ANDREW HUBERMAN: Welcome to the Huberman Lab podcast where we discuss science and science-based tools for everyday life. [MUSIC PLAYING] 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, changed 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, 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 the 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 typical or typically associated 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 long-standing 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 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 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 a decriminalized as opposed to actually legal. In other areas of the country, including Oakland, California, there are 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. Now, 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 1 to 3 degrees in order to fall asleep and stay deeply asleep. And waking up involves a heating up of your body by about 1 to 3 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 Pro cover. Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, that's eightsleep.com/huberman.

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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 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 in 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 in 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.

All 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 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 the 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 the sake of today's discussion, we're going to talk about how the serotonin 2A receptors are 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 cases, 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, OK, 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 is 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 leaning back from SSRIs as the be-all and 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 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, a.k.a. 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 non-specifically. So when you think about standard antidepressant treatments, at least for the sake of this discussion, you think of a sprinkling or a 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 of 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, 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 hanging out with friends, to being in a professional setting. You change your behavior, 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, in 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 fracturing of the outside world into geometric shapes. Sometimes it appears as a melting of things in the

Visual environment, including people's faces or a morphing of people's faces, has a strong draw for many seeking a highly unusual psilocybin experience. But for long-lasting benefit, an eye mask or eye covering is very useful. It limits focus on external visual changes, a.k.a. hallucinations, allowing inward focus on internal imagery, thoughts, memories, and emotions. Staying inward, via an eye mask, is critical for therapeutic effectiveness.

Now, I want to address safety precautions. I'll say this at least three times today. You might think I'm advocating psilocybin for everyone, but that's not true. Therapeutic use requires specific conditions and support. Psilocybin is contraindicated for some, particularly those with a predisposition to psychotic or bipolar episodes. A first-degree relative with bipolar, schizophrenia, or schizotypal issues is also a contraindication, potentially triggering psychotic episodes. This is critical.

Everything I discuss today, unless stated otherwise, focuses on adults (25+). Their brain's developmental neuroplasticity is complete. Most studies involve subjects aged 25-70, but no younger. Psilocybin is not for everyone. It's illegal except in clinical and research settings, with pockets of decriminalization and potential legalization, but only in clinical settings. I say this to protect myself and you. Psilocybin is a powerful drug, both acutely and long-term.

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Let's discuss psilocybin dosing and microdosing. There's loose thinking outside clinical settings, but clinical research provides data on safe and effective doses. This relates to psilocybin in "magic mushrooms." Studies don't use mushrooms; they use synthetic psilocybin intravenously or orally for precise control. Typical clinical dosages range from 1 milligram (microdosing, often daily for long periods) to 3 milligrams per day, up to 10 milligrams once or twice, or 25-30 milligrams once or twice.

These dosages (1-3mg, 10mg, 25-30mg) may not be meaningful without research context. You might hear of microdosing and macro or "heroic" dosing. That's popular nomenclature. I'll return to this. A frequent question is: How much psilocybin is in a certain amount of mushrooms? Mushrooms are discussed in grams or ounces. 1/8 of mushrooms is 1/8 of an ounce, or x grams. The conversion is simple: 1000 milligrams = 1 gram. Most magic mushrooms contain about 1% psilocybin. So, 1 gram (1000mg) contains approximately 10 milligrams of psilocybin. Studies show 25-30mg (once or twice) yields the most pronounced therapeutic outcomes, but with enhanced side effects.

We're discussing grams of mushrooms to psilocybin. 1 gram (1000mg) of mushrooms with 1% psilocybin contains 10mg of psilocybin. "Heroic doses," discussed by traditional psychonauts (long-time explorers often writers and spokespeople), translate to approximately a 5-gram mushroom dose, or 50 milligrams of psilocybin. Psilocybin concentration varies significantly by mushroom strain, batch, age, and storage. Some labs show a 0.5%-2% range. Sourcing is key. As psilocybin becomes more legal and regulated, synthetic psilocybin will offer more consistent dosing.

Let's step back from chemistry and discuss the structure of a psilocybin journey and its brain effects. Later, we'll discuss serotonin 2A receptors and lasting brain changes. Let's discuss an effective therapeutic psilocybin journey. I'm not detailing a self-administered therapy guide, but rather the consistent components of effective clinical trials for depression and compulsive/addictive disorders. Data and references will follow. We can't discuss psilocybin without "set and setting." These bias the probability of a beneficial journey.

What makes a safe and effective psilocybin journey? Safety means no self-harm risk (no windows, streets, water). It requires at least one, maybe two, non-psychedelic users present. I say this to prevent harm. There's increased interest in legal or decriminalized psychedelics. The 1960s/70s Controlled Substances Act criminalized psychedelics partly due to incidents neglecting set and setting (e.g., LSD and sun exposure). These are isolated incidents, but led to criminalization. There are many factors, and we could discuss the war on drugs, but getting the setting right is key.

The best way to ensure safety is responsible individuals present. Another crucial setting element is a seated or lying-down position, ideally with an eye mask, to combine visual hallucinations with internal thought processes. This differs from "taking mushrooms in the woods." Scientific data indicates subdued settings (one room, closed environment, one or two guides) maximize benefit. These settings are used in most studies on safety, efficacy, and positive brain rewiring.

Other setting components influencing experience: safety, eye mask, and music. Robin Carhart-Harris (UCSF) highlighted music's importance. Music impacts emotion and thought, influencing the psychedelic experience. It's a major driver of cognitive and emotional experience. Clinical studies use music that matches the psilocybin journey's contour. The journey lasts 4-6 hours (dose, metabolism, and gut contents dependent). Studies advise no food for four hours prior.

This 6-hour "journey" or "trip" starts 30-45 minutes after ingestion. There's a peak of emotion and anxiety (ego dissolution). This peaks and gradually decreases towards hour 6. Music matches this contour: initially low-volume, non-vocal classical music transitions to intense, high-volume music with percussion at the emotional peak (45-90 minutes), then softens to more melodic music (often female voices), then nature sounds.

Why does music matter? It contributes to subjective experience (perceptual blending/synesthesia: merging senses). People report their breathing linking to perceptions (e.g., breath linked to musical notes or visual perceptions). This is highly individual. Some report tactile sensations affecting music (fingertip rubbing affecting sound frequency). This links to emotional state. It's perceptual and emotional blending with a sense of unusual control.

Stepping back, what's happening biologically? Psilocybin converts to psilocin, crossing the blood-brain barrier. Psilocin activates the serotonin 2A receptor. Understanding where these receptors are and what those neurons do explains subjective experiences. Pyramidal neurons (pyramid-shaped) have a cell body (DNA, organelles) and dendrites (branches receiving signals).

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. 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, 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, like a snap of a finger is off to the right, I'll turn my head. And 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 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 a 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 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 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 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. 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 in a way station saying, hey, pay attention to the visual stuff, pay attention to the auditory stuff, or just to the visual and auditory stuff, and ignore 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 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.

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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 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 required 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 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, is 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. We hear this a lot. Psilocybin or other psychedelics lead to plasticity. They rewire your brain.

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. That's the goal of effective psychedelic therapies. Not simply rewiring of the brain. 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 that 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 it also has a lot of people excited about psychedelics, not just for the treatment of depression, but for expanding the brain's capabilities more generally.

So along those lines, I want to touch on the issues of creativity and the experience of life outside of psychedelic journeys is 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 music is being played. It's somewhat obvious perhaps. Sad music versus intense—you can think about heavy metal versus choir music versus Gregorian chants versus 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. I 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. Sounds like dum, dum, or ah, ah. These kinds of things—that was my attempt at low frequency versus high frequency 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. 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, 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, 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 crushed by feelings of sadness. 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. OK. 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 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 different patterns of thinking that one can actually practice to increase creativity. We had arguably one of the most creative people on the planet, Rick Rubin, come on this podcast and talk 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 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 implicit understanding and living out of the idea that A leads to B leads to C. You seek out a relationship, it doesn't work out. 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, 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 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. 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 the next couple of minutes, I'd like to focus on some of the key and stereotypical characteristic experiences that people tend to have during a psilocybin journey. Because 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. Well, 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 a 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 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 a 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 low-ish dose of 10 milligrams of psilocybin. And that would be equivalent to about 1 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 2.5 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 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. It probably means different things to different people. It's this idea that one is experiencing something extremely unusual, even mystical, 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 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 that you're not. Although some of you might be. I can't even imagine what this podcast would 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 and 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, or 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 2, which, if you're not looking at the paper, won't mean anything to you. But I'll describe it. And if you do want to take a look at Figure 2 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 blendings of visual, auditory, touch, and breathing, and things of that sort. And they addressed 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 the 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 was called a responder to the psilocybin treatment, meaning they got relief from their depression. Whereas people who felt less of that—OK, 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, less insightfulness, and so on. Whereas there were very few differences between the people that derived benefit from the psilocybin treatment and those that did not along the dimensions of synesthesia, this blending of different perceptions that ordinarily doesn't occur for most people, or complex imagery, right?

Put simply, everyone who took psilocybin in this study at 25 milligrams saw complex imagery; they saw a lot of hallucinations. But just seeing hallucinations did not lead to the positive clinical outcomes in terms of mood. Anxiety was a very interesting measure here because ordinarily, we think of the ego dissolution, the letting go, as such a key component of the psychedelic journey in terms of the positive therapeutic outcomes. This has been discussed quite a lot. And in full disclosure, Robin Carhart-Harris has already come on to record an episode of The Huberman Lab podcast. That episode hasn't been released yet, but it will be released soon. And he talks about the importance of this letting go in terms of the positive clinical outcomes of the psilocybin journey. And indeed that is true. And I should also mention that Dr. Matthew Johnson from Johns Hopkins, who also runs a laboratory exploring psychedelics and their role in treating things like eating disorders and depression, et cetera, also doing incredible work, also talked about the importance of letting go during the psilocybin journey—this ego dissolution, this ability to move through the anxiety.

And, again, I can't underscore this enough because it's been told to me over and over again by the top researchers in this area: that people head into that peaking phase of the psilocybin journey, and oftentimes it is not pleasant for them; they're feeling like it's uncomfortable, it's scary, and their heart rate is up, and their blood pressure is up, and they're having a hard time calming down, and they want to calm down. But it does seem that while the guides should not ramp them up and get them more stressed, that the ability to move through that stressful period, to somewhat guide oneself or to be encouraged to guide oneself through that peak and that anxiety and the fear of losing oneself and the so-called ego dissolution that occurs is an important feature for an effective therapeutic session. In this study, anxiety itself was inversely correlated with a positive therapeutic outcome.

So this is important and somewhat nuanced. On the one hand, I'm telling you that the letting go, the ego dissolution, does seem to be important in terms of reporting a psychedelic experience as effective, as having accomplished something, and perhaps even explaining some of the long-term positive effects to emerge from that psychedelic journey—in this case, psilocybin journey. However, non-responders—that is, people who did psilocybin but did not have a positive therapeutic outcome in comparison to the responders—those non-responders tended to have higher subjective ratings of anxiety than did the responders. So this is important. And what it speaks to is the fact that while yes, letting go during the session, experiencing some anxiety, perhaps even ego dissolution, and the dissolving of self and then the return of self is important, it is also important, it seems, that anxiety not be so, so high, or subjectively experienced as so high, that one does not experience the positive neuronal rewiring that leads to a more pervasive elevated mood.

So I'm definitely saying two things at once because I'm trying to capture the data accurately. It would not be fair for me to say, just let go, experience as much anxiety as is possible, and that's part of the process. Yes, letting go—again, in air quotes—seems to be important for one's experience of the psychedelic journey, in particular, around the peak that occurs about two hours in or so. However, extreme levels of anxiety seem inversely correlated, or negatively correlated would be the better way to put it, with the positive therapeutic outcome or relief from depression.

So this takes us back to all of the things we've been talking about thus far—not just the chemistry and biological action of psilocybin, but the key importance of getting dosage right, the key importance of making sure that you're in a safe environment, but also one in which the guides really know what they're doing. I think this is one of the biggest and most important reasons for having well-trained guides who really understand the contour of the psychedelic journey, but are also trained in how to help somebody with their anxiety in real-time while they're under the effects of psilocybin. And, of course, to help people integrate those feelings of high anxiety and maybe guide them back down to a calmer state during the psychedelic session itself.

And here I can just mention some unpublished data and studies. And, again, these are very preliminary. But through discussions with Dr. Matthew Johnson, who's running these psilocybin and other sorts of psychedelic trials at Johns Hopkins, he and I discussed the importance of having a real-time tool to adjust to anxiety while under the influence of psychedelics like psilocybin. And there he asked, and they've started to incorporate, as my understanding, some of the real-time respiration tools—that is, breathing tools—that we know based on work in my laboratory, Dr. David Spiegel's laboratory, can reduce anxiety very quickly in real-time. And that involves the use of the so-called physiological sigh. I've talked a lot about this before on previous podcasts. So rather than explain it to you again here now, we'll put a link to the physiological sigh—I do a demonstration of it—in the show note captions. I'll also link to a recent paper that we published in Cell Reports Medicine. This was a collaborative work that my laboratory did with Dr. David Spiegel's laboratory at Stanford School of Medicine, showing that the physiological sigh, among the different deliberate respiration techniques, is one of the fastest and most effective ways to reduce levels of autonomic arousal, a.k.a. anxiety or stress. And Dr. Matthew Johnson's laboratory has started to incorporate physiological sighs within these psychedelic sessions as a tool that the guides can refer people to before the session begins, teaching it to them so they realize they can calm themselves down if necessary in real-time. It works the first time; it works every time. This is not because it's some magic breathing technique that I created; it certainly is not. This is a naturally occurring pattern of breathing that occurs in sleep and in waking, but that when done deliberately, leads to very rapid and quite significant decreases in stress and anxiety. And then when people are inside of the psychedelic session, if they feel their anxiety levels are going too high, they're heading toward what might be called a quote-unquote bad trip, they're starting to panic or really think they're going to have a panic attack or die—again, the subjective experience is going to be layered on top of the physiological experience of one's heart rate being really elevated, so a stress and agitation—by using the physiological sigh inside of the psychedelic session, Dr. Johnson's laboratory, and I believe at least one other laboratory, are starting to use breathing techniques such as the physiological sigh as a way for these people who are under the influence of psilocybin to self-direct their own calm and to bring that level of anxiety down so that they can continue to move through the peak and move through the other phases of the psychedelic journey in ways that could be most beneficial for them.

So to close out the description of this really wonderful study—and by the way, it's another one from the Carhart-Harris laboratory—about the subjective experience of ego dissolution or oceanic boundlessness, this mystical state as so key as a component of a positive psilocybin journey, I'll just read for you the final sentence of this paper because it captures it so well: Quote, "It seems vital that appropriate consideration is paid to the importance of promoting a certain experience, as the quality of that experience may be the critical determinant of therapeutic success."

Now, before we move into what will be a very brief description of some of the other rewiring phenomena that psilocybin can induce, and then into some of the therapeutic applications of psilocybin as they relate to these recent, really exciting clinical trials for depression and addictive disorders and things of that sort, I just want to cue everybody to a paper that I think many people will want to take a look at in thinking about psilocybin. And I'll provide a link to this paper as well in the show note captions. This paper is entitled "Therapeutic use of psilocybin: practical considerations for dosing and administration." And this is a wonderful paper because it really goes step by step through the pharmacology of psilocybin, of which you now understand a bit, but it goes into a bit more detail. But then it also really nicely describes the contour of a psilocybin session and what's happening at the level of chemistry, early, middle, peak, and toward the end of the psilocybin session. And then also importantly, it gets into issues of dosage and translating from mushrooms to psilocybin itself, to psilocybin things I talked about earlier, but in a bit more detail, if you'd like to see that detail. And then perhaps most importantly, there's a section on contraindications where it points out that, of course, women who are pregnant or breastfeeding, people who have a predisposition to psychosis, those people should really avoid the use of psilocybin and other psychedelics entirely. It also talks about where the evidence is strong, moderate, and weak for the use of psilocybin for treatment of various disorders. And I can just summarize that very quickly because it's where we're going to head in a few minutes, which is that the most evidence for positive therapeutic outcomes in response to psilocybin taken and conducted in the manner that we've been describing today in terms of dosage and journey, set, and setting is for cancer-related depression, cancer-related anxiety, and treatment-resistant depression. That's where most of the evidence resides. There's also some evidence for the use of psilocybin journeys—and, again, this is typically one or two psilocybin journeys spaced, in the cases of two journeys, anywhere from one to two weeks apart—and, again, with all of the same contour of supports and set and setting that we've been talking about today. And there there's some evidence for improvement in terms of outcomes in alcohol use disorder and dependence and tobacco addiction. And then finally, there's the least amount of evidence, although there is clinical trial support for relief or partial relief for obsessive-compulsive disorder, cluster headaches and migraines, and demoralization due to AIDS diagnosis.

So this paper has a lot of really interesting information in terms of different conditions, in terms of dosage, and again, contraindications, and what's called adverse events—what sorts of bad things can and do happen as a consequence of psilocybin and other types of psychedelic journeys, both during and after those psilocybin or psychedelic sessions. And we'll talk a bit more about this when we go into some of those clinical studies because adverse reactions is always a key measure in any clinical study.

So very soon, we'll get into the more recent clinical studies related to psilocybin for the use of treating depression and some other conditions. But before we do that, I'd be remiss if I didn't talk about how psilocybin does and does not change the brain, what is and what is not known about that. In fact, when I put out the call for questions about psilocybin, many of the questions related to these issues. The first thing to understand is that a psilocybin journey is really a way to try and put that wedge under the boulder, as I described it, to try and invoke neuroplasticity of a particular kind. And in that way, it's remarkable, if you think about it, that everyone has different lives, different experiences. Psychedelics, in this case psilocybin, are activating these brain networks that each of us has more broadly than they would normally be activated. These are very abnormal patterns of thinking and perceiving and experiencing our emotional and physical life, et cetera. And yet so often the outcomes are positive. Not always, but the outcomes are positive; the experience is positive, even though it might have these anxiety moments or components within them.

It's very important to understand that psilocybin and the journey, while important, are not really what all of this is about. It's really about neuroplasticity. So researchers, in particular neuroscientists, are very intensely interested in understanding what sorts of neuroplasticity psilocybin creates because it turns out there are lots of different types or processes involved with neuroplasticity. For instance, brain networks, behavior, thinking, emotion, et cetera, can change because of the addition of new neurons. That's one form of neuroplasticity that's referred to as neurogenesis, the production of new neurons, most typically in the so-called dentate gyrus or other subregions of the hippocampus, a brain area involved in learning and memory. Neurogenesis in other regions of the adult human brain are exceedingly rare and, to be honest, may not occur at all. This is a debated area. We could do an entire episode about this, but for the most part, neuroscientists don't really believe that your neocortex, your striatum, your cerebellum has that much neurogenesis that's related to learning and memory of new things or new experiences. And we don't actually think that occurs as a consequence of taking psilocybin either.

Now, some of you who are familiar with, for instance, the cerebellum, you might be saying, wait, what about granular cell proliferation in the cerebellum? Or what about the rostral migratory stream from the subventricular zone where there are neuroblasts spitting out little new neurons that migrate in through the nose to replenish the olfactory neuron population? Yes, that's all true. That does occur. It's been observed in mice; it's been observed in monkeys; and to some extent, it's been observed in humans. But, again, I repeat, it is not a prominent feature of learning and acquisition of new skills, new ideas, or new emotional states. Perhaps the best-supported evidence for neurogenesis underlying new thoughts, experiences, abilities, emotions, et cetera, is the production of new neurons in that dentate gyrus subregion of the hippocampus. And that probably does occur in humans. But neurogenesis is not really the dominant mode of changing neural circuitry in adult humans. It might be a player in adolescence, in young childhood. It is certainly a player before we are born, when we are still in utero. But then the brain is being wired up in many different ways, including the addition of new neurons and changing of connections.

All of this is to say that while neurogenesis is a really sticky idea and it makes great headlines, the addition of new neurons is not really the way that the brain changes under psilocybin, other psychedelics, or just generally. It's perhaps responsible for maybe 1% to 2%, and I'm being generous there, of the rewiring events that are going to be most important for all of us. So we need to set that down and cement that there. Until further evidence comes out to the contrary, that's certainly where I—and here I feel comfortable speaking for the majority of neuroscientists out there, professional neuroscientists—that is, the papers showing adult neurogenesis are interesting, but they don't really explain most of the plasticity that occurs in the adult human brain.

So if neurogenesis ain't it, what is? Well, it's very clear that psilocybin, other psychedelics, and any behavioral or drug intervention that can induce neuroplasticity does so largely through the addition or strengthening of new neural connections or through the elimination or weakening of other neural connections. And if you look at the data exploring the mechanistic basis for psilocybin-induced neuroplasticity, it's mostly focused on animal brains, animal models, mice and rats in particular. A little bit on primates, but mostly mice and rats because that's where the interventions can be done of knock-out animals, of imaging the brain in real-time. Of course, there are the beautiful studies of Robin Carhart-Harris and others exploring neuroplasticity at the level of brain imaging, at the level of ultrasound measurements, of how active are certain brain areas in humans, how extensive is the modularity or not extensive is the modularity, et cetera, the stuff we talked about earlier. So in other words, there are neuroplasticity studies, the effects of psilocybin in humans. But in terms of underlying mechanisms of neuroplasticity, I think the predominant theory is that psilocybin induces neuroplasticity through the addition of novel connections in those pyramidal neurons of the frontal cortex, elsewhere in the cortex, and certainly also in the visual cortex. Probably also subcortical as well, below the cerebral cortex, in areas like the thalamus, maybe even in the brain stem as well. And that those neuroplasticity events are structural and functional. And they involve a couple of basic events, the most prominent of which is the growth of dendrites. Dendrites are those little branches or processes that come out of the neurons, not just the pyramidal neurons, but other neurons as well. But since we're talking mainly about pyramidal neurons today, both the apical, those ones that top—they're called the apical tufts; they're the ones that reach laterally to connect with other neurons, communicate with other neurons—that we talked about before, as well as the dendrites that come out of the base of those pyramidal neurons. Those processes grow in response to psilocybin, as well as the addition of what are called dendritic spines. So the dendrites are the branches; the spines are these little protrusions that grow out. Actually, here, I don't know if this is coincidence or not. Again, I always say I wasn't consulted at the design phase. But these little protrusions actually look like little mushrooms. They have a little stalk, and they have a little head, a little spine head. And those little spines—so think of these as like little tiny mushroom appearing. OK. They aren't actual mushrooms. OK. The first person that puts in the comments, "Oh, my goodness. I learned today that mushrooms grow out of our neurons when we take magic mushrooms," that is not what I'm saying. What I'm saying is that these little mushroom-shaped protrusions that we're calling dendritic spines do in fact grow out of dendritic branches of neurons when animals ingest psilocybin or are injected with psilocybin. And that those little mushroom-shaped protrusions are the…

Sites of new excitatory connections, new locations for input from other neurons to activate those neurons that have those little mushroom-shaped protrusions.

If you'd like to see examples of this, both movies and still shots, it's pretty remarkable. There's a paper that I'll provide a link to in the show note captions. This was published in the Journal Neuron, Cell Press Journal, Excellent Journal, entitled “Psilocybin Induces Rapid and Persistent Growth of Dendritic Spines in the frontal Cortex In Vivo.”

So these measurements were done in the mouse equivalent, more or less, of the prefrontal cortex. There are some interesting details in this paper, for instance, that those new connections persist. So they don't just grow out during the psilocybin being active in the bloodstream and brain of the animal; they persist. OK. So this may, again, may explain some of the persistent changes that occur in people after psilocybin journeys. They may too grow new spines.

I should also mention that a reduction in the number of dendritic spines, these little mushroom-shaped protrusions in the frontal cortex neurons of humans, occurs in depressed patients. We know that from postmortem tissue. And that drugs that relieve depression or that treatments, including behavioral treatments, that provide some relief from depression do seem to be correlated with increases in spine growth in frontal cortex neurons as well.

So this raises a very interesting idea, which is perhaps it's the growth of new connections, these new dendritic spines in particular neurons, that's created by administration of psilocybin, that explains the relief from depression that people experience.

So this is just one paper. But it's one paper of a growing body of work showing that, yes, indeed, psilocybin induces both structural and functional plasticity in the human and animal brain. It does that in the human brain at therapeutic doses of anywhere from 10 to 25, perhaps even 30 milligrams per session, one or two sessions.

I should mention that the mouse studies tended to use quite high doses of psilocybin. I wasn't shocked, but I was somewhat wide-eyed for a moment to realize that most of the studies looking at changes in plasticity in the mouse brain in response to psilocybin use the equivalent of 1 milligram per kilogram of body weight, which is, if you do the math and you translate what we were talking about before in terms of dosages, I'll just spare you all the time, it's about double the sorts of dosages that are typically used in humans. Maybe even triple in some cases.

Now, it's often the case in animal studies because of the metabolism of animals being different, but also because seeing effects of drugs in animal studies can be difficult. They did use a dose response anywhere from 0 to 0.25 to 0.5 to 1 to 2 milligrams per kilogram of psilocybin in the study. So they had a dose-response curve, but focused mainly on this 1 milligram per kilogram dosage.

In any event, the point is that many of the studies that describe these pretty dramatic structural changes in the animal brain, most typically the mouse brain, in response to psilocybin use dosages of psilocybin that, if translated to humans, would be about double the human therapeutic dose. So that is something that we need to take into consideration.

Nonetheless, it's very clear that in both animal studies and humans, psilocybin is inducing both structural and functional changes in brain circuitry. And that in humans, the network connectivity is being changed dramatically. We talked about those data earlier. And that the underlying basis for that might be, again, might be—we don't know for sure—the addition of new dendritic spines on these pyramidal neurons that we've been talking about repeatedly throughout today's episode.

Although neurogenesis perhaps and other modes of neuroplasticity, such as the elimination of certain connections, perhaps related to unhealthy maladaptive thoughts, or feeling that a particular sad song is overwhelmingly sad, it could be the case that those sorts of things change subjectively because of the removal of neural connections.

If you're going to think like a neurobiologist or scientist for that matter, you don't ever want to think that one mechanism can explain all the effects of a given drug or a given experience. It's almost certainly likely to be the consequence of multiple mechanisms acting in parallel.

And because I know there are people out there who would like to even more about the neuroplasticity induced by psychedelics, including psilocybin, there's a wonderful review that I provide a link to in the show note captions entitled, “Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics.”

This review is great because it goes a step beyond just psilocybin and psilocin binding to the serotonin to a receptor, and things like brain-derived neurotrophic factor. It actually talks a lot about the intracellular signaling and exactly how neurons change their excitability patterns based on this activation of the serotonin 2A receptor. It's probably more detail than most of you out there are interested in, but if you are interested in that level of detail, this is a wonderful open-access review.

So a few minutes ago, I talked about where there is strong, modest, and somewhat weak, or rather, I should say, minimal evidence for the therapeutic use of psilocybin to treat various disorders. And across the board, it really appears that major depression and so-called intractable depression, in some cases, is where we're seeing the most exciting research to date.

Now keep in mind that because of the Controlled Substances Act being invoked in 1970 in the United States, and because it was only just a few years ago really, only about five years ago, that psychedelics, including psilocybin, received what's called a breakthrough status at the FDA, that there are now a lot of clinical trials exploring how psilocybin can impact various things like mood disorders, addictive disorders, and so on.

Prior to 2018, when that therapeutic breakthrough potential was established in the United States, I think a lot of people in the so-called psychedelics community had the sense, and really the belief, that these drugs had enormous potential, but they just weren't being explored that extensively.

So I do want to give a nod to the incredible researchers such as Robin Carhart-Harris, but also Matthew Johnson, Roland Griffiths, Nolan Williams, and many others. OK. I'm certainly not listing off everybody; that would take hours. But those researchers have really pioneered both the legal efforts and the funding efforts, and most importantly, the research efforts defining the clinical data that I'm about to describe.

And here, I'm going to summarize the clinical data in a bit of a top-contour fashion, just giving you the kind of highlights. We will, of course, provide links to the papers if you'd like to look into it further, but I'm only giving you the top contour because I've had the great fortune of having Matthew Johnson on this podcast before. You can find that episode at hubermanlab.com. Just simply put Matt's name or psychedelics into the search function; it'll take you to that episode in all formats or links to all formats rather.

I've also had the great fortune of sitting down recently with Dr. Robin Carhart-Harris to talk about his work at University of California San Francisco on psilocybin, LSD, Ayahuasca, and DMT as it relates to depression and other disorders. And that episode, which also will be released at hubermanlab.com and on all platforms—YouTube, Apple, Spotify—really goes in depth into these clinical studies and what those studies really look like, who's in the room, whether or not people just get one dose or two doses, how far apart those are separated. All of that is covered in extensive detail in that what I found to be wonderful discussion with Dr. Robin Carhart-Harris.

So if you're interested in all of the details as it relates to clinical application of psychedelics, stay tuned for that episode soon. Again, you can find that at hubermanlab.com and on all platforms.

In the meantime, I would be remiss if I didn't include a bit of discussion about what has been observed in terms of using psilocybin journeys as a way to treat depression because the data are just oh, so exciting. Again, these data really started to surface as the consequence of studies that were initiated around 2006 in just a few select laboratories, and then really picked up in terms of the number of laboratories and number of studies between 2018 and now.

So what you'll notice is that most of the papers I'm about to describe were published in, for instance, Phenomenal Journals, New England Journal of Medicine in 2021, and New England Journal of Medicine November 2022, Journal of the American Medical Association Psychiatry just very recently, 2021. So these are very recent papers.

Essentially, all of these clinical studies involve either one or two psilocybin sessions. The dosages that were explored range from 0 milligrams—so placebo, if you will—10 milligrams, in some cases, 25 milligrams, in some cases, 30 milligrams. And most typically, people received the same dosage for both sessions if indeed they did both sessions. However, there's at least one study looking at just one single episode of psilocybin administration.

So this is the paper entitled—no surprise—“Single Dose Psilocybin for Treatment-Resistant Episode of Major Depression.” This was published in the New England Journal of Medicine in November of 2022. I'll just summarize the results of this single application study. They randomly assigned subjects who had treatment-resistant depression—so they had resisted treatment to other things—to receive a single dose of a synthetic formulation of psilocybin. So they're not eating mushrooms; they're getting a synthetic dose of psilocybin, but the dose is known, of either 25 milligrams, 10 milligrams, or 1 milligram, which was the control. And they receive psychological support.

There were a number of different tests, subjective tests of depression taken before and after the psilocybin journey. They had about 75 to 79 participants in each group, again, at the three different doses: 25, 10, or 1 milligram. And they looked at the changes in these scores, these depression-related scores on these tests.

There are many results from this paper one could summarize, but among the most important results I can summarize from the discussion—and here I'm paraphrasing—that the change in baseline levels of depression, that is at week three following the psilocybin session, was significantly better. That is, people experienced more relief, or more people experienced more relief from the 25-milligram dose than from the 1-milligram dose. And this is important: There was no significant difference between the 10-milligram dose and the 1-milligram dose.

This really points to the fact that the 25- to 30-milligram dose that's used in the largest numbers of studies exploring treatment-resistant depression really seems to be—I don't want to say the best dose, but the most effective dose, at least in this clinical context, in this set and setting and with this particular patient population. So we want to be careful to say that so that one doesn't just translate that 25 milligrams is better than 10 milligrams, although in this study it was for sake of treatment-resistant depression relief.

There were a number of other key aspects of this paper, in particular, the exploration of so-called adverse events. So things like headaches, propensity for self-harm, actual self-harm, anxiety, and so on. It's worth mentioning that there were adverse events in essentially every group. The number of adverse events was highest in the 25-milligram dose group. This is observed in other studies as well. With higher dosages, there tends to be greater relief from depressive symptoms, but also a greater chance for adverse events. Some of those adverse events can be quite severe—so feelings of suicidal ideation, et cetera. Some of them one could consider a little less severe: mild headache, or severe headache that was transient, or anxiety that was transient. Again, highly individual responses.

We could go line by line and table by table through this paper, which we won't because there's a lot of data. Again, we'll provide a link to this paper if you'd like to peruse it yourself. It's fairly straightforward to read. That's one thing that's nice about these clinical trials is they tend to be written in fairly non-technical language, although there's a little bit of technical language.

The important point is that a single dose of 25 milligrams of psilocybin provided significant relief from treatment-resistant depression in this particular patient population, but it is not the case that 100% of the people who took 25 milligrams of psilocybin experienced that relief. However, the majority of them did.

Now, when you say majority in science, you really need to look to numbers. And the reason I'm not telling you, oh, it was 75% or 60% or 50%, is because it depends on which time point people were analyzed. People were asked about their level of depression relief immediately, one week after, two weeks after, or three weeks after. And the degree of relief tended to change over time. In fact, it tended to diminish over time, but it was also stable, or remarkably stable, I should say, at least by my read in the 25-milligram dose group. And that is summarized nicely in figure 2 of the paper, because they explored these people's levels of depression out to week 12. And they still saw a significant degree of depression relief 12 weeks after the single 25-milligram psilocybin dose session.

So as I mentioned earlier, there are now about a dozen or so excellent studies, clinical trials exploring the use of single or two-session psilocybin treatment in that 25- to 30-milligram range, which seems to be the most effective dose for long-lasting relief from depression. Each one of those studies explored something different, as is important. Replication is also important, of course, in order to validate previous studies. But, for instance, there have been comparisons of psilocybin versus SSRIs or other antidepressants. There have been comparisons of psilocybin plus psychoanalysis or cognitive behavioral therapy versus cognitive behavioral therapy alone, or psychoanalysis alone. And so there's a lot of evaluation now of the clinical outcomes and the statistical outcomes of these subjective measures and even some objective measures of neurochemistry where that's possible in terms of trying to understand if and how psilocybin is effective for the treatment of depression.

And the major takeaway is that, indeed, it does seem to be the case. And the numbers that I feel comfortable not throwing out there, but putting out to you reflect my conversation with Robin Carhart-Harris. Again, that will be released soon at hubermanlab.com, as well as takeaways from what I would say are the six broadest studies, meaning they have the widest range of age groups, the broadest demographic in terms of the subjects, their backgrounds, their levels of education, men, women, ethnicity, et cetera.

And a lot of that can be summarized in the paper entitled, “Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder.” This was a particular randomized clinical trial, but in the discussion, I think they summarize it quite well, which is that if you look at the number of people who take this 25-milligram dose twice in sessions spaced about a week apart, what you will find is that anywhere from 60% to 75% of the people who have major depressive disorder who do these psilocybin sessions in the proper setting report a good experience with it, have minimal adverse events coming out of those sessions, and in the weeks following, those people experience substantial positive relief from major depression in ways that other treatments that they had explored, including antidepressant drugs, cognitive behavioral therapy, and other types of therapy alone could not provide.

Now, it's a general feature of these clinical trials focusing on psilocybin that people are asked to stop taking their antidepressants prior to participating in the trial. It's also a general feature of these trials that people are encouraged to not suddenly start their antidepressant treatment immediately afterwards because, of course, that could confound the results of the psilocybin treatment. However, and this is a very important thing to note, all subjects were encouraged not to avoid taking those antidepressant medications if, in fact, their clinician felt that it was important for their immediate and long-term survival. So no one should be reckless in thinking about what to add or delete from their drug protocol when dealing with depression. All right. The outcomes could be very severe in that case.

Nonetheless, we can paraphrase from the discussion of the paper I just mentioned because it really highlights the incredible results that psilocybin applied in these particular therapeutic settings are providing. And here, again, I'm paraphrasing: “The present trial showed that psilocybin administered in the context of supportive psychotherapy consisting of approximately 11 hours of psychotherapy”—so this is going to be two sessions of the psilocybin with proper therapeutic support—“produced large, rapid, and sustained antidepressant effects. The effect sizes reported in this study were approximately 2.5 times greater than the effect sizes found in psychotherapy and more than four times greater than the effect sizes found in psychopharmacologic depression treatment studies.” In other words, four times the positive effect observed with typical SSRIs or other pharmacology of that sort. “These findings are consistent with the literature that showed that combined pharmacotherapy and psychotherapy were more efficacious in the treatment of major depressive disorder than either intervention alone.”

So, again, this points to the fact that combining drug therapy with talk therapy, as it's often called, is going to be more effective than either treatment alone. Here the drug therapy is psilocybin therapy. And, again, please don't take the fact that in these studies they tended to ask people to not take their antidepressant medication heading into the study as a sign that one should stop taking their antidepressant medication. Rather, I think this study and other studies like it, again, which we'll provide links to in the show note captions that are discussed extensively in the episode with Dr. Carhart-Harris soon to come, really point to the incredible role that psilocybin can have in creating an experience inside of the session, the journey, or the trip as it's called, as well as initiating neuroplastic events, perhaps the addition of dendritic spines, maybe even some new neurons maybe, although I don't think that's the predominant mode. But that leads to these more extensive connectivities in the brain, the so-called reduction in modular networks, enhanced activity in brain areas that normally wouldn't be talking to one another, but not doing that in any kind of haphazard way.

It really does seem that the one or two sessions of psilocybin that induce these feelings of ego dissolution, that induce these feelings of oceanic boundlessness, right? So mystical. And in many ways, it's what I find so incredible about psilocybin and other psychedelics is that despite the highly mystical, highly subjective, and still at this time somewhat top-contour understanding of how they might exert their effects—you can highlight, boldface, and underline “might” there because it hasn't really been firmly established what the exact cell biological rewiring events are—but there is now what I would refer to as a center of mass of data that point to the fact that psilocybin, when taken in the appropriate set and setting, at the appropriate dosages, can invoke the sorts of neuroplasticity and changes in emotionality, in perceptual experience, not just during the psychedelic session, but for long periods of time after the psychedelic session, that can provide really remarkable relief from things like major depression and perhaps other psychiatric issues as well.

And, of course, I realize that many of you are listening to and/or watching this episode, and you're not necessarily depressed or thinking about psychedelics like psilocybin in the context of depression. I hope today's discussion allowed you to better understand how psychedelics and psilocybin, in particular, because that's what we've been talking about, are able to exert these incredible effects that they seem to exert. This is not a call for everyone to run out and do psilocybin. It is absolutely not that. It is, however, my attempt to really put a magnifying lens on this incredible area of research that's happening not just in the context of clinical trials, but in the context of trying to understand how serotonin and how drugs like psilocybin, which in many ways mimic serotonin, and more particularly, the activation of particular receptors in the brain like the serotonin 2A receptor—I mean, just sit back and think about that, the selective activation of this receptor, which is, by the way, associated with the expansion of the neocortex across evolution—didn't mention that before, but indeed it is—how that can lead to enhanced ways of thinking, changed ways of thinking, actual learning inside of this short 4-hour or 6-hour session that we call the psilocybin journey.

So as is often the case, perhaps as is always the case here on the Huberman Lab podcast, we did a deep dive into a topic today, into the topic of psilocybin: what it is, how it works, the different ways in which it changes brain circuitry, how it creates the experiences that we think of as the psilocybin journey, what the safety issues are, what the so-called set and setting are that can lend themselves to positive therapeutic outcomes. And in doing so, my goal was really to highlight several things. First of all, I am very excited about the potential for psychedelics such as psilocybin to provide relief for mental health issues that to date have been very hard for people to access. In addition to that, I'm just fundamentally interested in the brain and how it works and how it can change. This thing we call neuroplasticity. To me, neuroplasticity is the Holy Grail of the human nervous system. As far as we know, we are the animal that can have long-lasting neuroplasticity throughout the lifespan. And if it requires the use of compounds in a safe and controlled way, such as psilocybin, in order to achieve maximal plasticity in a short amount of time, that's exciting. But, of course, that also needs to be considered with all of the safety precautions in mind that we talked about earlier, including the fact that people who have a predisposition or who have psychosis or bipolar disorder or a relative that has psychosis or bipolar disorder, younger people, meaning people 25 years of age and younger, and really anyone who's not working with a dedicated and highly trained physician needs to be very cautious about these compounds as well. They're very exciting. I think psilocybin is an exciting and super interesting compound for basic and clinical reasons and for other reasons as well, but they are sharp blades, as we say. And with sharp blades, you can do incredible things, but you can also cut yourself very badly. So all those considerations need to be taken to mind.

So I consider the science and use of psilocybin to be an exciting, but still preliminary area that I certainly am paying a lot of attention to, and I know there's a lot of excitement about. So stay tuned for the episode with Dr. Robin Carhart-Harris. And we will probably revisit psilocybin, and we will certainly revisit the other psychedelics and non-classical psychedelics, including LSD, DMT, 5-MeO-DMT, ketamine, MDMA, mescaline, and all the rest in future episodes as well.

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Thank you once again for joining me for today's discussion all about psilocybin. And last, but certainly not least, thank you for your interest in science. [MUSIC PLAYING]

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How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks | Huberman Lab Podcast

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