NARRATOR: Meet Matthew Johnson.

MATTHEW JOHNSON: I'm Matt Johnson. I'm a professor of psychiatry and behavioral sciences at Johns Hopkins. I study drugs, all kinds of drugs: uppers, downers, all-arounders. The drug class that I've studied most over the last, nearly couple of decades, are the psychedelic compounds.

NARRATOR: Why are psychedelics unique among drugs?

JOHNSON: I developed an interest in drugs, including psychedelics, over 25 years ago in my early 20s. I was fascinated by the history of psychedelics in our culture; the fact that there was medical research in the early days; and I just had this growing fascination with psychoactive compounds in general. The idea that any of these substances, whether we're talking about cocaine, caffeine, you name it, including the psychedelics, how these things affect our behavior, how you put these small amounts of a substance in your body, and they can have, at times, radical changes in your subjective experience and what you do. It's hard to imagine a more interdisciplinary topic in the realm of drugs than psychedelics. I mean, psychedelics crosscut so many interesting domains. They've apparently been used for time immemorial by indigenous cultures throughout many different cultures on the planet. In our own Western cultural history, they really exploded on the scene in the 1960s, and were associated with some really radical changes to society. And what really is most interesting, to me, as someone who's really focused on the effects of drugs on behavior- whether it's the good, the bad, the ugly- psychedelics are the only drug class that I know of where you have not just one or two, but lots of stories of people saying they took this thing one time, some decades ago, maybe 50 years ago, and they say it had this profound impact on the course of their entire life. You know, I can't think of another drug class where people claim therapeutic or beneficial effects of any type when they used it only one time. I mean, you take cannabis, you know, plenty of examples of therapeutic effects, but I've never met anybody who said they smoked pot one time 20 years ago, never touched it again, and yet they can point to how this has radically improved their life. Those stories are countless with psychedelics. Not everybody, plenty of people just try them, and they have fun, and that's it. But it's surprisingly common for people to say really outlandish things, like Kary Mullis won the Nobel Prize inventing PCR, which revolutionized biology. He said he wouldn't have been able to do that had he not had experience in taking psychedelics. You move into the arts and then, I mean, gosh, I mean, who hasn't heard of musicians and other artists claiming that psychedelics had a profound impact on their creativity? I mean, I remember when I was coming of age and my late teens, discovering the music of earlier generations, and, "Hey, there's this band people have heard of, probably called The Beatles, you know? And wow, they're pretty good." But then you explore their music, and there's The Beatles before LSD, and then there's The Beatles after LSD. That's a big shift, and a lot of folks like the Beatles after LSD, especially so.

NARRATOR: What does the term 'psychedelic' mean?

JOHNSON: Okay, so the term 'psychedelic' was coined by Humphry Osmond, who was writing letters, back when people wrote letters, to Aldous Huxley. And they were sending letters back and forth- they had a friendship-and they were discussing, they were both profoundly intrigued by this new class of drugs. And they were trading ideas about what the ideal name for this new drug class would be. And Huxley came up with some unpronounceable term that Humphry Osmond dismissed. And let's see if I can recall the poem that Osmond wrote to Huxley. He said, "To fathom hell or soar angelic, just take a pinch of psychedelic." And what psychedelic means, from its linguistic roots, is "mind manifesting." And so I'd say that's a pretty good term. There's no perfect term for this drug class. Certainly hallucinogen, which is often used is not a great term 'cause very rarely do people have true hallucinations, and there's a misunderstanding of what that means. But the psychedelic, the idea that these are mind manifesting, that's consistent with this other notion that these are non-specific amplifiers. In other words, you could have a euphoric experience, you could have a hellish experience. You name it in the realm of human experience and emotions, that can be your experience, and it could be amplified. And it's very much a product of what's going on in your life at the time. It's not this reliable effect. So it seems like manifesting the mind, digging deeper into the mind, amplifying what is already there in the mind, that sort of generally fits with clinical observations with these drugs. Terminology is so difficult in this area, and even the experts will disagree. Psychedelic can be used to refer to what are called the 'classic psychedelic compounds': psilocybin, which is in magic mushrooms, LSD, DMT, which is in ayahuasca, mescaline, which is in peyote- those are the classic psychedelics. They affect a certain particular type of serotonin receptor, and that's their primary mechanism of action. But then you have other drugs that are called psychedelic, and I think it's appropriate to call them psychedelic. Other scientists will disagree, but they have a different mechanism. They're not classic psychedelics. So for example, MDMA will work by releasing serotonin; so that's a different mechanism. And its effects are different than the classic psychedelics, typically not as intense, typically more focused on one's emotional experience, more of a heart trip than a head trip. And you have other drugs, such as ketamine. So that affects the glutamate system in the brain primarily rather than the serotonin system. Even though there's evidence that the classic psychedelics downstream for serotonin, they also affect glutamate. But nonetheless, the drugs like ketamine and PCP, which are in the same class as each other, they initially affect the glutamatergic system in the brain. So what does psychedelic mean, then, if it refers to multiple underlying classes, pharmacological classes of drugs that work in different ways? And the answer for me is that these are all drugs that can have a profound effect on one's sense of reality, including one's sense of self. And I would say that typically isn't the case for what we think of as the stimulants or the sedatives or the opioids. People feel different, but not as extremely as with these psychedelic compounds.

NARRATOR: What is hallucinogen versus entheogen versus psychedelic?

JOHNSON: When I first started in psychedelic research in 2004, it was hard to get a paper published using the word psychedelic. Hallucinogen, by far, was the preferred term in academia in science. Thankfully, that's changed. And I think it's because enough scientists, like myself, kept trying to use the term, in arguing that it's a better term. You know, hallucinogen, one, the reasons I don't like hallucinogen as a term, is that it focuses on the perceptual realm, which a lot of people who aren't very familiar with psychedelics, they just assume that's the primary mechanism. In other words, someone will hear about some of the research and say, "I don't get it, why would seeing things, hallucinations, what are you seeing, pink elephants, and that makes you want to quit smoking? Like, I don't get it," people will say. And that's 'cause they're focused on this perceptual aspect of psychedelics. And probably the reason that the perceptual effects have gotten so much attention is those are the aspects that are easier to describe. Like, "Yeah, the walls look like they were waving." That's not normal. I can describe what that is. Like, what the hell is going on? Trying to wrap language around dissolving the sense of identity, having some sense of who I am beyond the normal descriptors, you know, "I'm so old, I'm a male, I'm this, I'm from this country," all these ways we define ourselves, just when they're completely stripped away and what's left, I mean, we're getting into deep philosophical realms there that are really hard to describe. It's easy to describe, "I saw some crazy-ass colors." So I think this is sort of stuck, the focus on perceptual effects has sort of stuck as sort of the lay understanding of what these drugs do. Hallucinogen, therefore, it focuses on this one relatively arbitrary aspect of psychedelic effects. And that's why, actually, in therapy, one of the reasons we have people wear eye shades is we don't want them focusing the entire time on the wavy walls and the intense colors. And that's great. It's a six-hour drug effect. They're gonna have to get up and take a pee at some point. They'll get to see the wavy walls. You know, not everyone has those perceptual effects, but they'll have that opportunity. By blocking out the external distractions, the idea is one can focus the experience more internally about the nature of yourself, about these patterns in your life, about the big picture of what's going on in the world. The idea is you might get stuck at the pretty colors. And the pretty colors are great, but there might be something even more valuable underneath that if you dig deeper into that experience. And so I don't like the word 'hallucinogen' in that it just focuses on that perceptual realm, which is kind of just a trivial aspect and not even the key therapeutic aspect of these compounds. Also, hallucinogen implies that these drugs cause hallucinations, and the strict psychiatric definition of a hallucination, these drugs rarely cause those. If you have a hallucination, it means you are observing something, you're perceiving something in the environment that you actually believe is there. Someone really thinks a pink elephant, to use a classic example, is really in the room. That's a hallucination. You thought you were talking to a friend and having this long conversation, and then you look over and realize, "Oh, that friend was never there." That's a hallucination. What you typically get with psychedelics are more visual illusions or what you could call 'pseudohallucinations.' Typically, reality testing is intact, which is a fancy way of saying the wall's waving like a blanket or like waves on the beach. That might be really impressive. But typically, the person knows, in reality, the walls really aren't waving. They realize the reason they're seeing walls waving is because they've taken this substance. So you, you really don't get, typically, true hallucinations, so it's not a great word. Entheogen, I've never been a fan of that word to refer to a drug class. I'm a fan of using that word in its anthropological sense. In other words, so what 'entheogen' means, one of the common definitions from its linguistic roots is "awakening the divine within," or "awakening God within." So it's really referring to this sacramental, spiritual religious use of these compounds. My beef with that is that you name the psychoactive substance, it's been used as an entheogen. You know, tobacco, coca leaves, which contain cocaine, opioids. I mean, you'd be harder pressed to find the drug that hasn't been used as part of a sacrament at some point. So I like to refer to the entheogenic use of a particular substance. It could be the entheogenic use of tobacco by indigenous tribes. It could be the entheogenic use of ayahuasca. But I don't wanna define that particular substance as entheogenic. And then as a counterpoint, a couple of, yeah, high school kids that take some mushrooms, and they do a lot of giggling, and they see some pretty colors that really amaze them, and they don't really have anything that they would describe as a spiritual effect, that doesn't sound like an entheogen to me. So it's kind of an arbitrary- you're assigning just one portion of what these drugs can do, but you're defining the entire drug class with that one effect. So that's why I think the psychedelic is a broad enough term to encompass all of those experiences: the perceptual effects, the potential spiritual effects, and any other personal insights etc.

NARRATOR: The first wave: Hofmann, Leary, and the CIA.

JOHNSON: The first big wave of that scientific interest for psychedelics was in the 1950s. So this was, yeah, about a decade after Albert Hofmann had first discovered the psychoactive properties of LSD. And in that following decade, essentially the pharmaceutical company, Sandoz, that he worked for in Switzerland, pretty liberally sent out samples of LSD for physicians to do research with. And when I say research there, it's not like research now where you need a year's worth of approvals with this highly restricted access and everything. It was like "Hey, I'm a doctor, and I'm curious to give this to some of my patients to see what's up." "Sure, here you go." You know, put it in the post from Switzerland. And so, there was a lot of sort of casual research use, but there were also some early clinical trials. I would say one of the most important groups in the history of this work was this group led by Abram Hoffer and Humphry Osmond in Saskatchewan, Canada. And they were really the first group that I would say developed what we now call 'psychedelic therapy,' this idea of that you're not just mimicking psychosis, which is what originally was thought by the very early researchers. All this stuff did was mimic people having a psychotic break, having a schizophrenic episode. These Saskatchewan researchers figured out if you prepare people and have a comfortable environment and just have them introspect, lay on a couch and pay attention to their experience, you had these experiences that oftentimes were anything but psychotic. I mean, they were reported to be some of the most meaningful, clear, lucid experiences of people's lives. And you could use many names, a transcendental experience, mystical experience, insightful experience. And so there was some development, there was other groups. There was a group in Maryland called the Spring Grove group. A lot of early research there, particularly with cancer patients. But then the research was really put on hold for several decades after this period. In the first wave of research from the 1950s through early '70s, there was this growing appreciation of some of the risks and the safeguards needed to minimize those risks. But not every investigator was aware of this. And some of them were only aware of this as time went on, so it was an evolution. But some of the research just, hey, they gave a giant dose of LSD to someone and then locked them in a padded room. So one of the trials looking to see if LSD could help people with alcoholism, they literally tied people down in restraints to their hospital bed, gave them a massive dose of LSD, 800 micrograms, which is a really big dose. And they didn't give them any warning that, like, they took this substance that would profoundly alter their conscious experience. So we've figured out a lot since then, that sort of research. Those are the conditions under which, when you do get experiences that look more like psychosis, you treat the person like they're gonna go crazy. And a lot of times they, at least temporarily, they feel like they're going crazy. And then there was controversies surrounding Timothy Leary at Harvard. He did some really great research early on. And even while he was at Harvard, having people over at his house on a Saturday night, and everyone taking it, including the researchers. So we've moved away from that, thankfully. And gosh, I should mention in that earlier era, this is also when the CIA was seriously investigating these drugs as part of their MKUltra program. This is not urban legend. There's lots of declassified material through the Freedom of Information Act that has revealed this history. They were giving it, at times, to just American citizens without their knowledge or consent behind a mirror. People visiting a sex worker, for example. Glass of water they're given and big dose of LSD, and these goons from the CIA are standing behind this one-way mirror, like, just observing to see what would happen. So you had, obviously, highly unethical research like that going on. Yeah, on a lot of these dimensions, I mean, I think it's pretty clear today what the major risks of these compounds are. And hopefully, just ethics have improved the recognition of it. This is very serious, and don't underestimate the damage you can do to someone, like slipping out LSD into their drink.

NARRATOR: Are psychedelics legal?

JOHNSON: Most psychedelics aren't legal in most countries in the world. There are some exceptions, but the primary classic psychedelics we know of, psilocybin mushrooms, or so-called magic mushrooms, or LSD, ayahuasca, which contains the compound DMT, mescaline in peyote and other cacti. In most countries, these are not just illegal, but in the most restrictive class. So for example, in the United States, they're in Schedule 1, or in the United Kingdom, they're in schedule A, same thing; it's the most restrictive class for the most dangerous compounds with the greatest abuse potential, and with no recognized medical use. Now, there are some nuances to that. There have been some states in the U.S. that have decriminalized, or even in Oregon, recently, have legalized the use of psilocybin in the context of a therapeutic-like situation with a guide. But for the most part, these are illegal. Now, the research that's happening now, a lot of it is exploring medical applications through the FDA process where there's FDA approval and DEA approval. So the hope is as these trials advance, and as we move into what's called 'phase 3 research,' that's the final level of a clinical trial, typically with a larger number of participants. That's the final phase that can decide whether or not this drug is gonna be approved as a medication by the FDA. And so we're likely only two, three, four years away from multiple psychedelics potentially- depending on those phase 3 results- being approved for treatment. So if that happens, then they would be legal to be used medically, but they would still be illegal in another context. Similar to what a lot of people may not realize that cocaine is legal to use in certain medical settings. Methamphetamine is legal to use in certain medical settings. All kinds of opioids, as most of us know, are legal to use in many medical settings. So it would be moving these compounds into more of that category: legal for medical use. The compounds that are likely to be approved, depending on the final results, in the next few years for medical use are MDMA, which some people might know as Molly or ecstasy on the street, and psilocybin, which is in so-called magic mushrooms.

NARRATOR: What are the main effects of psychedelics?

JOHNSON: Yeah, so psychedelics can prompt a wide variety of subjective changes. And so that can span thoughts: the way you think, your cognition. Feelings: very profoundly at times, the intensity of your feelings, the variability. You can swing from a terrifying experience to this beautific, sort of like most amazing experience of your life. So the variability, the intensity is there. So really any aspect of subjective experience, including self-identification, how one holds- how they define themselves, how they define reality. These are sort of the deepest aspects that I think and the aspects that are most aligned with the psychedelics' therapeutic effects. One aspect that we typically talk about with drugs, in general, that's relatively low for the psychedelics, are just their effect on physiology. Compared to the intensity of the subjective effects, it's remarkable how little impact these substances have on our biological functioning. So your heart rate, your blood pressure. How do people overdose on other drug classes? They drink so much, they take so many opioids, they stop breathing. Some drug kills their liver 'cause they've taken too much of it. They had too much of a stimulant, and they have a stroke or heart attack. Psychedelics are really robustly safe at the physiological level. There are exceptions. For example, people at very high risk for heart disease. It does raise the blood pressure and pulse somewhat, but all of those physiological effects really pale in comparison- compared to other drug classes-pale in comparison to the intensity of the subjective effects. So it really is those levels of subjective effects that are relate to one's conception about the big picture of their life, how they define themselves, how do they define reality, which is why I think something like the mystical experience, which includes this sense of oneness, being at one with the rest of the Universe, or being at one with the rest of humanity, someone comes out of that, and that has the potential to reframe whatever disorder we're talking about, reframing this addiction that they've convinced themselves, "Oh, I'm just a failure, I can never do it." Having an experience like that can really reframe that as, frankly, as small potatoes, and thinking about yourself in terms of depression, and this sort of self-fulfilling prophecy. So it really are those, how one defines themselves, I think, it's at the deepest levels.

NARRATOR: How do psychedelics work in the brain?

JOHNSON: Yeah, the huge question that's always thrown out is: How do these psychedelics work? And you can just come at that from so many different angles. Kind of the biggest divide is whether we're talking about on the psychological side or the biological side. Does it work by hitting these brain receptors and then having other effects, or does it work because of the experience? And the first thing I like to say about that is these are two sides of the same coin. Presumably, every psychological experience has a biological correlate, whether we're aware of that now. Like, you see the color green, there's something happening in your brain that's coding that experience of the color green. So we need to move away from thinking it's one or the other. And psychedelics are really interesting 'cause I think they're just, like, they're placed right at that interesting interface. Clearly, there's this very real biological effect. Something dramatic happens to the brain when you put the psychedelic in the system, but then someone has this experience. And when they change their life because of that, that ends up sounding more like they went through a really good course of psychotherapy, or they had a life-transforming experience, the way someone might say, "Well, having children changed them, or getting married changed them, or falling in love for the first time or visiting another culture for the first time." Sort of like these life experiences that change people. So psychedelics are really interesting at that bridge, philosophically, between the biological and the psychological. Now, to go down that biological path, what's happening, there's a lot going on, and we know a lot, but there's a whole lot more to figure out. The first thing that happens is that psilocybin, once it's circulating through your blood after you've eaten some of it, well, it actually converts to a related compound called psilocin, which is the thing that's actually hitting the brain receptors, and it activates a subtype of serotonin receptor. So we have lots of different types of serotonin receptors in our brain. One is called the serotonin 2A receptor. And psilocybin and the other classic psychedelics can latch onto that the same way that serotonin latches onto these brain receptors. But they do something different, 'cause clearly serotonin itself, which we all have floating in our brains right now, is not psychedelic. But when this activates the receptor, something different happens within that neuron, and it propagates this effect downstream. And we now know that, then, other neurotransmitter systems are involved. For example, we know the glutamate system is involved. So psilocybin effects serotonin, but then serotonin affects the glutamate system. And so you can think about it as if the serotonin 2A is the first domino. I think one of those set-ups with the million dominoes in the room where one knocks down the other, and then it goes up a ladder, and it spins a little thing and falls down, and all of that. The serotonin 2A is just the beginning part of the story. It's that first domino you knock over, and then you have the glutamate system. And then at another level, maybe this is sort of panning back and viewing that whole room full of dominoes, but at another level of analysis beyond what receptors are affected, and even, like, beyond what brain areas are become more active or less active, a really interesting level of analysis is: What's the nature of the communication across the brain that's changed? This is referred to as 'resting state.' What are the brain network dynamics? What's the relationship between the activity across different areas of the brain? And what's interesting is when the psychedelic is on, in the system, you see a massive increase in communication across brain areas that don't normally communicate. And you could tell this by the activity in those different areas is all of a sudden much more correlated with each other. And so they're normally moving and grooving and doing their own things. Much of our psyche and our mental processes are compartmentalized. You know, "You do your own thing, and you do your own thing," and we only sort of integrate it when it's necessary. But it seems like you kind of, like, have this massive increase in communication across these different silos in the brain. That is probably an important level of analysis that is underlying, at the psychological level, claims of insight, claims of extraordinary experiences, viewing themselves from a radically different perspective, from a different lens. It's sort of this, like, massive shake-up in one's experience of reality. And so, here we've gone through the receptor level to the brain activation level to the network communication levels of the brain, to what's the psychological experience that unfolds from that. And then, presumably, the way we get long-term behavior change is that that person starts to change their life. They actually learn lessons. And there also seems like there may be, based on animal research, increased plasticity, neuroplasticity in the system so that in the days following the psychedelic experience, people are more primed to learn new things. You know, there's a greater sticking power, there's a greater ability to establish a new and hopefully a more optimal normal state. And then if that is sort of reinforced and maintained, then that just becomes the new habit. And that's why we are seeing people six months later that are feeling better, whether they're smoking less, or they're less depressed. So a major difference between the classic psychedelics and MDMA is in how they're interacting with the serotonin system. They're both interacting with the serotonin system, but in very different ways. I mean, we should keep in mind that typical antidepressants also interact with the serotonin system, but in a very different way. So the classic psychedelics, they're mimicking the effects of serotonin on that receptor site. So the way neurotransmission works, brain communication works, is you have one neuron here, one brain cell and neuron here, and one here. And in order to have a signal propagate, a communication, a messenger is sent across this little gap in-between those two neurons, and those what we call neurotransmitters. A little serotonin is released into this space, and it travels over and it activates, it sits in this little pocket on this side. This is like, you know, baseball, the receptor is the the catcher's mitt. In the case of the classic psychedelics, it's normally a regular baseball that is thrown into that catcher's mitt, Now we imagine we've swapped out, we've taken the pitcher, and we've taken the regular white baseball, and now we've put like this tie-dye baseball in there- this is like the psilocybin baseball. Now that's being thrown out into that space in between the two cells. And that's being captured in that catcher's glove. And that has a different reaction on the, I guess, the catcher in this analogy, than serotonin itself would. MDMA is very different. MDMA is working with natural serotonin. It's causing not this differential effect on the catcher's side, but it's causing the pitcher, the neuron that's normally sending out serotonin into that space between the two neurons, it's causing the pitcher to just throw out a massive increase in balls. So now, the catcher is on the mound, and they're just getting balls thrown at them left and right 'cause this pitcher's just going crazy, throwing out way more serotonin, or more normal baseballs than normally would. And so that has a different effect on the system than the classic psychedelics. So there's a fundamentally different way in which the biology works, and most experienced users will tell you it feels fundamentally different. And there's more commonalities between the classic psychedelics, let's say LSD and magic mushrooms or psilocybin, shades of difference, but in the grand scheme of things, those are very similar compared to, on the other hand, MDMA. And we have some edge cases, some more exotic compounds, 5-methoxy-DMT. We're still early in the research. It might be that serotonin 2A plays less of a role in the primary effects of 5-methoxy-DMT, but that's not definitively shown yet. A lot of these compounds, well we have a simplistic story about serotonin 2A being the primary receptor, but, in fact, most of them hit a large number of receptors to a different degree, so it can be a complex process. There's substantial evidence that 2A is the key receptor that mediates the effects of classic psychedelics. How do we know that? We know that there are these compounds called 'antagonists' that people can take, and that will block a specific receptor. And so there are compounds, like ketanserin, that will block the serotonin 2A and not other receptors. It does a little bit, but it's primary blocking action is on the serotonin 2A. And if you block serotonin 2A, all of a sudden, you can give a big old dose of psilocybin to people, and they don't feel anything. And the same thing happens in rats. You can train rats to say, "When I've given you an injection of psilocybin in the belly, 10 minutes before your session, we put you in a sort of a skinner box where you can press levers- give you psilocybin on those days, the left lever is the one that gives you a little food pellet if you press it. And on other days where you just give you a saline injection, a placebo, essentially, in the belly, on those days, the right lever is what gives you, is produces the food pellet." And then if we do that for a few weeks, all of a sudden, that animal is able to reliably tell us whether they've gotten psilocybin or not, which is really remarkable. And then you could do interesting things, like give another compound, like LSD, and all of a sudden, they'll treat it as if it was psilocybin. So it's a powerful pharmacological assay in animals. And so if we block the serotonin 2A receptor in those rats, they are no longer able to distinguish, to discriminate between a psychedelic and a saline injection- very consistent with the human work. And there's other layers. You can create rodents that are so-called 'knockouts,' where, from birth, they're lacking the serotonin 2A receptor. And in those genetically modified knockouts, psychedelics don't work. So there's all kinds, and there's also a very, very tight correlation amongst the existing classic psychedelics. If you plot how many milligrams you need to give, so this is the potency, whether you need to give 400 milligrams or just a 10th of a milligram in the case of LSD, and you correlate that with the affinity for this serotonin 2A receptor, which is like the stickiness for that receptor, how is it likely that that compound, that drug is gonna stick into that receptor? That's an astonishingly tight correlation. So there really is substantial evidence that the serotonin 2A is the primary site of action for these psychedelics. And it's probably the case that these other receptor sites add some coloring to the effect, but we know that, in different ways, if you take out 2A, you don't have any substantial experience there. So only what are we call the classic psychedelics hit 2A. So the primary examples being LSD, psilocybin, mescaline, DMT. Drugs like ketamine and PCP affect the glutamate system primarily as their first sort of site of action. And then you have other compounds: MDMA releases serotonin, so that's a different form of action on the serotonin system. You have compounds like salvinorin A, which I did the first human trials that were blinded that actually found an effect of that as the primary agent in salvia divinorum. That activates a type of opioid receptor called the kappa opioid receptor, which is different. Most of the opioids we think of are mu opioids: morphine, heroin, oxycodone, very addictive compounds. The kappa opioid system is very different and leads to a very different variety of psychedelic effects. So that has its own distinct pathway. Ibogaine, that's an interesting one. That affects a lot of these various mechanisms that are at play with different psychedelics. So it's almost like a jack of all trades psychedelic with different points of entry. It's pharmacologically pretty promiscuous. Ibogaine is of interest because of the anecdotes of people overcoming opioid addiction with it. And there does seem to be some really compelling evidence, even in animals, in rats. Ibogaine will substantially decrease their self-administration of drugs, like opioids and cocaine. It seems to normalize the wild fluctuations that happen within addiction and our so-called reward system, our mesolimbic system, the rewards pathway. And that becomes dysregulated in addiction. Even in an animal like a rat, you'll see these wild fluctuations of dopamine. And with ibogaine, you'll see this kind of more normalizing, kind of tamping down those wild fluctuations into more of the normal range. However, there are concerns with ibogaine that it can hurt someone with heart disease, and that's more of a concern than with the classic psychedelics. There's concerns about prolonging the so-called QT interval in the heart. So there's debate about whether there's a clinical future for ibogaine. Some people argue that its top potential toxic effects are such that it's not gonna be ever approved as an FDA treatment. There's others that disagree. I'm actually most interested in using something like psilocybin and LSD to treat opioid addiction because compared to ibogaine, these are remarkably low in physical toxicity. And I think some of these mechanisms may, in fact, be shared. It may be that some of those properties that we think that are unique to ibogaine aren't so unique and maybe that we're seeing them with psilocybin and the other classic psychedelics as well- but we'll need more research to figure that out.

NARRATOR: Are psychedelics dangerous? What is the link to schizophrenia?

JOHNSON: So some critique over the use of psychedelics as medical treatments is that they're particularly dangerous. Now, I want to be clear, every medical intervention and every psychoactive compound has risks. So caffeine has very real risks to it. A wide variety of compounds will have risks. The key question is: What are those risks, and what can we do to minimize those risks? In the big picture, the harms you see from psychedelics, even though they're real, and we know what they are, the prevalence of these dangers pale in comparison to other psychoactive substances, both illegal and legal substances. So numerous scientific investigations have had experts rank order the harms to the user and the harms to society in general, to other people, across a wide variety of compounds, legal and illegal. What's happened time and time again when people bring objective data to these questions, as you see at the top of the list, some of the compounds that, it really bears little relationship at all to legal status. So at the top of that list, you'll get compounds like tobacco and alcohol. Consistently at the far other end of that continuum are psilocybin mushrooms, ranked as the lowest amongst all the major psychoactive compounds in terms of harm to self and harm to others. And LSD is in a very similar position. So that's not to say that there aren't dangers. There are very real dangers, but we know what they are. And in the grand scheme of things, they're just far less prevalent than the harms we see from some of these other compounds out there. And one of the amazing things about the classic psychedelics, like psilocybin and LSD, is that they're not addictive. They can be abused, meaning they can be used in a dangerous way to the person. A couple of teenagers takes mushrooms, and they go driving on it, that's abuse. They're using it in a way that can hurt themselves and other people, but they're not addictive. No one's jonesing for their next shroom fix. And the other category is their physical safety. Relative to other psychoactive substances, they're really freakishly physically safe. For most people, there's no known lethal overdose amount for psilocybin or for LSD. Now, you could do something stupid when you're on it and get yourself killed, wander into traffic. But in terms of just killing your liver, giving you a stroke, making you stop breathing, these are the ways that you take too much of a drug, and they do you in, none of that stuff happens, doesn't cause organ damage or death. So we know a lot about these risks of psychedelics, and one of the major factors that we know that separates riskier use from less risky use is the presence of a sober guide. Or if you're outside of a clinical context, simply having a friend there, another human being you trust, not a bunch of strangers, but a person or people that one trusts with them during the experience. Ideally not on the substance too, because they may not be able to respond to your psychological crisis when they're dealing with their own. And also be in a situation where one can really let go. So you're not able to fully let go when you're at a concert or hanging out in public, wandering the sidewalks of a city street. You should be worried about someone's gonna steal your purse or your wallet. I mean, you can't trust everyone out there. And sexual assault is real, and being on highly intoxicated substances in public, that's a major concern. So the less risky use is gonna be with someone that they trust, and it's gonna be with a substance that they know something about its purity and the dose that they're taking, they're not just not just winging it. And it's gonna be in a safe environment where they're not worried about making sure no one assaults them or steals their wallet, and they're able to really let go into this experience. And I don't encourage people to do psychedelics on their own. I don't encourage any drug use, including caffeine use, but I have no problem telling people, and I like to tell people, what we know can separate riskier use from less risky use. And the more it looks like the clinical research where we're doing, where there is control over the dose and the person is not alone, they're with someone they trust, they know what they're taking, the less likely that they're going to run into pitfalls. There were a lot of overstatements and urban legends in the 1960s about the dangers of these compounds, things like that it was common for teenagers to stare into the sun and burn their eyes blind because they were on LSD. There's no credible evidence that ever happened. There's concerns about frying your chromosomes, that it causes genetic damage. There was a lot of concern over that, especially because this was not too many years after the thalidomide tragedies, where young people were being born with deformed limbs, and this type of thing. So there's really heightened concern over genetic damage. And it was found that LSD could scramble chromosomes in a Petri dish, but no evidence- and apparently a lot of substances, a lot of things will scramble chromosomes in a Petri dish- no evidence whatsoever in real living organisms that that's a concern. Certainly the bad trip is a real phenomenon. It's relatively rare, but sometimes people have accidents, and sometimes people die when they're having a bad trip, and they panic, and they fall from a height, or they wander into traffic or wander in a neighbor's house, and they get shot by the police. These things have happened. However, you'll run across some old, you can see some amazing YouTube clips of folks saying if someone has a bad trip, there's only one solution, and that's to commit suicide. And so someone who's having a bad trip is gonna seek out, in any possible way, to end their life, just a massive overstatement. Most bad trips, as horrific as they are, if the person is in a safe environment, the drug will wear off, and they'll be fine. I'm not encouraging it, but there a lot of overstatements. And there is the concern about exacerbating mental illness in the form of psychotic disorders like schizophrenia. The evidence really suggests that it's people who have an identifiable predisposition, there's some early signs that they're the type of person who can get this. And a big piece of evidence for that is the fact that out of the thousands of people that have been treated by psilocybin and LSD in the older era and modern era of medical research, there hasn't been a single case of someone who's gone through the screening in a clinical context where schizophrenia has been instigated. But there are a number of cases, just observationally, where it looks like someone showed those early signs, and they did a bunch of LSD, and they went over the edge. I think of Syd Barrett, as a Pink Floyd fan, the first lead singer of Pink Floyd, looked like he was showing those signs. A highly creative person, it kind of fits a pattern of a lot of folks with that trajectory and that tendency. It was probably the LSD and a very vulnerable person that really pushed him over the edge for a full-blown psychotic disorder. Unfortunately, people aren't the best judge about whether they are predisposed, especially young people, especially since first psychotic breaks happen in people in either their teenage years or their early 20s around the same time when people are first experimenting with drugs. So that is an area of concern. You don't necessarily know whether you're the type of person who might have those tendencies, that genetic predisposition or not. But it's certainly a minority of the population.

NARRATOR: What are the biggest risks of psychedelics?

JOHNSON: Yeah, the biggest risks of psychedelics are, for a small percentage of people that have active psychosis like schizophrenia or bipolar disorder, those people can be destabilized. It's been misstated that people have gone on trips, and they never come back. I mean, that's an overstatement in the sense that the drug is metabolized, and it gets out of their system. But the way I view it, it's the same way that a destabilizing life event can harm these people and worsen their circumstances, their disease state. Becoming homeless, for example, from someone who has that predisposition, can massively destabilize that person. Being attacked or having some other traumatic event can destabilize that person. Having a big psychedelic experience can destabilize that person. So the way we address that risk is by screening people, and we can reliably identify people with structured psychiatric interviews to conclude, "Yep, you're not at a high risk for these disorders. It seems very clear." The other big risk is that anyone can have a bad trip, and that's referring to anxiety, fear, panic that could potentially lead to dangerous behavior. And the way that we address those in the clinic is to prepare people that it can be very scary. And we're going to describe all kinds of those experiences. More importantly, is developing that rapport and trust between the guides, the people who would be with them during the experience and the participant, so that when they're in the session, if they're having some level of anxiety, they can let the guide know, and the guide can reassure them, say like, "I'm here with you, I'm not leaving. You're perfectly safe. It's perfectly normal to feel this fear, and keep going through it."

NARRATOR: How do all-arounders get to the core of psychiatric disorders?

JOHNSON: So I study all kinds of classes of psychedelic drugs: cocaine, alcohol, methamphetamine, tobacco, nicotine. So I refer to the uppers, the downers, and the all-arounders. And the reason I refer to the psychedelics as the all-arounders, well, first I have to appropriately cite it, as a scientist, my source. I'm taking that from Cheech & Chong, some of my favorite comedians. But so the all-arounders, the reason psychedelics are all-arounders is because you can't reliably explain their effects in a very simple way to a person. If someone's never taken cocaine before, you can do a decent job of describing the effects. Have you had a bunch of coffee? You know what it's like to be hopped up on too much caffeine? Not identical, but imagine that, but you're just very happy. Imagine you're getting some of the best news of your life and being wired on a bunch of coffee. Not perfect, but people can get the flavor of what you're talking about. The downers, whether you're talking about the benzodiazepines, like Valium and Xanax, or you're talking about the opioids, the pain relievers, you know what it's like to be really, really sleepy and feel like really, really cozy, and this type of thing. They're more within the normal range of human experience, and they're more reliable. Very few people take cocaine and fall asleep afterwards. As an example, that's why they're called uppers. The psychedelics, all bets are off. I think kind of the only bet you can make is that if you have the dose high enough, something really interesting is gonna happen. But what that is, you don't know. You might find yourself in your mind's eye, soaring in the heavens, the secrets of the Universe seemingly revealed to you, this bliss and this love for humanity. I mean, right? These descriptions can be amongst the most extreme experiences, positive experiences that you can imagine. On the other hand, five seconds later, it might collapse into what folks call a 'bad trip,' or I call, in this research, a 'challenging experience,' where one could feel that they're gonna die. They could feel like they've gone permanently crazy, and they're never gonna come back. I mean, so just on the positive side, on the difficult side, it's impossible to overstate how extreme these experiences can be for people, and how unpredictable these experiences can be; which is why when you administer them, it seems like the best thing to do is to encourage the person to be aware of this wide range of experiences, but don't try to control it. Whatever the experience is, take the orientation of: "This is what I need to deal with." If, in my mind's eye, it seems like I'm being devoured by a monster, don't run away from it. Look the monster in the eye and say, "What are you doing in my head? Let's figure something out here," you know? So don't flee the- accept it, take a mindfulness approach, and just observe your own experience, whatever that is, without trying to alter it and say, "Oh, no, I wanted this type of experience. I didn't want that type of experience." Good luck with that. That's just gonna snowball the experience towards something even more difficult. Going into this type of treatment is not easy at all. And, in fact, when people come in for their session days, and so this is after weeks of preparation, many hours of preparation, if I'm meeting with them that morning, and they say, "Oh, I'm feeling great, bring it on, like, no worries whatsoever," that gives me some pause. If if you're not worried at all, then we haven't done our job correctly because this is a big deal. You should at least have some butterflies because that's the gravity of what you're about to go into.

NARRATOR: What is the role of a guide in a psychedelic session?

JOHNSON: I started my research with psychedelics over 18 years ago, right after I obtained my Ph.D., and I've done a lot of studies, many lab studies addressing different questions. I've supervised these studies, designed them, analyzed them, but really one of the most rewarding aspects has been serving as one of the people that guides these sessions. In other words, being the person in the room with the individual who's taken a high dose of a psychedelic. And I've guided over 100 sessions with various psychedelics, and that's been exceptionally rewarding. So there's a lot of names for this role: You could use the word guide, therapist, facilitator. You might liken it to the role of a shaman. I like the word "guide." It's not really perfect. In some sense in these sessions, one is instructed to trust, let go, be open. And the guide, if they've established that rapport, their really- job at that point is as a safety net. So, it's not like the guide is providing specific instructions, like you're guiding folks along a path through the mountains. Like, "Oh, be sure to make a left up here when you get to that turn." It's not like that, so in some sense it can be misleading. But in terms of a general orientation, which is mostly done before the session itself, instructing the person to take this orientation of surrender, no matter what the particular challenge may look like on the surface, the solution always has a common theme of just not fighting it, surrendering to it, treating it as a learning experience. There's other names like "shaman." I mean, I think we have to be careful to learn as much as we can from indigenous cultures that have used these compounds, but we're not replicating exactly what they're doing. That would not be appropriate. So I think, in a lot of ways, the shaman term is not appropriate for the mainstream clinical, medical use of these compounds. Especially as we're moving towards the medical development of psychedelics as potentially approved medicines, we can really think of that role as that of a therapist. And as these compounds move into more mainstream treatment, it probably will be a variety of forms of therapists, counselors, psychologist, psychiatrists, social workers who are playing those roles. Even when you're in a study where there's not a therapeutic intent, let's just say it's a study where you're examining the effects of a psychedelic on a certain aspect of behavior on their brain, what have you, in order to administer a psychedelic safely, I'd argue you really have to establish the same sort of therapeutic rapport, that tight relationship, that trusting relationship that any therapist should have with their client. Because particularly so in a psychedelic session, people can be left in extremely vulnerable situations. People can literally feel that they are dying, and that it's one of the most vulnerable, sensitive states that they could be put in. So it's really just critical to minimize paranoia and to maximize the safety in order to have that kind of strong trust and rapport with their guide.

NARRATOR: What is the focus and impact of your research?

JOHNSON: I focused on a lot of topics within the psychedelic area, trying to understand the nature of these experiences just to characterize them. Part of that work has been this focus on what's called the 'mystical experience,' which sounds a little woo-woo, but it's actually describing a really validated psychological construct. It's really divorced from any supernatural beliefs that someone may have or not. What it describes is this type of experience where someone feels that they are one with the Universe, one with the rest of humanity, some sort of sense of unity. It also involves feeling that one has stepped out of the domains of time and space, so it's a timeless and spaceless type of experience. And there's a sense of ineffability, in other words, that no matter how hard the person tries, this is ultimately beyond words. Those descriptors surround the mystical experience, which, even outside of psychedelics, was an area of interest. Going back 100 years ago, William James, the founder of American Psychology, was fascinated by these experiences across the globe and the commonalities among them. So that's been a major focus, and as I've moved into more therapeutic studies, in other words, seeing if psilocybin sessions can help to treat any number of disorders, one of the findings that's really shaken out is that the more mystical the actual session was, in other words, the more likely the person is to endorse, "Yes, I felt one with the Universe," this type of thing, the more likely the person is gonna be less depressed and less anxious, if they're a cancer patient who's been dealing with depression and anxiety, the more likely the person trying to quit smoking is gonna successfully quit smoking six months down the road. So there's seem to really be something important about the nature of the experience that people have during these sessions. So it's not just about hitting a certain type of serotonin receptor in the brain. There's something about the psychology of the experience that unfolds during that session that tends to be important, which is, in some sense, what makes the psilocybin treatments a bit more like psychotherapy than traditional psychiatric medications where you just take the pill, and just you forget it. It does its magic in your brain, and you don't have to worry about what you do with that biological effect. And so, in terms of the therapeutic studies, there's been a number of areas of focus treating cancer patients who have substantial depression and anxiety because of a very serious cancer diagnosis. This is following up from work that happened in the 1960s with LSD trying to help terminal cancer patients. And that work has resulted in some really impressive findings with dramatic reductions from only a single high-dose psilocybin session. You see large reductions, on average, into the normal range of depression and anxiety scale. So really bringing people into that level of depression and anxiety that where people wouldn't be diagnosed with a disorder anymore, so substantial reductions. Another major area of focus for me has been addiction. And where I started out was in helping people quit tobacco smoking. And so that area has also seen some really dramatic results. We conducted a small open-label pilot study, just to test the waters initially, with 15 people, but we found some dramatic results. Six months later, 80% of these people were biologically verified as smoke-free, which really swamps any current treatments. Now, that was very early, and the real question was: Is that worthy od follow-up with more rigorous research? And I'm in the midst of that research now, and that's been such a successful line of research that the United States federal government recently awarded a federal grant for us to expand that research into a multi-site study. And this is the first time where the U.S. government has explicitly devoted funding for administering a classic psychedelic compound, like psilocybin, for a therapeutic purpose, the first time in about a half century since the late '60s, so we're really excited about that. And I've also conducted other studies looking at the effects of psilocybin on a meditation practice, so people who are starting a meditation practice. Does a psilocybin experience help to jumpstart that practice? Does it help the person to get more value out of their meditation experience? And we found results consistent with that, that particularly with more pro-social benefits, improvements in people's lives, helping others, these sort of altruistic traits, that having the psilocybin experiences on top of the meditation practice, you seem to get more bang for your buck.

NARRATOR: What really amazes you in your research?

JOHNSON: I'm floored when people with really substantial life experience will say things like, "This was the most meaningful experience of their life, or the most intense experience of their life." I've had combat veterans say that their high-dose psilocybin session replaced combat as being the most intense experience of their life. I mean, so it's those types of situations where, I've never been in combat, so you pay attention when people say things like that. And in fact, I repeat that to new participants. Like, "Many people say this is beyond words, but in the spirit of informed consent, I'm gonna try my best to describe the range of what people say about this." And people say extreme things like that. I mean, there are folks who have engaged in all manner of impressive life experience, people who have traveled the world, who have volunteered feeding the poor in Third World countries, clergy members from various religious faiths, people who have been spiritual seekers of one variety or another, people who have been on a meditation path and they've had thousands of hours of meditation in their lifetime. To be floored by their experiences on psychedelics, it's just really impressive. I mean, in thinking about the meditation research, you'd kind of think that, 'Well, these are people that have really spent years combing the depths of their own mind, and, ah, what are they gonna, it might be interesting, but what new is gonna be there for them? And if there is something, it's gonna be sort of highfalutin, philosophical, 'cause they've kind of cleaned up their own mess in their psychological basement,' so to speak. But I remember the first or second participant in that line of research, the person was completely focused on all the kind of baggage that came from being the sort of the second-fiddle child in the family of origin dynamic, jealous of the older sibling and this type of stuff. Like, you would've thought, "Oh, you would've handled all this kind of, like, low-level psychological baggage decades ago." But no, people, they can be profoundly hit by these experiences. And also I think of people with trauma that comes up sometimes from decades in the past. And even when that's not what they're there in that study to address, I mean, they might be in a study to quit smoking, and they have some unresolved trauma from some horrific relationship from 40 years ago. Wow, I mean, that just seems to come to the surface. There does seem to be something, and we still need to figure out how this works scientifically and verify that it works this way scientifically. But it seems, through observation, that the material that needs to come up psychologically for that person is the material that comes up. So the way I express this sometimes to participants, sometimes it seems like it's like the Rolling Stones lyric, "You may not get what you want, but you may get what you need," which is consistent with that orientation of just whatever it is, trust, let go, treat that as a learning experience, and deal with it. There are many times where I've witnessed things that have touched my heart. I remember one participant in a study that was looking at the nature of the experiences that unfolded with psilocybin. And we weren't trying to treat any disorder, but we're all human, we all have our baggage. And I remember this one gentleman who just, his son had committed suicide not too many years in the past, and it really seemed like, in the context of the psilocybin session, he did deep, deep psychological processing of that, including his own feelings of guilt for his role in the family dynamic, things that he felt guilty about. And you think, 'Well, it's been some time, it's been years,' but gosh, the floodgates really open. And when someone's having an experience like that, the only thing you can do is just try to stay present for them, pay attention, and to be open to what's happening, but also realize there's nothing you can say, other than, "I'm here with you, I'm not going anywhere." If the person is sobbing with tears, it's letting them know that's all welcomed. That's exactly what you should be doing right now. Sometimes you deal with the people feel guilty about being the center of attention. And especially when they're experiencing these high-dose effects of a psychedelic, it might seem weird to them, "Why am I having this experience, and you two other people in the room, the guides, you're not? This is weird." And you try to let the person know that, "Hey, we're just playing different roles. You're the astronaut, we're ground control, but we're a team. We just have different roles on this day." And to let the person know, "This is your day." And this is one of the ways where it differs very much from a lot of recreational use where, let's say you're at a party, and you took too many mushrooms, and you end up in the back room, someone's bedroom, just crying your eyes out at the relationship with your mom. And then the next day, your friends tell you, "Oh, man, not so many mushrooms for you next time. Whew, you should have had one or two more beers to kind of chill out a little bit." And even if it's friendly, it's just a subtle sort of dismissal of that experience. In the therapeutic context, it's like, "Oh, you're crying about your mom. Perfect, more of that. It's all welcome." The laughter, the tears, everything in between, that's exactly what this process is for, for you to fully absorb into whatever those emotions are.

NARRATOR: Why are we in a psychedelic renaissance?

JOHNSON: There's some interacting reasons why the 'psychedelic renaissance' is happening now. One is that, even before COVID-19 hit, our society has been in a mental health crisis, and it's been stagnating. Pharmaceutical companies don't make the investments in new mental healthcare treatments like they did decades ago. And I would say for the treatment of depression, really we haven't seen much in the way of major advances, really since 70 years ago. Even in the '80s, Prozac and the newer sort of antidepressants, the SSRIs, the serotonin selective reuptake inhibitors, those were essentially safer versions of the same types of drugs that we had going back to the 1950s that essentially augmented the amount of serotonin floating around between your brain cells. These newer antidepressants are safer. It's harder to overdose on them than some of the older generation drugs. That's great when you're treating a depressed population. Nonetheless, the success rates weren't really improved. And we know that a large portion of people treated with traditional antidepressants don't see benefit. There is modest benefit, on average, for people. And I don't want to take that away, and I'm all for having more tools in the toolbox than fewer tools in the toolbox. But I think society's been acutely aware of the limitations. We've been hitting the ceiling with mental health treatment and I mentioned depression, but gosh, addiction, same exact thing. I mean, the best medical treatments that we have for many addictions are substitution treatments, also known as 'agonist treatments.' And again, I think these are good. I'm glad those are tools that are out there. But methadone for opioid addiction, nicotine replacement, like the patch or the gum for smoking, I mean, these are essentially safer forms of the essential same drug that someone can take. While those have many benefits, when you don't see success, I would say it's probably 'cause they failed to get to the roots of these mental disorders, including addiction- and that's why I think psychedelics have been so successful. I mean, aside from the mental health crisis and the stagnation and the treatment of mental health, the other thread has been enough time had to pass since the late 1960s, early 1970s where that initial, about 15-year period of exciting psychedelic research- it all came to a halt. I mean, there were researchers that were running sessions and got the notices they just had to stop. And the rug was just pulled out from folks. And while there was some unethical research- there was some wild research- the majority of the research was done by responsible folks who were aware of risks, and they were safeguarding against those risks. But psychedelics became so associated with the counterculture in the late 1960s, with the anti-Vietnam War protests, with the worldwide youth movement, the countercultural movement, and all of those changes in society that really scared a lot of people in power- and psychedelics got an unfair portion of that blame. I mean, I think the biggest reason for the Vietnam War protests wasn't LSD, it was because of the war in Vietnam. So it was a complex situation where the science and medical use really was, it was sacrificed. But I also like to remind folks that this is not unprecedented. In fact, in Thomas Kuhn's classic 1962 volume, "The Structure of Scientific Revolutions," he introduced the concept of paradigm shift. And he said the way that paradigm shifts happen in science is it takes the old guard, the old guard does not adopt the new method, the new theory- they essentially have to die out, enough time has to pass. And the examples are numerous and staggering. So Isaac Newton published the Principia, the laws of motion in the late 1600s. I mean, arguably the most important scientific publication of all time. That was ignored for about a half century before other scientists really paid attention and started applying it. Another biggie: Charles Darwin wrote "The Origin of Species." And I tell you, at the end of the volume "Origin of Species" where he introduced the concept of evolution by natural selection, he said, and I'm paraphrasing, "I'm not holding my breath for the naturalists," which was their word for biologists, essentially. "I'm not holding my breath for the naturalists of today to accept my theory and run with it. They're not going to. I'm looking to the younger generation and the generations yet, to come who will pick up on these ideas and move with it." And very similarly, it took a half century or more. And arguably even today, it hasn't been widespread adoption in the culture at large. So we're really in more good company than we realize when we're in this situation where, 'Hey, there was this initial burst of excitement about these drugs and their potential ability to have major effects in improving mental healthcare if we use them in a judicious, proper way.' And then it just sort of, the rug is pulled out for decades before there's a reinitiation. And I like to think that society was, in a sense, traumatized from that. We weren't quite ready, perhaps, for the introduction, especially high doses of LSD by a lot of young people. A lot of people claim benefit from that exposure, and some people were harmed. But I think now, society is more ready to kind of accept these compounds, and the whole picture of them. They're not panaceas in this- nothing is gonna be a miracle cure for everyone. Nonetheless, they have so much promise, and we have to have that balance. I think that's more possible today. One of the nice things in science, even if it feels like you're being ignored by everyone- and this is how I felt 18 years ago with my initial interest in psychedelic science- if you feel like the world is ignoring you, at least you're getting those papers out there in the scientific literature. It might be a hundred years from now, but some graduate student somewhere, if we haven't blown ourselves up by then, is gonna read this paper and say, "Huh, wow," just like I picked up those papers and read about that early research from the '50s and '60s. So it's been great that it hasn't taken 100 years, and that people are actually paying attention to this research while I'm still alive- that's awesome.

NARRATOR: What are some pitfalls of psychedelic medicine?

JOHNSON: One of the pitfalls of this clinical work is that you'd be hard pressed to find a more intimate and vulnerable psychological intervention for a person. People are at their most vulnerable in these psychedelic experiences, and you can't overstate the weight that comes with being in one of these sessions, having orchestrated one of these sessions as a guide, as a scientist. Some people will describe as the most important experience of their life. That's just a situation that is ripe for abuses if we don't have the right safeguards there. So all of the abuses that we normally know about, sexual abuse being right up there, and that's why it's important to have certain mechanisms in place. I think it's better to have multiple guides that are witnessing the session, whether they're both in the room or one is outside, at least watching on camera. But we need to make sure multiple people are involved. We need to limit the use of therapeutic touch and have informed consent surrounding that. So holding someone's hand, holding their shoulder, but not doing extensive body work as some folks would like to call it during the session, because that's just gonna, for some people, that's gonna lead to boundary issues. And unfortunately, I think in this area with psychedelics, clinicians can get into, and scientists can get into a space that I call 'psychedelic exceptionalism,' where the idea is that these experiences are so big, and this is so far beyond what we normally deal with in medicine, in clinical psychology, you name it, that new rules apply. Tim Leary said this a lot: "This is too big for the science game." This is like our normal games can't contain this. We need to take the opposite approach and say, "Because of that vulnerability, because of the incredible gravity of these sessions, we need to even more tenaciously cling to those clinical boundaries," that ethics training that you learn when you're becoming a physician or a clinical psychologist or a social worker or a nurse, all of these professions. We need to really a adhere to those, what might seem like boring old ethical codes because they're gonna really be tested here. So the second pitfall would be 'metaphysical neutrality.' Essentially, when people butt up against those big picture questions, what's happening in these sessions is an experience of God, is an experience of ancestors, visiting different dimensions, you name it, all kinds of explanations that are provided, we just have to really let the patient drive the bus in terms of making any of those claims. We have to be metaphysically neutral. That doesn't mean we should correct someone. If someone thought that was an experience of Jesus or the Buddha, it's not on us to say, "No, no, no, no, no, that wasn't. We're being neutral here." What it means is we're just not making that inference for them. That we're just supporting whatever their process and their conclusions from this; it's not our job. And a very concrete aspect of this is really staying away from the imposition of religious icons in these sessions. Unfortunately, it's become commonplace and typical to have a Buddhist statue in these rooms. I have nothing personally against Buddhist statues. They're very pleasant, but I don't think it's appropriate in mainstreaming this treatment. I say BYOB, "bring your own Buddha" or any other meaningful object, be it a crucifix, be it a flying spaghetti monster painting. Whatever it is for you, the pictures of yourself and your kids, bring those meaningful objects. And we just have to check ourselves into playing guru, playing priest, playing at this metaphysical level where we're filling in those answers for patients. And then the third pitfall is being loose with the term consciousness, and the conclusions we're making about what psychedelics have scientifically told us about consciousness. One part of that is we just need more precision in our language. Consciousness is a pretty sloppy term; it means many things. Kind of the most impressive use of the term is what we refer to as 'phenomenal consciousness.' And this relates to the so-called hard problem of consciousness. That is like: Why is there an experience at all? Why is not the universe just made out of these objects? Whether they're people, animals, other things that are interacting. Why is there an inside experience to anybody? It appears impossible to answer that question. That's why philosophers call it "the hard problem of consciousness." So, never say never. I'm open to psychedelic research addressing the hard problem of consciousness. Right now, I don't think anyone can think of a way in which psychedelics can do that, but it's a worthy effort. But we need to check ourselves. Other things, when we use the term consciousness, sometimes we mean self-identity, having a self-concept. That relates to these experiences of unity or so-called 'ego death.' I think there's a lot that we can learn with psychedelics on that aspect of consciousness because sometimes people don't have a sense of self, or at least they have a radically altered sense of self. So we can learn a lot more about the brain mechanisms underlying the sense of self. And there's other things called consciousness, 'access consciousness.' This is sort of you have- you weren't thinking about your grandmother two seconds ago, but now you are 'cause I used the word grandmother. That's come from somewhere in your brain. There was a memory there. It wasn't in your awareness at the moment, but now it is. What is that process of being called forth of things being brought into awareness? That's also in the category where I think psychedelics can be brought to bear in answering some of these questions. However, most of the work that's been done with psychedelics in terms of the brain mechanisms, it has not addressed any of these questions of consciousness. Most of those, most of the psychedelic work in the brain has addressed how psychedelics work in the brain. And I think when we automatically make that leap of, "Well, psychedelics seem so fundamentally important to consciousness that if we figure out how psychedelics are working, that's telling us something fundamental about how consciousness is working," we're on a slippery slope there, we can start to fool ourselves. So we really have to have more precision in our language, and drill down more rigorously on these questions of consciousness.

NARRATOR: Will psychedelics answer the hard problem of consciousness?

JOHNSON: The hard problem of consciousness refers to this seemingly unsolvable problem of: How and why is anybody aware? Why is there an experience there? The only evidence that we have for phenomenal consciousness, the idea that there is some experience being had is that I feel that I'm having this experience. I feel that I'm conscious. And because other creatures walking around that look like me, other human beings, it's a presumption, probably pretty good one, that they were having a similar experience- but there's really no evidence. Like, how would I prove that you are conscious? That seems outside of the bounds of empirical science. What experiment could you ever do to prove that there is an experience to be like somebody else? And that's what the hard problem is. That's one way it's been expressed. What is it like to be a bat? That's a classic example by Nagel. What is it like to be my dog? What is it like to be another person? Presumably, there is something that it's like to be you, but there seems to be no way, scientifically, to account for why that is- so that's the hard problem of consciousness. How do you explain this? And a lot of is made out of psychedelics and their ability to inform the nature of consciousness. And so this would be the ultimate kind of task. If psychedelics could help us to crack the hard problem of consciousness, I mean, perhaps that's the biggest question out there. I mean, it's up there with like, where did the Universe come from? What is the nature of reality? It's really one of the biggies. In fact, some of the really interesting questions about: Is mind, or subjective experience, something that pops out of the physical world? Do we live in this material world where sort of experience is just some sort of epiphenomenon? Or, perhaps, consciousness or experience is something more fundamental to the very nature of reality. And you can go into realms of philosophical ideas, such as panpsychism, the idea that consciousness really pervades. It doesn't just emerge, but it pervades the material universe in that these are two different sides of the same coin. But it seems pretty routine for people to kind of grapple with those big questions. That's why I'm- I think it's really important that we separate, you know, "Hey, a bunch of people say, based on their experiences, that they believe psychedelics open some window into consciousness or give them sort of insights into the nature of consciousness." But that doesn't constitute scientific evidence that what they're saying is actually true. So it's kind of a weak argument, really. Just the fact that people tend to think that psychedelics have provided them with answers about the nature of consciousness, it makes it intriguing to see if we can go further, if we can do anything to really objectively harness psychedelics to solve some problems of consciousness. So that's why the inclination is there to explore psychedelics in the experience of consciousness. But we should just be very well-grounded. And like with any scientific question, we shouldn't hold our breaths for the answer. It's like just pursuing that journey of questioning will no doubt come up with important answers. They might not be to the questions we were asking, but maybe they're to other questions. And so, if I could think of an experiment I could do with psychedelics to address that question, I would've already done that experiment. And right now, I don't think anyone can, but I think we should remain open to the possibility that psychedelics could be used to address the hard problem. But we need to think about it because that really seems like a difficult problem to crack.

NARRATOR: What medicine is used in psychedelic therapy sessions?

JOHNSON: In the modern psychedelic medical renaissance, the compounds that we're using are psilocybin, MDMA, which people may know as Molly or ecstasy in recreational use, and LSD. So psilocybin, which people may know is the active agent in so-called magic mushrooms. And in these studies, it's a plain, white powder that's identical to what occurs in the mushrooms, but it's not the whole mushrooms. It's the exact number of milligrams of psilocybin. A lot of times, we've used 30 milligrams as a high dose of psilocybin. So it's a little capsule, and it contains that. The other substances are MDMA, which is also a white powder. MDMA is not naturally occurring like psilocybin. So that's, of course, just gonna be the synthetic, white powder given in capsules. Another drug that's being studied, I've recently received approval to use LSD to treat chronic pain. Most of the research in the older era with psychedelics in the '50s and '60s was using LSD. And so it'll be exciting to pick back up on that research. And LSD is, again, not a naturally occurring compound. So it's gonna be delivered, in this study, dissolved in water. So ketamine is a weird one because ketamine has been approved for medical use for decades as an anesthetic. But, during the last 20 years, there's been some really interesting advancements in using lower doses of ketamine, more in the range that produces psychedelic effects, using ketamine to treat depression. And so now one form of ketamine is actually approved by the FDA in the United States as a treatment for depression. And so, work continues to go on with that. So right now, one of the interesting things about ketamine is that, and one of the reasons ketamine has been considered a breakthrough for the treatment of depression is that its antidepressant effects are virtually immediate. So one of the really big problems with traditional antidepressants like SSRIs, it takes two to three weeks for them to kick in to start working, if they work at all. That's really tough, especially when you have people that may be potentially suicidal. Like, you don't wanna wait three weeks or four weeks for these effects to kick in. So that's really impressive. But on average, ketamine's antidepressant effects will only last about a week. So that's a pretty short amount of time, and so it's given repeatedly. The work from our cancer study with psilocybin found that a single high dose of psilocybin reduced depressive symptoms for at least six months with no sign of them returning to normal. That was just the longest term follow-up that we had. Is that because psilocybin is much longer in its antidepressant effects? We know that, for both drugs, it's cleared out of your system in several hours, but somehow are the long-term effects on the brain of psilocybin more powerful? Or, is it because we are treating psilocybin as a psychedelic, as a psychedelic therapy? And what I mean by that is when ketamine is given, the person is told, "You might feel a little different, but ignore that. That's a side effect. You'll get through it. Here, you can watch some TV, whatever, distract yourself." And the drug is gonna hit the right brain receptors, and hopefully you'll feel better. And that does seem to work. That does work. However, if we really treat it as a psychedelic by saying, "You're gonna have an experience, you're gonna feel very different. We want you to pay attention to that, and we're gonna discuss that experience. And our hope is that something about that experience can speak to the problems that you're having. We're hoping you can gain some insights out of this. We're hoping that it can kind of reestablish a new normal for you." That would be more in the spirit of a psychedelic therapy. My bet is that psilocybin is a superior drug in treating some of these mental health disorders. Actually has some real advantages. Ketamine can be addictive. I'm not against its therapeutic use, but it's no cocaine on the continuum of addiction, but one can develop a daily use habit. It can be a problem for some people. Psilocybin, it's really unheard of for someone to be addicted to psilocybin. We know that from the way it works in the brain. So there's some real advantages, and psilocybin is really robustly, there's no known lethal overdose for most people. There's zero indication of causing organ damage, that type of thing. So psilocybin, on a lot of dimensions, is just kind of a wonder drug, and everything has its risk, to be clear. But if you just came up with a description of like a really perfect drug to treat a psychiatric disorder, you know, psilocybin checks a lot of those spaces. Hey, it'd be great if something wasn't addictive at all itself, that it was robustly safe at the physiological level. You can say that about few things that are over-the-counter. So there are some advantages over ketamine, and I do get the impression- although I do want the head-to-head comparison research, I'd love to do some of that research- but my gut tells me that psilocybin is gonna have more profound, longer acting effects than something like ketamine.

NARRATOR: What is the 'heroic dose' given in a psychedelic therapy session?

JOHNSON: My therapeutic research with psychedelics has primarily used psilocybin, comes in a capsule with a pure compound. We administer a high dose, in fact, a dose that's been called a 'heroic dose;' it's actually larger than most recreational doses. So if a microdose is over here and a recreational dose is over here, we're way over here on the continuum. It'll really knock the socks off of most people that are experienced recreational psychedelic users. The doses we've given have really spanned a wide range. I've done research where we've given one milligram of psilocybin, which is going to be equivalent to what people are shooting for with a so-called microdose. So one milligram of pure psilocybin would be a microdose. A recreational dose, you might say a typical recreational dose might be 10 milligrams of pure psilocybin. Now, it's important to keep in mind, people aren't taking pure psilocybin outside of the clinic. They're taking mushrooms. A microdose may be something like one gram or half gram of dried mushroom. A recreational dose might be, I don't know, maybe an eighth ounce of mushrooms, a typical way they're sold. They might split it three ways, two or three ways. It's probably gonna be about 10 milligrams of psilocybin. 30 milligrams is sort of the heroic dose level. And that's has been sort of the high dose in most of my research. In terms of typical mushrooms on the illicit market, that would be somewhere in between an eighth-ounce and a quarter-ounce of mushrooms- that's a really high dose of mushrooms. So it's about five dried grams of mushrooms, which Terrence McKenna, who's the famous psychedelic bard, would refer to repeatedly as the heroic dose. Most of my research over the years has adjusted that dose by body weight. So when we've given 30 milligrams, it's actually been 30 milligrams per 70 kilograms of a person's body weight; 70 kilograms being about 150 pounds. So although we've adjusted the dose that we deliver of psilocybin by the person's body weight for most of our research, we've recently pulled all the data and figured out, "Hey, we don't need to be doing that. We can just give the same dose for everyone, no matter how big or small they are." The dose we now give to patients is anywhere from 30 milligrams to 40 milligrams, depending on the study. And a lot of people these days talk about microdosing. There's a lot of buzz about that. The idea there is taking a very small amount, 1/20th or 1/10th the amount of a sort of a normal recreational dose. So a really trivial amount of the substance that's really is gonna cause a psychedelic experience. A handful of really credible, rigorous studies that have carefully looked at it have failed to demonstrate any benefit of microdosing. So the jury is still out. There may, in fact, be some truth to these claims of various benefits, antidepressant effects, anti-ADHD type effects, pro-creativity effects. We just don't have the research yet to conclusively demonstrate that at this point.

NARRATOR: What is a psychedelic therapy session like?

JOHNSON: When someone comes in for the day of their psychedelic session, they've already spent several hours with us on previous days preparing for the experience, developing that rapport. So when they come in on the session day, we make them feel comfortable. There's a ceremonial-type setting. The environment is one- it's within a hospital, but it looks more like a living room than it does a typical hospital room. So beautiful carpet, beautiful artwork on the walls; trying to make it as warm and inviting as possible and somewhat ceremonial. We hand the person the capsule and sort of a chalice, and have them swallow that capsule with a glass of water. And then it's gonna be anywhere from 20 minutes to an hour before the effects start kicking in. And during that time, we engage in light discussion. The center of the room really has this couch. And when the experience unfolds, the person is gonna lay down with our encouragement, wear eye shades and headphones through which music is played. So in waiting for those effects to kick in, light discussion, we have some art books in the room, they can look through some art books. The idea is can get out of your normal, everyday, discursive, analyzing intellect. And then when those effects kick in, we really just encourage them to trust, let go, and be open. Try to resist the urge of describing the entire experience. We say give your thinking side of your intellect the day off. You can reunite at the end of the day and put on your thinking cap. But during that experience, embrace more of the absorptive side of your mind. Just sort of experience, collect experiences without judgment, and we'll discuss it later. And so at that point, the guides are really there for support. If the person's having some fear or anxiety, holding the hand or embracing the shoulder. We keep it at that 'cause we're mindful of sexual abuses, and so wanna keep boundaries to that physical touch, but clasping a patient's hand can be so powerful in reminding them that there's another human being that you trust here that's watching out for you. We're not gonna leave you alone. And it's a five to six-hour experience, and at some point in the afternoon, the effects will start to wear off. And when they do, then the person, we invite them to sit up and start processing, start discussing, just describe what happened today. What was it like? The guides aren't there to provide any sort of dream analysis, or, I don't know, if you had a vision of this monster, this is exactly what that means. Nothing like that. It's really just supportive. We're letting the person find their own meaning in the experience, and we're there to just support them and encourage them to take the experience seriously and to process it. We know that all drugs are, in part, shaped by the context in which they're given. But for the psychedelic substances, that's particularly more so. So the idea is in the early research, give someone a big dose of LSD and stick them in a padded room, the type of room where you'd keep someone that's gonna injure themselves if they're schizophrenic. So what you get there is typically a psychotic type of reaction. So when you provide it in more of a warm, welcoming situation, you tend to get more meaningful reactions to the substance. There's variability, but the less likely you are to have challenging experiences or so-called bad trips. And there's a lot of aspects to this. So the music is one aspect of that. I did some research finding that we can switch up the music, and we found actually, compared to a classical music playlist, which has been sort of the mainstay since the 1950s, we found that this alternative playlist- lots of gongs and didgeridoos and drones, these types of instruments- found a trend for a little bit better response. But it's astonishing how little work has actually examined, like, randomized set and setting variables. No study, for example has ever put someone in a rubber room with a horrible set and setting versus a really optimized set and setting to compare the difference. So much of what we learn has really just come from clinical observation, just the judgment of what we've looked at. We do have somewhat of a generic ceremonial style. So for example, we hand the capsule over in a chalice, but it's really divorced from any particular tradition. We don't emphasize any, it just sort of at the level of this is being taken seriously, and this is an important moment, but we're really trying carefully not to tap into any particular tradition of any type, per se.

NARRATOR: What are some experiences people have in their sessions?

JOHNSON: These experiences are often called "ineffable," but as a scientist, I do my best to F it up by trying to describe it as much as I can. So I'll go ahead and do that. For some people, a high dose will hit them like a freight train. They're feeling barely anything. And then within a minute, they're floored. I mean, they're really kind of psychologically spinning. It's sort of like, in a sense, vertigo. Other people, even at a high dose, it'll creep up over the next 20 minutes or so. So there's some variability, but someone can often be overwhelmed at the beginning, and that's particularly challenging. So that's where our instruction's to trust, let go, be open: It can be really helpful to just surrender to the experience. If you're just being thrown around, and you feel like you're in this ocean, and tidal waves are kind of taking you one way or another, just try not to control it. Just let go and float in that ocean. Now, this is all in the mind's eye, so it's hard to give exact instructions. So whatever the experience is, we say to surrender to it. If you feel like you're being eaten by a monster, look that monster in the eye, and ask that monster why it's there, this type of thing. But the range of experiences are just so broad. Some random examples, I remember a participant saying that she just is reached the end of reality, this kind of plane of existence and actually found that, and it was like this conveyor belt, and teacups and other objects were kind of falling across, falling off the table of existence, so to speak. And she took away from that that she can let go of things. Like, sometimes you need to let go of things, and when it's gone, it's gone, and you need to move on. People have sometimes similar experiences where they feel like they're witnessing the birth of the Universe, for example. Or they confront this infinite void, this void where there is no reality, it's completely empty, but at the same time, pregnant with potential and all of the meaning in the Universe; so some very paradoxical experiences. People can just have bizarre experience. Remember one experience where someone, they were really focused on the "Foghorn Leghorn" cartoon, for some reason, during the experience. People can, oh, reflect on family members, oftentimes deceased family members, and feeling like they've had this revisiting. Now, people will vary, I think depending on their personality and their belief system coming, whether that's an actual confrontation with someone on the astral plane or what have you, or if it's just a meaningful interaction within their own mind of their conception of their loved one who's passed away. In some sense, I think it doesn't really matter how someone holds it, but people have had some of these profoundly meaningful experiences where they, for example, talk to a parent during their childhood, and in some, you know, addressing abusive relationships and things of this sort. So really a wide variety of experiences. Sometimes people can feel, they'll say that they can feel the suffering across the entire planet, sort of having this sort of experience of universal empathy, and just kind of overwhelmed with the level. Like, you really can't process how much suffering there is in the world. It's just we're not designed to handle it. And it seems like, temporarily, people can kind of be in that place where they're just aware of how much suffering there is, and it can be overwhelming. Yeah, we say "trust, let go, be open" as sort of a mission statement, something easy to remind yourself and we can remind you during the session. What does trust mean? It means trust the overall process, the fact that this is being contained within a study at a respected institution, that there are people involved with that process that truly care for your well-being. The guides in the room with you want this to be a helpful, meaningful experience for you. You know, trust all of these figures that are involved that have orchestrated, that have come to this one point in time for this experience to happen. Trust your own mind. This is most I important. Trust yourself that you're robust, you're gonna get through this experience. There is nothing in here that can ultimately harm you when you're in this safe setting for this experience. So let go. What does let go mean? Let go means whatever your preconceived notions of what this experience might be or what experience you should have, don't let that get in the way for the experience that you will have. Don't try to control it. Try to flow with it. Easier said than done, but every moment is a new moment to practice that, like letting go, that acceptance of what is, and to try to learn from whatever that is; even if it's difficult and horrendous at the moment. And be open. No matter where this takes you, go there. This is the optimal situation to follow this experience wherever it leads. If you're taking a bunch of mushrooms at a Phish show, you don't wanna necessarily follow every lead. You're surrounded by a bunch of strangers. Some of them shouldn't be trusted. Here, you're in this very safe container at every possible level. And so you can really explore that inner experience, from laughter to tears, and knowing that you're in a safe situation. I could go on and on, but I don't know. Hopefully, that, yeah.

NARRATOR: What does the integration phase entail?

JOHNSON: So the integration phase is where we're discussing the experience with them. They write essentially an essay. We don't call it an essay 'cause that sounds like schoolwork, but they write a narrative about the experience when they go home the night of their session. And we use that as a basis for discussion the next day. We have them read it to us when they come in, and we start to then unpack it, just kind of explore the meaning. And the themes that come up are so varied. One of the aspects is one of, you could call, 'revealed truth.' These are experiences where people will feel like they've learned something at such a fundamental level that they now truly absorb it, and know it at a deeper level than normal. So I think of examples in the work we've done with cancer patients where oftentimes people will say, coming in, "I know I'm allowing this to create my own suffering. I can still get out there and plan vacations and spend time in the sunshine. The cancer hasn't killed me yet. I can still live life. But I'm letting it do this to me. I'm letting it bury me." And they've told themselves that, like, a million times. But sometimes people have experiences where they get that, during the psilocybin session, where they get that so deep down. The way I put it is like, they knew it up here, they could tell you the words, but now they feel it in their bones, they feel it in their heart. So that kind of has its flavor of revealed truth. Same thing with smoking. These things, people come out, sometimes people say, "I just realize I could just decide to quit. I could just really flick it off and move on." I mean, it sounds like, and I call these "duh" moments, like, 'cause when people often say it, they'll tell you, like, "I realize this sounds stupid. Like, I've told myself this a million times, I know smoking's bad for me. I've wanted to quit. What do you mean I could just decide to quit? Of course I could decide to quit." But they feel it so deeply at this other level, and we really have a lot to figure out what's going on there, but this conviction that can remain with them. And I think sometimes these situations, the reason they feel it so deeply is that there is a truth there that somehow they're normally guarded against. It's kind of scary to think that the decision is ultimately in your- you have the agency to quit this or that that's not good for you. And that's kind of hard to own that. And people are kind of reminded about this power they have to choose their own destiny, to choose how they're handling all the horrible input that they get from the world. Next to revealed truth, I'd say there's other experiences where people say there was nothing new. And this is pretty common as well, where they say they were reminded of things that they've known and that they've forgotten. Sometimes they'll say, like, they haven't thought about these things for years or even decades. And I remember one participant that said she just loved poetry. She wrote poetry in college, and it was such a meaningful part of her life and helped her. And just, "Why don't I write poetry anymore?" So these reminders about these are things you can do in life that can help.

NARRATOR: Why does psychedelic therapy seem to be so effective?

JOHNSON: We don't know much about how these things interact. I'll say that the sense of, and it goes by different terms, but going beyond the sense of self or the dissolving of the ego, it appears that we're tapping into the same construct as that sense of oneness or unity, which is part of the mystical experience. So there's many different ways, it seems, to describe this, somehow this experience of moving outside of your own self narrative. And this might be important with certain disorders in the sense that, a lot of times, it seems like you're getting in your own way, and you need to get out of your way to address an addiction or this pattern of depressive thought, self-persecutory thought. And it often occurs to me that sometimes when someone has those experiences, they can step out of it and have this sense of: "This is how I would view another person who had this experience." I mean, maybe they feel guilty about this thing they've been struggling with or that they've done in their past or a trauma that they've gone through. And they're just so self-critical. They're so self-critical. And once they have that kind of experience where they kind of more broadly identify beyond themselves, they're able to view themselves with the compassion with which they would view another person. In the science, we know that in rodents, in rats, that multiple forms of neuroplasticity are unfolding in the days after administering a psychedelic. What does neuroplasticity mean? It's just a term that refers to different ways in which brain cells, neurons, can be flexible. They can grow new branches off of them. They can form new connections with different neurons. Sometimes you can grow new neurons. So these are different forms of neuroplasticity. That's very intriguing, and it's thought, although not known, that that might be part of what's going on in the integration in these human clinical trials with psychedelics, that the same neuroplasticity that's unfolding in rats in the days following a psychedelic experience, that this may be unfolding for people as well. And that might be part of why people sometimes claim that they feel that they have greater flexibility, they have greater agency. There's seems like there's this greater ability to just make a decision and follow through with it. The work I've done, and generally in the field, we've avoided doing acute neuroimaging during these sessions 'cause the strong suspicion is that you're not gonna get as good of results because it's just, yeah, being in a scanner is probably the worst set and setting that you can imagine. And a lot of people have difficult times with that. And that's been shown in research in Switzerland. They found, not surprisingly, that people have worse experiences when they're in a scanner. So others in the field have figured out some things in non-therapeutic studies in terms of what's happening in the brain. But in terms of my research, what I think is kind of the biggest question: What's changed about the brain long-term? Obviously, it's interesting what's happening during the psychedelic experience, and something interesting is gonna be happening, giving how intense the experience is. But the million dollar question is: What's different about the brain six months from now when someone's successfully quit smoking? And that's what we're hoping to address, but I don't have an answer to that yet. For some studies, like where we're helping people quit smoking, we're seeing them for several weeks afterwards for weekly check-in. And that shifts into more of discussion about their ongoing journey in quitting smoking and kind of fade out the discussion of the psychedelic session. Although the amount of integration contact differs across studies, it really is about helping the person just take seriously the experience, explore it, find meaning for them. And we need to figure out what the key elements of that are. I mean, really, it seems clinically that talking about your experience afterwards seems to be important and helpful, but we don't know what the key elements of that are. I think just this exploration of all aspects of your experience and then searching for what it means for you seems that that's very important.

NARRATOR: What role do mystical experiences play? Are DMT elves real?

JOHNSON: We find that about 2/3 of people on a high dose of psilocybin will have a so-called mystical experience. And we found time and time again that that is predictive of whether they're gonna be improved six months or longer down the road across a number of disorders. However, it's been overstated at times that, a mystical experience is not necessary for someone to have therapeutic benefit. There's a correlation there, and it's astonishing to me that any type of subjective effect, especially after controlling for just how strong the drug felt, that any sort of the nature of that subjective experience is predictive of how much benefit you're getting six months later. That's astonishing, but it's not a perfect correlation. So plenty of people that fall short of having the "Full Monty" mystical experience claim incredible benefit. And there are some people that have the "Full Monty" mystical experience that aren't helped so much. So there is variability, and we have a whole lot more to figure out there. I think it's really clear when conducting this type of research that you separate your exploration of phenomenology, that is trying to understand what people are saying about what their experience was, versus validating the ground truth of those experiences. So it's quite scientifically appropriate to say, "How many people felt like they were at one with the Universe?" But we have to keep in mind, that says absolutely zero in terms of scientific proof that they were in fact one with the Universe- and you could say the same thing about whether they had an experience with God or any other type of supernatural experience. So we just need to be careful to separate those two things. I liken it to the research on relationships, for example. You can look at what personality styles, what behavioral patterns are predictive of a successful marriage, for example. You can study what people say about their relationship and how that relates to whether it's gonna be successful- yet you've never captured love. We're never gonna do that scientifically, nor will we capture the existence of God or any other similar concept. And that really is, though, a struggle. I did some research on these so-called entity experiences that people sometimes have, whether it's interpreted as an alien or an angel or an elf. But sometimes when people, especially when they do very powerful psychedelics, like they smoke DMT, they'll report encountering an entity. It's scientifically credible to say, "Yeah, a good number of people that do this drug think they encountered some entity." And hopefully we can figure out eventually what specific brain mechanisms are underlying that and the therapeutic import that may or may not have. But it says exactly zero about whether you actually encountered an angel or an alien, etc.

NARRATOR: Why are psychedelics poised to treat so many conditions?

JOHNSON: The work, so far, that most advanced research, is using psychedelics in the treatment of depression and end of life or, in the context of serious illness, such as cancer, anxiety, and depression, within that context, and then depression outside of medical illness, and then a variety of forms of addiction. Other disorders that either I'm studying or colleagues are studying are obsessive compulsive disorder, anorexia, different forms of addiction, including cocaine addiction, alcohol addiction. I'm about to start work on using psilocybin to treat PTSD. And based on that rat research of neuroplasticity, of athletes that have sustained injury through repetitive head impact that are claiming that using psychedelics have restored cognitive ability, as well as doing things like helping them with depression and addiction. So I'm interested in pursuing that work. So there's just a whole lot that's out there. So some of those areas are being researched, and we don't have results yet, and so we can't get ahead of the data. I think there's a good rationale to study all of these things. Some of them might work out, hopefully, and some of them, we might run up against a boundary. It might be good for this, this, and that, but not this and that. The research, so far, has been focused on adults that are 18 or older in most of the studies. However, as we continue the research, we're gonna need to look at younger populations. In fact, this is something that the FDA really wants. It doesn't matter whether it's psychedelics or something else. Like, if it looks really beneficial in adults, there's a mandate to really explore this because adolescents suffer from depression and addictions, etc. The way I view it is that just an extra level of caution. That's not where you start. First, see how things work in adults, and there are extra concerns about the developing brain, but there's concerns about untreated mental illness, right? Including suicides, including overdoses, etc. So there's a risk in not exploring this, but being very, very cautious. In the biggest picture, aside from psychedelic's ability to treat one disorder or another, I think they're just poised to really help us to understand the nature of psychiatric disorders. I mean, the fact that we're seeing a similar, the same intervention, really, be helpful for depression and anxiety, whether it's in the context of cancer or outside of it, helping with not just one form of addiction but multiple forms of addiction, this is really unheard of, and it should be screaming to us to look for these so-called 'trans-diagnostic processes.' Like, what's underlying these different disorders? What commonalities do they have with each other that are somehow being addressed by psychedelic treatment? I mean, I've come to think of it- perhaps because understanding addiction is really kind of a foundation for me- I kind of think of all of these disorders as different forms of addiction. So whether it's to a substance, like tobacco or alcohol, cocaine, or a way of thinking about yourself in depression, the self-persecutory thoughts that we all have, but that are overexpressed in someone with depression, and once you're in it, it becomes a self-fulfilling prophecy. Once you spend a lot of your day calling yourself a failure and then that rubs off on other people, and you spiral downward- that is an addiction. It's this narrowed mental and behavioral repertoire. You have been narrowed. Reality used to be like this, and now your reality is like this. And wherever that's taking to a substance, or to a certain suboptimal way of thinking about yourself. And psychedelics, when done well in the right setting, have the ability to just blow people out of that narrowed story. So I think that's like really big picture. It holds a lot of promise in helping us figure out what the nature of mental disorders are, and also how to prevent those disorders. How can we move towards a society where we're not just primarily focused on treating disorders? But what creates, for the psychologically healthy person, how can we have preventative care and mental health care? And it really just hits home for me because I've done lots of studies treating disorders with psychedelics and a lot of other studies where we're just treating so-called healthy normals, as if they don't have any problems. And guess what? You give a big dose of a psychedelic to a human being in a prepared setting, and boy, that stuff, those problems, whether you're diagnosable or not, that trauma from the past, those various forms of addiction of whatever type, they kind of come to the surface. And so I think psychedelics, big picture, can help us move towards a world where we start to understand what it takes for the human being to be mentally healthy. What can we do in the spirit of prevention? Maybe psychedelics will play some role in that, but maybe they'll also point us to other techniques that will allow us to keep ourselves healthy. Some people come out of these sessions as participants and say that one six-hour experience with psilocybin is like 1,000 hours of therapy. It does seem that psychedelics, when they work, it's because they're getting closer to the roots of psychological problems rather than treating them at the surface level, which is the way most psychiatric medications will treat mental health disorders, more at the surface level. But this is why it appears, so far, that it might only take one, two, or three exposures in the right setting to a psychedelic, and that may be enough to really treat these disorders. In some cases, it can appear more like a cure, not always, but I don't use that term lightly. But sometimes it looks like a cure 'cause it really looks like people have resolved deep, underlying psychological issues that are kind of manifesting these various symptoms for whatever disorder. I'm not aware of any evidence that big pharma has been blocking or is scared of psychedelic research. They certainly traditionally haven't invested in it. I think they're sort of sitting back. It's mainly small venture capitalist start-ups that are exploring psychedelics and investing in their potential development through the FDA pathway. But that's been the trend for mental health drugs for a while now. Let the small companies make these investments, and if they come up with promising findings early on, then the big pharma companies come in and pay the millions of dollars to buy those companies out and move forward with it. So I think they're waiting in the wings, but it's a very different model where you're not gonna be making a whole lot of money selling that pill on a daily basis. Hopefully, you're only selling one, two, or three pills to someone over their lifetime if it works. So more of the business model, but it would be one of the infrastructure and the professional guidance through these sessions.

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