Essentials: Psychedelics for Treating Mental Disorders

00:00:00.000 | Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and

00:00:05.400 | actionable science-based tools for mental health, physical health, and performance.

00:00:10.000 | I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford

00:00:15.980 | School of Medicine. And now, my conversation with Dr. Matthew Johnson. Well, Matthew,

00:00:21.000 | I've been looking forward to this for a long time. I'm a huge fan of your scientific work,

00:00:26.300 | and I'm eager to learn from you. Likewise. Big fan and happy to do this with you.

00:00:31.420 | All right. Well, thank you. My first question is a very basic one, which is what qualifies a substance

00:00:37.480 | as a psychedelic? Nomenclature is a real challenge in this area of psychedelics. So, starting with the

00:00:45.420 | word psychedelic, it just, if you're a pharmacologist, it's not very satisfying because that term really

00:00:54.240 | spans different pharmacological classes. In other words, if you're really concerned about receptor

00:00:59.500 | effects and the basic effects of a compound, it spans several classes of compounds. But overall,

00:01:07.600 | so it's really more of a cultural term or it does have a relationship to drug effects, but it's at the

00:01:17.280 | at a very high level. So, all of the so-called psychedelics across these distinct classes that I

00:01:25.260 | can talk more about, the way I put it is they all have the ability to profoundly alter one's sense of

00:01:33.260 | reality. And that can mean many things. Part of that is profoundly altering the sense of self

00:01:38.380 | acutely. So, when someone's on the psychedelic. So, the different classes that can be the specific

00:01:47.760 | pharmacological classes that can be called a psychedelic are one that what are called the

00:01:53.720 | classic psychedelics. So, in the literature, you'll see that term. And hallucinogen and psychedelic are all

00:02:00.020 | have traditionally been used synonymously. I think there was a little of a tendency to stay away from

00:02:05.940 | psychedelics of the baggage, but there's been a return to that in the last several years. But the

00:02:10.900 | classic psychedelics or classic hallucinogens are things like LSD, psilocybin, which is in so-called

00:02:19.300 | magic mushrooms. It's in over 200 species that we know of so far of mushrooms. Dimethyltryptamine or DMT,

00:02:27.540 | which is in dozens and dozens of plants. Mescaline, which is in the peyote cacti and some other cacti like

00:02:35.940 | San Pedro. And even amongst these classic psychedelics, there are two structural classes. So, that's the

00:02:45.060 | chemistry. There's the tryptamine based compounds like psilocybin and DMT. And then there's the

00:02:50.980 | phenethylamine based compounds. So, these are the basic two basically building blocks that you're

00:02:57.380 | starting from, either a tryptamine structure or a phenethylamine structure. But that's just the

00:03:02.500 | chemistry. All of the, what's more important, or at least to someone like me, are the receptor effects.

00:03:09.700 | And then ultimately, that's going to have a relationship to the behavioral and subjective

00:03:13.380 | effects. So, all of these classic psychedelics serve as agonists or partial agonists at the

00:03:18.660 | serotonin-2A receptor. So, subtype of serotonin receptor. Then you have these other classes of

00:03:25.860 | that you, compounds that you could call psychedelic. Another big one would be the NMDA antagonists. So,

00:03:33.060 | this would include ketamine, PCP, and dextromethorphan, something I've done some research

00:03:38.340 | with which folks might recognize from like robo-tripping, guzzling like, you know, call syrup.

00:03:44.900 | A large overlap in the types of subjective effects that you get from those compounds compared to the

00:03:50.420 | 2A agonist classic psychedelics. But then you have another big one of MDMA, which really stands in a

00:03:57.620 | class by itself. So, it's been called an intactogen. What does that mean? It means like touching within.

00:04:05.460 | It sort of eludes to the idea that it can really put someone in touch with their emotions. It's also

00:04:12.020 | been called an empathogen, meaning it can afford empathy. So, I get the impression that

00:04:18.020 | the psychedelic space is an enormous cloud of partially overlapping compounds.

00:04:22.980 | Right.

00:04:23.540 | Meaning, some are impacting the serotonin system more than the dopamine system. Others are

00:04:28.820 | impacting the dopamine system more than the serotonin system.

00:04:31.860 | Given that the definition of a psychedelic is that it profoundly alters sense of self,

00:04:38.100 | at least that's included as a partial definition.

00:04:42.260 | Mm-hmm. I think of psychedelics as profoundly altering models. You know, we're prediction machines,

00:04:52.100 | and so much of that is top-down. And psychedelics have a good way of, loosely speaking, dissolving those

00:05:03.860 | models. And one of the reality…

00:05:07.060 | Can you give us an example of a model? Like, I know that when

00:05:11.460 | I throw a ball in the air, it falls down, not up.

00:05:14.100 | This might sound extreme, but there are these cases. It was overblown in sort of the propaganda

00:05:19.300 | of the late '60s, early '70s, but there are credible cases of people, and it's very atypical, of

00:05:25.860 | sounds like they really thought they could fly and, you know, jump out of a window. Now,

00:05:33.060 | far more people every year fall, I mean, who knows, you know, they fall and die out of, you know,

00:05:41.140 | from height because they're drunk, you know. So, this is extremely rare. But, you know,

00:05:46.340 | there are some, like, pretty convincing cases. There was one research volunteer in our studies

00:05:52.180 | that she looked like she was, in one of our studies, like, she was trying to dive through

00:05:59.780 | a painting on the wall. She was fine, but she, reviewing the video, it looked like

00:06:06.660 | she really thought that she was going to go through that painting, and who knows?

00:06:12.580 | - So, she was- - In the other dimension.

00:06:14.900 | - Yeah. So, they're violating these predictions. The reason I ask it, the question the way I did,

00:06:19.860 | is because given the enormous cloud of different substances, and given the range of

00:06:24.660 | previous experiences that people show up to a psychedelic experience with,

00:06:29.140 | I feel like the ability to extract some universal themes is useful, especially for people who haven't

00:06:36.260 | done them before, right? - Yeah.

00:06:37.540 | - Who might not have an understanding of what their effects are like. Can we just briefly touch on

00:06:43.540 | the serotonin system? - Mm-hmm.

00:06:46.980 | - So, compounds like LSD, lysergic acid, diethylamide, and psilocybin, my understanding is that they

00:06:55.300 | primarily target the serotonin system. How do they do that at a, kind of, general level? And why would

00:07:05.460 | increasing the activity of a particular serotonin receptor, or batch of serotonin receptors, lead to

00:07:11.060 | these profoundly different experiences that we're calling model challenges, challenging pre-existing

00:07:19.300 | models and predictions? - Yeah.

00:07:20.500 | - I mean, at the end of the day, it's a chemical, and these receptors are scattered around the brain with

00:07:25.940 | billions of other receptors. - Yeah.

00:07:27.780 | - What do we think is going on in a general sense?

00:07:32.740 | - Yeah. Yeah. And this is really the area of active exploration, and we don't have great answers. We know

00:07:39.140 | a good amount about the receptor-level pharmacology. Some things about post-receptor signaling pathways.

00:07:45.220 | In other words, just fitting into the receptor. Clearly, you know, serotonin itself is not

00:07:50.580 | psychedelic, you know, or else we'd be tripping all of us all the time.

00:07:53.780 | - Because when I eat a bagel, I get serotonin release, right? - Uh-huh.

00:07:56.820 | - I mean, there's— - And it's very different than LSD.

00:07:58.580 | - Or turkey. I mean, there's triptophan, right. - Mm-hmm.

00:08:00.660 | - My understanding of serotonin is that in very broad strokes, that it generally leads to a state of being

00:08:07.620 | fairly—it pushes the mind and body towards a state of contentment within the immediate experience.

00:08:14.980 | Whereas the dopamine system really places us into an external view of what's out there in the world

00:08:20.740 | and what's possible. - Yeah.

00:08:22.020 | - Is that fair to say? - Need to do something.

00:08:23.700 | I mean, that's consistent with my understanding.

00:08:26.740 | And I'll certainly not in terms of—I don't primarily identify as a neuroscientist.

00:08:32.980 | I'll definitely tell the, you know, the viewers that we're far more in your domain here than mine,

00:08:38.580 | but in terms of how psychedelics and other drugs, you know, interface at the neuroscience level.

00:08:43.700 | - Well, feel free to explain it at the experiential level.

00:08:46.660 | - Yeah. - I mean, it doesn't have—let's say I were to come to one of your clinical trials,

00:08:50.820 | because these are clinical trials, right, at your lab at Hopkins.

00:08:54.020 | - Yeah. - And would I need to be depressed,

00:08:56.340 | or could I just be somebody who wanted to explore psychedelics?

00:08:59.220 | - We've had studies for all of these. - Okay.

00:09:02.340 | - And a number of other disorders.

00:09:03.700 | So healthy normal studies—the code for not a problem to fix, but we're all—

00:09:08.340 | that's what's amazing about psychedelics, though, because if you administer them under this model,

00:09:13.700 | and you develop a relationship and give a high dose of psychedelic,

00:09:16.500 | you can be a healthy normal without a diagnosable issue, but, man, we're all human,

00:09:21.060 | and the issues seem to come to the surface. - Sure, yeah.

00:09:23.620 | - So, but we've done work with smoking cessation, so people trying to quit tobacco and haven't been successful.

00:09:29.140 | - So, a variety of reasons. - Right.

00:09:30.820 | - So, maybe I'll just ask some very simple questions that would kind of step us through the process.

00:09:35.060 | So, let's say I were to sign up for one of these trials, and I qualified for one of these trials.

00:09:39.620 | I'd show up—you said I would do several hours in advance of getting to know the team that would,

00:09:43.860 | that would be present during this psychedelic journey.

00:09:47.620 | - First, there's screening, so it's kind of like a couple of days of both psychiatric,

00:09:52.020 | like structured psychiatric interviews about your whole, your past, and symptoms across the

00:09:58.260 | the DSM, the psychiatric bible, to see if you might have various disorders that could disqualify you,

00:10:04.900 | like the main ones being the psychotic disorders, schizophrenia, and also including

00:10:09.940 | bipolar, so the manic side of bipolar. So, so after that, and also cardiovascular screening,

00:10:16.020 | heart disease, after that screening, then the preparation where you get, you're both,

00:10:19.940 | you get, you develop a therapeutic rapport with the people who are going to be in the room with you,

00:10:24.740 | your guides, but you're also then didactically sort of explained about what the psychedelic could be

00:10:32.100 | like, and that's kind of a laundry list because they're more known by their variability.

00:10:37.380 | You could have the most beautiful experience of your life, or the most terrifying experience of

00:10:42.500 | your life. So it's this kind of laundry list of like the things that could happen, so there's

00:10:45.940 | no surprises.

00:10:46.900 | - I think it's so important for people to hear because you really can't predict how somebody is going to

00:10:52.340 | react internally. Let's say that somebody passes all the prerequisites, and it's the day.

00:11:00.180 | Comes the day that they're going to have this experience. Are they eating mushrooms like you

00:11:07.300 | hear about, or are they taking it in capsule form, and how do they get it into their body?

00:11:11.460 | - So they receive pure psilocybin. Most of our studies are looking at where we want a psychedelic

00:11:18.020 | effect are in the 20 to 30 milligram range. The session day itself is not full of, for most of our studies,

00:11:25.540 | is not full of tasks. We really want to look at the therapeutic response. Obviously, if it's a

00:11:30.020 | therapeutic study, we want it to be a meaningful experience. And research has found, not surprisingly,

00:11:36.100 | that you get a less meaningful experience when you're in an fMRI, or when you're doing a lot of

00:11:41.620 | cognitive tasks. So our typical therapeutic model, which again, isn't just limited necessarily to the

00:11:47.380 | therapeutic studies where we're trying to treat a specific disorder, is to have that preparation.

00:11:54.020 | So the person feels very comfortable with their guides. I mean, ultimately, what I tell people is

00:12:00.740 | like, any emotional response, it's all welcome. I mean, you could be crying like a baby hysterically,

00:12:09.220 | like that's what you should be doing if that's what you feel like.

00:12:11.780 | - I mean, you're doing therapy for people. This is, it's not just about the experience.

00:12:15.940 | - Right. And the experience itself is very much shaped by that container, by the environment,

00:12:22.420 | and the degree to which one allows it to happen. Like one should let go of control.

00:12:27.780 | - The letting go of control is an interesting feature, actually, because one of the common

00:12:32.420 | themes of good psychoanalysis or psychotherapy of any kind is that there's a trust built between

00:12:38.500 | the patient and the analyst and that relationship becomes a template for trust more generally and

00:12:45.540 | trust in oneself. How do you convince people to go further and further down that path? What do you

00:12:51.460 | think allows them to do that? Because I think that that to me is one of the more unusual aspects to

00:12:57.780 | psychedelics is that normally the, the social pressure, but also just our internal pressure

00:13:04.020 | from our own brain is pay attention to many things at once, not just one. Is that-

00:13:09.940 | - Especially these days. Yeah.

00:13:11.300 | - Exactly. - Multi-task, yeah.

00:13:12.340 | - Multi-task. And the more that we focus on one thing, the more bizarre that thing actually can appear to

00:13:18.260 | us, right? - Right.

00:13:19.300 | - I mean, even if it's the tip of your finger and you're not taking any psychedelics, you spend a long

00:13:22.740 | enough looking at the tip of your finger, you will notice some very weird things, right?

00:13:27.140 | - That's, I think of that as the classic psychedelic effect or one classic effect and one I've used many

00:13:32.980 | times of this example of why people shouldn't necessarily, you know, these aren't, these,

00:13:40.340 | one should be judicious in putting themselves in these circumstances. Someone could be, you know,

00:13:46.420 | having a very strong psilocybin experience and they're trying to navigate their way in

00:13:51.460 | Manhattan crossing the street and they might be staring into the hand and real like that's,

00:13:56.740 | their hand is the most amazing miracle. Like the entire universe has essentially conspired to come

00:14:02.740 | to this one point to make this absolutely breathtaking. It's almost like, I think of the simplest form of,

00:14:08.660 | of, of what we know, the simplest form of learning is habituation. Simply keep applying stimuli and there's

00:14:13.780 | less response. Like, this is what organisms do. This is what we have to do. And it's like,

00:14:17.940 | there's this dis habituation component that like-

00:14:20.820 | - Dis habituation.

00:14:21.780 | - Yes. Like we wouldn't be able to get through life if we wouldn't be able to cross that street,

00:14:25.380 | if we were like, hold, like this is a miracle.

00:14:28.580 | - It sounds like on psychedelics, the, one of the primary goals therapeutically is to really drill into one of

00:14:34.260 | these perceptual bubbles and expand that bubble and the safety it seems is the safety. It's sort of like

00:14:41.300 | a permission to, to do that without worrying that something's going to happen.

00:14:46.420 | - Right. Because, you know, I've had people there on the couch.

00:14:50.980 | Yeah. I remember one lady said, this is probably, uh, 13, 14 years ago said,

00:14:56.180 | "Matt, tell me again. I can't die. Like, I feel like my heart is going to rip through my chest."

00:15:01.620 | I mean, she was feeling her, and I should say, typically cardiovascular response is, is modest.

00:15:07.300 | The, the pulse and blood pressure go up. And if it goes over a certain level, we have a protocol and

00:15:12.420 | we've had to do this only a few times, but the physician comes in, gives them a little nitroglycerin

00:15:16.580 | under the tongue, uh, and, uh, you know, knocks the blood pressure down a little bit,

00:15:19.860 | doesn't affect the experience. So we have it all in place, even though they'd probably be fine out of

00:15:23.700 | an abundance of caution. Um, but, but yeah, but someone can feel that, my God, I'm going to die.

00:15:31.300 | Like I, I have never felt my heart beat like this before.

00:15:36.260 | So there's a, an expansion of a particular, fairly narrow percept. It could be sound,

00:15:42.340 | could be an emotion, could be sadness, could be a historical event or a fear of the future.

00:15:47.380 | And you've mentioned before that there's something to be learned in that experience.

00:15:53.620 | Yeah.

00:15:54.180 | There's something about going into that experience in a, in an, um, in an, in an undeterred way

00:16:02.580 | that allows somebody to bring something back into more standard reality.

00:16:08.180 | Yeah.

00:16:08.740 | Given the huge variety of experiences that people have on psychedelics, given the huge variety of

00:16:13.940 | humans that are out there, but what are now very clear therapeutic effects in the realm of depression,

00:16:20.900 | what do you think is the value of going into this fairly restricted perceptual bubble? What we are

00:16:28.900 | calling letting go or giving up control, because if the experiences are many, but the value of what

00:16:36.420 | one exports from that experience is kind of similar across individuals, that raises all sorts of

00:16:42.340 | interesting questions. And this is not a philosophy discussion. We're talking about biology and

00:16:46.740 | psychology here.

00:16:47.620 | Yeah.

00:16:47.940 | So what are your thoughts on that?

00:16:49.460 | This is in the terrain we're figuring out, you know, so there's no, the educated speculations,

00:16:55.140 | the best I can provide, but I, I think the best, the, the, the, the most, I think the common denominator

00:17:04.100 | are persisting changes in self-representation.

00:17:08.900 | Okay. Tell me more about self-representation.

00:17:11.140 | That's, uh, the way one holds the sense of self, the relate, the fundamental relationship

00:17:18.580 | of a person in the world. I mentioned earlier that these experiences seem to alter the models we hold

00:17:24.820 | of reality. And I think that the self is the biggest model that I am a thing that's separate from other

00:17:29.860 | things. And that's, I am defined by certain, I have a certain personality and I, I'm a smoker that's

00:17:37.460 | having a hard time quitting, or I'm a depressed person that, you know, views myself as a failure and all of

00:17:43.220 | these things. Those are models too. So this is this expansion of the perceptual bubble, a narrow,

00:17:48.820 | a narrow, uh, percept that then grows within the confines of that narrow percept.

00:17:54.740 | Yeah.

00:17:54.980 | The, so sense of self is a very interesting, uh, phenomenon. And if we could dissect it a little

00:18:00.180 | bit, um, there's the somatic sense of self. So the ability to literally feel the self, uh,

00:18:06.260 | into this process we call interoception. And then there's the, the, the title of the self,

00:18:11.140 | the I am blank. Yeah. And I noticed you said that several times and it's intriguing to me how one

00:18:16.340 | defines themselves internally, not just to other people, but how one psychologically and by default

00:18:25.700 | in, uh, defines themselves, I think is very powerful. Like, um, and depressed people as well as happy

00:18:32.020 | people seem to define themselves in terms of these categories of emotional states. So I think it's,

00:18:36.980 | it's so interesting that letting go and going into this perceptual bubble, which is facilitated by

00:18:44.500 | obviously a really wonderful team of, of therapists, but also the serotonergic agent allows us to, um,

00:18:51.460 | potentially reshape the perception of self. That's, that's a tremendous feat of neuroplasticity.

00:18:57.780 | Right. I think there's something about this change in, in sense of self. There is, it seems to be

00:19:02.660 | something on the identity level, both with, I think of the, the work we did with cancer patients who had

00:19:07.060 | substantial depression and anxiety because of their cancer, and also our work with people trying to quit

00:19:11.940 | cigarette smoking. I mean, there's this real, there seems to be when it really works, this change in how

00:19:19.700 | people view themselves like smoking, like really stepping out of this model. Like I'm a smoker.

00:19:29.140 | It's tough to quit smoking cigarettes. I can't do it. I failed a bunch of times. I remember one

00:19:34.980 | participant during the session, but he held onto this afterwards said, my God, it's like, I can really

00:19:40.980 | just decide like flicking off a bike. I can decide not to smoke. And it's, I call these duh experiences

00:19:47.380 | with psychedelics because people often like in the cancer studies say, I'm causing most of my own

00:19:53.060 | suffering. Like I can, I can follow my appointments. I can do everything, but I can still plan for the,

00:19:57.860 | I'm not getting outside in the sunshine. I'm not playing with my grandkids. I'm choosing to do that.

00:20:03.540 | And it's like, they told themselves that before. And the smoker has told themselves a million times

00:20:08.020 | I can, so it sounds when it comes out of their mouths and folks will say, this is part of the

00:20:13.460 | ineffability of a psychedelic experience. Folks say, I know this sounds like bullshit. And this sounds like,

00:20:18.180 | but my God, I could just decide. Like they're feeling this gravity of agency that seems to be at times

00:20:26.980 | fundamentally like supercharged from a psychedelic experience. This idea, like I'm just going to make

00:20:32.980 | make a decision. Like normally, like you tell a depressed person, like, don't,

00:20:37.140 | don't think of yourself that way. You're not a failure. You're looking at all that. It's just,

00:20:40.180 | yeah. It's like, and you can actually, in one of these states have an experience where you realize

00:20:44.820 | like, my God, just like using MDMA to treat PTSD. And we're going to be starting work with psilocybin

00:20:50.020 | to treat PTSD. Someone could really reprocess their trauma in a way that like has lasting effects.

00:20:57.700 | And clearly there's probably something, you know, reconsolidation of those memories. They are,

00:21:01.620 | they are, they are altered, you know, very consistent with what the, our understanding of the

00:21:07.460 | way memory works. So the whole idea of people can actually, in a few hours, have a, such a profound

00:21:13.860 | experience that they, they decide to make these changes in who they are and it sticks.

00:21:19.780 | I'm fascinated by this idea that a, a somatic and a perceptual experience, but a real experience of

00:21:27.220 | the sort that you're describing is what allows us to reshape our neural circuitry and to feel

00:21:32.100 | differently about ourselves. And I know there's been really tremendous success in many individuals of

00:21:40.180 | alleviating depression, of treating trauma with these different compounds. If we could,

00:21:46.020 | I'd like to just ask about some of the more dopaminergic compounds, in particular MDMA.

00:21:51.060 | Yeah. And my understanding is that MDMA leads to very robust increases in both dopamine and serotonin

00:21:59.700 | simultaneously. So why would it be that having this increased dopamine and increased serotonin would

00:22:08.020 | provide an experience that is beneficial? And how do you, to the extent that you can describe it,

00:22:15.060 | how do you think that experience differs from the sorts of experiences that people have on psilocybin

00:22:19.620 | or more serotonergic agents? Speculating, but it may be that MDMA for a broader number of people

00:22:27.940 | is better for, for trauma because the chances of having an extremely challenging experience, what I call

00:22:35.780 | the bad trip, like really freaking out is much lower with MDMA. People can have bad trips, but they're of a

00:22:43.380 | different nature. It's not, it's not sort of like freaking out because all of reality is sort of

00:22:49.540 | shattering and it's less of this. It can take so many forms with the classic psychedelics, but like

00:22:56.180 | typically you'll, you'll hear something like, I didn't know it was going to be like this, no matter how

00:23:02.500 | hard you tried to prepare them that like, this is like, get me off this. You're talking about LSD or

00:23:09.220 | psilocybin. Yeah. Yeah. And just the sense of like, I'm going insane. This is so far beyond anything I've

00:23:18.260 | ever experienced. And it's scaring the out of me. I don't have a toehold on anything, even that I exist

00:23:26.580 | as, as, as, as an entity. And that can be really, I think, frankly, experientially, that's kind of the

00:23:32.420 | gateway to both the transcendental mystical experiences, the, the, the sense, uh, of unity

00:23:39.540 | with all things, which we know our data suggests is related, um, to long-term positive outcomes.

00:23:46.260 | Wait, I want to make sure I understand. So you're saying the bad trip can be related to the

00:23:49.780 | transcendental experience. Right. I think those are both speculating, but you, you have to pass through

00:23:56.020 | this sort of like, you know, reality shattering, including your sense of self. And one can handle

00:24:02.660 | that in one of two ways. You can either completely surrender to it, or you can try to hang on. And if

00:24:09.380 | you try to hang on, it's going to be more like a bad trip. So again, I wish there was more, and hopefully

00:24:13.780 | there will be more experimentation. There's a lot going on here in the black box in terms of the operant

00:24:19.220 | behavior of how you are, you know, within yourself choosing to handle like letting go, you know,

00:24:26.420 | and eventually we'll be able to see this in real time with brain imaging. Ah, there they are surrendering

00:24:31.540 | to the psychedelic experience here. They are trying to hold on, but we we're not there yet. But I think

00:24:37.460 | it's a good through clinical observation seems pretty clear that something like that is going on.

00:24:42.580 | There has been an attempt at creating this movement toward openness about psychedelics and their positive

00:24:50.020 | effects. This has happened before. The difference is that now there are people like you inside the walls

00:24:55.380 | of the university or publishing peer reviewed studies and things of that sort. The question is to me,

00:25:00.660 | you know, what are the, what are the valuable exports, right? And where does the extreme lie? I mean,

00:25:06.580 | clearly there's a, there's a problem with tinkering with reality through pharmacology and there's a

00:25:14.980 | benefit. It sounds like to tinkering with reality through pharmacology and for the average person,

00:25:22.900 | right? Or for kids that are hearing this kids that are in their teens, right? Yeah. What are the,

00:25:27.940 | I want to talk about what are the dangers of psychedelics? This is something you don't hear a lot

00:25:32.100 | about these days and it's not because I'm anti-psychotic at all, but what are the dangers?

00:25:36.660 | Yeah. So these can be profoundly destabilizing experiences and ones that, you know, ideally

00:25:45.860 | are had in a safe container, you know, sort of where, where someone, you know,

00:25:54.660 | what are the relevant dangers and what can we do to mitigate those? So there's two biggies.

00:26:00.660 | One, and I've already mentioned, it's people with very severe psychiatric illness, not, not depression,

00:26:09.860 | not anxiety. I'm talking about psychotic disorders like schizophrenia or mania as part of bipolar disorder.

00:26:18.260 | The far more likely danger is the bad trip.

00:26:21.220 | Anyone can have this, the most psychologically healthy person in the world, probably.

00:26:25.540 | You jack the dose high enough and especially in, in, in a less than an ideal environment,

00:26:31.540 | you can have a bad trip. You can, you even get it in an ideal environment like ours at,

00:26:36.020 | at a high dose of around 30 milligrams of psilocybin. After, you know, the best preparation we can provide,

00:26:42.340 | about a third of people will say, essentially at some point they have a bad trip, you know, and we.

00:26:47.460 | At some point within the entire journey. Right. Now they could have one of the most beautiful

00:26:52.260 | experiences of their life, sometimes like a couple minutes later. Right. But at some point they had a

00:26:57.220 | sense of strong anxiety, fear, losing their mind, feeling trapped, something like that.

00:27:03.780 | I definitely want to ask you about micro dose versus standard or macro dosing psilocybin.

00:27:10.500 | I'm micro cynical, if you will, about this term micro dose. Is there any clinical evidence or peer

00:27:17.140 | reviewed published evidence that it works, quote unquote, to make people feel better about anything?

00:27:22.340 | So yeah, the claims are in their number of them. There's two general ones. One is, is sort of acting

00:27:29.460 | in place of the ADHD treating drugs. So the psychomotor stimulants, so like a better version of Adderall.

00:27:36.740 | The other claims are essentially a better version of, of the traditional antidepressants,

00:27:42.820 | a better version of Prozac. None of the peer reviewed studies that are, have much credibility.

00:27:48.900 | Um, none of them have shown a benefit. The handful of studies that have done that have shown

00:27:56.340 | they've ranged from finding no effect whatsoever to just a little bit of impairment, like impairing

00:28:02.420 | someone's ability to do, um, time estimation and production tasks. So you want an accurate sense of

00:28:08.420 | time, at least if you're navigating in the real world, it's different if you're on the couch on

00:28:12.820 | a heroic dose for therapeutic reasons where you're safe. But if you're crossing the street,

00:28:17.460 | if you're getting, you know, in your work life, which is what the way people are claiming to, you know,

00:28:22.660 | use that it helps them be a better CEO. Like you want an accurate sense of time. So if anything,

00:28:27.860 | the data suggests that it makes it a little bit less accurate. And, and there's evidence that someone

00:28:33.460 | feels, uh, a little bit impaired, um, and they feel a little bit high. So in terms of, you know,

00:28:40.580 | you call that abuse liability and research so far, no studies have, have shown, you know,

00:28:46.980 | any increase in creativity, enhancement of any form of cognition or, or, or a sustained improvement in mood.

00:28:55.940 | Now, no studies have actually looked at the, the, the, the system of microdosing that the

00:29:03.380 | aficionados are claiming folks like, um, Paul Stamets and others, they'll have particular formulas.

00:29:09.220 | They're like, you need to take it one day and then take so many days off and take it every four days.

00:29:14.100 | And they really say, you need to be on it for a while. Like a few weeks in, you may start to notice

00:29:18.340 | through this pattern of, of, of using it. And you, you're, you're feeling the benefits

00:29:22.900 | on those off days, like the three or two days in between your active doses. So those are the claims.

00:29:30.100 | Again, we don't know that there's any truth to that working, but studies have not been done

00:29:34.500 | to model that. So that's a big caveat. My bet is, and this is totally based on anecdotes that I think

00:29:42.580 | there is probably a reality to the antidepressant effects. I find that more intriguing because of

00:29:48.180 | the suffering with depression, right? Even if it's an, it, it wouldn't be as interesting as I think

00:29:53.140 | what we're doing with high dose psilocybin or psychedelics to treat, um, depression. It would

00:29:58.580 | be, if this is developed and there's a reality, it would be more like a better, you know, perhaps a

00:30:03.780 | better SSRI, a better Prozac, which are similar, more tools than fewer tools in the toolbox. And it

00:30:11.220 | shouldn't be that surprised. Like even before the, as going back to the tricyclics and the MAO

00:30:17.140 | inhibitors going back to the fifties, like augmenting extracellular serotonin in one way or another

00:30:23.140 | for many people leads to a, to reduction in depressive symptoms. It wouldn't be that crazy

00:30:29.460 | for chronically stimulating a subtype of serotonin receptor that you have an antidepressant effect.

00:30:35.380 | So I think if I had put my bets on it, that there's, if there's anything real, it is in that category.

00:30:40.980 | Although I'm very open to like, maybe there is something to the creativity,

00:30:43.940 | to the, you know, improved cognition, which covers many domains in and of itself. But, um, my, my

00:30:52.820 | greatest hopes are on the, uh, on the antidepressant effects that said in the big picture, I think all of

00:30:59.700 | the most interesting thing about psychedelics are the heroic doses. I mean, the idea that you can give

00:31:04.020 | something one, two, three times and you see improvements in depression months later and in

00:31:09.700 | addiction, you know, over a year later and with these, you know, people dealing with potentially

00:31:15.540 | terminal illness. I mean, it's, I mean, I'm interested in big effects.

00:31:19.860 | Right. I want to make sure that I ask you about the other really important mission that you're

00:31:24.340 | involved in with respect to psychedelics, which is not about depression per se, but is about

00:31:29.700 | neurological, a neurologic injury or head injury. You know, we always think sports, but there are many

00:31:34.820 | people who make a living in a way that is, um, over time is detrimental to their brain. What do you

00:31:42.420 | think is the potential for these compounds, particular psilocybin, but other compounds as well for the, um,

00:31:48.820 | treatment and possible even reversal of neurological injuries? There are anecdotes of, of people saying,

00:31:56.580 | uh, that, that psychedelics have helped heal their brain. You know, they've been in one of these

00:32:03.860 | situations like in sports, uh, a sport where there's repetitive head impact and they're claiming that,

00:32:10.180 | you know, using psychedelics has actually improved their cognitive function. For example, improved their

00:32:15.860 | memory. If you take these anecdotes and you combine it way across orders of analysis to the rodent research

00:32:22.980 | from, um, several labs like David Olson, Brian, uh, Roth, these folks that have shown different forms of

00:32:29.780 | neuroplasticity unfolding. Those effects may be at play and they improve in the psychiatric treatments

00:32:38.500 | that we're dealing with that hat. We don't know that it seems like a decent guess. And we're going

00:32:42.980 | to be figuring out whether that's the case, but another potential that that sets up is that maybe

00:32:48.260 | that's what's going on with, um, with, um, with, with, with, with these claims of improvements from

00:32:56.020 | neurological issues that there's actually, you know, uh, a repair of the brain, uh, uh, from injuries,

00:33:06.420 | underlying, you know, things that, you know, situations where there's repetitive head impact,

00:33:11.140 | perhaps there's a potential for, for helping folks recover from stroke, um, and disorders like that.

00:33:17.620 | Um, it is more exploratory, but what I'm hoping to do is some work with retired athletes who have been

00:33:24.260 | exposed, but by the nature of their sport, for example, in an a athletes in the UFC who have been

00:33:29.940 | exposed to, um, repetitive head impacts, like a lot of sports, um, a lot of, uh, you know, sports expose

00:33:36.580 | people to, and, and, and who are retired from the sport and are suffering from say depression,

00:33:42.100 | which can, uh, in part result from those types of, of, of that history of head impact.

00:33:49.540 | Um, see if we can fix the depression, but then also as a cherry on top in a more exploratory aim,

00:33:57.380 | see if we can have evidence of, of improvement in cognitive function and associate like using MRI,

00:34:04.500 | see if it affects gray matter over time, these types of things to see if there are actually some

00:34:08.980 | evidence of this improved, um, like this more direct repair of the brain. But again, it is very

00:34:16.740 | sort of like, we've got some rodent data, we've got some human anecdotes. We, we, we will acknowledge

00:34:23.780 | it's early days and we look forward to seeing the data. Um, I, I appreciate how cautious you are

00:34:30.020 | and tentative you are. You're not drawing any conclusions. Thank you so much for your time.

00:34:34.260 | Thank you for your time, for your knowledge. And I think you put it best earlier for, uh, holding

00:34:38.580 | the candle in a very dark time. And then now there's light.

Essentials: Psychedelics for Treating Mental Disorders | Dr. Matthew Johnson

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