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Dr. Matthew Johnson on Huberman Lab: How Psilocybin Heals

Psilocybin reshapes self-identity to treat depression and addiction at high doses. Johnson covers clinical dosing, set and setting, and bad-trip risks.

Andrew HubermanhostDr. Matthew Johnsonguest
Jul 24, 202534mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 1:44

    Matthew Johnson; Psychedelics

    1. AH

      Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now, my conversation with Dr. Matthew Johnson. Well, Matthew, I've been looking forward to this for a long time. I'm a huge fan of your scientific work, and I'm eager to learn from you. So-

    2. MJ

      Likewise. Big fan and happy to do this with you.

    3. AH

      Great. Well, thank you. My first question is a very basic one, which is, what qualifies a substance to- as a psychedelic?

    4. MJ

      Nomenclature is a real challenge in this area of psychedelics. So starting with the word psychedelic, it just- if- if you're a pharmacologist, it's- it's not very satisfying, because that term really spans different pharmacological classes. In other words, if you're really concerned about receptor effects and the basic effects of a compound, it spans several com- classes of compounds. But overall- so it's really more of a- a cultural term or a- it does have a relationship to drug effects, but it's at the- at- at a very high level. So all of the so-called psychedelics across these distinct, uh, classes that I can talk more about, um, the way I put it is, they all have the ability to profoundly alter one's sense of reality, and that can mean many things. Part of that is profoundly altering the sense of self, um, acutely, so when someone's on the psychedelic. Um, so

  2. 1:44 – 4:33

    Different Classes of Psychedelics

    1. MJ

      the different classes that can be- the specific pharmacological classes that can be called a psychedelic are, one, the- what are called the classic psychedelics. So in the literature, you'll see that term. And hallucinogen and psychedelic all have traditionally been used synonymously. Um, I think there was a little of a tendency to stay away from psychedelic 'cause of the baggage, but there's been a return to that in the last several years. But the classic psychedelics or classic hallucinogens are things like LSD, um, psilocybin, which is in so-called magic mushrooms. It's in over 200 species that we know of so far of mushrooms. Uh, dimethyltryptamine, or DMT, which is in dozens and dozens of- of- of plants. Um, mescaline, which is in the peyote cacti and some other cacti like San Pedro. And even amongst these classic psychedelics, um, there are two structural- structural classes. So that's the chemistry. There's the tryptamine-based compounds like psilocybin and DMT, and then there's the phenethylamine-based compounds. So these are the basic- two of the basic, the building blocks that- that you're starting from, either a tryptamine structure or a phenethylamine structure. But that's just the chemistry. The- all of the- what's more important, or at least to- to someone like me, are the receptor effects, and then ultimately, that's going to have a relationship to the behavioral and subjective effects. So all of these classic psychedelics serve as agonist or partial agonist at the serotonin-2A receptor, so subtype of serotonin receptor. Then you have these other classes of- of- of- that you- compounds that you could call a psychedelic. Another bi- big one would be the NMDA antagonist, so this would include ketamine, PCP, and dextromethorphan, something I've done some research with, which folks might recognize from, like, robo tripping, guzzling, like, you know, uh, cough syrup. A large overlap in the types of subjective effects that you get from those compounds compared to the 2A agonist classic psychedelics. Um, but then you have another big one, MDMA, which really stands in a class by itself. So it's been called an entactogen, and- and, uh-

    2. AH

      What does that mean?

    3. MJ

      It means, like, uh, uh, touching within. It sort of alludes the idea that it can really put someone in touch with their emotions. Um, it's also been called an empathogen, meaning can- it can afford empathy.

    4. AH

      So I get the impression that the s- psychedelic space is a enormous cloud of partially overlapping compounds-

    5. MJ

      Right.

    6. AH

      ... uh, meaning some are impacting the serotonin system more than the dopamine system, others are impacting the dopamine system more than- than the serotonin system.

  3. 4:33 – 6:18

    Psychedelics & Altering Models

    1. AH

      Given that the definition of a psychedelic is that it profoundly alters sense of self, at least that's included as a partial definition.

    2. MJ

      Mm-hmm. And I think o- of these as- as psychedelics as profoundly altering models. You know, you know, we're all- you know, we're prediction machines, and that's lar- so much of that is- is top down, and, uh, and- and- and psychedelics have a good way of, you know, loosely speaking, dissolving those models. And- and one of- the- the reality-

    3. AH

      Can you give us an example of one of- like, a model? Like, like, I know that when, um, I throw a ball in the air, it falls down, not up.

    4. MJ

      This might sound extreme, but there are these cases, it was over- overblown in sort of the propaganda, the late '60s, early '70s, but there are credible cases of people, and it- it's very atypical, of sounds like they really thought they could fly, and, you know, jump out of a- a- a- a- of a window. Now, far more people every year (laughs) fall, ju- I mean, who knows, you know?

    5. AH

      Sure.

    6. MJ

      They- they- they- they fall and die out of- you know, from height because they're drunk, you know? So this is extremely rare. But, you know, there are some, like, pretty convincing, um, cases. There was one research volunteer in our studies, uh, that, uh, it- she l- looked like she was, in one of our studies, like she was trying to dive through a painting on the wall. She was fine, but she (laughs) -... reviewing the video, it looked like she really thought that she was going to go through that painting, and who knows? (laughs) You know what I mean?

    7. AH

      Right. So, so she would-

    8. MJ

      Into the other dimension.

    9. NA

      Yeah.

    10. AH

      Yeah. So they're violating these predictions. The reason I ask

  4. 6:18 – 8:44

    LSD, Psylocibin & Serotonin

    1. AH

      it, the, the question the way I did, is because, um, given the enormous cloud of different substances, and given the range of previous experiences that people show up to a psychedelic experience with, uh, I feel like the ability to extract some universal themes is, is useful.

    2. MJ

      Mm-hmm.

    3. AH

      Especially for people who haven't done them before, right?

    4. MJ

      Yeah.

    5. AH

      Who might j- uh, not have an understanding of what their effects are like. Can, uh, we just briefly touch on the serotonin system?

    6. MJ

      Mm-hmm.

    7. AH

      So, compounds like LSD, lysergic acid diethylamide, and psilocybin, my understanding is that they primarily target the serotonin system. How do they do that at a kind of general level? And why would increasing the activity of a particular serotonin receptor, or batch of serotonin receptors lead to these profoundly different experiences that we're calling, um, m- model challenges, challenging preexisting models and predictions?

    8. MJ

      Yeah.

    9. AH

      I mean, at the end of the day, it's a chemical, and these receptors are scattered around the brain with billions of other receptors.

    10. MJ

      Yeah.

    11. AH

      W- w- uh, what do we think is going on at a, in a general sense?

    12. MJ

      Yeah, yeah. And this is really the area of active exploration, and we don't have great answers. We know a good amount about the receptor level pharmacology. Some things about post-receptor signaling pathways. In other words, just fitting into the receptor. Clearly, you know, serotonin itself is not psychedelic, you know, (laughs) or else we'd be tripping all of us all the time.

    13. AH

      Right. 'Cause when I eat a bagel, I get serotonin release, right?

    14. MJ

      Uh-huh.

    15. AH

      I mean, there's, uh, uh, or turkey-

    16. MJ

      And it's very different than LSD.

    17. AH

      I mean, there's tryptophan and ... Right?

    18. MJ

      Mm-hmm.

    19. AH

      My understanding of serotonin is, is that in j- in very broad strokes, that it, it generally leads to a state of being fairly ... It pushes the mind and body towards a state of contentment-

    20. MJ

      Right.

    21. AH

      ... within the immediate experience. Whereas the dopamine system really places us into an external view of what's out there in the world and what's possible.

    22. MJ

      Yeah.

    23. AH

      Is that fair to say?

    24. MJ

      Need to do something. I mean, that's consistent with my u- understanding. And, uh, and, and, and I'll certainly not in terms of ... I don't primarily identify as a, a neuroscientist. I definitely tell the, you know, the viewers that we're h- far more in your domai- domain here than mine. But in terms of how psychedelics and other drugs, you know, interface at the, at the neuroscience level.

    25. AH

      Well,

  5. 8:44 – 12:28

    Psychedelic Clinical Trials

    1. AH

      feel free to, to explain it at the experiential level.

    2. MJ

      Yeah.

    3. AH

      I mean, it doesn't have ... Let's say I were to come to one of your clinical trials. 'Cause these are clinical trials, right?

    4. MJ

      Mm-hmm.

    5. AH

      And in your, at your lab at Hopkins.

    6. MJ

      Yeah.

    7. AH

      And, uh, would I need to be depressed or could I just be somebody who wanted to explore psychedelics?

    8. MJ

      It, we've had studies for all of these.

    9. AH

      Okay.

    10. MJ

      And, and, and a number of other disorders.

    11. AH

      Okay.

    12. MJ

      So healthy/normal studies-

    13. AH

      Okay.

    14. MJ

      ... they, they code for not a problem to fix, but we're all hu- ... That's what's amazing about p- psychedelics though, because you, if you administer them under this model, and you develop a relationship and give a high dose of psychedelic, you could be healthy/normal without a, a diagnosable issue. But man, we're all human and the issues seem to come to the surface.

    15. AH

      Sure. Yeah. I mean-

    16. MJ

      So but we've done work with, uh, smoking cessation, so people trying to quit tobacco and haven't been successful.

    17. AH

      So a variety of reasons.

    18. MJ

      Right.

    19. AH

      So, um, maybe I'll just ask some very simple questions that, that would kind of step us through the process. So let's say I were to sign up for one of these trials, and, and I qualified for one of these trials. I'd show up. You said I would do several hours in advance of getting to know the team that would-

    20. MJ

      Mm-hmm.

    21. AH

      ... that would be present during this psychedelic journey.

    22. MJ

      Right. First, there's screening. So it's kind of like a, a couple of days of both psychiatric, like s- structured in- psychiatric interviews about your whole, your, your, your past and symptoms across the, the, the DSM, the psychiatric bible, to see if you might have various disorders that, that could, um, disqualify you. Like the, the main ones being the psychotic disorders, schizophrenia, and we're also including, um, bipolar.

    23. AH

      Right.

    24. MJ

      So the manic side of, of bipolar.

    25. AH

      Mm-hmm.

    26. MJ

      So, so after that's ... And also cardiovascular screening, heart disease. After that screening, then the preparation where you get, you're both, you get, you develop a therapeutic rapport with the people who are going to be in the room with you, your guides. Um, but you're also then didactically sort of explained about what the psychedelic could be like. And that's kind of a laundry list, because they're more known by their variability.

    27. AH

      Mm-hmm.

    28. MJ

      You could have the most beautiful experience of your life or the most terrifying experience of your life. So it's just kind of a laundry list of like the things that could happen so there's no surprises.

    29. AH

      Mm-hmm. I think that's so important for people to hear, because you really can't predict how somebody is going to react internally. Let's say that somebody passes all the prerequisites, um, and th- and it's the day.

    30. MJ

      Yeah.

  6. 12:28 – 15:36

    Therapy, Trust, Psychedelics

    1. MJ

    2. AH

      The letting go of control is an interesting feature, actually. Because, uh, one of the common themes of- of good psychoanalysis is, or psychotherapy of any kind, is that there's a trust built between the patient and the analyst, and that relationship becomes a template for trust more generally, and trust in one's self. How do you convince people to go further and further down that path? What do you think allows them to do that? Because I think that- that to me is one of the more unusual, uh, aspects to psychedelics, is that normally the- the social pressure, but also just our internal pressure from our own brain, is pay attention to many things at once.

    3. MJ

      Mm-hmm.

    4. AH

      Not just one. Is that- is-

    5. MJ

      Especially these days. You got to multitask.

    6. AH

      Exactly. Right.

    7. MJ

      Yeah.

    8. AH

      Multitask, and the more that we focus on one thing, the more bizarre that thing actually can appear to us, right?

    9. MJ

      Right. (laughs)

    10. AH

      I mean, even if it's the tip of your finger and you're not taking any psychedelics, you spend long enough looking at the tip of your finger, you will notice-

    11. MJ

      Yeah. It's weird.

    12. AH

      ... some very weird things.

    13. MJ

      Yeah.

    14. AH

      Right?

    15. MJ

      That's- I think of it as the classic psychedelic effect that- or one classic effect, and- and one I've used many times of this example of why people shouldn't necessarily, you know, uh, these aren't- these- uh, one should be judicious in putting themselves in these circumstances. Someone could be, you know, having a- a very strong psilocybin experience and they're trying to navigate their way in Manhattan-

    16. AH

      Right.

    17. MJ

      ... crossing the street, and they might be staring into their hand and real- like, that's- their hand is the most amazing miracle. Like, the entire universe has essentially conspired to come to this one point to make this absolutely breathtaking. It's almost like, I think of the simplest form of- of- of- well, we know that the simplest form of learning is habituation. Simply keep applying stimuli and there's less response. Like, this is what organisms do. This is what we have to do, and it's like there's this dishabituation component that like-

    18. AH

      Dishabituation?

    19. MJ

      Yes.

    20. AH

      Yeah.

    21. MJ

      Like, we wouldn't be able to get through life, and we wouldn't be able to cross that street if we were like, "Ho- like, this is a miracle."

    22. AH

      It sounds like on psychedelics, the- one of the primary goals therapeutically is to really drill into one of these perceptual bubbles and expand that bubble, and the safety-

    23. MJ

      Yeah.

    24. AH

      ... it seems, is the safety- it's sort of like a permission to- to do that without worrying that something's going to happen.

    25. MJ

      Right. Because, you know, I've had people there on the couch, um, yeah, I remember one lady said, this is probably, uh, 13, 14 years ago, said, "Matt, tell me again I can't die. Like, I feel like my heart is going to rip through my chest." I mean, she was feeling her he- and I should say, typically, cardiovascular response is- is modest, the- the, uh, pulse and blood pressure go up. Then if it goes over a certain level, we have a protocol. And we've had to do this only a few times, but the physician comes in, gives them a little nitroglycerin under the tongue, uh, and, uh, you know, knocks the blood pressure down a little bit, doesn't affect the experience. So, we have it all in place, even though they'd probably be fine out of an abundance of caution.

    26. AH

      Sure.

    27. MJ

      Um, but- but yeah, but someone can feel that, "My God, I'm going to die. Like, I- I have never felt my heart beat like this (laughs) before."

  7. 15:36 – 21:19

    Letting Go & Psychedelic Experience, Self-Representation, Lasting Changes

    1. MJ

    2. AH

      So there's a per- an expansion of a particular fairly narrow percept. It could be sound-

    3. MJ

      Yeah.

    4. AH

      ... could be an emotion, could be sadness, could be a historical event or a fear of the future.

    5. MJ

      Yes.

    6. AH

      And you've mentioned before that there's something to be learned in that experience.

    7. MJ

      Yeah.

    8. AH

      There's something about going into that experience in a- in an un- um, in an- in an undeterred way that allows somebody to bring something back into more standard reality.

    9. MJ

      Yeah.

    10. AH

      Given the huge r- variety of experiences that people have on psychedelics, given the huge variety of humans that are out there, but what are now very clear therapeutic effects in the realm of depression, w- what do you think is the value of going into this fairly restricted perceptual bubble? What we are calling letting go, or giving up control. Because if the experiences are many, but the value of what one exports from that experience is kind of similar across individuals-

    11. MJ

      Yeah.

    12. AH

      ... that raises all sorts of interesting questions, and this is not a- a philosophy discussion. We're talking about biology and psychology here.

    13. MJ

      Yeah.

    14. AH

      So what are your thoughts on that?

    15. MJ

      This is in the terrain we're figuring out, you know? So there's no- the educated speculation is the best I can provide. But I- I- I think the best- the- the- the- the mo- I think the common denominator are persisting changes in self-representation.

    16. AH

      Okay.

    17. MJ

      And-

    18. AH

      Tell me more about self-representation. Yeah.

    19. MJ

      That's, uh, the way one holds th- the sense of self.

    20. AH

      Mm-hmm.

    21. MJ

      The relate- the fundamental relationship of a person in the world. I mentioned earlier that these experience seems to alter the models we hold of reality, and I think of the self as the biggest model.

    22. AH

      Mm-hmm.

    23. MJ

      That I am a thing that's separate from other things.

    24. AH

      Mm-hmm.

    25. MJ

      And that's- I am defined by certain- I have a certain personality, and like, I'm a smoker that's having a hard time quitting, or I'm a depressed person that, you know, views myself as a failure, and all of these things. Those are models too. And- and like-

    26. AH

      So this is this expansion of the perceptual bubble. A narrow- a narrow, uh, percept that then grows within the confines of that narrow percept.

    27. MJ

      Yeah.

    28. AH

      The- y- so sense of self is a very interesting, uh, phenomenon, and if we could dissect it a little bit, um, there's the somatic sense of self, so the ability to literally feel the self, uh, inter- this process we call interoception. And then there's the- the- the title of the self, the I am blank.

    29. MJ

      Yeah.

    30. AH

      And I noticed you said that several times, and it's intriguing to me how one defines themselves...... internally, not just to other people.

  8. 21:19 – 24:43

    MDMA, Dopamine & Serotonin; Bad Trips & Transcendental Experience

    1. MJ

      sticks.

    2. AH

      I'm fascinated by this idea that a- a somatic and a perceptual experience, but a real experience of the sort that you're describing-

    3. MJ

      Yeah.

    4. AH

      ... is what allows us to reshape our neural circuitry and to feel differently about ourselves. And, uh, I know there's been, um, really tremendous success in many individuals of alleviating depression.

    5. MJ

      Mm-hmm.

    6. AH

      Of treating trauma with these different compounds. If we could, I'd like to just ask about some of the more dopaminergic compounds.

    7. MJ

      Uh-huh.

    8. AH

      In particular, MDMA.

    9. MJ

      Yeah.

    10. AH

      And my understanding is that MDMA leads to very robust increases in both dopamine and serotonin simultaneously. So, why would it be that having this, uh, increased dopamine and increased serotonin would provide an experience that is beneficial, and how do you, to the extent that you can describe it, how do you think that experience differs from the sorts of experiences that people have on psilocybin or more serotonergic agents?

    11. MJ

      Speculating, but it may be that MDMA, for a broader number of people, is better for- for trauma, because the chances of having an extremely challenging experience, what I call the bad trip, like really freaking out, is much lower with MDMA. People can have bad trips, but they're of a different nature.

    12. AH

      Well, what is-

    13. MJ

      It's not-

    14. AH

      You've been- Oh, sorry.

    15. MJ

      It's not sort of, like, freaking out, because all of reality is sort of shattering, and it's less of this... It can take so many forms with the classic psychedelics, but, like, typically you'll- you'll hear something like, "I didn't know it was going to be like this." No matter how hard you tried to prepare them, that like, "This is, like, get me off this ride."

    16. AH

      You're talking about LSD or psilocybin?

    17. MJ

      LSD, psilocybin, ayahuasca.

    18. AH

      Bad trip.

    19. MJ

      Yeah. Yeah. And- and just this sense of like, "I'm going insane. This is so far beyond anything I've ever experienced, and it's scaring the shit out of me."

    20. AH

      How often does that happen?

    21. MJ

      "Like, I can't have a toehold on anything-

    22. AH

      Yeah.

    23. MJ

      ... even that I exist as a- as- as- as an entity." And that can be really... I think, frankly, experientially, that's kind of the gateway to both the transcendental mystical experiences, the- the- the sense, uh, o- of unity with all things, which we know, our data suggests, is related, um, to long-term positive outcomes.

    24. AH

      Wait, I want to make sure I understand.

    25. MJ

      But I'll-

    26. AH

      So you're saying the bad trip can be related to the transcendental experience?

    27. MJ

      Right. I think those are both speculating, but you- you have to pass through this sort of like, you know, reality shattering, including your sense of self. And one can handle that in one of two ways. You can either completely surrender to it, or you can try to hang on. And if you try to hang on, it's going to be more like a- a bad trip. So again, I wish there was more, and hopefully there will be more experimentation. There's a lot going on here in the black box in terms of the operant behavior of how you are, you know, within yourself.... choosing to handle, like, letting go, you know. And eventually, we'll be able to see this in real time with brain imaging, "Ah, there they are surrendering to the psychedelic experience. Here they are trying to hold on." But we- we're not there yet. But I think it's a good... Through clinical observation, it seems pretty clear that something like that is going on.

    28. AH

      There has

  9. 24:43 – 27:04

    Dangers of Psychedelics

    1. AH

      been an attempt at creating this movement toward, um, openness about psychedelics and their positive effects. This has happened before.

    2. MJ

      Yeah.

    3. AH

      The difference is that now there are people like you inside the walls of the university who are publishing peer-reviewed studies and things of that sort. The question is, to me, you know, what are the- what are the valuable exports, right? And where does the extreme lie? I mean, clearly there's a- there's a problem with, um, tinkering with reality through pharmacology, and there's a benefit, it sounds like-

    4. MJ

      Mm-hmm.

    5. AH

      ... to tinkering with (laughs) re- uh, reality through pharmacology.

    6. MJ

      Yeah.

    7. AH

      And for the average person, right? Or for kids that are hearing this, kids that are in their teens, right?

    8. MJ

      Yeah.

    9. AH

      What are the... I want to talk about, what are the- the dangers of psychedelics?

    10. MJ

      Mm-hmm.

    11. AH

      This is something you don't hear a lot about these days, and it's not because I'm anti-psychedelic at all, but what are the dangers?

    12. MJ

      Yeah, so these can be profoundly destabilizing experiences, and ones that, you know, ideally, um, uh, are- are- are had in a safe container, you know, sort of where- where someone... You know, what are the relevant dangers and what can we do to mitigate those? So, there's two biggies. One, and I've already mentioned, it's people with very severe psychiatric illness. Not- not depression, not anxiety. I'm talking about psychotic disorders like schizophrenia or, you know, mania as part of bipolar disorder. The far more likely danger is the bad trip. Anyone can have this. The most psychologically healthy person in the world probably, you jack the dose high enough and especially in- in- in- in a less than, uh, ideal environment, you can have a bad trip. You c- you even get it in an ideal environment like ours at- at a high dose of around 30 milligrams of psilocybin after, you know, the best preparation we can provide. About a third of the people will say... Essentially, at some point they have a bad trip, you know? And we-

    13. AH

      At some point within the- the entire journey.

    14. MJ

      Right.

    15. AH

      Yeah.

    16. MJ

      Now they could have one of the most beautiful experiences of their life, sometimes, like, a couple minutes later.

    17. AH

      Right.

    18. MJ

      But at some point they had a sense of strong anxiety, fear, losing their mind, um, feeling trapped, something like that.

  10. 27:04 – 31:20

    Microdosing Psychedelics, Antidepressant

    1. MJ

    2. AH

      I definitely want to ask you about microdose versus standard or macrodosing psilocybin. I'm micro-cynical (laughs) , uh, if you will, about this term microdose. Is there any clinical evidence or peer-reviewed published evidence that it "works," quote unquote, to make people feel better about anything?

    3. MJ

      So yeah, it... The- the claims are, and there are a number of them... There's two general ones. One is- is sort of acting, uh, i- in- in place of the ADHD treating drugs, so the psychomotor stimulants. So like, a better version of Adderall. The other claims are essentially a better version of- of the tr- traditional antidepressants, a better version of Prozac. None of the peer-reviewed studies that are... Have much credibility, um, none of them have shown a benefit. The handful of studies that have done that have shown... They've ranged from finding no effect whatsoever to just a little bit of impairment, like impairing someone's ability to do, um, time estimation and production tasks, so... You want an accurate sense of time, at least if you're navigating in the real world. It's different if you're on the couch on a heroic dose for therapeutic reasons where you're safe, but if you're crossing the street, if you're g-... You know.

    4. AH

      Yeah, you have to function in the world.

    5. MJ

      In your work life. Yeah, which is why- the way people are claiming t-... You know, use that it helps them be a better CEO. Like, you want an accurate sense of time. So if anything, the data suggests that it makes it a little bit less accurate, and- and there's evidence that someone feels, uh, uh, a little bit impaired, um, and they feel a little bit high. So in terms of... You know, you call that abuse liability in research. So far, no studies have- have shown, you know, s- an increase in creativity, enhancement of any form of cognition, or- or- or a sustained improvement in mood. Now, no studies have actually looked at the- the- the- the system of microdosing that the aficionados are claiming. Folks like, um, Paul Stamets and others, they'll have particular formulas. They're like, "You need to take it one day and then take so many days off, and take it every four days." And they really say you need to be on it for a while. Like a few weeks in, you may start to notice through this pattern of- of- of using it, and you- you're- you're feeling the benefits on those off days, like the three or- or two days in between your active doses. So those are the claims. Again, we don't know that there's any truth to that working, but studies have not been done to model that, so that's a big caveat. My bet is, and this is totally based on anecdotes, that I think there is probably a reality to the antidepressant effects. I find that more intriguing.

    6. AH

      Well, so would-

    7. MJ

      Because of the suffering with depression.

    8. AH

      Right.

    9. MJ

      Even if it's an... It- it wouldn't be as interesting as, I think, what we're doing with high dose psilocybin or psychedelics to treat, um, depression. It would be, if this is developed and there's a reality, it would be more like a better... You know, perhaps a better SSRI, a better Prozac. Which are similar. That being said, we need more tools than fewer tools in the toolbox.

    10. AH

      Right.

    11. MJ

      A- and it shouldn't be that surprise. Like even before the... As... Going back to the tricyclics and the MAO inhibitors going back to the '50s, like, augmenting extracellular serotonin in one way or another-... for many people, leads to a de- reduction in depressive symptoms. It wouldn't be that crazy for chronically stimulating a subtype of serotonin receptor that you have an antidepressant effect. So, I think, if I had to put my bets on it, that there's, if there's anything real, it is in that category. Although, I'm very open to, like, maybe there is something to the creativity, to the, you know, improved cognition, which covers many domains in and of itself. But, um, my, m- my greatest hopes are on the, uh, on the antidepressant effect. That said, in the big picture, I think all of... the most interesting thing about psychedelics are the heroic doses. I mean, the idea that you can give something one, two, three times, and you see improvements in depression months later-

    12. AH

      Right.

    13. MJ

      ... and an addiction, you know, over a year later, and with these, you know, people dealing with potentially terminal illness. I mean, it's st- I mean, I'm interested in big effects.

  11. 31:20 – 34:47

    Head Injuries, Psychedelics, Depression

    1. MJ

    2. AH

      Right. I want to make sure that I ask you about the other really important mission that you're involved in with respect to psychedelics, which is not about depression per se, but is about neurological- uh, neurologic injury, or head injury. You know, we always think sports, but there are many people who make a living in a way that is, um, over time, is detrimental to their brain. What do you think is the potential for these compounds, particular psilocybin, but other compounds as well, for the, um, treatment and possible even reversal of neurological injuries?

    3. MJ

      There are anecdotes of, of people saying, uh, that, that psychedelics have helped heal their brain. You know, they've been in one of these situations, like in sports, uh, a sport where there's repetitive head impact, and they're claiming that, you know, using psychedelics has actually improved their cognitive function. For example, improved their memory. If you take these anecdotes and you combine it way across orders of analysis to the rodent research from, um, several labs like David Olsen, Brian, uh, Roth, eh, these folks that have shown different forms of neuroplasticity unfolding, those effects may be at play in the improved... i- in the psychiatric treatments that we're dealing with. That ha- we don't know that. It seems like a decent guess, and we're going to be figuring out whether that's the case. But another potential that that sets up is that maybe that's what's going on with, um, w- with, w- with, with these claims of improvements from neuron- neurological issues, that there's actually, you know, uh, a repair of the brain, uh, uh, from injuries underlying, you know, things that, you know, situations where there's repetitive head impact. Perhaps there's a potential for, for helping folks recover from stroke, um, and disorders like that, um. It is more exploratory, but what I'm hoping to do is some work with retired athletes who had been exposed, but by the nature of their sport, for example, MMA athletes in the UFC, who have been exposed to, um, repetitive head impacts, like a lot of sports, um, a lot of, uh, you know, sports expose people to, and, and, and who are retired from the sport, and are suffering from, say, depression, which can, uh, in part result from those types of, of, of... that history of head impact, um. See if we can fix the depression, but then also as a cherry on top and a more explorator- tory aim, see if we can have evidence of, of improvement in cognitive function and associate... Like, using MRI, see if it affects gray matter over time, these types of things, to see if there actually is some evidence of this improved, um, like, this more direct repair of the brain.

    4. AH

      Mm-hmm.

    5. MJ

      But again, it is very sort of like, we've got some rodent data, we've got some human anecdotes.

    6. AH

      We, we, we will ack- acknowledge it's early days, and we look forward to seeing the data. Um, I, I appreciate how cautious you are and tentative you are. You're not drawing any conclusions. Thank you so much for your time-

    7. MJ

      Thank you, Andrew.

    8. AH

      ... for your knowledge, and I think you put it best earlier, for, uh, holding the candle in a very dark time, and then now, there's light. (instrumental music plays)

Episode duration: 34:47

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