Dr. Daniel Knoepflmacher: Hello and welcome to On the Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. I'm your host, Dr. Daniel Knoepflmacher. In this podcast, I'll be hosting discussions with experts in our field on a variety of topics about the brain mental health, and important questions on the mind.

In our inaugural episode today, I'm joined by Dr. Richard Friedman. Dr. Friedman is a professor of clinical psychiatry and the director of the Psycho-Pharmacology Clinic here at Weill Cornell Medicine. He's also a contributing author to several renowned media outlets, including the New York Times, the Washington Post, and The Atlantic.

In today's episode, Dr. Friedman and I will explore one of his most recent editorial topic. The effects of psychedelics on our brains and mental health, a topic of great interest in our field, but also in popular culture and media. While psychedelics are not currently an FDA-approved treatment for mental health disorders, they're being used off-label to treat various conditions, including depression and PTs d, and they're the subject of lots of active research in psychiatry.

Currently, there have been more than 75 bills proposed across 25 states that aim to loosen legal restrictions on psychedelics. . With all of this interest and activity, many questions arise. What do psychedelics do to the brain? What is their potential for positive change and what risks come from using these powerful substances today?

We'll discuss these questions in more in our first episode of On The Mind, Dr. Friedman, it's such a pleasure to have you as our first podcast guest. before we dive into our discussion of psychedelics, I'd love to have you share with us what got you interested in psychiatry and in rating.

Dr. Richard Friedman: Right. Well, Daniel, it's great to be here and especially in the first episode and to talk about something that's so intriguing, psychedelics. So, I actually started off in college, studying physical sciences, physics, and decided somewhere along the line that the brain was more interesting than the universe, especially after taking a few classes in psychology and neuroscience and knew when I went to medical school that I was going to become a psychiatrist, because humans and behavior and the mind are so intrinsically fascinating.

And writing for me is basically a way to explore things that are intriguing. Most people think they know what they're going to write about, and then they write something. For me, writing is an act of discovering something. I write because I'm interested in something. And in writing about it, it helps me think about it. So, it's basically a form of exploration and thinking.

Dr. Daniel Knoepflmacher: Well, I always enjoy reading your pieces because they're so clear and I always do learn something from reading them. I want to specifically talk about the piece that you wrote in the Atlantic recently about psychedelics. And certainly, as I said, there's interest in psychedelics within psychiatry. There's been a growing amount of research in this area. And of course, in popular culture, it's come up a lot.

But this is something that has been going on for over 50 years. And my sense is in the age of Timothy Leary and maybe the period prior to that, there was a lot of focus on psychedelics as well. So, would you be able to tell us a little bit about the history of psychedelics in America in the 20th century to the present?

Dr. Richard Friedman: Sure. I mean, to start, just as you were saying, there's nothing new essentially about psychedelics. I mean, plant hallucinogens have been known for centuries, if not longer, part of rituals in different cultures. And then in the 20th Century, Albert Hofmann, the Swiss chemist who first synthesized LSD in '38. And then, he described this fantastic experience that he had, you know, essentially hallucinations and extraordinary shapes, kaleidoscopic colors. In the '60s, Timothy Leary, notorious Harvard psychologist, experimented with psilocybin as a sort of adjuvant to psychotherapy, and he's the one who basically coined tune in, turn on and drop out.

And I think the illicit use of LSD along with other drugs in the '60s as part of the countercultural reaction drew a lot of concern and provoked a huge legal response. And in 1970, Congress passed the Drug Abuse Prevention and Control Act making LSD illegal and basically initiating the war on drugs that still continues to this day. So, all psychedelics starting in the '70s were suddenly classified as schedule I drugs by the Drug Enforcement Administration, meaning there's no accepted medical use until the present, when all of a sudden there's a resurgence in scientific study of psychedelics and for a good reason.

Dr. Daniel Knoepflmacher: So, we are using this word psychedelics, but I think it might be helpful to say what they are, what fits in this category, what is a psychedelic.

Dr. Richard Friedman: Right. So, psychedelics, the so-called classic psychedelics are drugs LSD, psilocybin, mescaline, ayahuasca. These drugs have particular properties and effects in the brain, which we can get into. And then, there are some atypical psychedelic-like compounds, ecstasy or MDMA. These are so-called empathogens that promote trust and have some hallucinogenic, psychedelic-like effects, but other effects as well. And then, there are dissociative anesthetics like ketamine and PCP, phencyclidine, that have some effects in the brain that are like psychedelics, but some that are not. And so, taken together, all of these are loosely referred to as psychedelic compounds.

Dr. Daniel Knoepflmacher: And part of this psychedelic experience is this alteration of consciousness. I think people are captivated by what they hear about psychedelic "trips" that people have when they've ingested these substances. What is happening in the brain when people are having these experiences?

Dr. Richard Friedman: So, psychedelics have a main effect on a particular serotonin receptor in the brain, what's called the 5-HT2A receptor, and 5-HT just means the hydroxytryptamine that is serotonin. So, these receptors are located densely in the prefrontal cortex, which is, you know, our reasoner-in-chief. The executive control of our brain is in the prefrontal cortex. And these drugs, the psychedelics, specifically target these receptors and they excite them, they excite these neurons in the prefrontal cortex. But the curious thing is the net effect of psychedelics is to cause a decrease in connectivity, the kind of communication between different regions. So, it decreases connectivity. It's got an inhibitory effect on executive control. And it promotes what seems to be this freer cognitive state in which people can associate and see things and think about things in ways they ordinarily wouldn't. And these brain connector hubs constitute what we call the default mode network of the brain. And usually, the default mode is active when we're monitoring ourselves and thinking about the future, and our mind is wandering and we're focused on ourselves, that's when the default mode network is most active.

Psychedelics curiously decrease the activity and the connectivity of these default mode networks and make us less self-conscious promoting what we think of as this characteristic egoless state. And it's believed that this has an effect to make these transcendent experiences happen when people take psychedelics.

Dr. Daniel Knoepflmacher: So, that obviously, I think, was very captivating for people in this part of the popular appeal of psychedelics. But why we're so interested in them in science and psychiatry is the potential for actually effectively treating psychiatric conditions like depression. I'm wondering, do we know if it's these trips, this kind of ineffable, psychedelic experience that is part and parcel of the anti-, let's say, depressant effects that are occurring potentially with psychedelics. So in other words, do you need to have a trip in order to become less depressed if you're taking psychedelics to treat depression potentially?

Dr. Richard Friedman: That's a fascinating and critical question. And it seems like the answer might be it may not be necessary to have therapeutic effects. You don't necessarily have to have a trip, a transcendent, ineffable experience, in order to benefit from some of the therapeutic effects. And one of the reasons is that a drug like ketamine, for example, may not necessarily produce a trip or even a hallucination-like experience. However, it can still help people who have serious depression get better. So, it appears as if the trip part of a psychedelic may not be necessary or sufficient to have a clinical effect. And we didn't talk about it yet, but one thing that psychedelics do is they induce rapid changes in the brain or so-called neuroplastic changes in a way that no other drugs that we have ever used are capable of doing within the order of a couple of hours.

Dr. Daniel Knoepflmacher: That's fascinating. So, you just brought up neuroplasticity, which is a fascinating and important aspect of this discussion. And it's something I know that you highlighted specifically in your article in The Atlantic. And I'm curious to learn more about what neuroplasticity is. Why is it important to us as human beings in our development and potentially in its impact on therapeutic change for people who are suffering from psychiatric problems?

Dr. Richard Friedman: So, neuroplasticity is key to understanding how psychedelics work, and neuroplasticity really refers to the innate capacity of the human brain and also other animal brains for that matter to change its function and structure in response to various environmental inputs and experiences. And all of us go through a period of heightened neuroplasticity. You could say neuroplasticity is a state of being influenceable, being easily influenced. So when we're neuroplastic, we're exquisitely sensitive and highly impressionable. And we all go through that phase when we're young, when our brains are developing. Say, between the age of one and five, we're super learners. You know how easy it is for kids to learn to ride a bike or to speak a foreign language or learn mathematics in a way that, you know, adults would have a very hard time to doing it because the brain is in a state of enhanced neuroplasticity.

And then, that sensitive period during childhood comes to an end and we lose that enhanced neuroplasticity. And you can think of what psychedelics are doing, is to enhance adult neuroplasticity, which essentially makes the brain more sensitive and impressionable. It's a bit like taking a glass vase, for example, and putting it back in the kiln, softening the vase and making it easy to remold, which means of course you can make a more functional and beautiful vase, or you can make a mess out of it. So, plasticity doesn't necessarily intrinsically mean good or bad, it just means easily influenced. So, we're more likely to be better learners for better or worse, depending on the experiences and the environment in which we are when we're using the drug.

Dr. Daniel Knoepflmacher: You're hitting on something really important that these are powerful substances in the way that they can have this effect on neuroplasticity create a change that's positive in the brain. But if that is in a situation where it isn't therapeutic, then the opposite could happen. That this could actually cause problems or create instead of therapeutic change, it could actually be damaging. So, could you speak to that some more?

Dr. Richard Friedman: Yes. So if you think of neuroplasticity as enhanced capacity for learning, which is essentially one large component of therapy, if you're in a situation in which you're surrounded by, let's say, a positive effect, you know, people you love, therapists you trust, a benign situation, something that is fun; compare that to being in a situation in which there are scary things going on, or you're likely to be encountering a situation that frightens you. Those situations could promote a very negative experience if you're using a psychedelic. And those experiences can be enduring long-lasting. You could have a bad trip.

Now, you don't necessarily have to have a bad influence around you in order to have a bad trip. You can do it, just your brain, all by itself. If, let's say, you have a genetic loading for a particular psychiatric illness like, let's say, an anxiety disorder or a mood disorder with psychotic features, it might trigger some of those symptoms while you're under the influence of a psychedelic.

Dr. Daniel Knoepflmacher: So really, the therapy piece, which, I mean, it sounds like going back to Timothy Leary, he actually, despite some of the controversy and notoriety, was onto something, that having a guide, somebody who is going to be a therapeutic influence on you as you're going through this experience, is key. And I'm wondering if you can tell us more about the psychotherapy side of this, because clearly we focus on the neuroscience and what's going on potentially inside the brain. But what about therapy and is there research kind of looking at the different types of therapy or what potential there is on the therapy side of this?

Dr. Richard Friedman: Yes. So, there have been studies looking at MDMA in particular in post-traumatic stress disorder in which people have had traumatic experiences, a variety of traumatic experiences, let's say, assaults or violent assault or sexual assault, and those experiences have been burned into the brain. And patients in these studies who have had, let's say, a cognitive behavior therapy that was of limited value were able to benefit further by psychotherapy that was under the direction of a therapist while the patient was taking MDMA. And it promoted benefit in a way that these patients had not experienced without MDMA, and it may be because the brain was in an increased state of neuroplasticity with a therapist who was essentially there to help the person reprocess and rethink and reappraise the experience and then change how they felt and thought about what happened to them. So, it was a powerful learning experience and a positive one because you had somebody there who was essentially curating the experience. And while you were thinking about and experiencing the emotions that were attached to the trauma, they helped you reprocess them in a way that you weren't able to do before, something that was enhanced by the MDMA.

Dr. Daniel Knoepflmacher: So, this piece of the therapy reminds me of some terms that, I think, go back to the early days of psychedelics research. There's two words that are often used, set and setting, which refer to the non-neurobiological, non-pharmacological factors in this psychedelics experience. In other words, factors that weren't caused by the drug itself. So, set refers to the mindset of the individual, and you described somebody who might have a proclivity based on their mindset to potentially have a more bad trip, perhaps. And then, the setting refers to that environment and the external factors that impact the person while they're undergoing the psychedelics experience. So, that could be in this nice therapeutic setting or just a supportive calming setting versus a really scary isolating, potentially traumatic setting. And this is something which I'm not sure that people keep in mind because I've read about people taking psychedelics without any of this in mind. Just thinking that, "Oh, I've heard that these substances can cure depression or are beneficial for my thinking and are just taking them." Is that something that you've heard about in just from the work you've done in looking into this?

Dr. Richard Friedman: Well, many people think magically if you take a psychedelic, you have a wonderful experience in that you don't really have to do anything in order to promote a positive experience. And if you think of a psychedelic as really just creating a state in which you're more easily influenced, it's I think a nice way to consider how psychedelics might be used and leveraged for positive versus negative outcomes. Because, you know, going back to, you know, when we were young in our neuroplastic state, we learned because we were also not just biologically primed in this state, but because we had an environment around us that gave us the input in order to use this remarkable state of enhanced learning, meaning teachers, role models, parents, loving figures around us that provided us with experiences and knowledge that we could do something with.

So, I don't think you magically get something. I think you have to do something when you're in a neuroplastic state in order to leverage it and just be mindful that you're in an enhanced state of influence and you want to select people and environments to be in that are positive, meaning you trust people, you love these people, you know, you can be with them.

Dr. Daniel Knoepflmacher: That's a really helpful distinction. You know, again, that you're like an impressionable child or you're incredibly receptive to change, but that needs to be done in the safest, most positive way. Along these lines, there's a talk of microdosing, which would be taking substances like LSD perhaps or psilocybin in doses that aren't inducing the psychedelic experience, but there's questions as to whether there might be benefit.

In doing that, and again, I think this is being done in, a somewhat unregulated way based on popular, discussions online or in the media. Is there any research that shows that microdosing is particularly effective? Do we have good research to back that up?

Dr. Richard Friedman: So, there have been some randomized clinical trials in which people are randomly assigned to take microdoses of LSD or psilocybin, compared with a group that gets placebo. And what's interesting is people seem not to be able to distinguish between placebo and the microdosed form of various psychedelics, they can't tell the difference subjectively.

But what's curious is if you brain image these two groups, you do see slightly different changes in the brain. So even though subjectively people can't distinguish between a microdose and a placebo, the brain seems to be distinguishing. So, there might be something that we just in these randomized trials can't tap into in the way that we are, measuring or evaluating the outcomes because the idea never seems to go away. You hear from people, very thoughtful people, who say that under the influence of microdosing they feel more creative. And it gets back to, Daniel, what you were saying before, can you have positive effects, either therapeutic effects for anxiety or depression, or perhaps other forms of learning in the absence of a trip, meaning a microdose which may promote a neuroplastic state in a smaller sense; less intense, but not have the trip or the hallucinatory experiences? And there's a new class of psychedelics, so-called non-hallucinogenic psychedelics, the next generation of psychedelics that have been synthesized and are being tested in animals, not yet ready for primetime in testing in humans, that appear not to produce the trip or the hallucinations, but produce neuroplastic changes and may have therapeutic implications for people.

Dr. Daniel Knoepflmacher: Fascinating. So, I guess what's difficult about that research, I mean, on a double blind basis, people can't tell the difference between a placebo and the small dose of the psychedelic substance. In brain imaging, you're seeing some difference, but actual outcomes in terms of, let's say, therapeutic outcomes, if they're feeling less depressed, if they're feeling less anxious, if there's some sort of wellness or general quality of life benefits, we don't really have any data that is fairly conclusive on benefit in that sense. We're just seeing some difference in the brains. Is that accurate?

Dr. Richard Friedman: I would agree with you. And also, I think it's fair to say that placebos themselves can be beneficial, even though, let's say there's not a direct neurobiological effect that one can see. Just feeling hopeful that you're doing something that is promoting your wellbeing has a positive effect on people. So, it's easy to dismiss these studies and say there's absolutely no evidence from a randomized trial that microdosing has any discernible effect. From a pure methodologic point of view, there's no question that's correct. And yet, the idea doesn't seem to go away. People like to do it and will swear by it that, if they do this, they're more creative. So, I think it needs further investigation.

Dr. Daniel Knoepflmacher: We don't have a great scale for creativity. So, I think it's harder to measure than depression. Well, I could keep talking about this topic and maybe we will actually. I mean, I know I'm going to want to have you back for further episodes about this or other things, but thank you so much.

I want to ask you one final question that I think is just a take home that I'd like to have at the end of every episode of On the Mind. And that's something that people who are listening maybe can take for themselves listening to the wonderful guests that we're going to have on this show. And I guess the question is as simple as this: what is the most important thing that you, Richard Friedman, do to help maintain your own mental health?

Dr. Richard Friedman: Well, there's two things. The first would be swimming. I'm a lifelong swimmer. It's a passion of mine, long distance swimming, because you get into a state of flow in which you're unselfconscious. And it's both competitively and just for what I call a pleasurable swim. It promotes a state of calm euphoria. And I've also done a fair amount of work in the background when I'm swimming. It's not that I'm thinking, but when I get out of the water, all of a sudden some problem or something that's been bothering me suddenly appears clear and I know what to do or I know how to think about it. So, swimming. And the other is I'm a pianist. And so, I play classical music and I love to play chamber music. But above all else, I would say the water. There's something just remarkable about being submerged and freed from the world, the sensory world where the noise and the hectic pace of life when you go into the water, whether it's a pool or it's a lake or the ocean.

Dr. Daniel Knoepflmacher: I know you've written about this. I think there was a New York Times op-ed about this. Is that right?

Dr. Richard Friedman: Yes.

Dr. Daniel Knoepflmacher: So, people who are interested in hearing more about that can find the op-ed piece that you wrote. Well, thank you so much for joining us. And again, I feel like we just barely delved into this topic that is going to be in discussion in psychiatry and in our culture and in America in the years to come. So, we'll be talking about it some more. But thank you so much for helping us record our first episode of On The Mind.

Dr. Richard Friedman: My pleasure, Daniel.

Dr. Daniel Knoepflmacher: Thank you to Dr. Richard Friedman for joining us today and for engaging in an intriguing discussion on the connections between psychedelics and mental health, Also, thank you to everyone that tuned in to listen to On the Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. We have many more episodes to come on. A variety of fascinating topics related to psychiatry, mental health, and important questions on the mind. Join us again next time.

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