So let's talk about psilocybin journeys from the subjective side and from the structural side. And when I say the structural side, what I mean is what does a psychedelic journey actually include? And here are the words set and setting become extremely important. Some of you may have heard that set and setting are the foundation of a well done or even therapeutically beneficial psychedelic journey.

And all of that really hinges on safety and outcomes. So set refers to mindset, the mindset of the person taking the psychedelic. And setting refers to, as the name suggests, the setting in which they're taking it in and the people that are present there. So let's talk about setting first.

The setting for a psychedelic journey needs to be one in which the person under the influence of the psilocybin or other psychedelic is safe. That means no windows they can jump out of. That means no streets of moving cars they can run out into. That means no opportunity for getting lost.

That means no opportunity for getting into bodies of water. In other words, it requires that there be at least one and perhaps even two or more other individuals who are not also taking psychedelics, right? Who are not also taking psychedelics present in that setting to ensure that the person taking the psilocybin is not going to harm themselves or others.

I say this not to sound like a school teacher, even though technically I'm a school teacher, but because of course I don't want anyone to get harmed. And I'm also aware that there's a lot of interest nowadays in psychedelics such as psilocybin becoming legal or decriminalized for their therapeutic applications.

And if we look back to the late 1960s and early 1970s, when the Controlled Substances Act was invoked to make psychedelics like psilocybin illegal, one of the bases for that was not just the geopolitical unrest at the time and things like the Vietnam War, but also some highlighted instances in which people did not take set and setting into consideration, took things like LSD, stared at the sun, went blind, or took psilocybin, went out and harmed somebody else.

Again, these are very, very isolated instances, but these are the exact sort of instances that lead to criminalization or the fact that things like psilocybin and LSD and MDMA for that matter are considered illegal. Again, I completely acknowledge that there are a number of different factors making them illegal.

We could have a whole discussion about that. We talk about the drug trade, the war on drugs, but right now is such a critical time in the history and the use of psychedelics for therapeutic and other reasons. And getting setting correct, meaning making it absolutely as safe as possible for the person taking the psychedelic is absolutely key.

And one of the best ways to ensure that it's safe is to have responsible individuals who are not under the influence of psychedelics present in that environment. So that's one component of setting. The other component of setting that we talked about earlier, which turns out to be very important, is the opportunity and perhaps even the bias toward the person on the psychedelic being seated or ideally lying down and being in the eye mask, or at least having their eyes covered so that they can combine any spontaneous visual hallucinations that occur with the various thought processes that are occurring while under the influence of psychedelics.

This is far in a way different than quote unquote, taking mushrooms and going into the woods or taking mushrooms and going to the beach. What we're talking about today is the use of psychedelics for particular brain rewiring outcomes that yes, can involve things like changing one's relationship to nature or changing one's relationship to somebody else by interacting with nature or somebody else.

And while I'm not trying to diminish the potential value of those sorts of psychedelic journeys, if we look at the scientific data, the vast majority of it, not just in the clinical setting, but in terms of understanding the safety and efficacy and positive rewiring of brain circuitry that allows people to feel better, to understand themselves better, and to interact with life in more adaptive ways going forward out of the psychedelic journey, involve these very, let's say, subdued settings that are typically in one room, a closed environment with one or two other individuals acting as sort of guides or helping the individual by talking to them from time to time if they feel like they have to sort through a particular aspect of the psychedelic journey that's creating anxiety.

And we'll talk about the contour of the psychedelic journey that almost everyone who takes psilocybin at somewhere between 20 and 30 milligram dosages tends to experience. But the setting that I'm describing is not just a list of things to make sure you're safe, but they're really the list of things that also ensure that one can get the maximum benefit out of the psilocybin journey.

Now, other things included in setting that are known, again, from scientific literature, to be very influential in terms of the experience that one has and to bias things towards a positive experience are, again, safety, eye mask, but also the presence of music. Now, when I first heard about this from one of the premier researchers on psilocybin and other psychedelics, which is Robin Cardart-Harris, he's a professor at University of California, San Francisco, who's one of the major pioneers in the studies of psychedelics.

And when he first started telling me about the critical role that music plays, I thought, okay, that makes sense. Music can impact our emotion, impact the way that we think, and could therefore impact what one experiences during the psychedelic journey. But he really underscored for me the extent to which music is not just a sort of incidental feature of the setting, in psychedelic setting, but that it is one of the major drivers of the actual cognitive and emotional experience that somebody has on something like psilocybin that allows the psilocybin journey to be looked at or viewed, not just as beneficial, but, and this is quoted in the scientific literature, as one of the most profound and important positive experiences that one ever experienced in their life.

So let's talk about the sorts of music that have been used in these clinical studies. Well, first of all, we need to think about how long the psilocybin journey itself is going to be. And the typical duration of the psilocybin journey is anywhere from four to six hours. It's going to depend somewhat on dose.

It's going to depend somewhat on variability in people's liver metabolism. And it's also going to depend somewhat on how much food people have in their gut. In all the clinical studies that I read, it was advised that people not have any food in their gut at the time at which they ingest or are injected with the psilocybin.

It's particularly true if people are going to be taking psilocybin mushrooms in order to get their psilocybin. And that has been done in a few studies. Most studies, however, use synthetic psilocybin taken orally. Again, that's converted to psilocin in the gut by the acidity of the gut. And the acidity of the gut is going to be impacted by the various foods that people eat.

And so that's one of the major reasons why people are advised to not eat for at least four hours prior to the psilocybin journey. So here we've got this six-hour, what we're calling journey, 'cause that's what everyone calls it, or trip, that people start experiencing about 30 to 45 minutes after ingesting psilocybin or taking psilocybin.

There's a peak component in which there's a maximal intensity of emotion, and often that's also associated with anxiety. And this is very important to understand. The anxiety component is part of what, in the therapeutic setting, they refer to as ego dissolution. And that anxiety around the peak, and I think most people would probably hear peak experience and think, oh, we're talking about a peak positive experience.

But no, we're referring to a peak experience in anxiety that people stay with and then come down from gradually as one goes from the second or third hour after taking psilocybin, and that tapers off slowly toward the six-hour mark, what sometimes people refer to as parachuting back in. Of course, they're not.

Hopefully, I would very much hope people aren't actually parachuting back in while on psilocybin, but I think you get the idea. The music that's typically played in the clinical studies using psilocybin for the treatment of depression or for compulsive disorders or addiction tends to have a particular contour that matches with and can also drive that contour of the psilocybin journey that I just described.

Again, we're talking about people wearing an eye mask with guides present, so people who are not taking psilocybin there as well to ensure that the person feels supported and is safe. The person is typically lying down, sometimes sitting down, but more often than not lying down, wearing an eye mask, and the music that's played at the beginning of the psilocybin session tends to be music that doesn't have a lot of vocalizations.

It tends to be things like classical music. It tends to be fairly low volume, but that then transitions into music that has a lot of percussion, so often drums, that tends to be higher volume, that has a lot of intensity at about the time that one would be experiencing the peak in emotion and in perception, the so-called peak of the journey.

That intense music tends to be played for about 45 minutes to 90 minutes, depending on the study one looks at, and then tends to transition into softer music again, sometimes choral type or more melodic music, often female voices in particular, and then transition into nature sounds and things that more or less mimic the outside natural world and less so synthetic things like drums or instruments and vocalizations and things of that sort.

So why would it be so important that music match and even contribute to the subjective experience that people have on psychedelics? And here we should probably take a couple of moments and just talk about what those subjective experiences are like. So for people that haven't done psilocybin or any psychedelics, it's a little hard to describe, but one way to describe it is that there's a lot of so-called perceptual blending.

So for instance, people in the eye mask will report seeing some geometric shapes and colors, but perhaps the music they're listening to will then start to change the intensity or the movement of whatever it is that they're seeing, hallucinating inside of the eye mask in ways that are linked.

This is referred to as synesthesia or the merging of different senses that are not ordinarily merged. In addition, people under the influence of psilocybin or other psychedelics for that matter, often will report that their pattern of breathing becomes linked to the perceptions of things that they are hearing or seeing or feeling.

So for instance, if they take a big deep breath in and then a long exhale out, they may find that during the long exhale out that the notes of music that they're hearing in those moments are also drawn out for the duration of the breath, and they'll inhale and that they're getting at least what they perceive as control over the music, which of course they are not actually controlling by using their breath.

And that perhaps their visual perceptions are also being merged with that. So those are just a couple of examples of how perceptual blending, aka synesthesia, can occur while under the influence of psilocybin. And this really is highly individual from one person to the next. Some people, for instance, will find that if they take their fingertips and rub them across the couch or the chair that they happen to be lying down or sitting on, that they will experience a change in the music.

Maybe even if they move their hand up, they hear an increase in frequency of sound, they move their hand down, they hear a decrease in frequency of sound, and that all of this is linked to their emotional state at the same time and vice versa. Okay, so we're talking about a lot of perceptual and emotional blending and some sense of control over one's perceptions and emotions in a way that's very unordinary, even extraordinary.

Now, we can step back from all of this very subjective description of the psychedelic journey and ask what is going on that would allow these sorts of things to occur? And there you are already equipped with an understanding of the cell biology and the chemistry that makes all of this possible.

And that is that when psilocybin is ingested and then converted to psilocin, and it's the psilocin that crosses the blood-brain barrier, and then even though psilocin looks a lot like serotonin, psilocin has this incredible ability to predominantly activate the serotonin 2A receptor. Well, we can understand much of what's happening at a subjective level during the psychedelic journey, even right down to the sorts of emotions and perceptual blending, the synesthesia.

We can understand a lot of that by understanding where the serotonin 2A receptors are expressed on neurons and what those particular neurons are doing. And the simplest way to describe this is that there's a category of neurons that we call pyramidal neurons. Pyramidal neurons are found lots of places in the brain, but they're called pyramidal neurons 'cause they're shaped like a pyramid.

They have a cell body, which is the part of the cell that has the DNA in it, and a lot of other important things like the organelles, mitochondria, et cetera. And then they also have what are called dendrites. Dendrites are the little branches or processes that reach out both from the bottom of these cells, and then these pyramidal cells are interesting because they also grow a branch up, up, up, up, up, up into layers of neural tissue above them, and they have what's called an apical branch.

That's the part that grows up, and then they fan out at the top. And that fanning out at the top allows them to communicate with other neurons in their environment. Okay, so if you're not getting a good picture of this in your mind for my description, I apologize, but simply think about putting your arms out to the side, and by doing that, you're able to interact with things that are some distance from your body, sort of an obvious thing in that case.

These cells are effectively doing the same thing by extending little processes out into layers above them and to the sides. And this is really important because much of the serotonin 2A receptors that are present on neurons in the brain are present in those apical dendrites, those branches of these pyramidal neurons that are above and that extend out to the side of those neurons.

And so when somebody is under the influence of psilocybin, that means that psilocin has bound to the receptors on those apical dendrites, and it's increasing lateral communication across brain areas. In fact, this is perhaps one of the most well-documented effects of psilocybin and other psychedelics, which is that there's a shift from the brain being more modular, meaning more segmented, like auditory neurons are communicating electrically and chemically largely with other auditory neurons.

Of course, they'll communicate with other types of neurons too, right? When I hear something off to my right, you know, like a snap of fingers 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 sort of a way station. It's like a switchboard that sends visual stuff to the visual centers, and auditory stuff to the auditory centers, and touch stuff to the touch centers, and things that 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.

Okay, and that has to do with what's called thalamic gating. The thalamus is a very interesting structure. We probably don't want to go into it in too much detail right now, but it really is like a switchboard and a 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 why when under the influence of psilocybin, one's breathing can be linked to a sound, and then suddenly the sound, one thinks, is being controlled by one's breathing, or that the sound itself can be linked to something that we see in our mind's eye while in the eye mask.

Essentially what I'm describing here is that serotonin 2A receptor activation allows for more broad, less precise, and less hierarchical activation of brain circuitry. And when I say hierarchical, what I mean is that normally things go from periphery, from eyes to thalamus to visual cortex. However, when under the influence of psilocybin, as I mentioned before, even in the eye mask, the visual cortex is going to be very activated even in the absence of any visual input.

So then if one hears a sound, perhaps from music, a particular motif or voice, and that's linked to a particular emotional state, that is now being blended with visual phenomenon occurring within the brain that have no external stimulus. And so while the patterns of activation in the brain while under the influence of psilocybin aren't random, they are far less channeled, far less modular, and far less hierarchical than would ever be the case when not under the influence of psilocybin.

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