellular level. I'll talk about how it changes brain circuitry. I'll talk about the clinical effects, what's been demonstrated in controlled laboratory studies. I'll talk about dosages and translating from psilocybin mushrooms to actual psilocybin and the compound that actually exerts the effects of psilocybin, which it turns out is not psilocybin, but something called psilocin. Psilocin is the actual compound that goes into the brain to create all the changes in consciousness and all the rewiring effects and that we associate with psilocybin. So understanding how psilocybin is converted to psilocin has tremendous impact on the duration of a psilocybin journey, whether or not that psilocybin journey is going to lead to a short or longer window for neuroplasticity. In fact, many people don't realize this, but much of the positive changes that are possible with proper, and I do want to underscore proper psilocybin therapeutic approaches takes place after the session in which one feels all the, you know, typical or typically associated effects of psilocybin, like hallucinations and changes in thought patterns, etc. So today we are going to talk a little bit about chemistry, but I promise to make it accessible to anyone and everyone, regardless of whether or not you have a background in chemistry or biology. We're going to talk about some cell biology, the actual neuronal changes that occur when one takes psilocybin. And we're going to talk about how neural circuits change over time and how all of that impacts the change that most people are interested in when they go on a psilocybin journey. Things such as long standing improvements in mood, things such as tremendous insight into themselves, into others, into their past, their present and their future, and even changes in their levels of creativity, or their ability to experience joy from music, or their ability to dissociate in a positive way from things that formerly were depressing or triggers for depression. In fact, we're going to talk quite a lot about the conditions inside of a psilocybin journey that make it actually positive and therapeutic. This is a very important point that I'll make several times throughout today's episode, which is that just because something invokes neuroplasticity, changes in brain circuitry does not mean that it's therapeutic. Or I should say, does not necessarily mean that it's therapeutic. For neuroplasticity to be therapeutic, it has to be adaptive. It has to allow someone to function better in life than they did previously. So today we will talk about how the conditions of a psilocybin journey, including whether or not it's done with eyes closed or eyes open, or whether or not people alternate between eyes closed and eyes open phases of that journey, as well as whether or not music is played during that journey, and even what types of music are played, will dictate whether or not somebody will feel better or worse in the days and weeks and years following that psilocybin journey, as well as the dosage level. Because as you'll soon learn as well, there are clinical studies showing that just one psilocybin journey can improve mood in a long standing way. But most clinical trials involve two dosages spaced in very precise ways from one another with appropriate follow up. But in both of those particular journeys, the structure of the journey, who's present, who's not present, eyes open or eyes closed, the particular music that's played, all of those features make up part of a larger neuroplasticity trigger of which psilocybin is critical. But psilocybin is not the only variable. So whether or not you're interested in participating in a clinical study or whether or not you're interested in psilocybin for other reasons, this is critical information to understand. So today we're going to talk about nearly every feature of psilocybin possible, including what psilocybin is, how it works at the level of chemistry, cell biology and neural networks, and neuroplasticity. We'll talk about the clinical studies, we'll talk about dosages, we will talk about conditions of clinical studies, and we will talk about the post psilocybin journey period in which neuroplasticity and the various activities, including therapy, or perhaps not therapy, can contribute to positive therapeutic changes from psilocybin. Now, as we go into this discussion, I do want to underscore the fact that at the time of recording this episode, meaning now, May 2023, psilocybin is still a Schedule 1 drug. It is considered illegal in the United States. There's perhaps just one exception to that, maybe a few others, but the main exception is in the state of Oregon, psilocybin has been approved in particular therapeutic settings for use in particular conditions, namely depression and some forms of addiction. So in Oregon, it's more or less in the domain of decriminalized, as opposed to actually legal in other areas of the country, including Oakland, California, there's some areas in which it has been decriminalized, and perhaps there are a few others that I'm not aware of. But in general, psilocybin and other psychedelics are still considered illegal. And this is very important, not just saying this to protect me, I'm saying this to protect you. Possessing or certainly selling psilocybin, except for rare instances such as clinical studies, and these decriminalized areas that I talked about a moment ago, is still very much not allowed under the law today. I'll also discuss safety issues. I'll talk about whether or not young people, meaning people 25 or younger, should consider psilocybin, given that their brain is still in a rampant period of naturally occurring neuroplasticity. I will also talk about dosages as it relates to people who have formerly been on or may currently be on different forms of antidepressants. And I will talk about people who are at risk for psychotic episodes, either because they know they themselves have a propensity for psychosis, or they have close family members who have psychosis, which includes things like schizophrenia, bipolar depression, as well as things like borderline personality and some related psychiatric conditions. So today's episode really will be a deep dive into psilocybin. So whether or not you think you're already familiar with psilocybin and its effects, or whether or not you're just curious about them, I do encourage if you're willing to try and ratchet through some of the understanding of how psilocybin works and what it is leading up to some of the therapeutic applications and different patterns of dosing, spacing of different sessions, et cetera. Because I do believe that with that knowledge in hand, you will be able to make far better, much more informed decisions about whether or not psilocybin is right for you. 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 eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating and sleep tracking capacity. Now sleep is the foundation of mental health, physical health and performance. Everything goes far better when we are sleeping well on a consistent basis. One of the key things to getting a great night's sleep is to make sure that the temperature of your sleeping environment is correct. 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I find that when taking ketone iq, even if I'm eating a standard omnivore diet, which is the diet that I follow by taking ketone IQ prior to workouts, sometimes on an empty stomach, and especially prior to doing any kind of cognitive work, so researching podcasts or doing work related to my lab or teaching, et cetera, that I can maintain mental clarity for a longer period of time. And it does seem to enhance my mental clarity as well. If you'd like to try Ketone IQ, you can go to hvmn.com and use the code HUBERMAN to get 20 off. Again, that's hvmn.comand use the code HUBERMAN to get 20 off. Let's talk about psilocybin. And again today we're going to focus specifically on psilocybin and we're going to set aside all the other psychedelics for future episodes. Psilocybin is what's called a tryptamine that refers to its chemical composition, not to the so called psychedelic trp. In fact, it's spelled differently. Triptamine is T R Y P Trip T R I P. Of course, tryptamines include psilocybin, but Also things like DMT and 5MEO. DMT. The tryptamine psychedelics very closely resemble serotonin itself. That's right, most of you have probably heard of the chemical serotonin. And serotonin is what's called a neuromodulator, which means your brain and body naturally make it, and that it modifies or changes the activity of other neurons and neural circuits. And it does that generally by either increasing or decreasing the activity of those neural circuits. If I were to show you a picture of the chemical structure of psilocybin or its active derivative psilocin, and I were to also put right alongside it an image of the chemical structure of serotonin, provided that you weren't a chemist who really likes to focus on the detailed differences between things. You would say those look very similar. And indeed psilocybin and its active form, psilocin, are very similar structurally and chemically to serotonin itself. Now, as I mentioned before, serotonin is something that you naturally make. And yes, it's true that about 90% of the serotonin in your brain and body is manufactured in your gut. However, contrary to popular belief, the serotonin in your brain is not manufactured from the serotonin in your gut. You have separate independent sources of serotonin. That is, you have particular neurons that make serotonin in your brain. You also have serotonin in your gut, and those work more or less in parallel, separately. Now, what does serotonin do? This is really important to understand because of the similarity between psilocybin and and its active form, psilocin and serotonin. Serotonin in that it's a neuromodulator, changes the activity of other neurons. And the net effects of those changes are things that you're familiar with. For instance, satiety, or the feeling that we've had enough of various things, Such as food, or a social interaction, or sex or pleasure of any kind. Serotonin is involved in all of that and an enormous number of other things, Such as mood regulation, Such as our sense of pleasure itself, or lack of pleasure, such as whether or not we feel motivated or not motivated. It works in concert with other neuromodulators, Such as dopamine and epinephrine and norepinephrine. In fact, if this were an episode about serotonin, which it is not. You would soon realize that serotonin is involved in so many different functions that impact our daily life. And that is one reason why certain antidepressant medications. Which alter, either increase or decrease the amount of serotonin transmission in the brain. Will often have a lot of side effects related to things like mood, libido, appetite, sleep, et cetera. It's because serotonin is involved in so many different things. And serotonin is involved in so many different things. Because there are a lot of different so called serotonin receptors. Serotonin is a chemical that we call a ligand. And the chemical ligand is simply the thing that plugs into the receptor for that chemical or ligand. The receptors, in this case serotonin receptors, have the opportunity to do all sorts of different things. They can change the activity of neurons, Making them more active or less active. They can cause growth factors to be released, Making sure that those neurons reinforce or even build up stronger connections. So that they're more likely to be active in the future. Serotonin binding to particular receptors can even change the gene expression in particular cells. Making those cells proliferate. So make more of them, making those cells more robust, Making those cells interact with new elements of the brain and body. Basically, serotonin and all these different receptors that it binds to. Has dozens, if not hundreds, and maybe even thousands of different functions. So the fact that psilocybin so closely resembles serotonin. Leads to a very important question that we should all be asking ourselves, which is, why is it that psilocybin, which looks so much like serotonin when one takes it in the form of magic mushrooms or some other form, maybe the synthetic form of psilocybin itself, which nowadays is manufactured in laboratories. And placed in different psilocybin containing foods and pills, et cetera why that leads to complex yet fairly circumscribed sets of experience like visual and auditory hallucinations, changes in particular thought patterns and neuroplasticity that in many cases in the clinical setting, provided things are done correctly, improvements in mood, relief from depression, relief from various compulsive disorders, et cetera. Right. This is really what you need to understand if you want to understand psilocybin and how it works and how to make it work optimally for a given condition or goal. You have to understand what it's actually doing and what allows psilocybin to do fairly specific things in comparison to serotonin, even though psilocybin and serotonin are so similar, is that psilocybin mainly binds to and activates the so called serotonin 2A receptor. The serotonin 2A receptor is one of again, many different serotonin receptors. But serotonin 2A is expressed in particular areas of the brain and even on particular areas of neurons in the brain that allow for very specific types of changes in neural circuitry to take place, not just when one is under the influence of psilocybin, but afterwards as well. So, really, in order to have a useful discussion about psilocybin, we need to talk a lot about the serotonin 2A receptor. But you know, fortunately for you, unless you're somebody really interested in structural biology or cell biology, that discussion is not going to be about the binding pocket for serotonin on serotonin 2A receptor or, or a lot of the downstream signaling of the serotonin 2A receptor. We'll talk a little bit about that where it's relevant. But more importantly, at least for sake of today's discussion, we're going to talk about how the serotonin 2A receptor is really the one responsible for triggering all the changes in neural circuitry that lead to the changes, that is the improvements in mood, the relief from compulsive disorders in many case. But really it's the serotonin 2A receptor selectivity of psilocybin that is leading to all the excitement that you hear about in terms of psilocybin as a therapeutic tool. Let me say that from a slightly different angle. There are data that I'll talk about today which show that one, although in most cases, two psilocybin journeys done with particular dosages of psilocybin lead to maximal binding or occupancy of those serotonin 2a receptors in ways that lead to significant and unprecedented relief for major depression. In fact, you'll soon learn that the clinical trials for psilocybin are outperforming standard therapy and outperforming so called SSRIs and various other antidepressants in terms of providing depression relief in ways that are frankly staggering, not just to me, but to the psychiatric community at large. And this is where so much of the excitement is coming from. Now, that statement could be taken one way, which is to just say, okay, well, here's a compound, psilocybin, that outperforms SSRIs and therefore all the attention should be on psilocybin. But SSRI stands for selective serotonin reuptake inhibitor. In other words, the SSRIs of which there's now a lot of controversy, things like Prozac, Zoloft, et cetera. I'm sure you've heard some of this controversy. There are people who are very pro SSRIs, although there are a growing number of people who really feel that the SSRIs are probably most appropriate for things like obsessive Compulsive Disorder, where they in fact can be very beneficial. But there's a lot of kind of leaning back from SSRIs as the be all end all for the treatment of depression nowadays because of the side effect profiles and the fact that it's not even really clear that serotonin deficiencies are the major cause of depression in the first place. Now, again, we're talking about psilocybin, not about SSRIs, but you should be thinking, wait, how is it that that two molecules, psilocybin and some particular ssri, both of which look like and or increase serotonin transmission in the brain, are leading to either incredibly positive and interesting outcomes or to kind of troubling side effect riddled outcomes. And again, it all boils back down to the selectivity of psilocybin to bind that serotonin 2A receptor. And so, in order to understand how psilocybin works, and in order to understand proper dosing profiles and spacing of sessions, AKA journeys, we really need to talk a little bit more about the serotonin 2A receptor, where it is in the brain, what sorts of things happen when psilocybin binds the serotonin 2A receptor and how those things set in motion the various changes, the neuroplasticity that allows people to feel better in terms of their mood, and as you'll soon learn, can experience more pleasure and joy from things like music and enhanced creativity. All the things that I do believe whether or not people are thinking about, or maybe even exploring psilocybin for recreational or therapeutic purposes, all the things that people want and are really talking about and perhaps even doing psilocybin in order to obtain. So before going any further, I just want to place an image in your mind. You can place an image in your mind whereby when serotonin is released in the brain naturally, not having taken any compound, any drug, anything, it's getting released at a lot of different sites, binding to a lot of different serotonin receptors, doing a lot of different things. When somebody takes an ssri, the net effect of that selective serotonin reuptake inhibitor is that there's more serotonin around to exert its effects. Because it's a reuptake inhibitor at the synapse, the connections between neurons, the serotonin can do its thing more extensively and for longer periods of time, but it's doing it kind of nonspecifically. So when you think about standard antidepressant treatments, at least for sake of this discussion, you kind of think of a sprinkling or a kind of, you know, spraying of serotonin at different locations in the brain and binding to lots of different receptors. Whereas when you think about psilocybin, even though the subjective effects are pretty diverse, we'll talk about those in a few moments. What you're really talking about is a molecule, psilocybin, that looks a lot like serotonin, that is selectively and very strongly binding to and activating that serotonin 2A receptor. So that's the image I'd like you to embed in your mind. And then the next image I'd like you to embed in your mind is where these serotonin 2a receptors are located in the brain. Now, the serotonin 2a receptors are located in multiple brain regions, but they have a tremendous amount of expression in the so called neocortex, the outside of the brain. That includes things like our prefrontal cortex, which is involved in understanding context, right? Which behaviors, thoughts and speech patterns are appropriate for certain circumstances. How to switch context and category switch. When you go from playing sports to hang out with friends to being in a professional setting, you change your behavior in the way that you speak and perhaps even the way that you think. You might think some things that are out of context, but you probably keep those to yourself, and your ability to keep those to yourself are dependent on a functional prefrontal cortex. There are a lot of 5ht 2a and by the way 5ht is the abbreviation for serotonin. So there are a lot of serotonin 2a receptors in the prefrontal cortex, also in other areas of the cortex that are associated with sensation and perception, that is hearing of sounds, that is seeing of particular things. And in particular, there is a very, very, very high expression of serotonin 2a receptors in the visual cortex. And that is one of the reasons why psilocybin triggers visual hallucinations. And provided psilocybin is present at sufficient enough concentration that is taken at a sufficient dosage, one will experience profound visual hallucinations regardless of whether or not their eyes are open or their eyes are closed. Now, that's an important fact because it explains one of the major effects of psilocybin that people experience while they are on the drug. Now, as I'll talk about a little bit later, in terms of what constitutes a useful psilocybin session, useful meaning that it's leading to adaptive improvements in mood, adaptive improvements in creativity and cognition, et cetera, is that people not have their eyes open for at least the majority of the psilocybin session. This is something I've discussed with several experts who are running clinical studies on psilocybin in their laboratories, some of whom are going to be guests on the Huberman Lab podcast in upcoming episodes. Again, I can't underscore this enough. Because your visual cortex contains so many of these serotonin 2a receptors, and because psilocybin binds so strongly to that serotonin 2A receptor, you're going to experience a lot of visual hallucinations when you are under the influence of psilocybin. There's no surprise there. This has been known for hundreds, if not thousands of years. It's one of the main reasons why people take psilocybin. However, as I mentioned earlier, these hallucinations occur even when the eyes are closed. And it's now fairly well established that if people are to take psilocybin and have their eyes open, much of their cognition, much of their thinking, much of the time spent in that psilocybin journey is focused on the altered perceptions of things in the outside environment. Sometimes this looks like a sort of a fracturing of the outside world into kind of geometric shapes. Sometimes it appears as a kind of melting of things in the visual environment, including people's faces or a morphing of people's faces. All of that has a strong. Let's just call it a draw. For a lot of people who are looking for a Highly unusual experience inside of the psilocybin journey. But I think if one's goal is to derive long lasting benefit from the psilocybin experience, it's very clear that having an eye mask or some other eye covering or something that ensures that one's eyes are closed for the majority, if not the entire psilocybin session is going to be very useful because it's going to limit the extent to which one is focused on those outside changes in visual perception, AKA hallucinations, and rather will allow the person to go inward to combine whatever it is that they happen to be seeing in their mind's eye with the different thoughts and memories and changes in their emotions that are occurring. And that going inward by staying in the eye mask, at least for the majority of the time, seems to be a very, if not the critical feature of making the psilocybin journey effective in the therapeutic sense. Now, once again, I want to cue to some of the safety precautions here. Going to say this at least three times throughout today's episode, as I'm talking now and various other times throughout today's episode, you may get the impression that I'm all for everybody doing psilocybin and that is simply not the case. In order for a psilocybin journey to be therapeutically useful, it does require certain conditions and supports and there are certain people for which psilocybin use is going to be contraindicated, meaning they should not do psilocybin in particular, people who have existing or have a predisposition to psychotic episodes or bipolar episodes. Even having a first relative who has bipolar or schizophrenic or schizotypal issues can be a rule out condition. That is can get someone eliminated from a clinical study on psilocybin for fear of triggering psychotic episodes, not just during the psilocybin journey, but potentially in a long standing way. So again, that's really critical. The other thing is that everything I'm talking about today, unless I say otherwise, is really focused on adults, meaning people who are 25 years old or older, that is their basic wiring and rewiring of the brain that we call developmental neuroplasticity is completed. All right? Most of the studies today that I'll talk about involve subjects ranging from 25 years of age out to about 70 years of age, but no one younger. So again, psilocybin and its use is certainly not for everybody. It's still illegal. It's being used in the clinical setting and research setting. There are these pockets of decriminalized areas and potentially soon legalization of psilocybin, but again, only in the proper clinical setting. Okay, again, I say that not just to protect myself, but I say that also to protect all of you. Psilocybin is a powerful, powerful drug, not just to be under the influence of, but also in terms of its long standing changes. After the effects of psilocybin have worn off, I'd like to take a quick break and acknowledge one of our sponsors, athletic Greens. Athletic greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, 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 usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, athletic greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road, in the car, on the plane, et cetera. And they'll give you a year's supply of vitamin D3K2. Again, that's athleticgreens.com Huberman. To get the five free travel packs and the year supply of vitamin D3K2, let's talk a little bit about dosing of psilocybin and also about microdosing of psilocybin. Now, this is an area that I wouldn't say is controversial, but that there's. How should we say this? There's a lot of loose thinking around this in the non clinical, non research communities, but within the clinical and research communities, there's a lot of data that's come out indicating what effective and safe doses provided all other things are considered safe, safe doses of psilocybin actually are. And here we really can go back to our discussion of psilocybin as quote, unquote, magic mushrooms or mushrooms. And if one were to translate from the mushroom form of psilocybin to the psilocybin that's actually used in various studies. Because, frankly, in these studies, people aren't eating mushrooms. They're typically taking synthetic psilocybin, either intravenously injected into a vein.