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 tryp. In fact, it's spelled differently. Tryptamine is T-R-Y-P, tryp, T-R-I-P, of course.

Tryptamines include psilocybin, but also things like DMT and 5-MeO-DMT. The tryptamine psychedelics very closely resemble serotonin itself. That's right. Most of you have probably heard of the chemical serotonin. And serotonin is what's called a neuromodulator, which means your brain and body naturally make it, and that it modifies or changes the activity of other neurons and neural circuits.

And it does that generally by either increasing or decreasing the activity of those neural circuits. If I were to show you a picture of the chemical structure of psilocybin or its active derivative, psilocin, and I were to also put right alongside it an image of the chemical structure of serotonin, provided that you weren't a chemist who really likes to focus on the detailed differences between things, you would say those look very similar.

And indeed, psilocybin and its active form, psilocin, are very similar structurally and chemically to serotonin itself. Now, as I mentioned before, serotonin is something that you naturally make. And yes, it's true that about 90% of the serotonin in your brain and body is manufactured in your gut. However, contrary to popular belief, the serotonin in your brain is not manufactured from the serotonin in your gut.

You have separate independent sources of serotonin. That is, you have particular neurons that make serotonin in your brain. You also have serotonin in your gut, and those work more or less in parallel, separately. Now, what does serotonin do? This is really important to understand because of the similarity between psilocybin and its active form, psilocin, and serotonin.

Serotonin, in that it's a neuromodulator, changes the activity of other neurons, and the net effects of those changes are things that you're familiar with. For instance, satiety, or the feeling that we've had enough of various things, such as food, or a social interaction, or sex, or pleasure of any kind.

Serotonin is involved in all of that and an enormous number of other things, such as mood regulation, such as our sense of pleasure itself, or lack of pleasure, such as whether or not we feel motivated or not motivated. It works in concert with other neuromodulators, such as dopamine, and epinephrine, and norepinephrine.

In fact, if this were an episode about serotonin, which it is not, you would soon realize that serotonin is involved in so many different functions that impact our daily life. And that is one reason why certain antidepressant medications, which alter, either increase or decrease, the amount of serotonin transmission in the brain, will often have a lot of side effects related to things like mood, libido, appetite, sleep, et cetera.

It's because serotonin is involved in so many different things. And serotonin is involved in so many different things because there are a lot of different so-called serotonin receptors. Serotonin is a chemical that we call a ligand, and the chemical ligand is simply the thing that plugs into the receptor for that chemical or ligand.

The receptors, in this case, serotonin receptors, have the opportunity to do all sorts of different things. They can change the activity of neurons, making them more active or less active. They can cause growth factors to be released, making sure that those neurons reinforce or even build up stronger connections so that they're more likely to be active in the future.

Serotonin binding to particular receptors can even change the gene expression in particular cells, making those cells proliferate, so make more of them, making those cells more robust, making those cells interact with new elements of the brain and body. Basically, serotonin and all these different receptors that it binds to has dozens, if not hundreds, and maybe even thousands of different functions.

So the fact that psilocybin so closely resembles serotonin leads to a very important question that we should all be asking ourselves, which is why is it that psilocybin, which looks so much like serotonin, when one takes it in the form of magic mushrooms or some other form, maybe the synthetic form of psilocybin itself, which nowadays is manufactured in laboratories and placed in different psilocybin-containing foods and pills, et cetera, why that leads to complex yet fairly circumscribed sets of experience like visual and auditory hallucinations, changes in particular thought patterns, and neuroplasticity that, in many cases, in the clinical setting, provided things are done correctly, improvements in mood, relief from depression, relief from various compulsive disorders, et cetera, right?

This is really what you need to understand if you want to understand psilocybin and how it works and how to make it work optimally for a given condition or goal. You have to understand what it's actually doing and what allows psilocybin to do fairly specific things in comparison to serotonin, even though psilocybin and serotonin are so similar, is that psilocybin mainly binds to and activates the so-called serotonin 2A receptor.

The serotonin 2A receptor is one of, again, many different serotonin receptors, but serotonin 2A is expressed in particular areas of the brain and even on particular areas of neurons in the brain that allow for very specific types of changes in neural circuitry to take place, not just when one is under the influence of psilocybin, but afterwards as well.

So really, in order to have a useful discussion about psilocybin, we need to talk a lot about the serotonin 2A receptor, but fortunately for you, unless you're somebody really interested in structural biology or cell biology, that discussion is not going to be about the binding pocket for serotonin on serotonin 2A receptor, or a lot of the downstream signaling of the serotonin 2A receptor.

We'll talk a little bit about that where it's relevant, but more importantly, at least for sake of today's discussion, we're going to talk about how the serotonin 2A receptor is really the one responsible for triggering all the changes in neural circuitry that lead to the changes, that is the improvements in mood, the relief from compulsive disorders in many case, but really it's the serotonin 2A receptor selectivity of psilocybin that is leading to all the excitement that you hear about in terms of psilocybin as a therapeutic tool.

Let me say that from a slightly different angle. There are data that I'll talk about today, which show that one, although in most cases, two psilocybin journeys done with particular dosages of psilocybin lead to maximal binding or occupancy of those serotonin 2A receptors in ways that lead to significant and unprecedented relief for major depression.

In fact, you'll soon learn that the clinical trials for psilocybin are outperforming standard therapy and outperforming so-called SSRIs and various other antidepressants in terms of providing depression relief in ways that are frankly staggering, not just to me, but to the psychiatric community at large. And this is where so much of the excitement is coming from.

Now, that statement could be taken one way, which is to just say, okay, well, here's a compound psilocybin that outperforms SSRIs and therefore all the attention should be on psilocybin. But SSRI stands for Selective Serotonin Reuptake Inhibitor. In other words, the SSRIs of which there's now a lot of controversy, things like Prozac, Zoloft, et cetera.

I'm sure you've heard some of this controversy. There are people who are very pro-SSRIs, although there are a growing number of people who really feel that the SSRIs are probably most appropriate for things like obsessive compulsive disorder, where they in fact can be very beneficial. But there's a lot of kind of leaning back from SSRIs as the be-all end-all for the treatment of depression nowadays because of the side effect profiles.

And the fact that it's not even really clear that serotonin deficiencies are the major cause of depression in the first place. Now, again, we're talking about psilocybin, not about SSRIs, but you should be thinking, wait, how is it that two molecules, psilocybin and some particular SSRI, both of which look like and/or increase serotonin transmission in the brain, are leading to either incredibly positive and interesting outcomes or to kind of troubling side effect riddled outcomes.

And again, it all boils back down to the selectivity of psilocybin to bind that serotonin to a receptor. And so in order to understand how psilocybin works and in order to understand proper dosing profiles and spacing of sessions, aka journeys, we really need to talk a little bit more about the serotonin 2A receptor, where it is in the brain, what sorts of things happen when psilocybin binds the serotonin 2A receptor, and how those things set in motion the various changes, the neuroplasticity that allows people to feel better in terms of their mood.

And as you'll soon learn, can experience more pleasure and joy from things like music and enhanced creativity. All the things that I do believe, whether or not people are thinking about or maybe even exploring psilocybin for recreational or therapeutic purposes, all the things that people want and are really talking about and perhaps even doing psilocybin in order to obtain.

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