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Welcome to the Huberman Lab podcast, where.

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We discuss science and science based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today I have the pleasure of introducing Doctor Matthew Johnson. Doctor Johnson is a professor of psychiatry at Johns Hopkins School of Medicine, where he also directs the center for Psychedelic and Consciousness Research. As many of you know, there's extreme excitement about the use of psychedelics for the treatment of various disorders of the mind. Doctor Johnson's laboratory is among the premier laboratories in the world understanding how these compounds work, how things like psilocybin and LSD and related compounds allow neural circuitry in the brain to be shaped and change such that people can combat diseases like depression or trauma, or other disorders of the mind that cause tremendous suffering. Doctor Johnson is also an expert in understanding how different types of drugs impact different types of human behaviors, such as sexual behavior, risk taking, and crime. Doctor Johnson and his work have also been featured prominently in the popular press, such as articles in the New York Times, in Michael Pollan's book how to change your mind, and in a feature in 60 minutes about psychedelics and the new emerging science of psychedelic therapies for treating mental disorders. During the course of today's conversation, Doctor Johnson and I talk about psychedelics at the level of what's called microdosing, whether or not it is useful for the treatment of any mental disorders. We also talk about more typical macro dosing, what those macro doses entail, and he walks us through what an experiment of a patient taking psychedelics for the treatment of depression looks like in his laboratory from start to finish. The conversation was an absolutely fascinating one for me to partake in. I learned so much about the past, present, and future of psychedelic treatments and compounds, and indeed, I hope to have Doctor Johnson on this podcast again in the not too distant future, so that we can talk about other compounds that powerfully impact the mind and human behavior, and perhaps can also be used to treat various diseases. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Athletic Greens. Athletic greens is an all in one vitamin mineral probiotic drink. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast the reason I started taking athletic greens, and the reason I still take athletic greens once or twice a day is that it helps me cover all of my basic nutritional needs. It makes up for any deficiencies that I might have. In addition, it has probiotics, which are vital for microbiome health. I've done a couple of episodes, so it's now on the so called gut microbiome and the ways in which the microbiome interacts with your immune system, with your brain to regulate mood, and essentially with every biological system relevant to health throughout your brain and body. With athletic greens, I get the vitamins I need, the minerals I need, and the probiotics to support my microbiome. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and claim a special offer. They'll give you five free travel packs plus a year's supply of vitamin D three k too there are a ton of data now showing that vitamin D three is essential for various aspects of our brain and body health. Even if we're getting a lot of sunshine, many of us are still deficient in vitamin D three and k. Two is also important because it regulates things like cardiovascular function, calcium in the body, and so on. Again, go to athleticgreens.com huberman to claim the special offer of the five free travel packs and the year's supply of vitamin D three k two. Today's episode is also brought to us by element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the exact ratios of electrolytes are an element, and those are sodium, magnesium, and potassium, but it has no sugar. I've talked many times before on this podcast about the key role of hydration and electrolytes for nerve cell function, neuron function, as well as the function of all the cells and all the tissues and organ systems of the body. If we have sodium, magnesium, and potassium present in the proper ratios, all of those cells function properly and all our bodily systems can be optimized. If the electrolytes are not present and if hydration is low, we simply can't think as well as we would otherwise. Our mood is off, hormone systems go off, our ability to get into physical action, to engage in endurance and strength and all sorts of other things is diminished. So with element, you can make sure that you're staying on top of your hydration and that you're getting the proper ratios of electrolytes. If you'd like to try element, you can go to drink element. That's lMnt.com huberman and you'll get a free element sample pack with your purchase. They're all delicious. So again, if you want to try element, you can go to elementlmnt.com Huberman Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga Nidra sessions, and NSDR non sleep deep rest protocols. I started using the Waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app, turned out to be the waking up app, which could teach you meditations of different durations and that had a lot of different types of meditations to place the brain and body into different states and that he liked it very much.

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So I gave the waking up app.

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A try, and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up app has lots of different types of yoga Nidra sessions.

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For those of you who don't know.

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Yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations, and there's excellent scientific data to show that yoga Nidra and something similar to it called non sleep deep rest, or NSDR, I can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com huberman and access a free 30 day trial. Again, that's wakingup.com huberman to access a free 30 day trial. And now my conversation with doctor Matthew Johnson.

A

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.

C

Likewise, big fan and happy to do this with you.

A

Well, thank you. My first question is a very basic one, which is what is a psychedelic? We hear this term all the time, but what qualifies a substance as a psychedelic?

C

Nomenclature is a real challenge in this area of psychedelics. So starting with the word psychedelic, it just, if you're a pharmacologist. 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 classes of compounds, but overall, so it's really more of a cultural term or it does have a relationship to drug effects, but it's at a very high level. So all of the so called psychedelics across these distinct classes that I can talk more about, 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 acutely. So when someone's on the psychedelic, so the different classes that can be the specific pharmacological classes that can be called a psychedelic are what are called the classic psychedelics. So in the literature you'll see that term and hallucinogen and psychedelic are all have traditionally been used synonymously. I think there was a little of a tendency to stay away from psychedelic because 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, psilocybin, which is in so called magic mushrooms. It's in over 200 species that we know of so far of mushrooms. Dimethyltryptamine or DMT, which is in dozens and dozens of plants. Mescaline, which is in the peyote cacti and some other cacti like Sandhya, Pedro. And even amongst these classic psychedelics, there are two structural classes. That's the chemistry. There's the tryptamine based compounds like psilocybin and DMT. And then there's the phenethylamine based compound. So these are the basic two to basically building blocks that you're starting from either a tryptamine structure or a phenethylamine structure. But that's just the chemistry. All of the what's more important, or at least 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 agonists at the serotonin two way receptors. So subtype of serotonin receptor, then you have these other classes, compounds that you could call psychedelic. Another 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 cal syrup which is something kind of like high school kids are known to do and they can't get ahold of real drugs that type of thing. So a large overlap in the types of subjective effects that you get from those compounds compared to the two a agonist classic psychedelics. But then you have. And by the way this description, this framework I'm describing, not everyone will agree. Some people will say no, psychedelic only means classic psychedelic. So there's different opinions here. But you have gosh salvinornay which is a kappa opioid agonist which again where.

A

Does that come from?

C

Salvia divinorum. It's a plant it became 20 years ago. It sort of popped onto the legal high scene and there's a long history of this predating the Internet going back to the stuff one gador in the back of high Times magazine and most of this stuff never worked. Smoke enough of anything, maybe you get a little bit light header but this is one of those things that popped around 20 years ago when it quickly got the reputation of like holy shit this stuff actually works and works really strongly in these smoked extracts particularly. People have these reality altering experiences on par with smoked DMT, the classic psychedelic. So often and we did the first blinded controlled human research with Salvinorna. So lots of entity contact. So feeling that you in the experience of one is actually interacting with autonomous beings, that type of thing. And then you have another big one I probably should have mentioned even before the know Salvin Ornay but you have MDMA which really stands in a class by itself. So it's been called an intactogen. And what does that mean? It means like touching within. It sort of eludes the idea that it can really put someone in touch with their emotions. It's also been called an empathogen meaning it can afford empathy. But I think intactogen is probably that's the term that I. I tend to focus on and I know I'm not telling you anything you don't know. But for the viewers the primary mechanism of MDMA is serotonin release and to a degree other monoamine release dopamine serotonin. And so structurally that's also in the phenethylamine class which contains mescaline, the classic psychedelic, but also amphetamine. So just like Adderall is in that phenethylamine class. And so this is another example where chemistry doesn't dictate. I mean you can tweak a molecule. It might have that same basic structure but now you've profoundly changed the way it interacts with the receptors, so an MDMA does not exert its actions. Bye. I like to say by mimicking the baseball, entering the glove, the post synaptic receptor side acting as an agonist, mimicking the endogenous neurotransmitter serotonin. Like the classic psychedelics do, MDMA works on the pitcher side of just basically throwing out more of the natural, the endogenous, dumping more serotonin, dumping more serotonin, flooding the synapse.

A

So I get the impression that the psychedelic space is an enormous cloud of partially overlapping compounds, meaning some are impacting the serotonin system more than the dopamine system, others are impacting the dopamine system more than the serotonin system. Given that the definition of a psychedelic is that it profoundly alters sense of self, at least that's included as a partial definition. Can we break that down into a couple of subcategories? So, for instance, hallucinating, either auditory or visual synesthesia, perceptual blending, the sense that you can hear colors and see sounds, for instance, a common report of people that take psychedelics in sufficiently high doses. So hallucinating, synesthesia, and then in terms of sense of self, as a neuroscientist, I think, okay, what does it mean to alter a sense of reality? Really what the brain does in a very coarse way, is to try and figure out what's happening in space, physical space, and that physical space could be within us or outside us and what's happening in time. And as a vision scientist, the simplest explanation is when I move my hand from one location to another location, it's measuring the space, the location of my hand in space over time. And then you get a rate and a speed and all that kind of stuff. Right?

C

Yeah.

A

That gets more complicated as you get into the emotional realm. But is it fair to say that psychedelics are impacting the space time analysis that the brain is performing and thereby creating hallucinations and thereby altering, you know, the blending of senses? Is it fair to say that I.

C

Think it's fair to explore that area, and here's what I'm thinking. Clearly, there is a changed relationship, certainly at the right dose of orientation in space time. I think as a. I'm primarily a behaviorist, and in terms of human behavioral pharmacology, I always go to comparative pharmacology. Okay, what can we say that is it truly unique about the classic psychedelics or psychedelics in general? So, with that description, I'm thinking okay. Alcohol can really screw up your time. Space orientation.

A

Proprioception, your balance, proprioception, versibular.

C

And in many ways in those gross motorways, like, far worse. Of course, everything's dose dependent. But in the classic psychedelics, obviously, the benzodiazepines being very similar. Alcohol, same thing. You know, I'd want to dig in a little more in terms of, like, maybe there's something more specific we could say about that relationship to time and space that the psychedelics are tinkering with. But I'm not sure. It's an interesting hypothesis. The idea that that's a mediator, that there's something fundamental about changing that, the representation in time and space. There might be something to that. I think of these as psychedelics as profoundly altering models. We're prediction machines, and so much of that is top down. And psychedelics have a good way of, loosely speaking, dissolving those models. And one of the reality.

A

Can you give us an example of a model? I know that when I throw a ball in the air, it falls down, not up. That's a prediction that I learned as a child. I did not come into the world with a brain that knew that relationship between objects and gravity. But one of the first things that a child learns is the relationship between objects and gravity and their trajectory.

C

Yeah. And with a four year old, I mean, I saw that at earlier ages, like that experimentation of like, oh yeah, that's what happens, you know.

A

Right. So if he were to throw a ball, if your child were to throw a ball and it went up into the sky, that would be absolutely mind blowing. It would be for an adult too.

C

It'd be a pretty psychedelic experience, probably.

A

Right. And so there's a. There's a space, there's a rule there. You're saying there's a kind of a prediction. There's a rule that. That underlies a prediction, that when that rule is violated, all of a sudden the circuit, presumably for that prediction, it doesn't have a mind of its own, but somehow it creates a surprise element.

C

Or a recognition element and it's not filtered out. You know, and this might sound extreme, but there are these cases. It was overblown in sort of the propaganda, the late sixties, early seventies. But there are credible cases of people, I think it's very atypical of sounds like they really thought they could fly and jump out of a window. Now far more people every year fall. I mean, who knows? They fall and die out of. From height because they're drunk. So this is extremely rare. But there are some pretty convincing cases. There was one research volunteer in our study that she 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, reviewing the video, it looked like she really thought that she was going to go through that painting. And who knows? So she was the other dimension.

A

Yeah. So they're violating these predictions. Yeah. The reason I ask it, the question the way I did is because given the enormous cloud of different substances and given the range of previous experiences that people show up to, a psychedelic experience with, I feel like the ability to extract some universal themes is useful, especially for people who haven't done them before. Right. Who might not have an understanding of what their effects are like. Can we just briefly touch on the. The serotonin system and the dopamine system? I want to acknowledge that, as you already know, that there are many neuromodulator systems in the body and the opioid systems, cannabinoid systems. But there's something so profound about the serotonin system in the dopamine system, because the way I define a neuromodulator is it's a modulator. It changes the way that other circuits behave, essentially increases the probability that certain circuits will be active and decreases the probability that other circuits will be active in a general sense. 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 model challenges, challenging preexisting models and predictions. 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. What do we think is going on? In a general sense?

C

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, serotonin itself is not psychedelic, or else we'd be tripping all of us all the time.

A

Because when I eat a bagel, I get serotonin release, right?

C

Or turkey.

A

There's tryptophan. My understanding of serotonin is that 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 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.

C

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

A

Well, feel free to explain it. At the experiential level, I think there probably are some audience members that are interested in, is it the five h, two c? Is it the layer five neurons and cortex? That conversation we could hold, and that's an interesting conversation. But just in terms of the experience of serotonergic versus dopaminergic drugs, they do seem to create distinct classes of experience. So I think that's the appropriate level for us to discuss them.

C

And in terms of how they. And I'd like to explore the biology a little bit here and tell you, like, sort of what's known and what some of the ideas are.

A

Please.

C

You have this path, you know, as you know, like, these are levels of analysis, and it's not which one is going on. It's almost like, for the particular question, which level of analysis is most appropriate? Is it, you know, is it question best addressed by the biology, the chemistry, or the physics? That's how I think of, like, receptor level, post receptor signaling, downstream effects on other neurotransmitters, and then activation level effects, and then coordination of activation. So you've got the, clearly with the classic psychedelics, the two a activation. We do know that there are downstream effects in terms of increasing glutamate transmission. So this is likely a commonality. Why? You know, ketamine is very psychedelic in a slightly different way.

A

But do people hallucinate on ketamine?

C

Yes. Yes. And it's more dissociative. So someone is more likely to sort of be less behaviorally active. If they have a really high dose, they go into a k hole. And if they go in a really high dose, like, you get into subconscious. Yeah.

A

Not an a hole, but a k hole.

C

A k hole, yeah, it's very different, the k hole. And ketamine is interesting because people can take kind of bumps and kind of dance on it with the sort of an alcohol level strength of effect. And that's sort of the classic kind of raving, you know, use of it. But then those folks want to titrate their dose because if they do more of like a line, you get up to like 75, 100 milligrams, then you're talking about, you know, if you're on the dance floor, you're on the floor and your friends are trying to make sure people aren't stepping on you.

A

So that's like, why would somebody want to take a dissociative anesthetic? Like, to me, it's completely mysterious as to why someone will want to dissociate from their body.

C

People claim that these NMDA antagonist psychedelics are extremely insightful in a very similar way to the experiences with the classic psychedelics.

A

And ketamine is now legal for therapeutic users.

C

Right, right. Spravato, the intranasal form marketed by Janssen, which is s ketamine. It's prescription. Yeah, it's prescription.

A

So people are taking in the nasal spray and then are they undergoing talk therapy while they're doing this?

C

Typically not. So this is very interesting. And there's so much work that needs to be done. It's not treated as psychedelic therapy. And by that psychedelic therapy, I mean you tell the person they're going to have an altered experience. You tell them to pay attention to that experience, that they might learn something from that experience. And afterwards you discuss that experience with Spravato. The model is spravato is. Is s ketamine okay. It's the. Yeah, the spray form of ketamine that's, it's been FDA approved for treatment resistant depression, but it's. You'll probably feel different. Ignore that. That's a side effect. That's an adverse effect. Just ignore it. We don't think that has anything to do with the way it works. But just get this thing. It's a direct sort of chemotherapeutic effect in a sense. It's not facilitating a learning process. Now there's older work. There was a guy, Kropitsky in Russia that did extensive work with higher doses of ketamine. I should say Spravato at the prescribed doses isn't very, it's a pretty low dose. It's in the mild psychedelic range, but it's not very strong. But this older work that happened in the nineties and early two thousands in Russia, they were using very high doses and treating it like a psychedelic, treating it as if it was a psychedelic therapy. In other words, telling people, you're going to have this experience, it's going to. We're hoping you learn something from it. We're going to help you through it. We're going to discuss it afterwards. They found incredibly high rates of success and some pretty well controlled trials for both heroin addiction and alcohol addiction. I think a whole lot of work needs to be done now. You see some of the ketamine clinics that are using ketamine off label. A lot of them are treating it like psychedelic therapy. There's essentially no research at this point on that. Do you get better results? Straight abusive spravato, there's some good variability, but its antidepressant effects last about a week, but they kick in immediately. Now a week is a long time for most psychiatric drugs. You take it every day. That's amazing. But it's still just a week. We're seeing effects a year or more later with psilocybin and some of the classic psychedelics. That could be a pharmacological difference, or it could be that they'd get a lot more mileage out of ketamine if they treated it like psychedelic therapy. And so that's some. What would that look like, really? Just like our psilocybin sessions, which I know I haven't described, but briefly, you have anywhere from four to 8 hours of preparation, getting to know the people who are going to be the guides or the therapist in the room.

A

Walk us through this. So let's say I were to come to one of your clinical trials. Cause these are clinical trials, right at your lab at Hopkins. And would I need to be depressed or could I just be somebody who wanted to explore psychedelics?

C

We've had studies for all of these and a number of other disorders. So healthy, normal studies, the code for not a problem to fix. But we're all here. That's what's amazing about psychedelics, though, because if you administer them under this model and you develop a relationship and give a high dose of psychedelic, you can be a healthy, normal without a diagnosable issue. But man, we're all human and the issues seem to come to the surface. But we've done work with smoking cessation, so people trying to quit tobacco and haven't been successful.

A

So a variety of reasons. So maybe I'll just ask some very simple questions that will kind of step us through the process. So let's say I were to sign up for one of these trials 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 be present during this psychedelic journey.

C

First there's screening, so it's kind of like a couple of days of both psychiatric, structured psychiatric interviews about your past and symptoms across the DSM, the psychiatric Bible to see if you might have various disorders that could disqualify you, like the main ones being the psychotic disorders, schizophrenia, and also including bipolar. So the manic side of bipolar after that, and also cardiovascular screening, heart disease after that screening. Then the preparation where you get both, you develop a therapeutic rapport with the people who are going to be in the room with you, your guides, 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 than, you know. It's going to, it's not like cocaine, like you're going to feel stimulated. You're going to feel like, you know, you can do any, it's like, you know, or alcohol. You're probably going to feel more relaxed. It's like, I call them uppers, downers, and all arounders. And the psychedelics are all arounders. It's like, yeah, you could be, you could have the most beautiful experience of your life or the most terrifying experience of your life. So it's this kind of laundry list of like the things that could happen, so there's no surprises.

A

I think it's so important for people to hear because the all arounders, you really can't predict how somebody is going to react internally. I want to just briefly touch on something because we left that topic, but it occurred to me that a lot of these effects of psychedelics and how they function, et cetera, is still very mysterious. But then I recall to mind that how most prescription antidepressants work is also very mysterious. They increase serotonin or dopamine or epinephrine, et cetera. But why they take weeks on, several weeks to kick in, et cetera, is also mysterious. But going back to the experience of coming to your laboratory, let's say that somebody passes all the prerequisites and it's the day, comes the day that they're going to have this experience. Are they eating mushrooms like you hear about, or are they taking it in capsule form? And what sorts of doses are you prescribing? Is there a dose response curve? And then secondary to that, I'd like to talk about micro dose versus macrodose. So how do they get this stuff into, how do people receive it, and how do they get it into their body?

C

So they receive pure psilocybin. So the mushroom, and there are many species the most. If people have taken mushrooms in the United States, it's most likely psilocybin cubensis. They're easy to grow. They grow in cow patties. It's easy for anybody to grow them in their closet. It doesn't take a thousand watt light like cannabis. It takes, like, a little ten watt light bulb and a Tupperware bin. So those are the types of mushrooms that people typically tape. We're not administering those. Psilocybin is the compound. You could draw a molecule, psilocybin, again, based on the tryptamine structure, that's a single molecular entity. So it's a white powder.

A

Does it look like serotonin? Molecularly?

C

Yes. Yes, yes.

A

So if I looked at. If I were to show people the chemical structure of serotonin, chemical structure of psilocybin, it would look quite similar.

C

Right. Right.

A

And they're basically taking serotonin, a modified.

C

Version of serotonin, which makes sense. But then again, this repeated theme of the chemistry doesn't always neatly line up because, like, mescaline looks more like dopamine than it does like serotonin. But yet at the receptor activation level, the pharmacology, neural pharmacological effect, those are similar, but, yeah, I mean, and what it does at the receptor is an alternate. It's hitting the same switch, but then having an alternate response at the receptor.

A

Yeah. So for people that don't necessarily understand the relationship between what we call ligand, the thing that parks in the receptor and the receptor is the parking spot. One of the reasons that you can get such a variety of effects from different compounds is, for instance, serotonin might affect a certain pathway at a particular rate, and psilocybin might trigger activation of different components of that pathway at different rates. And so you can get vastly different experiences from two things that look chemically similar. This is also a good reason why people shouldn't just assume that they can cowboy their own chemistry, that what you see on paper and what you can mix up in a vial is often vastly different than what you predict.

C

And there's a dose effect curve that's really interesting. Some of our early work with psilocybin in healthy normals looked at a true placebo plus four active doses, 510, 20, and 30 milligrams of psilocybin. Body weight adjusted so those milligrams per 70 body weight. We've recently published a paper in our newer trials, wherever we're dropping the body weight adjustment, because going across hundreds of volunteers, we've kind of figured out that you shouldn't really be. You don't need to be adjusting by body weight. So.

A

Yeah, well, brain size doesn't vary that much between individuals.

C

Yeah.

A

The end. This is a brain effect mostly, probably body as well. Okay, so the person ingests the powder.

C

In a little pill. Yeah. And it does take 30 milligrams is a small. Fit it into a tiny little capsule and it'll take about a half hour, anywhere from 15 minutes to an hour to kick in.

A

And you said whatever dose range was.

C

Most of our studies are looking at where we want a psychedelic effect are in the 20 to 30 milligram range. Again, because we have adjusted by body weight, and the average american is over 70 kg, about 150 pounds. People, in fact, have gotten more like 40, 45 in a lot of cases, but it's still a small pill. The session day itself is not full of, for most of our studies, is not full of tasks. We really want to look at the therapeutic response. Obviously, if it's a therapeutic study, we want it to be a meaningful experience. And research has found, not surprisingly, that you get a less meaningful experience when you're in an fMRI or when you're doing a lot of cognitive tasks. We've done some research of that type for sure, and plenty of colleagues have. But when you're in a therapeutic study, or if you're trying to understand the therapeutic effects, you have to recognize there's this trade off of what you can do. So our typical therapeutic model, which again, isn't just limited necessarily to the therapeutic studies where we're trying to treat a specific disorder, is to have that preparation so the person feels very comfortable with their guides. I mean, ultimately what I tell people is like any emotional response, it's all welcome. I mean, you could be crying like a baby hysterically. Like that's what you should be doing if that's what you feel like. And so in a lot of ways, sometimes people with psychedelic experience on their own, it can be harder to train them in this model because in the real world, people with psychedelic experience, a lot of times the rule is, you know, hold your shit. So several friends go to a party, they split a bag of mushrooms. It's like there's a social pressure for good reason, not to be the guy in the corner of the room where everyone's trying to just have a good time, relax. Like crying about your mother, your other friends, they're having an experience too, and you're being a drama king and blah, blah, blah. And so compose yourself, hold your people.

A

You're doing therapy for people, it's not just about the experience.

C

Right. And the experience itself is very much shaped by that container, by the environment and the degree to which one allows it to happen. Like one should let go of control.

A

Yeah, let's talk about the letting go of control and then as we march through this hypothetical experience that does take place in your lab. But we're using a sort of generic case example, if you will. The letting go of control is an interesting feature, actually, because one of the common themes of good psychoanalysis 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 oneself. It's actually the end goal of good psychoanalysis is that the patient actually one of the end goals is that they develop an empathy for themselves, which almost sounds like an oxymoron, but if you spend a little time with that statement, it actually pans out. So the psychedelic experience is one in which chemically you're under a new set of conditions, right?

C

Yeah.

A

Let's coarsely, space and time are altered in some way. Sense of self. For instance, I might be going to a strongly interoceptive mode where I'm focusing on everything within the confines of my skin, whereas normally we're sort of interacting in space and pens and conversation. And I'm sort of. If I had occasionally I'll pay attention to my breathing, but I'm sort of dilating and contracting my focus for different things all the time. The letting go of control, it seems to me, could be sort of the expansion of one perceptual bubble to the point where you're not actually worried that that perceptual bubble is going to pop or that. Meaning you're not worried about what people think of you?

C

Yeah.

A

You're not worried whether or not your brain is going to explode. Even though a thought could feel enormous if I keep going like this, it almost sounds psychedelic, but that's the idea here. Or if I'm paying attention, for instance, to some somatic experience like the coursing of waves of heat through my body that I'm not suddenly saying, is that weird? I'm actually just going deeper and deeper into it. So it's essentially expanding a perceptual phenomenon. How do you convince people to go further and further down that path? What do you think allows them to do that? That to me is one of the more unusual aspects to psychedelics is that normally the social pressure but also just our internal pressure from our own brain is pay attention to many things at once, not just one.

C

Is that especially these days. Yeah. Multitask.

A

Multitask. And the more that we focus on one thing, the more bizarre that thing actually can appear to us. Right, right. 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 weird things. Right.

C

I think of that as the classic psychedelic effect, or one classic effect and one I've used many times of this example of why people should necessarily, you know, these aren't. One should be judicious in putting themselves in these circumstances. Someone could be, you know, having a very strong psilocybin experience, and they're trying to navigate their way in Manhattan, crossing the street, and they might be staring into their hand and realize 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 what we know, 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 dish habituation component that, like, dish habituation? Yes. Like, we wouldn't be able to get through life if we wouldn't be able to cross that street. If we were like, oh, like, this is a miracle.

A

Like, no, I'm so glad you brought this up. I mean, here I'm reflecting my bias as a vision scientist, but most people don't realize this, but if you look at something long enough, it eventually disappears. It doesn't actually disappear, but perceptually, it disappears. You have these little microsuccides that ensure that it doesn't have. But most of us don't look at any one thing for very long. The brain's default is to perceptually jump around like crazy. With the visual system, with the auditory system, we all add. People talk about add a lot is sort of baked into our underlying networks at some level, and then we can force attention. But it sounds like, on psychedelics, one of the primary goals therapeutically, is to really drill into one of these perceptual bubbles and expand that bubble. And the safety, it seems, is the safety. It's sort of like a permission to do that without worrying that something's gonna happen, right?

C

Because I've had people there on the couch. I remember one lady said, this is probably 1314 years ago said, matt, tell me again, I can't die. I feel like my heart is gonna rip through my chest. I mean, she was feeling, and I should say, typically, cardiovascular response is modest. The pulse and blood pressure go up somewhat. It can be dangerous for people if they're at severe heart risk. And we do.

A

Are you monitoring this the whole time? We do, yeah, we do monitor a variety of devices.

C

Yeah. So every half hour or so, we take their on protocol and we space it out a little further, further into the time course. But we take their blood pressure and their pulse, and if it goes over a certain level, we have a protocol, and we've had to do this only a few times. The physician comes in, gives them a little nitroglycerin under the tongue, and 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. But someone can feel that, my God, I'm going to die. I have never felt my heart beat like this before. And the experience of the breath can be just absolutely fantastic. And the breath is obviously interesting because it's this automatic control, but it can also be voluntary. So people get into a sense of, like, my God, what if I. It sounds silly, like, what if.

A

I don't realize.

C

Exactly. But people. That can be so compelling. And so one of the reasons. Get back to one of your questions. It's like, what do we do to kind of allow them to go further into these bubbles? It's like one is wearing the eye shades. We don't call them blindfolds because that has a negative connotation, like being kidnapped.

A

And they're probably seeing a lot in there anyway, so blind isn't the appropriate.

C

Right, right. I've never thought of it. These should be like inner sight shades.

A

But when you close the eyes, the levels of activity in the retina actually are maintained. It's just spontaneous activity, and it seems.

C

And I'd be curious about your thoughts on this, but the way I describe it is that the mind's eye, this kind of loose term we use, can be on rocket boosters. So a lot of times, for some people, like a compound like psilocybin, for some people, there's no perceptual effect. Like, if they're looking at this room, it would pretty much look the same. Sometimes folks say, yeah, things seem a little bit brighter now. Some people will say, oh, my God, there's waves. That wall is waving, and these curtains on these compounds. People don't typically see pink elephants. You do actually get that in another class. I didn't mention the anticholinergics, sort of like atropine and scopolamine. Those drugs, those are the true hallucinations where you thought you were having a conversation with someone who was never there.

A

We will definitely get to those. But the reason I kind of cringe and say, oh my when you talked about those is that knowing a little bit about the pharmacology of acetylcholine, the idea of manipulating that system to me sounds very uncomfortable because, like, the whole idea of witches and flying, there was a whole history there hundreds of years ago. So called witches taking these agents and then thinking they were flying around on broomsticks and things of that sort. And there's a lot of mythology around the broomstick. It's complicated, but that sounds very unpleasant. One thing about the serotonergic, let's just. For with psilocybin, so there's an expansion of a particular fairly narrow percept. It could be sound, could be an emotion, could be sadness, could be a historical event or a fear of the future. And you've mentioned before that there's something to be learned in that experience. There's something about going into that experience in an undeterred way that allows somebody to bring something back into more standard reality.

C

Yeah.

A

Given the huge 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? 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. That raises all sorts of interesting questions. And this is not a philosophy discussion. We're talking about biology and psychology here. So let's say I decide that I'm going to focus on the tip of my pen. I mean, in a psychedelic state, I could fall in love with this pen. I do happen to like these pilot v five s and v seven s very much, but I could feel real love for the pen. That's not an unreasonable thing to expect in a psychedelic journey. And in the context of your laboratory model, which I think is a great one, that experience would be just as valid as me going into the experience of some of the deep friction that I might have with a family member over my entire lifespan. And yet the export from those two vastly different experiences is one of feeling a better relationship to the world and to oneself. So what does this tell us about?

C

How can the pen and the processing, your childhood trauma, both lead to.

A

Right.

C

Yeah.

A

So what does this. I mean, at that level, it raises this question, like, first of all, how, why? I mean, or just what are your thoughts on that?

C

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

A

Okay, tell me more about self representation.

C

That's the way one holds the sense of self, the fundamental relationship of a person in the world. I mentioned earlier that these experiences seem to alter the models we hold of reality. And I think that the self is the biggest model that I am, a thing that's separate from other things, and that's. I am defined by certain. I have a certain personality, I'm a smoker that's having a hard time quitting, or I'm a depressed person that views myself as a failure. And all of these things, those are models, too. And I think that change in self representation may be an endpoint for these different experiences. Maybe the falling in love with the pen, the whole idea that you're especially in contemplation afterwards, and obviously, I'm speculating here, but the whole idea that you could have such a deep connection with this random, obviously random aspect of the universe could potentially lead to this transformed understanding of the self. And, like the pen, may be a proxy for the miracle of reality in a way that relies nothing on no supernatural thinking. You could be a hard atheist and take this ultimately, oh, my God. I just like the pen. This is amazing, the fact that we exist. And so there could be an extrapolation chair, and you used the pen. But I think it sounds so similar to Aldous Huxley's classic description in the doors of perception of the chair and the drapes. Like, he took 500 milligrams of mescaline. He was just like, is that a.

A

High dose of mescaline?

C

Yeah. Yeah. And that's, you know, that's a heroic dose for sure. And he's just going off on the cherry ness of the chair. Like, this chair is exuding the quality of being chair.

A

This is this expansion of the perceptual bubble, a narrow percept that then grows within the confines of that narrow percept. So sense of self is a very interesting phenomenon. If we could dissect it a little bit, there's the somatic sense of self. So the ability to literally feel the self in this process we call interoception. And then there's the. The title of the self, the I am blank. And I notice you said that several times. And it's intriguing to me of a good friend. I don't think I can or should mention his name, but he had a very long and successful career within one of the more elite teams and within the SEAL teams. And he's a fairly philosophical guy, also very practical guy. But he has said many times to me that the most powerful words in any language are I am. Because whatever follows that, if you repeat it enough, tends to have this kind of feedback effect on how you are in the world. And the first pass, it sounded to me a little bit like kind of like Internet psychology type thing, like the secret or something, which frankly, I'm just not particularly. Yeah, you kind of like the whole fake it till you make it. I don't actually subscribe to any of that. But in dissecting that a little bit further with him, I came to realize that these words I am are very powerful. I don't think you reprogram your brain just by saying them. But how one defines themselves internally, not just to other people, but how one psychologically and by default defines themselves, I think, is a very powerful like. And depressed people, as well as happy people seem to define themselves in terms of these categories of emotional states. So I think it's so interesting that letting go and going into this perceptual bubble, which is facilitated by obviously a really wonderful team of therapists, but also the serotonergic agent, allows us to potentially reshape the perception of self. That's a tremendous feat of neuroplasticity.

C

Right. And I think certainly more work needs to be done. This is the horizon. And I should credit Chris Letheby, a philosopher in Australia, who has a forthcoming book. It might be out right about now or soon, within the coming months. Psychedelics and philosophy.

A

That's the title of the book.

C

It might be psychedelic philosophy. It's really close.