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

**Andrew Huberman** (0:00)
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.

**Matthew Johnson** (0:28)
Likewise, big fan, and happy to do this with you.

**Andrew Huberman** (0:31)
Well, thank you. My first question is a very basic one, which is, what qualifies a substance as a psychedelic?

**Matthew Johnson** (0:39)
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 had 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 one, 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 bit tendency to stay away from psychedelics 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. These are the basic two, 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 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 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, call 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 intactogen.

**Andrew Huberman** (4:02)
What does that mean?

**Matthew Johnson** (4:03)
It means like touching within. It sort of elutes the idea that it can really put someone in touch with their emotions. It's also been called an empathogen, meaning can afford empathy.

**Andrew Huberman** (4:16)
So I get the impression that this psychedelic space is a enormous cloud of partially overlapping compounds.

**Matthew Johnson** (4:23)
Right.

**Andrew Huberman** (4:24)
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.

**Matthew Johnson** (4:43)
I think of these as psychedelics is profoundly altering models.
You know, we're all prediction machines and so much of that is top-down, and psychedelics have a good way of, you know, loosely speaking, dissolving those models. And one of the realities...

**Andrew Huberman** (5:07)
Can you give us an example of one of like a model? Like I know that when I throw a ball in the air, it falls down, not up.

**Matthew Johnson** (5:14)
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. I mean, it's very atypical of... Sounds like they really thought they could fly and, you know, jump out of a window. Now, far more people every year fall. I mean, who knows, you know, 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 cases. There was one research volunteer in our studies 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?