Podcast: Can psychedelic drugs help treat mental illness?

Jim Dryden (host): Hello, and welcome to “Show Me the Science,” conversations about science and health with the people of Washington University School of Medicine in St. Louis, Missouri … the Show-Me State. In this episode, studying psychedelic drugs as potential treatments for mental illness. Washington University psychiatry researchers have begun looking at what happens in the brain when people take the psychedelic drug psilocybin, also known as magic mushrooms. They are among researchers at a few dozen medical centers in the United States who now are looking at the safety and efficacy of psychedelic drugs as therapies. Such drugs were studied as long ago as the 1950s, and some of those studies did suggest that drugs might be useful in treating anxiety, depression, post-traumatic stress disorder, even addiction, but then came the war on drugs, and the research was halted. In a recent lecture, Washington University psychiatrist Dr. Ginger Nicol explained that psychedelics were classified as Schedule 1 drugs, meaning that it was not possible to investigate their potential as therapeutics.

Ginger E. Nicol, MD: Schedule 1 is where these drugs live. That means there is no accepted medical use and high abuse potential. But as we’ve gotten to know these drugs a little bit better, it’s actually not the case that they don’t have medicinal purposes, or that they have high abuse/addiction potential. In fact, some are being studied to treat addictions in certain populations. And so this is really a paradigm shift. And part of what we want to see happen is to pull those drugs out of that Schedule 1 category so that they can actually be accessed for treatment.

Dryden: Dr. Nicol spoke as part of a series of public lectures sponsored by Washington University’s Taylor Family Institute for Innovative Psychiatric Research, where since 2013, scientists have focused on developing new medications and new uses for existing medications in the treatment of psychiatric problems. Another drug that has been studied and eventually was approved for use as a psychiatric treatment is the anesthesia drug ketamine, which makes some people hallucinate but also has shown promise in treating depression. Now, Nicol is one of the few dozen researchers around the country who’s been given permission to study the psychedelic drug psilocybin. She’s been using brain-scanning techniques to look at what happens in the brain when a person takes psilocybin.

Nicol: And these drugs work so quickly that we actually can visualize what’s happening while you’re on the drug. And so this is quite novel in psychiatry. We don’t have agents that work that quickly. But these are going to be important, I think, in the science moving forward because it’s going to allow us to be able to make attributions that we couldn’t attribute to drugs before to these drugs because they work so quickly.

Dryden: Nicol works with Dr. Josh Siegel, another researcher at the Department of Psychiatry. Siegel also spoke at the Taylor Family Institute event and said that although much research still is needed to demonstrate that psychedelic drugs help with problems like depression or anxiety, as well as to figure out exactly how they might be working, he says it’s already clear that they’re doing something pretty substantial in the brain.

Joshua S. Siegel, MD, PhD: The more I think about it, about how psychedelics work and about what they have to offer, the more I think about this metaphor of they’re just disrupting the system very quickly and powerfully. And when I say system, I mean the brain and the patterns of thought and behavior that both are central to the brain and are central to mood disorders. Most treatments kind of slowly nudge the brain in a better direction, but psychedelics are a snowstorm. I think that was the analogy Michael Pollan used actually. And so you have these well-trodden tracks in the snow, and then a blizzard comes along and shakes everything up and allows for new connections, new pathways, and it does that quickly. It’s easy to see how that’s dangerous, but also, it’s easy to see how that is a powerful tool when combined with the right set and setting and approach.

Dryden: Psychedelics can make people hallucinate. They can potentially change the way people see, hear, smell or even feel, at least temporarily. They also seem to have an effect on mood and thinking. Because of those major effects, Siegel and Nicol’s first study involved only people who already had used such drugs at least once in the past, and all were considered to be psychiatrically healthy. They’ll be part of a phase 3 clinical trial of depressed patients next, but in the first study, they simply wanted to look at how the drug was affecting brain networks. Siegel says the Washington University study used a brain-imaging technique called precision functional mapping to compare the functioning of a person’s brain before and after that person got a dose of psilocybin.

Siegel: Two things, I would say two separate things, really: One is, how is psilocybin acutely changing the brain, and then what, if any, persisting changes do we see in brain networks in the weeks after a high dose of psilocybin?

Dryden: It sounds like because you’re able to look at brain mapping in the individual, that the person sort of serves as the control as well. It’s the before and after state. Is that correct?

Siegel: Yeah, that’s exactly right, and that’s part of what’s made this powerful.

Dryden: Siegel and Nicol have been able to compare what’s happening in a single person’s brain before taking psilocybin and compare it to what the brain does afterwards. And they’ve noticed particular changes in a network of brain structures called the default mode network. That term first was used by Washington University scientist Dr. Marcus Raichle more than 20 years ago. It describes what the brain normally does when it’s not really engaged in an active task. In other words, the default mode network is a network of brain structures that becomes active when the brain is considered to be sort of resting. Changes in the default mode network have been linked to a wide number of diseases, including Alzheimer’s disease, depression, post-traumatic stress disorder, bipolar disorder and more. So any treatment that affects that brain network could be doing something pretty major.

Siegel: I can identify the default mode network across our participants and say, “Here’s what’s happening to the default mode network.” In every participant, when they take psilocybin, there is disorganization of the normally highly-structured default mode network.

Nicol: This study was really important for two reasons. First, it’s helping us understand the brain networks better, and it’s this really novel imaging paradigm that hasn’t been used very much, and certainly not with psilocybin. And then it’s also important because we’re imaging people while they’re actively under the influence of the drug. And because the drug acts so quickly with this really high-powered imaging approach, we can see the changes in real time. And that’s really novel. So it’s also helpful for us to use it to refine our precision approaches because of that proximity to the drugs, dose and then the effect.

Dryden: In their first study, Nicol and Siegel did multiple brain scans on each study participant who got the drug. In addition, Nicol or Siegel also stayed with each person taking psilocybin to talk to them and try to make them feel safe while the drug was having its effects. Nicol says some of the people had positive experiences, and a few had so-called bad trips. But she says a bad trip didn’t necessarily mean the drug was having a negative effect in the brain.

Nicol: Helping someone understand a bad trip can sometimes also be part of the transformation. So there are lots of stories of people describing a trip that feels like a recapitulation of their own birth. They’re going through a tunnel. It’s like a death/rebirth experience, and it’s very physical and it can be alarming. But people come out of that experience with a story that they can kind of use to make sense of, “What did I just get through?” Like weathering a storm and coming out the other end still intact. And so the facilitation part of the treatment is us helping people understand their experience. And so a challenging experience is not a bad experience necessarily. It might not feel good, but that’s, I think, a misconception a lot of people have with therapy, is that they always expect it to feel good, and it doesn’t. Sometimes progress isn’t comfortable. In fact, the best change happens outside your comfort zone. And so this is really getting people outside of their comfort zone. And it does require someone who knows how to interpret that to help, I think, really, people to get the full recovery opportunity.

Dryden: If I come see one of you for cognitive-behavior therapy or I take an antidepressant or whatever, I’m probably not going to have what might feel to me like a mystical experience. Maybe I’ll feel better, but this is qualitatively different, is it not?

Nicol: Well, yes. I mean, it’s psilocybin, but I think probably most of the psychedelic drugs or molecules that are being studied, they work really fast. And not only do they work really fast doing the things that we can see happening in the brain, but they work really fast in terms of you experiencing it. And those things kind of are happening in real time together. That is partly where the mystical experience comes from, but it probably also comes from preparation. What do you expect to happen during your session? But guiding people to sort of think about, “What’s important to you? What are the questions that you want to answer? What things do you want to change about your life?” And so those are, I think, the important parts of the experience, are guiding people through it. But it’s happening right away, immediately, which is a lot different than our other treatments. We don’t have anything like this. And so I think helping people understand what it is and also what it isn’t is really important. So having that mystical experience, which we equate with how therapeutic it is, that may or may not be important. We’ve yet to really understand that whole mystical experience. But from the perspective of a person who’s seeking the treatment and looking for what is therapeutic, that’s what most people expect.

Siegel: I guess just to add to that, you said, “Well, psychotherapy is usually slow and gradual.” Because what you’re doing is you’re helping somebody to do two things. One, to have insight into their pattern of this kind of cycle of emotion to thought to behavior, help them have insight into it. And at the same time, help them to figure out more healthy cycles of thought and of emotion and behavior. And then it’s kind of on them to do this incredibly hard work of breaking habits. I can’t emphasize that enough. Breaking habits is incredibly hard. And a lot of what we do as humans is create — the reason we can do so much is because so much of what we do becomes automated and becomes habitual. And that’s a great thing, but it’s also a very difficult thing when those automated processes are causing you pain and suffering. The process of psychotherapy is the slow and difficult shifting of those habits. And to me, at least, the way I think of pharmacotherapy is it’s loosening — because it turns out that all effective antidepressants are actually stimulating plasticity. So all antidepressants do that. And so to me, what that tells us is all antidepressants are making the brain and, in particular, emotion circuits more plastic and adaptable and making it easier to break those habits. Psilocybin just happens to do that very rapidly, so it stimulates plasticity rapidly. And then when it’s combined with the psychotherapy that Ginger was describing with preparation and integration, that not only breaks the circuit rapidly, but kind of helps somebody to make sense of that experience and choose new patterns of behavior and thinking.

Dryden: You do a lot of preparation of the subject before they get — whether it be spending time in the scanner, preparation for what you might feel, some of the things that you might think, because you don’t want to freak them out, right? I’m wondering if this thing is so rapid that sometimes when you’re looking at the scans, you get a little freaked out.

Siegel: No, we can’t see anything other than a picture of a brain. Participants have asked me this, too. They’re like, “Did you see that?” You still look like — your brain still looks like a brain. But after I do enough analysis, I can see the 1% change, which looks like a 1% change in the fMRI signal, but to you, felt like demons and going on a mystical journey, so.

Nicol: I was freaked out before we started because I’m like, “How are we going to do this? No one’s ever done this here before. No one’s ever done anything like this here before. So how do we have a protocol that really makes sure we’re safe, but that we also are getting all the good scientific data that we want.” And sometimes you have to anticipate things you don’t know you’re going to want information on, and so you just collect a whole bunch of stuff. And with this, I think that’s really been true, that we would sit around and think about what we wanted to measure, and I mean, it’s like a candy store. There’s so many questions that still need to be answered. And so many questions that kind of can only be answered in a place like WashU with the type of neuroscience and imaging and collaborations between psychiatry and neurology and brain sciences. It’s just a fantastic place to do this work and a kind of perfect combination of timing and expertise with Josh and his neuroscience background to be able to do this work here. And we were lucky. We got to be the first ones in Missouri. First ones to give a legal dose of psilocybin.

Dryden: You have completed the phase of studying people who were not depressed. I’m assuming that the hope is that there will be another phase where you will be treating people with, I guess, treatment-resistant depression to see if there are not only brain changes but clinical improvements. How soon could something like that begin?

Nicol: We will be part of the phase 3 clinical trial in treatment-resistant depression that will probably be starting up sometime this summer and will be recruiting people with treatment-resistant depression, so meaning that you’ve had trials of at least two antidepressants that didn’t work at a full therapeutic dose. That’s coming down the pipeline and soon, but again, only for treatment-resistant depression. We have lots of ideas for other studies to do, but that’s the next one.

Dryden: Depression is, again, sort of a self-perpetuating disorder, and this is designed to sort of interrupt that. Does it interrupt it forever? Obviously, you need to study these sorts of things, but I mean, would the thought be that one of these psychedelics could potentially change things so that the person doesn’t relapse? Or is that the hope? Do you suspect that, or is that so little known that you can’t even speculate?

Siegel: Yeah, it’s a great question. It’s a question that a lot of people are asking. In part, people are asking because we don’t know how long the benefits of a psychedelic might last for. But it’s not obvious, I don’t think, how confusing and complex of a question it is. Because to me, major depressive disorder is the propensity to fall into this kind of state of what we call a depressive episode, right? But the disorder is not the episode. The disorder is the propensity to fall into the episode, and we don’t have a clear answer as to how long the benefits are going to be and when somebody might need another dose. We don’t even have a clear answer of, can you respond to a dose, and then maybe six months later, get another dose and get as much benefit from it? So a lot of that is unknown. And this is a tangent, it’s not exactly your question, but part of the reason we don’t know that is because it’s also really difficult just to do really well-controlled studies with psychedelics because the whole model of randomized placebo-controlled trial kind of breaks down when you talk about something like a psychedelic and a mystical experience.

Dryden: That model, the randomized controlled trial, I’m wondering because of the imaging methods that you’re using and the potential ability to make the comparison to the person him or herself, if that helps get around it. Then you’d be like, everybody gets treatment, but we can see these changes took place. I mean, because I’m assuming I’m going to know whether or not I got the psychedelic as to whether or not I begin to hallucinate or whatever.

Siegel: Yeah, so the problem is what you state, which is that you’re going to know what you got because of the powerful subjective experience, which is increasingly kind of in the public space of knowledge. And not only does that unblind people, it also compounds selection bias because it tends to be people who are signing up for psychedelic clinical trials are people who have heard about psychedelics as a miracle cure or have some predisposed reason to believe that this might be a potential cure. But then the other part of your question was, well, can we use imaging biomarkers in some way to circumvent that problem or at least get a better handle on what’s placebo and what’s drug effect? And I think the answer is yes. I think drug companies and researchers are still figuring out the optimal way to do that, but it is something that is happening, and I think it is something that is increasing the power of clinical trials in psychiatry, which historically have been very difficult to conduct for a variety of reasons. Now — having biomarkers beyond just asking somebody to subjectively rate what their depression is on a depression scale — that we can actually see if the hypothesized circuits in the brain are responding in the way that we thought they would to the treatment.

Dryden: So far, Siegel and Nicol have seen pretty big responses in the brain. And because of those rapid and big effects and because researchers at other centers have found that psilocybin may rapidly improve symptoms of depression, the upcoming clinical trial will involve patients who have treatment-resistant depression. As we said earlier, between the 1950s and the early 1970s, several research studies had suggested that psychedelics may help with anxiety or depression, addiction or PTSD, but those studies all were halted when psychedelic drugs were classified as Schedule 1 drugs. But that has been changing slowly, and now the therapeutic potential of the drugs is being studied again.

“Show Me the Science” is a production of WashU Medicine Marketing and Communications. The goal of this project is to introduce you to the groundbreaking research, lifesaving, and just plain cool stuff being done by faculty, staff and students at the School of Medicine. If you’ve enjoyed what you’ve heard, please remember to subscribe and tell your friends. Thanks for tuning in. I’m Jim Dryden. Stay safe.