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

1. 0:00 – 8:32

   Psilocybin, Legal Considerations

   1. AHAndrew Huberman0:00

      (mellow 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, 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 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, 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, psilicibin'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 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 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 side effects of psilocybin, like hallucinations and changes in thought patterns, et cetera. 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 changes that most people are interested in when they go on a psilocybin journey. Things such as longstanding improvements in mood, things such as tremendous insight into themselves and to 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 longstanding 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 I 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. I'm 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, uh, 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. 'Cause 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

2. 8:32 – 12:00

   Sponsors: Eight Sleep, ROKA, HVMN

   1. AHAndrew Huberman8:32

      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. And 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. In fact, your body temperature has to drop by one to three degrees in order to fall asleep and stay deeply asleep, and waking up involves a heating up of your body by about one to three degrees. With Eight Sleep, you can program your mattress to be a specific temperature at the beginning, middle, and towards the end of your sleep night.Ever since I started sleeping on an Eight Sleep mattress, I've slept far better than I ever have. So it's an all-around great tool that has tremendous functionality, not just for measuring, but for improving your sleep. If you'd like to try Eight Sleep, you can go to EightSleep.com/Huberman and save $150 off their Pod 3 cover. Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, that's EightSleep.com/Huberman. Today's episode is also brought to us by ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. Now, I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order to make sure that you can see clearly under any conditions. ROKA understands all of that and has designed their eyeglasses and sunglasses so that regardless of whether or not you're in a very brightly lit area or a more shady area or you go from brightly lit to shady areas, you can always see with tremendous clarity. Now, even though they were initially designed for sport, ROKA eyeglasses and sunglasses come in a tremendous number of different aesthetics. So they have the kind of what I call cyborg versions that most people associate, uh, with triathlon glasses and sports-related glasses, but they also have a tremendous number of frames that you'd feel perfectly comfortable wearing to work or out to dinner, et cetera. If you'd like to try ROKA eyeglasses and sunglasses, you can go to ROKA, that's ROKA.com, and enter the code Huberman to save 20% off your first order. Again, that's ROKA, ROKA.com, and enter the code Huberman at checkout. Today's episode is also brought to us by HVMN Ketone IQ. Ketone IQ is a ketone supplement that increases blood ketones. Now, I know most people are familiar or at least have heard of the so-called ketogenic diet, which is essentially a very low-carbohydrate diet. It's designed to get your brain and body functioning off ketones, which are a great source of fuel for the body and brain. However, most people, including myself, are not ketogenic, that is, I'm not in a ketosis state, pretty much ever as far as I know. Nonetheless, with Ketone IQ, you can increase your blood ketones and thereby improve things like cognition and physical performance. 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 HVMN.com and use the code Huberman to get 20% off. Again, that's HVMN.com and use the code Huberman to get 20% off. Let's

3. 12:00 – 17:00

   Psilocybin Becomes Psilocin in the Gut, Serotonin

   1. AHAndrew Huberman12:00

      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 trip. In fact, it's spelled differently. Tryptamine is T-R-Y-P, trip, T-R-I-P, of course. Tryptamines include psilocybin, but also things like DMT and 5-MeO-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 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, uh, 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, uh, 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

4. 17:00 – 21:40

   The Serotonin 2A Receptor, Therapeutic Outcomes SSRIs vs. Psilocybin

   1. AHAndrew Huberman17:00

      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 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 is a lot of, um, 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 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 to a 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.

5. 21:40 – 27:21

   Serotonin Receptor Expression; Visual Hallucinations & Eyes Closed

   1. AHAndrew Huberman21:40

      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 non-specifically. 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, um, 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, you know, speech patterns are, uh, appropriate for certain circumstances, um, how to switch context and category switch when you go from, you know, playing sports to hanging out with friends to being in a professional setting. You change your behavior and 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 5-HT2A, and by the way, 5-HT 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, um, sort of a fracturing of the outside world into kind of, um, 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 just call it a draw for a lot of people who are looking for a highly unusual experience inside of, uh, 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

6. 27:21 – 29:13

   Safety & Cautions for Specific Patient Populations

   1. AHAndrew Huberman27:21

      sense. Now, once again, I want to cue to some of the safety precautions here. I'm 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 longstanding 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 longstanding changes after the effects of psilocybin have

7. 29:13 – 30:28

   Sponsor: AG1 (Athletic Greens)

   1. AHAndrew Huberman29:13

      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 in 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 D3 K2. Again, that's athleticgreens.com/huberman to get the five free travel packs and the year's supply of vitamin D3 K2.

8. 30:28 – 36:21

   Psilocybin, “Magic Mushrooms” Dosing, Micro-Dosing, “Heroic Doses”

   1. AHAndrew Huberman30:28

      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 a, how should we say this? There's a lot of, um, 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, or orally, and that's how the researchers are able to tightly control the amount of psilocybin. And the typical dosage that's used in clinical studies ranges from one milligram, often given repeatedly from day to day over long periods of time, so-called microdosing, and really, that one milligram per day or even up to three milligrams per day repeatedly over time is what people generally think of as microdosing, as compared to, say, a 10-milligram dose given once, maybe twice in two separate sessions, or a 25 to 30 milligram dosage that's given once or twice. Now, those amounts of one to three milligrams or 10 milligrams or 25 to 30 milligrams might not mean much to those of you that don't think about these things in the research terms. Perhaps you've heard of microdosing and you've also heard of macro or, quote unquote, heroic dosing, okay? That's sort of a common, uh, or I should say, popular nomenclature for psychedelics, and I'll circle back to that in a few minutes. But I think one of the questions that I hear a lot is how much psilocybin is present in a given amount of mushrooms, and so the way this typically works is that mushrooms are often discussed in terms of grams or ounces, so an eighth of mushrooms refers to an eighth of an ounce of mushrooms, or X number of grams of mushrooms. The breakdown is actually quite simple. One thousand milligrams equals one gram, and the concentration of psilocybin in most so-called magic mushrooms is about one percent. So one gram of mushrooms, being 1,000 milligrams, means that it contains approximately, and again, it's approximately, 10 milligrams of psilocybin. And in most of the clinical studies, it's been shown that the dosage of 25 to 30 milligrams given, or I should say, taken once or twice, and we'll talk about the spacing of sessions a little bit later, taken once or twice is what's leading to the most pronounced therapeutic outcomes. But of course, with enhanced therapeutic outcomes, one also observes enhanced side effect profiles, or what are called adverse events. So there's an important nuanced conversation that has to take place, but right now, we're talking about the conversion of grams of mushrooms to psilocybin. So one gram of mushrooms, being 1,000 milligrams, containing one percent psilocybin means that it contains 10 milligrams of psilocybin. Now, the so-called heroic doses that you've heard about, and this is something that's discussed more with the, uh, let's call them traditional or classic psychonauts. These are people that may have an advanced degree, but typically are not running laboratories exploring the effects of psilocybin in controlled clinical trials. These are people who, um, have been longtime explorers and often writers and, um, people who have been spokespeople for psilocybin and other psychedelics, and they will often refer to the so-called heroic doses. It's a little bit hard to translate from that informal community to the scientific data, but in discussing that topic with various researchers who run laboratories at major universities focused on psychedelic therapies, what I was told is that the, quote unquote, heroic dose that's often discussed really refers to a five-gram or so dose of mushrooms. So what that translates to is 50 milligrams of psilocybin. So when you hear someone talk about a, quote unquote, heroic dose, they're probably referring to ingestion of 50 milligrams or so of psilocybin, but in its mushroom form, so about five grams of mushrooms. And again, it's important to point out that the concentration of psilocybin in different strains of mushrooms and in different batches and depending on the age of those mushrooms and how they've been stored, et cetera, can vary tremendously from batch to batch. In fact, there are some laboratories that have explored the range of psilocybin concentration in different mushroom strains and different so-called magic mushrooms, and that range is pretty broad. It's anywhere from a half percent all the way up to two percent. What that means is that someone might get ahold of one gram of mushrooms thinking that they're taking 10 milligrams of psilocybin in those mushrooms when, in fact, they're actually taking 20. Or somebody could take three grams of mushrooms thinking they're taking 30 grams of psilocybin and, in fact, they're only taking 10 or 15 milligrams of psilocybin. So the sourcing is really key, uh, obviously, as things become more legal and more regulated and more used in the therapeutic setting, or, and this is what's happening more and more, or as people start to rely on synthetically made psilocybin as opposed to using mushrooms to ingest psilocybin, then certainly the dosaging is going to be more consistent from batch to batch because we're not talking about batches of mushrooms, we're talking about batches of psilocybin itself.

9. 36:21 – 43:43

   Psychedelic Journey: Set, Setting & Support

   1. AHAndrew Huberman36:21

      So now I'd like to take a step back from all this chemistry and cell biology and talk a little bit about the structure of a psilocybin journey itself and relate that to what we now know about what's happening in the brain during the psilocybin journey. And then a little bit later, we will return to that serotonin 2A receptor when we talk about some of the more lasting changes in brain chemistry and brain wiring that occur after the psilocybin journey is over. So let's take a couple of minutes and just discuss the various components of an effective therapeutic psilocybin journey, and here I'm not detailing a menu of things that people should do in order to pretend that they are a psilocybin-assisted therapy coach or, uh, to do self-administered psilocybin therapy. That is not what I'm doing. What I am trying to do is to share with you the consistent components that are present in the clinical trials that have demonstrated the effectiveness of psilocybin for the treatment of depression and for other compulsive and addictive disorders.... and those data, meaning the specific data related to those trials and the references themselves, we'll get into a little bit later. But we can't really have a conversation about psilocybin and what it does without talking about the so-called set and setting, as it's often referred to, that is known to at least bias the probability of the journey being beneficial and not a so-called bad trip. So what are the variables that make up an effective and safe psilocybin journey? And, again, when we say safe, we're referring to people who are not prone to psychotic episodes, that don't even have a first relative that's prone to psychotic episodes. We're talking about people that are 25 years or older. We're talking about people that, for instance, are not taking antidepressants that impact the serotonin system. This is very important to understand. I think a lot of people don't know this. But as far as I know, all of the studies that have explored psilocybin for its ability to positively impact brain chemistry and mood and function have required that people either not be on or abstain from antidepressants in the weeks leading up to the psilocybin journey. Now, that is not to say that if you are currently taking SSRIs or something similar that you should cease taking them and do psilocybin. I am absolutely not saying that. That could be very, very, very dangerous, if not catastrophic. Uh, any time you're going to take anything or stop taking anything for that matter, you do need to consult with your physician, in this case a psychiatrist as well. So let's talk about psilocybin journeys from the subjective side and from the structural side, and when I say the structural side, what I mean is, what does a psychedelic journey actually include? And here the words set and setting become extremely important. Some of you may have heard that set and setting are the foundation of a well-done or even therapeutically beneficial psychedelic journey, and all of that really hinges on safety and outcomes. So set refers to mindset, the mindset of the person taking the psychedelic, and setting refers to, as the name suggests, the setting in which they're taking it in and the people that are present there. So let's talk about setting first. The setting for a psychedelic journey needs to be one in which the person under the influence of the psilocybin or other psychedelic is safe. That means no windows they can jump out of. That means no streets of moving cars they can run out into. That means no opportunity for getting lost. That means no opportunity for getting into bodies of water. In other words, it requires that there be at least one, and perhaps even two or more, other individuals who are not also taking psychedelics, right, who are not also (laughs) taking psychedelics, present, uh, in that setting to ensure that the person taking the psilocybin is not going to harm themselves or others. And I say this not to sound like a schoolteacher, even though technically I'm a schoolteacher, but because, of course, I don't want anyone to get harmed. And I'm also aware that there's a lot of interest nowadays in psychedelics, such as psilocybin, becoming legal or decriminalized for their therapeutic applications, and if we look back to the late 1960s and early 1970s when the Controlled Substances Act was invoked to make psychedelics like psilocybin illegal, one of the bases for that was not just the geopolitical unrest at the time and things like the Vietnam War, but also some highlighted instances in which people did not take set and setting into consideration, took things like LSD, stared at the sun, went blind, or took psilocybin, went out, and harmed somebody else. Again, these are very, very isolated instances, but these are the exact sort of instances that lead to criminalization or the fact that things like psilocybin and LSD, and MDMA for that matter, are considered illegal. Again, I completely acknowledge that there are a number of different factors making them illegal. We could have a whole discussion about that. Um, you know, we talk about the drug trade, the war on drugs. But right now is such a critical time in the history and the use of psychedelics for therapeutic and other reasons, and getting setting correct, meaning making it absolutely as safe as possible for the person taking the psychedelic, is absolutely key. And one of the best ways to ensure that it's safe is to have responsible individuals who are not under the influence of psychedelics present in that environment. So that's one component of setting. The other component of setting that we talked about earlier, which turns out to be very important, is the opportunity and perhaps even the bias toward the person on the psychedelic being seated or ideally lying down and being in the eye mask, or at least having their eyes covered so that they can combine any spontaneous visual hallucinations that occur with the various thought processes that are occurring while under the influence of psychedelics. This is far and away different than, quote-unquote, "taking mushrooms and going into the woods" or "taking mushrooms and going to the beach." What we're talking about today is the use of psychedelics for particular brain-rewiring outcomes that, yes, can involve things like changing one's relationship to nature, or changing one's relationship to somebody else by interacting with nature or somebody else. And while I'm not trying to diminish the potential value of those sorts of psychedelic journeys, if we look at the scientific data, the vast majority of it, not just in the clinical setting but in terms of understanding the safety and efficacy and positive rewiring of brain circuitry that allows people to feel better, to understand themselves better, and to interact with life in more adaptive ways going forward out of the psychedelic journey, involve these very, I- uh, let's say, um, you know, subdued settings that, uh, are typically in one room, a closed environment, with one or two other individuals acting as sort of guides or, um, helping the individual, um, by talking to them from time to time if they feel like they have to sort through a particular aspect of the psychedelic journey that's creating anxiety. And we'll talk about the contour of the psychedelic journey that almost everyone who takes psilocybin at somewhere between 20 and 30 milligram dosages, um, tends to experience. But the setting that I'm describing is not just a list of things to, you know, make sure you're safe, but they're really the list of things that also ensure that one can get the maximum benefit out of the psilocybin journey.

10. 43:43 – 48:58

    Music & the Psilocybin Journey; Duration of Effects

    1. AHAndrew Huberman43:43

       Now, other things included in setting that are known, again, from scientific literature to be very influential in terms of the experience that one has and to bias things towards a positive experience are...... again, safety eye mask, but also the presence of music. Now, when I first heard about this from one of the premier researchers on psilocybin and other psychedelics, which is Robin Carhart-Harris, he's a professor at University of California, San Francisco, who's one of the major pioneers in the studies of psychedelics. And when he first started telling me about the critical role that music plays, I thought, "Okay, that makes sense." You know, um, music can impact our emotion, impact, um, the way that we think, um, and could therefore impact, uh, what one experiences during the psychedelic journey. But he really underscored for me the extent to which music is not just a, um, sort of incidental feature of the setting in psychedelic set and setting, but that it is one of the, but that it is one of the major drivers of the actual cognitive and emotional experience that somebody has on something like psilocybin that allows the psilocybin journey to be looked at or viewed not just as beneficial, but, and this is quoted in the scientific literature as, "One of the most profound and important positive experiences that one ever experienced in their life." So let's talk about the sorts of music that have been used in these clinical studies. Well, first of all, we need to think about how long the psilocybin journey itself is going to be, and the typical duration of the psilocybin journey is anywhere from four to six hours. It's going to depend somewhat on dose, it's going to depend somewhat on variability in people's, um, liver metabolism, and it's also going to depend somewhat on how much food people have in their gut. In all the clinical studies that I read, it was advised that people not have any food in their gut at the time at which they ingest or are injected with the psilocybin. It's particularly true if people are going to be taking psilocybin mushrooms in order to get their psilocybin, and that has been done in a few studies. Uh, most studies, however, use synthetic psilocybin taken orally. Again, that's converted to psilocin in the gut by the acidity of the gut, and the acidity of the gut is going to be impacted by the various foods that people eat. And so that's one of the major reasons why people are advised to not eat for at least four hours prior to the psilocybin journey. So here we've got this six-hour, what we're calling journey, 'cause that's what everyone calls it, or trip, that people start experiencing about 30 to 45 minutes after ingesting psilocybin or taking psilocybin. There's a peak component in which there's a maximal intensity of emotion and often it's also associated with anxiety, and this is very important to understand. The anxiety component is part of what in the therapeutic setting they refer to as ego dissolution and that anxiety around the peak, and I think most people would probably hear peak experience and think, "Oh, we're talking about a peak positive experience." But no, we are referring to a peak experience in anxiety that people stay with and then come down from gradually as one goes from the second or third hour after taking psilocybin, and that tapers off slowly toward the six-hour mark, what sometimes people refer to as parachuting back in. Of course, um, they're not, hopefully, I would very much hope people aren't actually parachuting back in while on psilocybin, but I think you get the idea. The music that's typically played in the clinical studies using psilocybin for the treatment of depression or for compulsive disorders or addiction tends to have a particular contour that matches with and can also drive that contour of the psilocybin journey that I just described. Again, we're talking about people wearing an eye mask with guides present, so people who are not taking psilocybin, there as well to ensure that the person feels supported and is safe. The person is typically lying down, sometimes sitting down, but more often than not lying down wearing an eye mask, and the music that's played at the beginning of the psilocybin session tends to be music that doesn't have a lot of vocalizations, it tends to be things like classical music, it tends to be fairly low volume, but th- then transitions into music that has a lot of percussion, so often drums, that tends to be higher volume, that has a lot of intensity at about the time that one would be experiencing the peak in emotion and in perception, the so-called peak of the journey. That intense music tends to be played for about 45 minutes to 90 minutes, depending on the study one looks at, and then tends to transition into softer music again, sometimes choral-type or more melodic music, often female voices in particular, and then transition into nature sounds and things that more or less mimic the outside natural world and less so, um, synthetic things like drums or instruments and vocalizations and things of that sort.

11. 48:58 – 58:36

    Psilocybin & the Brain: Subjective Experiences, Perception

    1. AHAndrew Huberman48:58

       So why would it be so important that music match and even contribute to the subjective experience that people have on psychedelics? And here we should probably take a couple of moments and just talk about what those subjective experiences are like. So for people that haven't done psilocybin or any psychedelics, it's a little hard to describe, but one way to describe it is that there's a lot of so-called perceptual blending. So for instance, uh, people in the eye mask will report seeing some geometric shapes and colors, but perhaps the music they're listening to will then start to change the intensity or the movement of whatever it is that they're seeing, hallucinating inside of the eye mask, in ways that are linked. This is referred to as synesthesia or the merging of different senses that are not ordinarily merged.In addition, people under the influence of psilocybin, or other psychedelics for that matter, often will report that their pattern of breathing becomes linked to the perceptions of things that they are hearing or seeing or feeling. So for instance, if they take a big deep breath in and then a long exhale out, they may find that during the long exhale out, that the notes of music that they're hearing in those moments are also drawn out for the duration of the breath. Then they'll inhale and that they're getting at least what they perceive as control over the music, which of course they are not actually controlling, by using their breath, and that perhaps their visual perceptions are also being merged with that. So those are just a couple of examples of how perceptual blending, AKA synesthesia, can occur while under the influence of psilocybin, and this really is highly individual from one person to the next. Some people, for instance, will find that if they take their fingertips and, you know, rub them across the couch or the chair that they happen to be lying down or sitting on, that they will experience a change in the music, um, maybe even if they, you know, they move their hand up, they hear an increase in frequency of sound. They move their hand down, they hear a decrease in frequency of sound, and that all of this is linked to their emotional state at the same time and vice versa. Okay, so we're talking about a lot of perceptual and emotional blending and some sense of control over one's perceptions and emotions in a way that's very unordinary, even extraordinary. Now, we can step back from all of this, uh, very subjective description of the psychedelic journey and ask, "What is going on that would allow these sorts of things to occur?" And there you are already equipped with an understanding of the cell biology and the chemistry that makes all of this possible, and that is that when psilocybin is ingested and then converted to psilocin, it's the psilocin that crosses the blood-brain barrier, and then even though psilocin looks a lot like serotonin, psilocin has this incredible ability to predominantly activate the serotonin 2A receptor. Well, we can understand much of what's happening at a subjective level during the psychedelic journey, even right down to the sorts of emotions and perceptual blending, the synesthesia. We can understand a lot of that by understanding where the serotonin 2A receptors are expressed on neurons and what those particular neurons are doing. And the simplest way to describe this is that there's a category of neurons that we call pyramidal neurons. Pyramidal neurons are found lots of places in the brain, but they're called pyramidal neurons 'cause they're sort of shaped like a pyramid. They have a cell body, which is the part of the cell that has the DNA in it, and a lot of other important, uh, things like the organelles, mitochondria, et cetera, and then they also have what are called dendrites. Dendrites are the little branches or processes that reach out both from the bottom of these cells and then these pyramidal cells are interesting because they also grow a branch up, up, up, up, up into layers of neural tissue above them, and they have what's called an apical branch. That's the part that grows up, and then they fan out at the top, and that fanning out at the top allows them to communicate with other neurons in their environment. Okay, so if you're not getting a good picture of this in your mind from my description, I apologize, but simply think about putting your arms out to the side, and by doing that, you're able to interact with things that are some distance from your body. Sort of an obvious thing in that case. These cells are effectively doing the same thing by extending little processes out into layers above them and to the sides, and this is really important because much of the serotonin 2A receptors that are present on neurons in the brain are present in those apical dendrites, those branches of these pyramidal neurons that are above and that extend out to the side of those neurons. And so when somebody is under the influence of psilocybin, that means that psilocin has bound to the receptors on those apical dendrites, and it's increasing lateral communication across brain areas. In fact, this is perhaps one of the most well-documented effects of psilocybin and other psychedelics, which is that there's a shift from the brain being more modular, meaning more segmented, like auditory neurons are communicating electrically and chemically largely with other auditory neurons. Of course, they'll communicate with other types of neurons too, right? When I hear something off to my right, you know, like (snaps fingers) a snap of the fingers off to the right, I'll turn my head and the, my ability to do that depends on my auditory neurons being linked up with things like my motor system and my visual system. But the key thing to understand is that when there is psilocybin present in one's system, that the communication of any of these pyramidal neurons, the ones involved in hearing, the ones involved in thinking, the ones involved in memory, the ones involved in visual perception or in the generation of visual hallucinations with eyes closed, those are all talking to many, many more other neurons more extensively. So what happens effectively is that there's a reduction in the modularity, the separateness of function in the brain, and an increase in what's called integration of communication across what would otherwise be disparate brain regions. We can say that really simply by saying psilocybin increases communication across the brain. Now, in addition to that, there's a reduction in what's called the hierarchical organization of the brain. Typically, sensory information comes in from the outside environment. So we hear something, we see something, we taste something, we smell something, and in what's called bottom up fashion, meaning bottom from the periphery up, meaning it propagates up through the eyes, through the nose, through the ears, through the skin or the senses in those regions I should say, up into areas of the brain that sit deep to the cortex, like the thalamus, and then the thalamus is sort of a way station. It's like a switchboard that sends visual stuff to the visual centers and auditory stuff to the auditory centers and touch stuff to the touch centers and...... things that, uh, maybe trigger a memory off to the memory centers of the brain, et cetera. That's the typical organization. It's hierarchical because it goes from the periphery up to the more complex processing regions of the brain that make decisions, that, uh, link all of that stuff to prior experience, maybe plans about the future. When psilocybin is present in the system, there's a broadening of the flow of that information from the bottom up as well, okay? And that has to do with what's called thalamic gating. The thalamus is a very interesting structure, we probably don't want to go into it in too much detail right now, but it really is like a switchboard and a waystation saying, "Hey pay attention to the visual stuff. Um, pay attention to the auditory stuff. Or just to the visual and auditory stuff and ignore, um, you know, touch sensation for the time being, or vice versa." When psilocybin is present in the system and when serotonin 2A receptors are activated very strongly, there's a tremendous broadening of the flow of information up and through the thalamus. So, not only is there more communication of so-called higher order brain centers, we refer to them as higher order because they're involved in thinking and decision making and emotion, et cetera, but there's also a shift in the flow of sensory information into the brain that can generally be described as broader and including more blending of the different senses. And when I say blending of the senses, I'm also referring to blending of the sense of interoception, of our sense of our body and what's happening inside of our body. And this, without question, at least partially explains why, when under the influence of psilocybin, one's breathing can be linked to a sound and then suddenly the sound one thinks is being controlled by one's breathing or that the sound itself can be linked to something that we see in our mind's eye while in the eye mask. Essentially what I'm describing here is that serotonin 2A receptor activation allows for more broad, less precise, and less hierarchical activation of brain circuitry. And when I say hierarchical, what I mean is that normally things go from periphery, from eyes to thalamus to visual cortex. However, when under the influence of psilocybin, as I mentioned before, even in the eye mask, the visual cortex is going to be very activated even in the absence of any visual input. So then if one hears a sound, perhaps from music, a particular motif or voice, and that's linked to a particular emotional state, that is now being blended with visual phenomenon occurring within the brain that have no external stimulus. And so while the patterns of activation in the brain while under the influence of psilocybin aren't random, they are far less channeled, far less modular, and far less hierarchical than would ever be the case when not under the influence of psilocybin.

12. 58:36 – 59:48

    Sponsor: LMNT

    1. AHAndrew Huberman58:36

       I'd like to just take a brief break and thank one of our sponsors, which is LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means plenty of salt, sodium, magnesium, and potassium, the so-called electrolytes, and no sugar. Now, salt, magnesium, and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. LMNT contains a science-backed electrolyte ratio of 1,000 milligrams, that's one gram, of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink LMNT first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes and while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot. And certainly I drink LMNT in my water when I'm in the sauna and after going in the sauna because that causes quite a lot of sweating. If you'd like to try LMNT, you can go to Drink LMNT, that's lmnt.com/huberman to claim a free LMNT sample pack with your purchase. Again, that's Drink LMNT, lmnt.com/huberman.

13. 59:48 – 1:05:23

    Brain Networks & Therapeutic Outcomes

    1. AHAndrew Huberman59:48

       Now in all fairness to the scientific literature, there are not one, not two, not three, but four prominent theories of which brain networks are most activated during a psilocybin or other psychedelic journey. And so for those of you that are interested in those different models, first of all, please know that they are not competing models. While some of them disagree about some of the details, it's very likely that all of these models are true. They include things like changes in the so-called default mode network. There's a lot of interest in this, I've talked about it before on this podcast. The default mode network is the network in the brain that's thought to be responsible for spontaneous imagination, for daydreaming, and that reflects sort of the base activation state of the brain when there's no drugs in our system. And the default mode network is one of the systems, or networks rather, that is thought to be rewired under conditions of psilocybin or other psychedelics. Again, if you're interested in these models and comparing and contrasting them, there's a very nice review from Brian Roth's lab at Duke, um, entitled The Neural Basis of Psychedelic Action. We'll provide a link to this in the show note captions. And, again, I just want to emphasize that all of these models have been shown to be true in different studies, and what they all point to is more extensive communication between areas of the brain that normally are not as active at the same time while under the influence of psychedelics such as psilocybin. The controversy in the field relates to which of these networks is the one that changes the most to explain the therapeutic outcomes that have been discovered in recent years. So again, check out that review if you're interested in that sort of thing. In the meantime, we can cut a broad swath through all of those models and just say that psilocybin expands the functional connectivity of the brain while one is under the influence of psilocybin, and it does seem that some of that expanded functional connectivity persists after the effects of psilocybin have worn off. And that statement about the functional connectivity of the brain being more expanded, not just during the psilocybin session but after as well, has been substantiated in a number of papers. But one of the key papers in this area is one that I recommend people check out if they're interested in this sort of thing. It's entitled The Effects of Psilocybin and MDMA on Between-Network Resting-State Functional Connectivity in Healthy Volunteers, and I like this paper for a number of reasons. First of all, it's a very high quality paper carried out in the laboratory of Robin Carhart-Harris at UCSF. Again, one of the premier researchers in this area of psychedelics and their...... function, what they do in the brain, and also their therapeutic applications. But also because it focused on healthy volunteers. They explored using brain imaging what brain areas are active in a resting state, so things like default mode network. Then they had people take psilocybin or MDMA, and then they looked at the connectivity between those brain areas in those same individuals when they were not under the influence of these drugs and found more extensive connectivity. All of which pointed to an enhanced lateral connectivity, less hierarchical organization, effectively more interconnection and communication between different brain areas. I think not only is the fact that they looked at healthy volunteers very interesting and important, but also that they looked at this resting state of the brain. They weren't providing a particular auditory or visual stimulus for people to hear or look at while they were in the brain imaging scanner, as it's called. Rather, they were simply looking at how the brain was behaving at rest. And so, it's very clear that for people that do two or even just one of these psilocybin journeys at a particular dose, that the brain is actually getting rewired. You know, we hear this a lot. Psilocybin or other psychedelics lead to plasticity. They rewire your brain. Well, let's go back to what we said at the beginning. Rewiring of the brain is not the goal. Adaptive rewiring of the brain is the goal, right? Rewiring that leads to new ideas that are interesting, that are accessible after the psychedelic journey. New ideas and new ways of thinking or feeling that allow people to function better in their lives. Th- that's the goal of effective psychedelic therapies, not simply rewiring of the brain. You know, a brain injury, for that matter, will lead to rewiring of the brain, but that's maladaptive rewiring. The use of things like amphetamines or methamphetamines, in particular, will lead to rewiring of the brain. But that is strongly maladaptive rewiring. So now, there are really dozens of studies conducted in humans using brain imaging and other techniques, have evaluated how things like psilocybin change connectivity in the brain. And I think the take-home message is it expands that connectivity. However, it seems to do so in ways that still allow people to function in their daily lives. And one of the key things that I gleaned from the literature on the therapeutic use of psilocybin for the treatment of depression is that very seldom do people who take psilocybin experience long-term issues with memory. Why is that so critical? Well, you could imagine that increasing connectivity in the brain, reducing modularity, reducing hierarchical organization of the brain would lead to disruptions in memory, right? It's as if you're shuffling books on the bookshelf, so to speak. But that doesn't seem to be the case. Rather, it seems that the increase in connectivity is leading, provided set and setting are correct, provided safety protocols are followed, to positive rewiring or adaptive rewiring of neural tissue. So that's one of the things that makes psychedelics and psilocybin, in particular, very exciting from the therapeutic standpoint. And of course, we have to acknowledge this also has a lot of people excited about psychedelics, not just for the treatment of depression, but for expanding the brain's capabilities more

14. 1:05:23 – 1:12:39

    Creativity; Music, Emotionality & Psychedelic Journeys

    1. AHAndrew Huberman1:05:23

       generally. So along those lines, I want to touch on the issues of creativity and the experience of life outside of psychedelic journeys as impacted by psychedelic journeys. And here, this relates to a question that I heard a lot when I put the call out on social media that I was going to do this episode, and I asked people, "What do you want to know about psilocybin?" And one of the more common questions that I got was, "Does it increase creativity? Does it increase our experience of life in ways that are beneficial, aside from its now documented positive effects in treating depression and compulsive disorders and addiction?" And the short answer to this is yes, but that the positive effects of psychedelics, psilocybin in particular, on creativity and our experience of life have only been explored in a fairly narrow set of dimensions. However, where it's been explored, there's some really interesting findings. So one of the more interesting findings, I think, is a paper entitled Increased Low-Frequency Brain Responses To Music After Psilocybin Therapy For Depression. I think this is a really interesting paper, because what the authors did is they took advantage of the fact that in these therapeutic psilocybin sessions that were carried out for the treatment of depression, music is being played, and there are prior studies showing that when music is played, you activate different brain areas depending on what sort of music is being played. It's somewhat obvious perhaps, you know, sad music versus, you know, intense, um, you know, if you think about heavy metal versus, um, choir music versus Gregorian chants versus, uh, punk rock music, and on and on. It makes sense that different brain areas would be activated when different patterns of music are played. However, there do seem to be some universal features of brain activation in response to music. This should probably be the topic of an entire episode of the Huberman Lab Podcast, and indeed it will be. For instance, there are areas of the auditory cortex that are activated, no surprise there, and areas of the brain's reward circuitry, the so-called ventral striatum and the so-called mesolimbic reward pathway. Talked a lot about these in the episodes about dopamine that I've done previously. These are brain areas that lead to the release of dopamine in other brain areas and that reinforce certain experiences and that tend to give us the subjective feeling of, "Yes, I like this. I want more." So in this particular paper, what the authors did is they took advantage of the fact that people are in the clinic, they're on psilocybin, they're listening to music, and as you recall, the music played at different stages of the psilocybin journey are different. They have a different emotional component, and music is a really nice stimulus in the laboratory, as we say, because like with visual stimuli, you can break it down into high frequency, low frequency, all right? Sounds like doom-doom or ah-ah. These kinds of things. That was my attempt at low frequency versus high frequency, um, auditory stimuli. Or at the spatial frequency, or what in the auditory domain would be called the temporal frequency. Is it boom, boom?... boom, or is it boom, boom, boom, boom? All we've changed there is the temporal frequency. The sound was somewhat the same, but the distance between those sounds was different. You get the idea. So they have access to these people and these different conditions, and they can put them in the brain scanner. And they can do that before and after having taken psilocybin. And, the long and short of this study is that psilocybin changes one's experience of music, not just during the psilocybin journey itself, but thereafter. And in fact, it changes one's emotional response to music in very interesting ways. For instance, one of the more common features of major depression is that people don't derive as much pleasure from different types of experiences, whether or not it's food or sex or social experiences, to the point where sometimes they just stop trying to seek out those experiences. People with depression often feel as if music no longer has the same impact. It just doesn't really lift them up very much. This study found that people who have taken psilocybin, according to the parameters we talked about earlier, can get a return of the elevated emotionality, the positive emotions associated with music that formerly made them feel good. Th- in other words, they can feel music again. They can feel good in response to music again. Now, this is interesting because, in theory, it could be that psilocybin simply allowed them to access the emotions around music again more generally, but that's actually not what this paper and some other papers that have been published report. Rather, it seems that taking psilocybin can increase one's positive perception of music that one likes and can tone down or reduce the depressiveness or the sadness of music that tends to make one sad, even after the psilocybin has worn off and for a long period of time afterwards, maybe even forever. Although, no study, of course, can be carried out forever because forever is forever. What we do know, however, is that psilocybin can rewire the connections between the emotion centers in the brain and the networks that control auditory perception of music and leads to this condition in which people who felt like, "Ugh, well, I was depressed," or, "I couldn't feel the music, I just wasn't getting the same lift and joy from it again," they can start to experience more joy from that music again. And that music that made them feel sad and depressed has a diminished capacity to make them feel sad and depressed. And there's a lot of neuroimaging data in this paper that point to the specific brain areas that include areas like the ventral tegmental area that can explain why these sorts of effects would occur. So this isn't just subjective reports of people saying, "Oh, yeah, you know, I was depressed and music didn't feel really good and now it feels great," or, "That used to make me feel so sad and now I feel like I have a capacity to listen to that without being, you know, crushed by, um, feelings of sadness." Uh, the paper included some subjective reports of that sort, but then was able to link those to changes in brain circuitry and brain activation in response to music using neuroimaging. So in that way, it really points to both the subjective and structural and functional changes that psilocybin can bring about through that expanded connectivity between brain areas. Because, remember, during the psilocybin session, it's not as if music or the perception of music is specifically being looked at or focused on in these studies. Rather, music is playing, people are in the eye mask, they're feeling all sorts of things, they're breathing, they're hearing, their touch, it's all happening all at once. There's a peak, it's long, there's a long taper, the music's changing. Okay, all of that took place in this study as well. But it is after the session when comparing brain activation states to music of a particular type, sad or happy, and comparing that to the patterns of brain activation that occurred before the psilocybin journey, that they discover that people's brains have rewired during the psilocybin session in a way that allows them to experience joy in response to music again. So that's one of the more rigorous studies I was able to find that addresses this question of whether or not psilocybin really does rewire the brain in ways that allows us to be more creative and experience life differently after the psilocybin

15. 1:12:39 – 1:16:53

    Depression & Psychedelics as Neuroplasticity “Wedge”

    1. AHAndrew Huberman1:12:39

       session. Now, that paper didn't focus specifically on creativity. I did an entire episode on creativity that talked about different types of meditation, like open monitoring meditation. It talked about, uh, different patterns of thinking that one can actually practice to increase creativity. We had arguably one of the most creative people, uh, on the planet, Rick Rubin came on this podcast, talked about the creative process from the perspective of music and his role in producing music. So you can check out those episodes if you're interested in the neural circuitry related to creativity. At least at the time of recording this episode, there haven't been a lot of studies looking specifically at the brain networks that we think are involved in creativity and how those change in response to psilocybin and other psychedelics. I imagine those studies are either happening now or will happen in the future. But the studies I just described referring to the changes in emotionality and responses to music I think provide a nice template for what's likely happening both during psilocybin journeys and after those psilocybin journeys when we talk about less hierarchical organization, more connectivity between brain areas. What it's pointing to is the fact that during the psilocybin journey people have the opportunity to learn new relationships between different sensory and emotional states, and those new relationships seem to persist long after the psychedelic journey has been finished. And a lot of people researching psilocybin in the clinical setting think that that's one of the major reasons why psilocybin and other psychedelics can rewire our relationship to things more broadly. It allows for new learning, new contingencies. And when we look at depression, we often think, you know, diminished mood, people don't have an appetite, they're not interested in social relationships or romantic relationships, they're really struggling. And all of that, of course, is true, but another lens to look at depression through is that...A lot of that thinking and a lot of those emotional states that are negative are somewhat habitual. They relate to a sort of implicit understanding and living out of the idea that A leads to B leads to C, okay? You seek out a relationship, it doesn't work out. You try a new job, you don't get the job. You get the job, it's no good. All these negative outcomes of if A, then B, then C. And it does seem that psilocybin can have this effect of invoking new patterns of learning, new considerations about what might be possible and indeed may even lead to actual rewiring of the emotion centers in the brain with these other brain areas and vice versa in ways that eject people from the psilocybin session thinking, "Oh, you know, yeah. I used to feel this way about something, work, relationships, myself, et cetera. But I'm willing to consider this other possibility or this other possibility seems at least partially true to the extent that I'm willing to go out and evaluate that." Now here I'm speaking very subjectively, but remember we have to tie back the subjective experiences and changes of things like music and emotion and our relationship to life and jobs and relationships back to the cell biology and chemistry of psilocybin because ultimately it really is just a chemical activating receptors, those receptors changing networks in the brain, and the journey itself seems to be the time when all of those changes are put in motion. It's like a boulder that gets rolling. In fact, I think the best way to think about psilocybin and other psychedelics is that they initiate the neuroplasticity process, but they are not the neuroplasticity process itself, and the journey itself is not where all the neuroplasticity occurs. We know that for sure. In fact, if you want to imagine how p- psilocybin and other psychedelics work to change the brain, think about them as a wedge that gets underneath the boulder that is the neuroplasticity that gets rolling forward, and then think about whether or not the plasticity is adaptive or maladaptive, whether or not it actually serves you in your life on a daily basis or not depending on whether or not you're using your conscious brain to move that boulder in a particular direction, right? Not just bulldozing through things and destroying them but clearing a path through old ineffective, maybe even destructive patterns of thoughts or emotions, et cetera. I give you that analogy because I think it more accurately captures what psychedelics like psilocybin are doing rather than the typical discussion around psychedelics that we tend to hear which is that, "Oh, it creates plasticity and plasticity is what you want." For

16. 1:16:53 – 1:25:23

    Positive Psychedelic Journeys, Unity, “Oceanic Boundlessness”

    1. AHAndrew Huberman1:16:53

       the next couple of minutes, I'd like to focus on some of the key and stereotype that is characteristic experiences that people tend to have during a psilocybin journey 'cause there's some really interesting research on this. These are phrases that perhaps you've heard before, things like letting go, ego dissolution, feelings of connectedness. While all of that is very subjective on the one hand, those words are heard often enough and repeatedly enough in psilocybin sessions and after psilocybin sessions along with this description of the psilocybin experience as one of the most profound of one's life or one of the most positive, in the ideal case, of one's life that they are worth exploring. We should also, of course, explore the so-called bad trip, the possibility that someone will have a not good time or even very frightening time while under the influence of psilocybin. So, there have been some scientific studies that have explored what sorts of subjective experiences, that is thoughts and feelings, insights that people have that relate to positive therapeutic outcomes and more generally with the sense that the psilocybin journey was positive or maybe even tremendously positive in one's life. So while there's a century or more of writings about psychedelics that describe things like enhanced feelings of connectedness or dissolution of the ego, the loss of one's sense of self and then the regaining of one's sense of self and so on, there's a particular paper that describes some of those things in terms of rating scales, that is the sorts of tests that people can take in which they answer particular questions and that link back to things like feelings of connectedness and ego dissolution that allows us to put some numbers to those experiences and to look at some of the statistics associated with those experiences. And this is really what's important about scientific studies, whether or not a measure is subjective, so if someone's self-reporting how they felt or feel, or whether or not it's measure of blood pressure or of a chemical in the bloodstream, et cetera, it's the use of numbers and statistics that allows comparison between different groups and that can be compared between studies that allows us to make some firm conclusions about what sorts of things psilocybin may or may not be doing, when it's effective or not. So the paper I'd like to highlight is entitled Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. I'll put a link to this paper in the show note captions, but the basic contour of this paper is that they looked at subjects that underwent two different psilocybin sessions, one at a relatively lowish dose of 10 milligrams of psilocybin, and that would be equivalent to about one gram of psychedelic mushrooms more or less, and a second session involving subjects taking 25 milligrams of psilocybin or what's roughly equivalent to somebody taking two and a half grams of psilocybin mushrooms. Those people then answered what's called the Altered States of Consciousness Questionnaire which allowed them to address, and here I'm paraphrasing, the quality of experiences in the 25-milligram psilocybin session. So without going into too much detail, it's often the case in these sorts of two-session studies that subjects will take a slightly lower dose of psilocybin to familiarize themselves with the experience and then the higher dose that leads to the more intense experience, intense meaning a bigger, more intense peak, a longer session overall, greater distortions in emotionality and perceptual experience, all the stuff we talked about before. So what this study found is that one of the key features, if not the key feature of a "positive," quote, unquote, psychedelic experience is this sense of oceanic boundlessness occurring at some point during the psychedelic journey. Now, oceanic boundlessness doesn't necessarily mean anything to any of us. Um, it probably means different things to different people.It's this idea that one is experiencing something extremely unusual, even mystical, and beyond this world and one's normal experience. But that it's not aligned with any specific outcome in the moment. It's not directly attached to any one feeling or memory or thought process. It's this, and it's a little bit tough to describe because I can guarantee you, I'm not on psilocybin or any psychedelics right now, and I can only imagine, um, that you're not, although some of you might be. I can't even imagine what this, uh, podcast would, um, be like for somebody on psilocybin at this moment. But in any case, oceanic boundlessness, a feeling of the experience being mystical and not really heading in any one particular direction. Just a feeling of massive connectedness with one's environment, both in the room in session perhaps with the guides, with oneself, with one's past, with one's present, people outside the room, with the entire world, maybe even the universe, that sort of thing. The intensity of that experience of oceanic boundlessness, the mystical experience, seems to be positively correlated with positive therapeutic outcomes. That is, relief from major depression. Now, during the psychedelic journey, as we talked about before, there are a number of steps that one typically goes through. So there's the build-up to first experiencing the effects of the drug, about maybe 20 to 45 minutes into the journey or trip. Then the peak, and it is during that peak that people often feel the sense of oceanic boundlessness. However, it's also often the case that it is during the peak where the maximum intensity of emotion, and we know based on direct measurements, also increases in blood pressure and heart rate, often very significant increases in anxiety and fear as well, that people will experience things like ego dissolution. And the guide's role at that point is of course to keep the person safe, make sure they don't run out of the room, jump out of a window, run into traffic. Sadly, these are things that have happened outside of a strong, healthy, safe set and setting. But, the guide's role is to keep the person safe, but also to encourage them to let go and move through that experience, to experience the anxiety, allow it to peak, allow them to see that they're not going to die from that anxiety, they're not going to dissolve, they won't lose their sense of self completely, or they may temporarily feel as if they lose their sense of self, but then they feel it restored at various intervals during the peak or as they exit that peak and move toward the, say, second, third, fourth, fifth hour of the session. So when exactly these feelings of oceanic boundlessness and ego dissolution occur varies from person to person. But typically, it's during the peak that the ego dissolution, the fear and the need to, quote-unquote, "let go" is most typical. I think perhaps the best way to describe the data in this paper in a way that's meaningful to everybody is to refer you to figure two, which if you're not looking at the paper, uh, won't mean anything to you, but I'll describe it, and if you do want to take a look at figure two, again, you can access the paper in the show note captions. What they did is they looked at a number of different subjective measures, things like experience of unity, the feeling that one is connected to others and to the world, things like spirituality, whether or not the whole thing felt like a spiritual experience, whether or not it was a blissful state, whether or not there were insights, whether or not somebody felt disembodied, out of body, whether or not somebody had a lot of anxiety, whether or not they had these synesthesias, these blending of visual auditory touch and breathing and things of that sort. And they address which of those measures related to the positive clinical outcomes that were observed later after the psilocybin wore off. And while I'm not going to go point-by-point through each one of these measures, there's a general feature to emerge from this study, which is that the experience of unity, the sense that the psilocybin journey was spiritual, an experience of bliss at some point inside of the psilocybin journey, the sense that there were insights, that there were learnings about one's life and one's self. When those things were experienced very strongly, that correlated with the person being what- what's called a responder to the psilocybin treatment, meaning they got relief from their depression. Whereas people who felt less of that, okay, so the non-responders, as they're called, the people who do not benefit so much in the long run from the psilocybin treatment, tended to report less of an experience of unity, less of a spiritual experience, less of a blissful state,

Episode duration: 2:09:01