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

Dr. Matthew Johnson:
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.

Andrew Huberman:
Likewise. Big fan and happy to do this with you.

Dr. Matthew Johnson:
Great. Well, thank you. My first question is a very basic one, which is what qualifies a substance as a psychedelic?

Andrew Huberman:
Nomenclature is a real challenge in this area of psychedelics. So starting with the word psychedelic, 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, the specific pharmacological classes that can be called a psychedelic are, one, what are called the classic psychedelics. So in the literature, you'll see that term, and hallucinogen and psychedelic 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 San Pedro. And even amongst these classic psychedelics, there are two 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 two basic building blocks that you're starting from, either a tryptamine structure or a phenethylamine structure. But that's just the chemistry. 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 agonists or partial agonists at the serotonin 2A receptor, so subtype of serotonin receptor. Then you have these other classes of compounds that you could call a 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 robo-tripping, guzzling cough syrup. A large overlap in the types of subjective effects that you get from those compounds compared to the 2A agonist classic psychedelics. But then you have another big one, MDMA, which really stands in a class by itself. So it's been called an entactogen and-

Dr. Matthew Johnson:
What does that mean?

Andrew Huberman:
It means touching within. It sort of alludes 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.

Dr. Matthew Johnson:
So I get the impression that this psychedelic space is a enormous cloud of partially overlapping compounds.

Andrew Huberman:
Right.

Dr. Matthew Johnson:
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.

Andrew Huberman:
Mm-hmm. I think of these 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-

Dr. Matthew Johnson:
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.

Andrew Huberman:
This might sound extreme, but there are these cases, it was overblown in sort of the propaganda of the late '60s, early '70s, but there are credible cases of people, and 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?

Dr. Matthew Johnson:
Sure.

Andrew Huberman:
They fall and die 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 studies, in one of our studies, she looked 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-

Dr. Matthew Johnson:
Who knows?

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
So she was-

Andrew Huberman:
Into the other dimension.

Dr. Matthew Johnson:
Yeah.

Andrew Huberman:
So they're violating these predictions.

Dr. Matthew Johnson:
I'd like to take a quick break and acknowledge one of our sponsors, David. David makes a protein bar unlike any other. It has 28 grams of protein, only 150 calories, and zero grams of sugar. That's right, 28 grams of protein and 75% of its calories come from protein. This is 50% higher than the next closest protein bar. David protein bars also taste amazing. Even the texture is amazing. My favorite bar is the chocolate chip cookie dough, but then again, I also like the new chocolate peanut butter flavor and the chocolate brownie flavor. Basically, I like all the flavors a lot. They're all incredibly delicious. In fact, the toughest challenge is knowing which ones to eat on which days and how many times per day. I limit myself to two per day, but I absolutely love them. With David, I'm able to get 28 grams of protein in the calories of a snack, which makes it easy to hit my protein goals of one gram of protein per pound of body weight per day, and it allows me to do so without ingesting too many calories. I'll eat a David protein bar most afternoons as a snack, and I always keep one with me when I'm out of the house or traveling. They're incredibly delicious, and given that they have 28 grams of protein, they're really satisfying for having just 150 calories. If you'd like to try David, you can go to davidprotein.com/huberman. Again, that's davidprotein.com/huberman. 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.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Johnson:
Especially for people who haven't done them before, right?

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
Who might not have an understanding of what their effects are like. Can we just briefly touch on the serotonin system?

Andrew Huberman:
Mm-hmm.

Dr. Matthew Johnson:
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 traditions?

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
At the end of the day, it's a chemical, and these receptors are scattered around the brain with billions of other receptors.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
What do we think is going on in a general sense?

Andrew Huberman:
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.

Dr. Matthew Johnson:
Because when I eat a bagel, I get serotonin release, right?

Andrew Huberman:
Uh-huh.

Dr. Matthew Johnson:
I mean, there's-

Andrew Huberman:
And it's very different than LSD

Dr. Matthew Johnson:
... or turkey. I mean, there's tryptophan.

Andrew Huberman:
Mm-hmm.

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

Andrew Huberman:
Right

Dr. Matthew Johnson:
... 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.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
Is that fair to say?

Andrew Huberman:
Need to do something. That's consistent with my understanding. And I'll certainly not in terms of I don't primarily identify as a neuroscientist, 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.

Dr. Matthew Johnson:
Well, feel free to explain it at the experiential level.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
Let's say I were to come to one of your clinical trials, because these are clinical trials, right?

Andrew Huberman:
Mm-hmm.

Dr. Matthew Johnson:
At your lab at Hopkins.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
And would I need to be depressed, or could I just be somebody who wanted to explore psychedelics?

Andrew Huberman:
We've had studies for all of these.

Dr. Matthew Johnson:
Okay.

Andrew Huberman:
And a number of other disorders.

Dr. Matthew Johnson:
Okay.

Andrew Huberman:
So healthy, normal studies.

Dr. Matthew Johnson:
Okay.

Andrew Huberman:
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 healthy, normal without a diagnosable issue. But man, we're all human, and the issues seem to come to the surface.

Dr. Matthew Johnson:
Sure. Yeah.

Andrew Huberman:
But we've done work with smoking cessation, so people trying to quit tobacco and haven't been successful.

Dr. Matthew Johnson:
So a variety of reasons.

Andrew Huberman:
Right.

Dr. Matthew Johnson:
So maybe I'll just ask some very simple questions that would 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-

Andrew Huberman:
Mm-hmm

Dr. Matthew Johnson:
... be present during this psychedelic journey.

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

Dr. Matthew Johnson:
Right.

Andrew Huberman:
So the manic side of bipolar.

Dr. Matthew Johnson:
Mm-hmm.

Andrew Huberman:
And also cardiovascular screening, heart disease. After that screening, then the preparation where 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.

Dr. Matthew Johnson:
Mm-hmm.

Andrew Huberman:
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 the things that could happen, so there are no surprises.

Dr. Matthew Johnson:
Mm-hmm. I think it'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 and And it's the day.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
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 how do they get it into their body?

Andrew Huberman:
So they receive pure psilocybin. Most of our studies are looking at where we want a psychedelic effect are in the 20 to 30 milligram range. The session day itself, 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-

Dr. Matthew Johnson:
Right

Andrew Huberman:
... or when you're doing a lot of cognitive tasks. 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. Ultimately, what I tell people is any emotional response, it's all welcome. You could be crying like a baby hysterically. That's what you should be doing if that's what you feel like.

Dr. Matthew Johnson:
You're doing therapy for people. It's not just about the experience.

Andrew Huberman:
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. One should let go of control.

Dr. Matthew Johnson:
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. 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, 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-

Andrew Huberman:
Mm-hmm

Dr. Matthew Johnson:
... not just one. Is that-

Andrew Huberman:
Especially these days. Yeah.

Dr. Matthew Johnson:
Exactly.

Andrew Huberman:
Multitask. Yeah.

Dr. Matthew Johnson:
Right. Multitask, and the more that we focus on one thing, the more bizarre that thing actually can appear to us, right?

Andrew Huberman:
Right.

Dr. Matthew Johnson:
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-

Andrew Huberman:
Yeah, it is weird

Dr. Matthew Johnson:
... some very weird things.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
Right?

Andrew Huberman:
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 shouldn't necessarily-- One should be judicious in putting themselves in these circumstances. Someone could be 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. 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, well, we know the simplest form of learning is habituation. Simply keep applying stimuli, and there's less response. This is what organisms do. This is what we have to do, and it's like there's this dishabituation component that-

Dr. Matthew Johnson:
Dishabituation.

Andrew Huberman:
Yes.

Dr. Matthew Johnson:
Yeah.

Andrew Huberman:
We wouldn't be able to get through life, and we wouldn't be able to cross that street if we were like, "Hold, this is a miracle."

Dr. Matthew Johnson:
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-

Andrew Huberman:
Yeah

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

Andrew Huberman:
Right. Because I've had people there on the couch. Yeah, I remember one lady said, this is probably 13, 14 years ago, said, "Matt, tell me again I can't die. I feel like my heart is going to rip through my chest." She was feeling her-- And I should say, typically, cardiovascular response is modest. The 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, 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.

Dr. Matthew Johnson:
Sure.

Andrew Huberman:
But someone can feel that, "My God, I'm going to die. I have never felt my heart beat like this before."

Dr. Matthew Johnson:
So there's an expansion of a particular, fairly narrow percept. It could be sound-

Andrew Huberman:
Yeah

Dr. Matthew Johnson:
... could be an emotion, could be sadness, could be a historical event or a fear of the future.

Andrew Huberman:
Yes.

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

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
There's something about going into that experience in an undeterred way that allows somebody to bring something back into more standard reality.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
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-

Andrew Huberman:
Yeah

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

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
So what are your thoughts on that?

Andrew Huberman:
This is in the terrain we're figuring out. So educated speculation is the best I can provide, but I- I think the common denominator are persisting changes in self-representation.

Dr. Matthew Johnson:
Okay. Tell me more about self-representation.

Andrew Huberman:
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.

Dr. Matthew Johnson:
Mm-hmm.

Andrew Huberman:
That I am a thing that's separate from other things, and I have a certain personality, and 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 like-

Dr. Matthew Johnson:
So this is this expansion of the perceptual bubble, a narrow percept that then grows within the confines of that narrow percept.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
So sense of self is a very interesting phenomenon, and if we could dissect it a little bit. There's the somatic sense of self, so the ability to literally feel the self, this process we call interoception. And then there's the title of the self, the I am blank.

Andrew Huberman:
Yeah.

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

Andrew Huberman:
Mm-hmm.

Dr. Matthew Johnson:
But how one psychologically and by default defines themselves, I think, is very powerful.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Johnson:
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-

Andrew Huberman:
Yeah

Dr. Matthew Johnson:
... allows us to potentially reshape the perception of self. That's a tremendous feat of neuroplasticity.

Andrew Huberman:
Right. I think there's something about this change in sense of self. There seems to be something on the identity level, both with, I think, of the work we did with cancer patients who had substantial depression, anxiety because of their cancer, and also our work with people trying to quit cigarette smoking. There seems to be, when it really works, this change in how people view themselves. Like with smoking-

Dr. Matthew Johnson:
Mm-hmm

Andrew Huberman:
... really stepping out of this model. Like, "I'm a smoker. It's tough to quit smoking cigarettes. I can't do it. I failed a bunch of times." I remember one participant during the session, but he held onto this afterwards, said, "My God, it's like I can really just decide," like flicking off a butt, "I can decide not to smoke." And I call these duh experiences with psychedelics because people often, like in the cancer study, you say, "I'm causing most of my own suffering. I can follow my appointments. I can do everything, but I can still plan for the vaca- I'm not getting outside in the sunshine. I'm not playing with my grandkids. I'm choosing to do that." And it's like they told themselves that before, and the smoker has told themselves a million times. When it comes out of their mouths, folks will say, this is part of the ineffability of a psychedelic experience, folks are like, "I know this sounds like bullshit, and this sounds like... But my God, I could just decide." They're feeling this gravity of agency that seems to be, at times, fundamentally supercharged from a psychedelic experience. This idea like, I'm just going to make a decision. Normally, you tell a depressed person, "Don't think of yourself that way. You're not a failure. Look at all the-"

Dr. Matthew Johnson:
They can't do it.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
Right.

Andrew Huberman:
But you can actually, in one of these states, have an experience where you realize like, my God. Just like using MDMA to treat PTSD, and we're going to be starting work with psilocybin to treat PTSD, someone could really reprocess their trauma in a way that has lasting effects, and clearly, there's probably something, reconsolidation of those memories. They are altered, very consistent with our understanding of the way memory works. So the whole idea, people can actually, in a few hours, have such a profound experience that they decide to make these changes in who they are, and it sticks.

Dr. Matthew Johnson:
I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens. As somebody who's been involved in research science for almost three decades and in health and fitness for equally as long, I'm constantly looking for the best tools to improve my mental health, physical health, and performance. I discovered AG1 back in 2012, long before I ever had a podcast, and I've been taking it every day since. I find it improves all aspects of my health, my energy, my focus, and I simply feel much better when I take it. AG1 uses the highest quality ingredients in the right combinations, and they're constantly improving their formulas without increasing the cost. In fact, AG1 just launched their latest formula upgrade. This next-gen formula is based on exciting new research on the effects of probiotics on the gut microbiome, and it now includes several clinically studied probiotic strains shown to support both digestive health and immune system health, as well as to improve bowel regularity and to reduce bloating. Whenever I'm asked if I could take just one supplement, what that supplement would be, I always say AG1. If you'd like to try AG1, you can go to drinkag1.com/huberman. For a limited time, AG1 is giving away a free one-month supply of omega-3 fish oil, along with a bottle of vitamin D3 plus K2. As I've highlighted before on this podcast, omega-3 fish oil and vitamin D3 K2 have been shown to help with everything from mood and brain health, to heart health, to healthy hormone status, and much more. Again, that's drinkag1.com/huberman to get a free one-month supply of omega-3 fish oil, plus a bottle of vitamin D3 plus K2 with your subscription. Today's episode is also brought to us by BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. I've been doing weekly therapy for well over 30 years. Initially, I didn't have a choice. It was a condition of being allowed to stay in school. But pretty soon, I realized that therapy is an extremely important component to overall health. In fact, I consider doing regular therapy just as important as getting regular exercise, including cardiovascular exercise and resistance training, which of course, I also do every week. There are essentially three things that great therapy provides. First of all, it provides a good rapport with somebody that you can trust and talk to about all issues that you're concerned about. Second of all, it can provide support in the form of emotional support or directed guidance. And third, expert therapy can provide useful insights. With BetterHelp, they make it very easy to find an expert therapist with whom you resonate with and can provide those benefits that come through effective therapy. Also, because BetterHelp allows therapy to be done entirely online, it's very time efficient. It's easy to fit into a busy schedule. There's no commuting to a therapist's office or sitting in a waiting room or anything like that. You simply go online and hold your appointment. If you would like to try BetterHelp, go to betterhelp.com/huberman to get 10% off your first month. Again, that's betterhelp.com/huberman. I'm fascinated by this idea that a somatic and a perceptual experience, but a real experience of the sort that you're describing-

Andrew Huberman:
Yeah

Dr. Matthew Johnson:
... is what allows us to reshape our neural circuitry and to feel differently about ourselves. And I know there's been really tremendous success in many individuals of alleviating depression-

Andrew Huberman:
Mm-hmm

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

Andrew Huberman:
Uh-huh.

Dr. Matthew Johnson:
In particular, MDMA.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
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 increased dopamine and increased serotonin would provide an experience that is beneficial, and 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?

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

Dr. Matthew Johnson:
Well, what is the-

Andrew Huberman:
It's not sort of 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 typically, 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."

Dr. Matthew Johnson:
You're talking about LSD or psilocybin?

Andrew Huberman:
LSD, psilocybin, ayahuasca.

Dr. Matthew Johnson:
Bad trip.

Andrew Huberman:
Yeah. 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."

Dr. Matthew Johnson:
How often does that happen?

Andrew Huberman:
"I don't have a toehold on anything-

Dr. Matthew Johnson:
Yeah

Andrew Huberman:
... even that I exist 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 sense of unity with all things, which we know our data suggests is related to long-term positive outcomes.

Dr. Matthew Johnson:
Wait, I want to make sure I understand.

Andrew Huberman:
But I'll-

Dr. Matthew Johnson:
So you're saying the bad trip can be related to the transcendental experience?

Andrew Huberman:
Right. I think those are both speculating, but you have to pass through this sort of 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 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 within yourself choosing to handle, like letting go. And eventually, we'll be able to see this in real-time with brain imaging. "There they are surrendering to the psychedelic experience. Here they are trying to hold on." But we're not there yet. But I think through clinical observation, it seems pretty clear that something like that is going on.

Dr. Matthew Johnson:
There has been an attempt at creating this movement toward openness about psychedelics and their positive effects. This has happened before.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
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, what are the valuable exports, right? And where does the extreme lie? Clearly, there's a problem with tinkering with reality through pharmacology, and there's a benefit, it sounds like-

Andrew Huberman:
Mm-hmm

Dr. Matthew Johnson:
... to tinkering with reality through pharmacology.

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
And for the average person, right, or for kids that are hearing this, kids that are in their teens, right?

Andrew Huberman:
Yeah.

Dr. Matthew Johnson:
I want to talk about what are the dangers of psychedelics?

Andrew Huberman:
Mm-hmm.

Dr. Matthew Johnson:
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?

Andrew Huberman:
Yeah. So these can be profoundly destabilizing experiences, and ones that ideally are had in a safe container, sort of where someone-- 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 depression, not anxiety. I'm talking about psychotic disorders like schizophrenia or 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 a less than an ideal environment, you can have a bad trip. You even get it in an ideal environment like ours at a high dose of around 30 milligrams of psilocybin, after the best preparation we can provide. About a third of people will say, essentially, at some point, they have a bad trip.

Dr. Matthew Johnson:
At some point within the entire journey?

Andrew Huberman:
Right. Now, they could have one of the most beautiful experiences of their life sometimes a couple of minutes later.

Dr. Matthew Johnson:
Right.

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

Dr. Matthew Johnson:
I definitely want to ask you about microdose versus standard or macrodosing psilocybin. I'm micro-cynical 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?

Andrew Huberman:
So yeah, the claims are, and there are a number of them, there's two general ones. One is sort of acting 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 the traditional antidepressants, a better version of Prozac. None of the peer-reviewed studies that have much credibility, 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 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 get--

Dr. Matthew Johnson:
You have to function in the world.

Andrew Huberman:
In your work life. Yeah, which is the way people are claiming to use it. It helps them be a better CEO. You want an accurate sense of time. So if anything, the data suggests that it makes it a little bit less accurate, and there's evidence that someone feels a little bit impaired, and they feel a little bit high. So in terms of, you call that abuse liability in research. So far, no studies have shown an increase in creativity, enhancement of any form of cognition, or a sustained improvement in mood. Now, no studies have actually looked at the system of microdosing that the aficionados are claiming. Folks like 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." 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 using it, and you're feeling the benefits on those off days, like the three 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-

Dr. Matthew Johnson:
Well, serotonin

Andrew Huberman:
... because of the suffering with depression.

Dr. Matthew Johnson:
Right.

Andrew Huberman:
It wouldn't be as interesting as I think what we're doing with high-dose psilocybin or psychedelics to treat depression. If this is developed and there's a reality, it would be more like perhaps a better SSRI, a better Prozac.

Dr. Matthew Johnson:
Which are similar.

Andrew Huberman:
That being said, we need more tools than fewer tools in the toolbox.

Dr. Matthew Johnson:
Right.

Andrew Huberman:
And it shouldn't be that surprise. Even before, going back to the tricyclics and the MAO inhibitors, going back to the '50s, augmenting extracellular serotonin in one way or another, for many people, leads to a 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 put my bets on it, that if there's anything real, it is in that category. Although I'm very open to maybe there is something to the creativity, to the improved cognition, which covers many domains in and of itself. But my greatest hopes are on the antidepressant effects. That said, in the big picture, I think all of the most interesting thing about psychedelics are the heroic doses. The idea that you can give something one, two, three times, and you see improvements in depression months later-

Dr. Matthew Johnson:
Right

Andrew Huberman:
... and in addiction, over a year later, and with these people dealing with potentially terminal illness. I'm interested in big effects.

Dr. Matthew Johnson:
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 neurologic injury or head injury. We always think sports, but there are many people who make a living in a way that is, over time, is detrimental to their brain. What do you think is the potential for these compounds, particularly psilocybin, but other compounds as well, for the treatment and possible even reversal of neurological injuries?

Andrew Huberman:
There are anecdotes of people saying that that psychedelics have helped heal their brain. They've been in one of these situations, like in sports, a sport where there's repetitive head impact, and they're claiming that 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 several labs like David Olson, Brian Roth, these folks that have shown different forms of neuroplasticity unfolding, those effects may be at play in the psychiatric treatments that we're dealing with. 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 sets up is that maybe that's what's going on with these claims of improvements from neurological issues, that there's actually a repair of the brain from injuries underlying situations where there's repetitive head impact. Perhaps there's a potential for helping folks recover from stroke and disorders like that. It is more exploratory, but what I'm hoping to do is some work with retired athletes who have been exposed by the nature of their sport, for example, MMA athletes in the UFC who have been exposed to repetitive head impacts like a lot of sports expose people to, and who are retired from the sport and are suffering from, say, depression, which can in part result from that history of head impact. See if we can fix the depression, but then also, as a cherry on top and a more exploratory aim, see if we can have evidence 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 are actually some evidence of this more direct repair of the brain.

Dr. Matthew Johnson:
Mm-hmm.

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

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

Andrew Huberman:
Thank you, Andrew

Dr. Matthew Johnson:
... for your knowledge, and I think you put it best earlier, for holding the candle in a very dark time, and then now there's light.

Speaker 3:
"I didn't like what you said," Odin pauses, "about the future." This is the love story of real Hinge couple Odin and Edward, written and read by me, Curtis Garner. Listen to the free audiobook now.