How Psychedelics Rewire the Brain

How could a single psychedelic treatment cause lasting change? Joshua Siegel, MD, PhD, is on a mission to find out. A leading expert on neuroimaging and neuropsychopharmacology at NYU Langone’s Center for Psychedelic Medicine, Dr. Siegel unpacks how psilocybin may spark neuroplasticity and reshape the depressed brain. He also gives us an inside look at the race to develop non-hallucinogenic psychedelic analogs. 

Dr. Siegel is an assistant professor at NYU Grossman School of Medicine.

🔍 Topics Covered:

00:00 Introduction
00:15 Dr. Siegel's Current Work
01:01 Past Research and Human Psilocybin Imaging Study
02:39 Understanding Brain Changes and Biomarkers
06:13 Mechanisms of Action and Plasticity
12:51 Surprising Findings and Context Dependence
16:34 Challenges and Future Directions in Psychedelic Research
20:46 Advanced Imaging and Personalized Treatment Plans
24:15 Setbacks and Lessons in Psychedelic Medicine
28:40 Emerging Areas in Neuropsychopharmacology
31:46 Conclusion

📚 Related Resources:

Joshua Siegel, MD, PhD 
NYU Langone Health’s Center for Psychedelic Medicine
The Multidisciplinary Association for Psychedelic Studies (MAPS)
“Psychedelic and Dissociative Drugs as Medicines” (NIH) 

🙌 Support & Engage: Enjoyed this episode? Like, comment, and share to support science-based conversations about mental health.

🔔 Don’t forget to subscribe for more interviews with top psychiatric researchers.

Visit our website for more Insights on Psychiatry.
Watch this episode on YouTube
Executive Producer: Jon Earle

Transcript

DR. THEA GALLAGHER:  Welcome to the Insights on Psychiatry podcast. I'm excited to introduce our guest today, Dr. Josh Siegel, who is an assistant professor here in the Department of Psychiatry. Josh, welcome to the show. Happy to have you. 

DR. JOSHUA SIEGEL:  Thank you very much, Thea. Pleasure to be here.

DR. THEA GALLAGHER:  Can you tell us a little bit about what your work is focusing on right now?

DR. JOSHUA SIEGEL:  Well, I joined NYU just about six months ago in August, and I had just wrapped up a big project at Washington University where I was before this and joined the Center for Psychedelic Medicine. And so at this point, you know there's a couple main focuses, but probably the biggest thing I'm doing is working on ongoing projects that they have, psychedelic clinical trials. And kind of my focus is translational neuroscience and the biomarkers side of things and so building that into ongoing clinical trials that they have with psychedelics. 

DR. THEA GALLAGHER:  Is there anything that you've done in the past with your research that you want to share or talk about? 

DR. JOSHUA SIEGEL:  Well, sure. The big project that I mentioned that wrapped up right before I came to NYU was this study that I did at WashU. I actually started it while I was in residency and it was a human psilocybin imaging study and the idea of this study was to use some of these very modern, recent tools for individual kind of brain connectome mapping, which we call collectively precision functional mapping, to answer some questions about psilocybin, both in terms of…which is psilocybin is the psychedelic in magic mushrooms, both in terms of what it's doing acutely when someone takes psilocybin and the way that the brain is affected produces this very unique psychedelic experience.  But then also, what are the lasting changes that can be observed in the weeks afterwards? And part of background of that is that, of course, there's been all of this interest with psychedelics as a potential treatment for a variety of things. I mean, depression, but also some studies with addiction, anxiety and so one of the big questions was what is changing in the weeks afterwards that might be related to some of these therapeutic effects that have been seen in clinical trials. 

DR. THEA GALLAGHER: And then some of the work that you're doing with biomarkers. What is that hoping to understand? 

DR. JOSHUA SIEGEL:  Well, it's a similar line of research. So can we understand how the brain is changing? And so there's a variety of tools that we use for that but fundamentally, you know the question is, okay, we see a clinical benefit. Maybe we see antidepressant response or anti addiction response, both of which are two big avenues that are promising with psychedelics. But the way that it works with clinical trials with psychedelics recently is that you have one dose or maybe one or two doses, a high dose of a psychedelic, often psilocybin, and then there's a benefit that lasts for weeks afterwards. And so the question is, what is changing in the brain? Of course, any dramatic behavioral change has to be sort of underpinned by some brain change. So what's changing in the brain that is allowing the benefits of a psychedelic? And you know there's a variety of reasons that that's kind of an important question to ask. One is to potentially develop safer future treatments. 

So just as a sort of quick example without going too much into the weeds, there's interest in what's called non-hallucinogenic psychedelic analogs. So taking the therapeutic benefit but without having this very intense experience that might be difficult or not accessible to some people. But the point is, if we can understand what's changing in the brain, then that helps us understand the treatment, develop better treatments, understand why and where and how there might be benefits and so that’s the idea of biomarkers, can we see how a drug is affecting the brain and can we use that to improve treatments in psychiatry? And there's a few different tools that primarily are used for that. So fMRI, EEG are some of the common, PET scan are probably the three biggest what you might call brain imaging tools in psychiatry that we use. 

The last thing I'll say, you know just as to why that that's really important, particularly in psychiatry, is because in some other areas of medicine, we have very good mouse models of a disease. I mean, even oftentimes in cancer, there's limitations in mouse models in cancer, but you can create a tumor in a mouse and pretty accurately test out whatever your novel treatment X is in the mouse. Whereas in many cases in psychiatry, that really just is not the case. I mean a lot of these very kind of well-characterized disorders, like obsessive compulsive disorder, I don't know why that randomly pops to mind, but you know it's this very well-characterized in humans, but really there's not any good animal model for it. And so it becomes even more important to understand the disease and to treat the disease to have biomarkers that we can measure in humans to understand both what's altered in the brain in this disease and what are treatments doing. 

DR. THEA GALLAGHER: And your research focuses on a lot of these novel treatments that can rapidly alleviate mood disorders. What are we learning about the mechanisms of action for these drugs? And what do they tell us about the etiology of the disorders like MDD? 

DR. JOSHUA SIEGEL: So with psychedelics, I think it's really been a fascinating story because the biomarker research and the mechanistic research has really changed the thinking you know compared to 20, 30 years ago. Because remember, there was actually a lot of interest in…and I'm not supposed to go back to the 1920s, right? So there was actually a lot of interest. We all know the '60s and what happened. But there was a lot of clinical interest with psychedelics kind of initially in a number of clinical trials and a lot of thinking about how they might be useful clinically. But what's really shifted compared to the clinical thinking back then has been on the mechanistic side, understanding how these drugs work and what they do. In particular, one discovery that's, I think, really at the center of the shift in thinking about what psychedelics do, which is this discovery that they are inducing plasticity in the brain and in particular in the limbic system and prefrontal cortex, which are these parts of the brain that are critical for emotion and for mood and for habits. And so there's been this whole sort of budding field of research maybe in the last 20 years, in general, linking plasticity to psychiatric illness. And it turns out that most effective treatments for depression actually sort of increase plasticity in neurons in the limbic system. 

Just recently, there's been the observation that psychedelics…so actually just to make one other kind of step back and make one other note, it was really ketamine that started a lot of this work. And so there was the observation that ketamine, which has now been approved for depression in the form of Spravato, but the observation that ketamine rapidly increases plasticity in sort of depression relevant parts of the brain. And that was followed a little bit more recently by the observation that psychedelics have this similar effect and maybe even longer-lasting than ketamine. 

So that's been, I think, the big observation scientifically and of interest with psychedelics. And so you know on the one side, you have this very unique perceptual experience, which can often be profound or mystical. That's kind of the old story of why these drugs are therapeutic. And I'm not saying it's wrong, but that's the more classic story. And then the newer story is they actually produce this burst of plasticity in these parts of the brain that are critical for depression. 

DR. THEA GALLAGHER: I think it dovetails nicely with what we're seeing in cognitive behavioral therapy research about the metacognitive process and how it's so important how we…our relationship to our thoughts. And it seems like one of the things that is coming out of this research is a lot of individuals feel like they get that separation where they can see their thoughts maybe as less enmeshed with their whole experience and they can see them more objectively and can analyze them maybe more healthily. That's kind of going on the psychological level. I don't know if you want to work your way back to the molecular level from there. 

DR. JOSHUA SIEGEL:  No, I think yeah, that's a very nice point because one of the things that has been a focus in my work is understanding in humans at the systems neuroscience level what's happening. And you can kind of draw a line connecting across from the molecular all the way up to the psychological because with psychedelics, for example, this acute experience produces what we call ego dissolution, which is you know there's particular parts of the brain, the default mode network is most classically associated with the sense of self, so a particular network in the brain that creates, you know we'll say our sense of self: who we are, how we relate to our environment. And you know what my research and other recent research has shown is that with the acute experience with a psychedelic, you have basically desynchronization and sort of disorder within this network that's creating this sense of self. And that's sort of acutely during the psychedelic experience, but then there seems to be this lasting sort of loosening of some of these ingrained senses of what is my identity? What are my habits? What is my relation to my thoughts, to my world, that becomes a little more flexible as a consequence of completely, transiently desynchronizing this part of the brain that's this default mode network? 

DR. THEA GALLAGHER: And it's kind of neat to hear you talk about what's actually happening functionally when you know we also know concepts like cognitive flexibility are so important and getting to see that that gets to happen with psilocybin and then understanding what's actually happening in the brain to explain it seems like it is taking us to the next level.

DR. JOSHUA SIEGEL: Yeah. That's my favorite thing is trying to connect these different…there's this great diagram from 1992 like philosophy of neuroscience of the levels of neuroscience. And you have the molecular and the circuits and systems and psychological and a lot of the folks that I work with at the center here now that I'm working with, you know their background and expertise is more in these psychological concepts like cognitive flexibility, like emotional avoidance. And so one of my favorite, things that I enjoy the most is connecting what's going on at the neurobiology level. 

DR. THEA GALLAGHER:  I think that's so important in moving this work forward and you have conducted studies using this precision functional mapping to understand how substances like psilocybin kind of alter the brain networks. What do you think has been the most surprising findings from the research and how might they inform future psychiatric treatments?

DR. JOSHUA SIEGEL:  The thing that comes to mind, one thing that was surprising was the degree of variability in the intensity of the experience and the intensity of the brain changes. And I'll give you a couple of examples of that. You can give the same person even, the same drug on different days and in some instances, we would see a much larger change in the brain and it often correlated pretty closely to how intense people reported the experience as being across different sessions, right? And so you know again, just to state that clearly, same dose of psilocybin, same person, these were a few months apart, essentially the same sort of protocol and on one session, sometimes we would see they would report having a very powerful, intense mystical experience. In the other session, they would report that there's one participant that's coming to mind, and he reported on the second session, oh, it wasn't nearly as powerful.  I was kind of distracted and fixating on he happened to be thinking about having to pee. And this is when he was in the scanner, of course, when we were scanning his brain on psilocybin. And just dramatically different magnitude of how much the brain was altered. And one of the things that was surprising and really cool was that we saw that that can actually be manipulated based on someone's focus. So when someone was in a state where they are kind of relaxed and engaged in the experience, there was actually much larger….you know we had talked about disruption of the default mode network, for example. If somebody was in an internal state where they were relaxed and just letting their mind wander, we actually saw a much larger disruption to the default mode network. And when we had people focus their attention, for example, on doing a task, we had them play a game in the scanner or either externally focus their attention, or as I mentioned, when a subject would report that they were distracted by attending to something sort of in their physical environment, the effects of the drug on the default mode network got much smaller. So this was this cool and kind of surprising sort of context dependence of the drug that seems to explain at least some of this wide amount of variability in people's experience.

DR. THEA GALLAGHER: It seems like it's kind of hopeful that it can be manipulated because when you were first saying it, I was like, oh my gosh, that must make it so difficult to study if someone's having such a different experience with all of the same essentially same variables. But it sounds like maybe you figured out something comes down to kind of context and focus?

DR. JOSHUA SIEGEL:  Yeah. And this connects to there's the whole idea of set and setting. Have you ever heard that term? So it's, you know of course, not coincidentally, but the clinical and therapeutic delivery of psychedelics is sort of designed to enable somebody to be in a context where they are allowed to be relaxed. I mean, typically, we have participants with a mask over their eyes and music playing on headphones specifically so that they can be in an internal state without having too many distractions from the outside world. So it is this interesting sort of neurobiological explanation or justification for that. 

DR. THEA GALLAGHER:  Are you surprised by the fact that it seems like it takes very few doses, if you will, to have long-lasting effects. And I think that's something that's very important to both patients and clinicians to say, wow, you don't have to be on maybe medication forever. You can do this twice, and it can have really long-lasting effects. Is that, again, something that's surprising, or is that something that we should kind of keep studying and understanding? 

DR. JOSHUA SIEGEL: It's surprising. I mean, certainly, it's exciting and promising, right? But there's, I think, some really important considerations. Some known things that need to be thought about, and some unknown things that we're still learning. So the known stuff, one is that you know I think psilocybin and psychedelics in general, very powerful. And you know when you give somebody the doses that are often used in clinical trials, that can be tremendously beneficial, but also potentially tremendously harmful in the wrong situation or in the wrong person so that points to the therapy surrounding it. And you look at the phase three trials that are going on right now. I mean, right now, we have two companies that are in phase three testing and looking at potentially applying for FDA approval within the next couple of years. Both of them include required preparation with two therapists present in the room and oversight and support from those therapists while you're on the dose and then integration afterwards and part of that is to minimize potential harm. Part of that is to increase potential benefit. And you know I think there is, maybe you could say, this period of a few weeks of plasticity but there's also the sort of meta question of is someone changing their habits? I mean, fundamentally, I'm a believer in the sort of cognitive behavioral model, that we are very prone to being stuck in habits between mood and thought and behavior and self-perpetuating habits. And so without shifting those habits, I don't think there's lasting benefit. But if the dose in combination with the therapy is an impetus to change those habits, then there is potentially indefinite benefit. So that's kind of some of the picture of how I think about what we know about the lasting benefit.

And just at the very concrete level, clinical trials are looking at about a month where there's still clear separation from placebo. But the things that we don't know, one is what is redosing going to be effective? So if somebody benefited from psilocybin, we honestly really don't know if they relapse, if another dose is as likely to give equal benefit and I'm sort of encouraged because that's one of the questions that I think we will get a good answer to with, I mentioned, these ongoing phase three clinical trials. Part of what they're going to look at is redosing and understanding, getting at least some information relevant to how these drugs might be used clinically. And so that's still a big question. 

DR. THEA GALLAGHER: And who might need the redosing too? 

DR. JOSHUA SIEGEL: Yeah. Who might need it, when, how likely are they to benefit from it?

DR. THEA GALLAGHER:  These are great research questions, because I think everyone's so excited about the work that's being done, and yet it's still early days in some ways. And I think it's exciting to see what will be ongoing. How do you envision the role of advanced imaging techniques in developing these personalized treatment plans for patients with mood disorders? Because I'm feeling that might be a challenge when you're thinking of dissemination and implementation. 

DR. JOSHUA SIEGEL:  I don't necessarily envision a world where someone comes in and gets an MRI to guide what decision for a medication we put them on. I think there are ways that imaging is working its way into being useful in developing treatments and in guiding treatment. That's not one of them. I'll give you two that I think are very promising. One is that I touched on a little bit non-hallucinogenic psychedelic analogs and I mentioned that psilocybin is being explored and maybe even approved by the FDA within a few years. Of course, we don't know, we'll see.  But there are a variety of other drugs that are earlier in testing that might be more targeted or safer, drugs working by a similar mechanism or targeting this sort of similar neurotrophic or sorry, plasticity effect. And so one way that imaging is really useful is all of those drugs, as I mentioned, the kind of animal testing is only going to tell you so much. And to be able to know, is this drug getting in the brain? Is it hitting the circuits that we think are relevant to depression or addiction? What's the optimal dose for it? Those are some of the questions where imaging as a biomarker becomes really valuable if you're developing a new treatment. So that's one way. 

And then another way, which I collaborate on, I'm not as directly involved with but I think really has a lot of promise is what I call precision functional mapping is going to be very useful for targeted brain stimulation. And so targeted brain stimulation, we have TMS, transcranial magnetic stimulation, approved as a treatment in psychiatry and there, we'll see how things play out, but there is very real potential that just the ability to map someone's brain relatively quickly, could dramatically improve how effective of a treatment TMS is. And then there's also a variety of other, there's deep brain stimulation and focused ultrasound, which is some approaches to non-invasive deep brain stimulation that's more in the experimental phase, but safe and it's actually already used in Parkinson's, for example. 

So I think you have this parallel thing where you have all of these approaches to brain stimulation that are maturing, and then you have the ability to more precisely map circuits that are related to mood disorders and psychiatric disorders. And I have no question that there's going to be a synergy between those two, like the computer and the microprocessor sort of co-developing together.

DR. THEA GALLAGHER: Advocates for psychedelic medicine suffered a setback this summer kind of with the FDA denying the approval of the use of MDMA to treat PTSD. What were your takeaways from this news? And how do you think it impacts the research going forward, maybe even specifically for psilocybin and psychedelics? 

DR. JOSHUA SIEGEL: That's a good question and you know I will say the Center for Psychedelic Medicine here and I think Michael Boganschutz was the principal investigator. They were a site for the clinical trial, I think. Certainly phase three, maybe phase two and three for MDMA for PTSD. And I have not been directly involved, so you can take my perspective with a grain of salt but essentially what happened is that the clinical trial results came out and both were very positive, and when I say both phase two study and the phase three study, very positive results suggesting that the treatment was effective. And this is, by the way, MDMA and it was kind of in the context of pretty intensive psychotherapy for people with post-traumatic stress disorder and so that wasn't…the statistics, so to speak, you couldn't argue about. But there was concern about the way the studies were conducted in a couple of areas. One, there was concern about maybe influence and bias of people conducting the study, pushing people to minimize adverse reactions and potentially maximize treatment benefit. And then two, relatedly, I guess, and also some misconduct. Maybe I think it was a very small number of cases, but misconduct from study therapists. And then relatedly, there was concern that there was more emergent suicidal ideations or adverse reactions that were minimized.

So that was what ultimately led to the FDA's decision, which certainly a lot of people feel is unfortunate and PTSD, I think, is a particularly hard-to-treat condition in psychiatry. But I think the lesson learned and possibly benefit is it certainly made it very clear to anybody involved in this research or involved with what's called the psychedelic renaissance that being extraordinarily careful in terms of conduct of therapists, in terms of how studies are overseen and reported…

DR. THEA GALLAGHER:  And I think it is important to not move this research too quickly.  You know I've had patients who are like, oh, yeah, I'm getting psilocybin from some guy because I read this study, it does seem like some of the rigor of these studies is important to really understand what works, how it works, and then how we can ultimately implement and disseminate the treatments in the long run. 

DR. JOSHUA SIEGEL:  To that end, I do want to make a point. I don't want to miss the opportunity to make a point that I kind of alluded to this earlier, but all of the studies, all the clinical studies that are done, really, for the most part, there have not been serious adverse outcomes. But part of the reason for that is because there is careful screening. And one of the things that is screened for is a psychosis history. And it's clear that particularly in people who have any history of schizophrenia spectrum, probably bipolar disorder as well, definitely bipolar with any psychosis associated, that there is a much higher risk of a psychedelic causing, lasting, psychotic-like symptoms. And so you know I mean, certainly, people are using the drug more recreationally and sort of underground and so I think it's important not to minimize the risks and the dangers. 

DR. THEA GALLAGHER:  Absolutely. And just kind of finally, looking ahead, what emerging areas of research in neuropsychopharmacology are you most excited about? And how do you anticipate they will transform the treatment landscape for psychiatric disorders? 

DR. JOSHUA SIEGEL:  A couple of things come to mind. One is that you know we all know anybody who's in psychiatric practice knows that SSRIs and SNRIs, too, will say, great treatment for depression, but often cause this emotional blunting and numbing. And so one of the things I'm excited about is there's the next generation of treatments and ketamine and psychedelics may be among them, that seem to do a much better job with these circuits related to emotion and motivation than classic antidepressants. So I think that's one area where there's going to be a lot of benefit. And there's also a lot of interesting advance on the neuroscience side understanding these critical circuits related to emotion and reward. So that's one thing. 

Another thing that I mentioned was this whole idea of non-hallucinogenic psychedelic analogs. I will say I'm skeptical and there's still a lot of open questions, but it's certainly fascinating and interesting idea that you could have this big, robust plasticity effect and either have a much shorter or smaller or no period of being in a very altered state, which certainly, for some people, that's going to be preferable or more feasible. I think in general, it's actually a good time in psychopharmacology. There was a period where there was really not a lot of innovation. I don't do a lot of schizophrenia research, but I'll use it as an example because, for I don't know, 50 years, we have had the first generation and second generation antipsychotics which were very similar or the same mechanism and just in the last year now we've had the first drug approved for schizophrenia that is a completely different mechanism. This is the xenomaline, the muscarinic antagonist. And that's very exciting and looks like it might really help with some of the areas where there was shortcomings with dopamine antagonist antipsychotics. But it's also just one example and there's been really, partly because we have made such advances in the neuroscience, there's been this kind of blossoming of a lot of new potential treatments. So I think it's a good time overall in sort of innovation in psychiatry. 

DR. THEA GALLAGHER: And I think it's you know getting the attention that it needs, and it will hopefully help a lot of people too, the more we can get closer to precision medicine, which is something we talk a lot about on this podcast. Well, thank you so much for being on our podcast. 

DR. JOSHUA SIEGEL: Thank you very much for having me. It was a pleasure.

DR. THEA GALLAGHER: All right, and thank you to all of our listeners and viewers. And if you liked this episode, please remember to rate and subscribe wherever you watch or view your podcasts. And from all of us here at NYU Langone Health, thank you for listening and watching.