Psychedelics for Treatment-Resistant Disorders

Michael Bogenschutz, MD, explains how psychedelic-assisted treatments may offer new options for patients with severe, treatment-refractory psychiatric conditions. He discusses why standard approaches often fall short for complex cases, how psychedelics like psilocybin and MDMA differ from conventional medications, and what careful screening and clinical structure make these treatments safe and effective.

Drawing on randomized clinical trials and years of clinical experience, Dr. Bogenschutz describes how psychedelic treatments can produce durable symptom improvement in disorders such as alcohol use disorder and trauma-related conditions. He also explores unresolved scientific questions, including whether the psychedelic experience itself is necessary for therapeutic benefit.

Michael Bogenschutz, MD, is Professor of Psychiatry and Director of the Center for Psychedelic Medicine at NYU Langone Health.

▶️ Watch Insights on Psychiatry on YouTube

00:00 A Remarkable Case: Sustained Sobriety After Psilocybin Treatment
00:39 Introducing Dr. Michael Bogenschutz
01:04 Why Psychiatry Is Re-Examining Psychedelics
02:50 Safety, Screening, and Managing the Psychedelic Experience
03:45 Landmark Trial: Psilocybin for Alcohol Use Disorder
06:16 How Psychedelics Work: Neuroplasticity vs. Subjective Experience
08:53 Can Non-Psychedelic Analogs Deliver the Same Benefits?
11:47 MDMA, Fear Reduction, and Emotional Processing
13:44 Who Benefits Most? A Composite of Treatment-Refractory Patients
15:45 The Future of Psychedelic Psychiatry at NYU

This episode is intended for psychiatrists, mental health clinicians, and others interested in complex and treatment-resistant psychiatric conditions.

This discussion is for educational purposes and does not substitute for individual clinical judgment or patient care.

Senior Producer: Jon Earle

Transcript

[00:00:00] MICHAEL BOGENSCHUTZ, MD: Some of our most impressive positive outcomes have been in people who had very high severity symptoms. I'm thinking of one of our alcohol use disorder study patients who had been through really all of the pharmacotherapies, residential treatment, inpatient treatment, multiple detoxifications, and just had not been able to put together any length of sobriety. And after really starting with the first psilocybin session in that study, never had a drink again.

[00:00:39] CHARLES MARMAR, MD: Welcome, I'm Dr. Charlie Marmar, Chair of Psychiatry at NYU. I'm delighted to be speaking this morning with my colleague and friend, Dr. Michael Bogenschutz. Dr. Bogenschutz is Professor of Psychiatry in our department, and he is the Director of the Psychedelic Psychiatry Clinical and Research Program at NYU. Michael, welcome. Good morning. 

[00:01:06] MICHAEL BOGENSCHUTZ, MD: Thank you. Good morning. 

[00:01:07] CHARLES MARMAR, MD: Could you start briefly by saying how do we get to this point where we're all deeply interested again in psychedelics, and then maybe say a little bit about what you think the best use case is for them? What kinds of complicated patients that we have, we struggle to treat, might benefit from psychedelic care?

[00:01:32] MICHAEL BOGENSCHUTZ, MD: Psychedelic drugs have been around for a long time. Some of them are naturally occurring, and some of them were synthesized in the 1950s and sixties. And they've traditionally been thought of primarily as drugs of abuse, primarily because of their strong subjective effects—psychoactive, mind-altering effects.

[00:01:57] And those effects definitely do complicate their potential use as treatments, but they may also have something to do with how these drugs might work. But after several decades of neglect, starting in the first decade of this century, there was gradually some renewed interest in starting to explore, first of all, just to understand what these drugs actually do and what their safety profile is and what the effects are.

[00:02:30] And then also to see what potential they might have as clinical treatments. And this was something that was explored to some extent back in the 1960s, but really went off the rails with the widespread illicit use of psychedelics, which really were causing a lot of problems. And so it really was taken off the table for several decades.

[00:02:56] But what we've seen over the past, going on 20 years now, is a gradual accumulation of data showing that, first of all, it is possible to manage these subjective effects. And as long as you screen patients for serious psychiatric disorders and other risk factors, you can administer high doses of these drugs safely.

[00:03:20] And what's been somewhat more surprising is that for many patients with a variety of disorders, one or two or three treatments with psychedelics such as psilocybin or MDMA can produce long-term changes in their symptoms—reduction in symptoms which can persist for months.

[00:03:52] CHARLES MARMAR, MD: You recently published a very high-profile publication, I think in JAMA Psychiatry, if I remember, on the use of a randomized controlled trial of psilocybin for patients with heavy drinking alcohol use disorder. Tell us about that trial. What were the main findings and what's the implication of this?

[00:04:13] MICHAEL BOGENSCHUTZ, MD: Yeah, so this was a study—first randomized trial that was done with psilocybin as a potential treatment for alcohol use disorder. We randomized 95 patients to psilocybin or control. Participants in both groups received two day-long sessions in which they received the drug in addition to some sort of straightforward psychosocial treatment for alcohol use disorder.

[00:04:42] And then we followed them for eight months after that first administration of study drug. And what we found was that for that entire duration after receiving the treatment, the participants who received psilocybin had much greater reductions in drinking overall. With all the attention and psychosocial treatment, both groups improved, but the drinking overall decreased by about 50 percent in the control group and about 75 percent in the group that received psilocybin.

[00:05:14] So in the last month of treatment, 48 percent of the people who received the control drug were still using; only 24 percent of the people in the psilocybin group were. 

[00:05:26] CHARLES MARMAR, MD: It's remarkable. Congratulations. That's really a landmark study, and I remember the enormous attention that study received. I think our colleagues—we all as psychiatrists practicing with complicated patients, particularly with AUD—often the results are quite heartbreaking in the cases of AUD. People frequently relapse even after rehab treatments and blow up their lives, have terrible family problems, have horrible health problems with liver and pancreatic disease and cardiac disease and other problems, and it can be very tragic outcomes. So this is very hopeful and interesting. You mentioned at the very beginning that part of the renewed interest in psychedelics like psilocybin is to understand what is their mechanism of action?

[00:06:22] And you and I have had the chance to talk this over. You're also a collaborator of mine on my own alcohol studies, for which I'm deeply grateful. And we've talked about two broad ideas. One is that these drugs have powerful molecular neuropharmacological properties. They reset molecular circuits and neural circuits in powerful ways. And the other thing is they lead to an altered state of consciousness, which may open up to some extent access to important psychological experiences and memories. How do you look at those two things? How are they related? And at the end of the day, is the psychedelic experience necessary for the benefits of these drugs?

[00:07:17] MICHAEL BOGENSCHUTZ, MD: Yeah, so you've focused on what's probably the most challenging and scientifically and clinically interesting question about these drugs. And it's complicated, but I think we know a couple of things at this point. We know that the classic psychedelic, like psilocybin, immediately produces a real surge in neuroplasticity and the potential for the brain synapses to be remodeled, new synapses to be formed. And acutely during the subjective effects, there's a global disorganization of brain function. The functional networks that are ordinarily pretty tightly organized and functioning in synchrony become much less tightly organized. There's more crosstalk between regions that usually have less functional connectivity. And so you have this—the term used is, one term is "entropy." It just—there's more randomness in what the brain is doing. And to some extent, when follow-up studies are done a week, a few weeks later, there continues to be some loosening in the overall patterns of brain function. And so both from the level of neuroplasticity and from the functional level, this potential for change and flexibility is thought to be part of what creates the conditions in which people can change their behavior and their symptoms and the way their brain functions in the long run.

[00:08:57] CHARLES MARMAR, MD: So let me ask a question then. There's a lot of interest in biotech startup companies and maybe even in big pharma to develop novel molecules, which are molecular first cousins of psychedelics, have many of the molecular properties you're describing in terms of altering brain connectivity and altering, for example, serotonin signaling and other monoamine signaling, but are not associated with the psychedelic state of mind, the psychoactive state. What are your thoughts about those, and do you think will we move in a direction where we have these drugs and we'll have powerful effects without the subjective effects, or do you think both are necessary for change?

[00:09:49] MICHAEL BOGENSCHUTZ, MD: That's another great question, and finding new compounds that could do the same thing and don't have the complexities of these subjective effects does have a lot of promise and is getting a lot of attention. I will say what I think, which is not what I know, because this is not something that—it's an open question. But what we see with our study participants and what they tell us is that months later, years later, many of them have a very vivid memory of what their experience was and what they learned and how it changed them. And so that's a memory that is something that is actually encoded in the brain. So it's not a spooky phenomenon. It's real, but whether or not it really is driving the change over time is much harder to say.

[00:10:44] CHARLES MARMAR, MD: What are the effects of these drugs on remote memories that people have that they may have conscious access to or may be suppressed or repressed to some extent, so it's difficult for them to access, for example, very painful experiences of childhood abuse, as an example, which people may remember only in a fragmentary way? How do these drugs open the doors to give access to very sensitive, important experiences that people have developmentally, which ordinarily are somewhat inaccessible for them?

[00:11:24] MICHAEL BOGENSCHUTZ, MD: It is very common for memories and emotional material to come up in the course of these sessions, which the participants may not have been aware of or may have been aware of but just had not really been thinking about or recognizing the importance of. And so this may be related to this overall sort of loosening of brain function. In the case of the empathogen or entactogen drugs like MDMA, part of the effect also is that there's a blunting of the arousal response and the sort of fear response to these memories. And so people are able to examine them without pushing them off or trying to avoid them or being overwhelmed by fear or negative emotion.

[00:12:16] CHARLES MARMAR, MD: That's extremely interesting because in my work in trauma, one of the models of recovery from trauma is that if you can allow a person an opportunity to deeply remember, reconsider, and even in some sense re-experience some aspect of their trauma—sexual assault, terrorism, combat experiences, disasters, and others—if they can remember them without the associated feelings of terror, horror, and helplessness that they experienced at the time of the actual trauma, that they laid down a new memory of that event with less negative affect attached to it. Are you saying that these psychedelic drugs could create that kind of opportunity?

[00:13:10] MICHAEL BOGENSCHUTZ, MD: That's an attractive model for what's happening. And it does describe what appears to be happening during some of these sessions and afterwards, because there continues to be—after the experience, which lasts a few hours—there is a period in which these memories remain accessible and that neuroplasticity is present as well— 

[00:13:35] CHARLES MARMAR, MD: And less frightening at the time they're accessible. So open to the memory with less terror associated with it.

[00:13:42] MICHAEL BOGENSCHUTZ, MD: Yes. And with the new memory of being able to experience that memory without that fear. 

[00:13:49] CHARLES MARMAR, MD: Without being overwhelmed. Amazing. In the few moments we have left, protecting individual patient privacy, can you tell me just briefly a kind of composite case description of a person with very difficult, very often treatment-refractory psychiatric problems who has not done well? Let's say that person or that type of patient has not done well with conventional psychotherapies, behavior therapies, and pharmacotherapies that we usually use, who might actually benefit from psychedelic treatment, which would be a radical new opportunity for them.

[00:14:33] MICHAEL BOGENSCHUTZ, MD: I think some of our most really impressive positive outcomes have been in people who had very high severity symptoms and had been refractory to pretty much all of the available treatments. I'm thinking of one of our alcohol use disorder study patients who was in their late twenties but had been through really all of the pharmacotherapies, residential treatment, inpatient treatment, multiple detoxifications, and just had not been able to put together any length of sobriety. And after really starting with the first psilocybin session in that study, never had a drink again. Remarkable. Has been in touch years later, and it's now been ten years.

[00:15:20] CHARLES MARMAR, MD: Amazing. So this person was essentially refractory to all reasonable treatments that were provided—rehab treatments, group, AA, whatever they were, medications, therapies—and multiple failed outcomes, great risk to the patient and their life, and a relatively brief set of several sessions of psilocybin therapy, and they've been sober since.

[00:15:50] MICHAEL BOGENSCHUTZ, MD: Yeah. Yes.

[00:15:51] CHARLES MARMAR, MD: So that's not a specific patient, but a kind of patient that you've seen over time, which is amazing. It's been a real pleasure speaking with you this morning, Michael. We're very fortunate to have Dr. Bogenschutz on our psychiatry faculty at NYU. He is a world leader in clinical trials in the area of psychedelic psychiatry and is pushing the boundaries of what we understand about how psychedelics work, both with regard to the altered state of mind which occurs at the time and with regard to the deep molecular neuropharmacology of psychedelics. So thank you, Michael, and it was really a pleasure having you on our podcast.

[00:16:38] MICHAEL BOGENSCHUTZ, MD: Thanks, Charlie. My pleasure as well.