What Is Psilocybin (Magic Mushrooms) & What Are Its Effects? | Dr. Andrew Huberman
00:00:00.000 | [Silence]
00:00:02.540 | Let's talk about psilocybin.
00:00:03.880 | And again, today we're going to focus
00:00:05.480 | specifically on psilocybin and we're going to set aside
00:00:07.960 | all the other psychedelics for future episodes.
00:00:10.760 | Psilocybin is what's called a tryptamine.
00:00:15.120 | That refers to its chemical composition,
00:00:17.960 | not to the so-called psychedelic tryp.
00:00:20.200 | In fact, it's spelled differently.
00:00:21.320 | Tryptamine is T-R-Y-P, tryp, T-R-I-P, of course.
00:00:26.320 | Tryptamines include psilocybin,
00:00:28.640 | but also things like DMT and 5-MeO-DMT.
00:00:32.000 | The tryptamine psychedelics
00:00:33.320 | very closely resemble serotonin itself.
00:00:36.960 | That's right.
00:00:37.800 | Most of you have probably heard of the chemical serotonin.
00:00:40.560 | And serotonin is what's called a neuromodulator,
00:00:43.120 | which means your brain and body naturally make it,
00:00:45.720 | and that it modifies or changes the activity
00:00:48.640 | of other neurons and neural circuits.
00:00:50.440 | And it does that generally by either increasing
00:00:53.440 | or decreasing the activity of those neural circuits.
00:00:56.700 | If I were to show you a picture of the chemical structure
00:00:59.260 | of psilocybin or its active derivative, psilocin,
00:01:03.640 | and I were to also put right alongside it
00:01:06.520 | an image of the chemical structure of serotonin,
00:01:08.920 | provided that you weren't a chemist
00:01:11.480 | who really likes to focus
00:01:12.680 | on the detailed differences between things,
00:01:15.280 | you would say those look very similar.
00:01:17.040 | And indeed, psilocybin and its active form, psilocin,
00:01:21.160 | are very similar structurally and chemically
00:01:24.360 | to serotonin itself.
00:01:26.060 | Now, as I mentioned before,
00:01:27.160 | serotonin is something that you naturally make.
00:01:29.160 | And yes, it's true that about 90% of the serotonin
00:01:32.520 | in your brain and body is manufactured in your gut.
00:01:35.760 | However, contrary to popular belief,
00:01:37.960 | the serotonin in your brain is not manufactured
00:01:42.120 | from the serotonin in your gut.
00:01:43.600 | You have separate independent sources of serotonin.
00:01:47.020 | That is, you have particular neurons
00:01:48.220 | that make serotonin in your brain.
00:01:50.000 | You also have serotonin in your gut,
00:01:51.680 | and those work more or less in parallel, separately.
00:01:54.640 | Now, what does serotonin do?
00:01:56.100 | This is really important to understand
00:01:58.180 | because of the similarity between psilocybin
00:02:01.060 | and its active form, psilocin, and serotonin.
00:02:04.340 | Serotonin, in that it's a neuromodulator,
00:02:08.220 | changes the activity of other neurons,
00:02:10.260 | and the net effects of those changes
00:02:12.980 | are things that you're familiar with.
00:02:14.340 | For instance, satiety,
00:02:16.280 | or the feeling that we've had enough of various things,
00:02:19.340 | such as food, or a social interaction, or sex,
00:02:23.540 | or pleasure of any kind.
00:02:25.940 | Serotonin is involved in all of that
00:02:28.020 | and an enormous number of other things,
00:02:30.940 | such as mood regulation,
00:02:32.940 | such as our sense of pleasure itself, or lack of pleasure,
00:02:36.420 | such as whether or not we feel motivated or not motivated.
00:02:39.740 | It works in concert with other neuromodulators,
00:02:42.220 | such as dopamine, and epinephrine, and norepinephrine.
00:02:44.740 | In fact, if this were an episode about serotonin,
00:02:47.040 | which it is not,
00:02:48.660 | you would soon realize that serotonin
00:02:50.380 | is involved in so many different functions
00:02:53.620 | that impact our daily life.
00:02:55.840 | And that is one reason why
00:02:57.860 | certain antidepressant medications,
00:03:00.180 | which alter, either increase or decrease,
00:03:03.420 | the amount of serotonin transmission in the brain,
00:03:06.540 | will often have a lot of side effects
00:03:08.820 | related to things like mood, libido,
00:03:10.700 | appetite, sleep, et cetera.
00:03:12.780 | It's because serotonin is involved
00:03:14.260 | in so many different things.
00:03:15.860 | And serotonin is involved in so many different things
00:03:18.540 | because there are a lot of different
00:03:19.960 | so-called serotonin receptors.
00:03:21.660 | Serotonin is a chemical that we call a ligand,
00:03:24.820 | and the chemical ligand is simply the thing
00:03:27.120 | that plugs into the receptor for that chemical or ligand.
00:03:30.860 | The receptors, in this case, serotonin receptors,
00:03:33.700 | have the opportunity to do all sorts of different things.
00:03:36.140 | They can change the activity of neurons,
00:03:38.060 | making them more active or less active.
00:03:39.820 | They can cause growth factors to be released,
00:03:41.900 | making sure that those neurons reinforce
00:03:44.580 | or even build up stronger connections
00:03:46.700 | so that they're more likely to be active in the future.
00:03:49.180 | Serotonin binding to particular receptors
00:03:51.080 | can even change the gene expression in particular cells,
00:03:54.140 | making those cells proliferate, so make more of them,
00:03:56.840 | making those cells more robust,
00:03:58.680 | making those cells interact with new elements
00:04:02.260 | of the brain and body.
00:04:03.480 | Basically, serotonin and all these different receptors
00:04:05.660 | that it binds to has dozens, if not hundreds,
00:04:08.380 | and maybe even thousands of different functions.
00:04:11.220 | So the fact that psilocybin so closely resembles serotonin
00:04:16.140 | leads to a very important question
00:04:18.780 | that we should all be asking ourselves,
00:04:20.060 | which is why is it that psilocybin,
00:04:22.820 | which looks so much like serotonin,
00:04:24.640 | when one takes it in the form of magic mushrooms
00:04:27.340 | or some other form,
00:04:29.180 | maybe the synthetic form of psilocybin itself,
00:04:31.220 | which nowadays is manufactured in laboratories
00:04:33.600 | and placed in different psilocybin-containing foods
00:04:36.620 | and pills, et cetera,
00:04:37.940 | why that leads to complex yet fairly circumscribed
00:04:43.980 | sets of experience like visual and auditory hallucinations,
00:04:47.280 | changes in particular thought patterns,
00:04:49.020 | and neuroplasticity that, in many cases,
00:04:52.580 | in the clinical setting, provided things are done correctly,
00:04:55.580 | improvements in mood, relief from depression,
00:04:58.980 | relief from various compulsive disorders, et cetera, right?
00:05:02.540 | This is really what you need to understand
00:05:04.000 | if you want to understand psilocybin and how it works
00:05:06.940 | and how to make it work optimally
00:05:09.140 | for a given condition or goal.
00:05:12.380 | You have to understand what it's actually doing
00:05:14.540 | and what allows psilocybin to do fairly specific things
00:05:18.940 | in comparison to serotonin,
00:05:20.420 | even though psilocybin and serotonin are so similar,
00:05:23.360 | is that psilocybin mainly binds to and activates
00:05:27.180 | the so-called serotonin 2A receptor.
00:05:30.820 | The serotonin 2A receptor is one of, again,
00:05:34.060 | many different serotonin receptors,
00:05:36.100 | but serotonin 2A is expressed in particular areas
00:05:39.920 | of the brain and even on particular areas of neurons
00:05:43.640 | in the brain that allow for very specific types of changes
00:05:47.600 | in neural circuitry to take place,
00:05:49.600 | not just when one is under the influence of psilocybin,
00:05:52.400 | but afterwards as well.
00:05:54.220 | So really, in order to have a useful discussion
00:05:56.320 | about psilocybin, we need to talk a lot
00:05:58.800 | about the serotonin 2A receptor,
00:06:01.000 | but fortunately for you,
00:06:02.720 | unless you're somebody really interested
00:06:03.920 | in structural biology or cell biology,
00:06:06.020 | that discussion is not going to be
00:06:07.880 | about the binding pocket for serotonin
00:06:10.000 | on serotonin 2A receptor,
00:06:11.880 | or a lot of the downstream signaling
00:06:13.480 | of the serotonin 2A receptor.
00:06:14.800 | We'll talk a little bit about that where it's relevant,
00:06:17.560 | but more importantly,
00:06:18.880 | at least for sake of today's discussion,
00:06:20.360 | we're going to talk about how the serotonin 2A receptor
00:06:23.560 | is really the one responsible for triggering
00:06:25.880 | all the changes in neural circuitry
00:06:28.200 | that lead to the changes, that is the improvements in mood,
00:06:32.240 | the relief from compulsive disorders in many case,
00:06:35.440 | but really it's the serotonin 2A receptor selectivity
00:06:38.840 | of psilocybin that is leading to all the excitement
00:06:42.620 | that you hear about in terms of psilocybin
00:06:45.480 | as a therapeutic tool.
00:06:47.020 | Let me say that from a slightly different angle.
00:06:50.840 | There are data that I'll talk about today,
00:06:52.580 | which show that one, although in most cases,
00:06:56.260 | two psilocybin journeys done with particular dosages
00:06:59.800 | of psilocybin lead to maximal binding or occupancy
00:07:04.060 | of those serotonin 2A receptors in ways that lead
00:07:06.840 | to significant and unprecedented relief
00:07:09.600 | for major depression.
00:07:10.900 | In fact, you'll soon learn that the clinical trials
00:07:12.840 | for psilocybin are outperforming standard therapy
00:07:17.040 | and outperforming so-called SSRIs
00:07:20.000 | and various other antidepressants
00:07:21.860 | in terms of providing depression relief
00:07:23.980 | in ways that are frankly staggering, not just to me,
00:07:28.000 | but to the psychiatric community at large.
00:07:29.900 | And this is where so much of the excitement is coming from.
00:07:32.880 | Now, that statement could be taken one way,
00:07:35.420 | which is to just say, okay, well,
00:07:37.320 | here's a compound psilocybin that outperforms SSRIs
00:07:40.740 | and therefore all the attention should be on psilocybin.
00:07:43.820 | But SSRI stands for Selective Serotonin Reuptake Inhibitor.
00:07:48.820 | In other words, the SSRIs of which there's now a lot
00:07:52.700 | of controversy, things like Prozac, Zoloft, et cetera.
00:07:55.780 | I'm sure you've heard some of this controversy.
00:07:57.240 | There are people who are very pro-SSRIs,
00:07:59.380 | although there are a growing number of people
00:08:01.280 | who really feel that the SSRIs are probably most appropriate
00:08:04.140 | for things like obsessive compulsive disorder,
00:08:06.340 | where they in fact can be very beneficial.
00:08:09.460 | But there's a lot of kind of leaning back from SSRIs
00:08:13.340 | as the be-all end-all for the treatment
00:08:16.620 | of depression nowadays because of the side effect profiles.
00:08:19.860 | And the fact that it's not even really clear
00:08:21.880 | that serotonin deficiencies are the major cause
00:08:24.420 | of depression in the first place.
00:08:26.660 | Now, again, we're talking about psilocybin,
00:08:28.620 | not about SSRIs, but you should be thinking,
00:08:30.620 | wait, how is it that two molecules, psilocybin
00:08:34.940 | and some particular SSRI, both of which look like
00:08:39.940 | and/or increase serotonin transmission in the brain,
00:08:42.860 | are leading to either incredibly positive
00:08:45.440 | and interesting outcomes or to kind
00:08:47.620 | of troubling side effect riddled outcomes.
00:08:50.300 | And again, it all boils back down to the selectivity
00:08:53.980 | of psilocybin to bind that serotonin to a receptor.
00:08:57.620 | And so in order to understand how psilocybin works
00:09:00.060 | and in order to understand proper dosing profiles
00:09:02.260 | and spacing of sessions, aka journeys,
00:09:04.540 | we really need to talk a little bit more
00:09:06.060 | about the serotonin 2A receptor, where it is in the brain,
00:09:10.260 | what sorts of things happen when psilocybin binds
00:09:13.340 | the serotonin 2A receptor, and how those things set
00:09:16.520 | in motion the various changes, the neuroplasticity
00:09:20.300 | that allows people to feel better in terms of their mood.
00:09:23.140 | And as you'll soon learn, can experience more pleasure
00:09:25.700 | and joy from things like music and enhanced creativity.
00:09:29.040 | All the things that I do believe,
00:09:30.780 | whether or not people are thinking about
00:09:32.700 | or maybe even exploring psilocybin for recreational
00:09:35.360 | or therapeutic purposes, all the things that people want
00:09:38.380 | and are really talking about and perhaps even doing
00:09:41.020 | psilocybin in order to obtain.
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