Psychedelics and the Placebo Effect with Dr. Boris Heifets

Can psychedelics under anesthesia heal trauma? What is the latest research around ketamine, MDMA, and psilocybin? That’s part of what we explore this week on Science of Perception Box. Stanford anesthesiologist Dr. Boris Heifets joins Dr. Heather Berlin and Dr. Christoph Koch to discuss the latest research on the first double-blind study on Ketamine, the placebo effect, and the therapeutic value of anesthesia-induced dreams. Dr. Boris Heifets, MD, PhD, is a board certified anesthesiologist who specializes in providing anesthesia for neurological surgery. He has practiced at Stanford since 2010. After completing residency training at Stanford, Dr. Heifets completed fellowship training in neuroanesthesiology, also at Stanford. In addition to treating patients, Dr. Heifets directs both clinical research and basic neuroscience. His research group studies how new rapid-acting psychiatric therapies like ketamine, MDMA, and psilocybin produce lasting changes in nervous system function, behavior, and therapeutic outcomes. Dr. Heather Berlin is a neuroscientist, clinical psychologist, and Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Christof Koch is Chief Scientist for the Tiny Blue Dot Foundation and the current Meritorious Investigator and former President of the Allen Institute for Brain Science. Join us for new episodes every Thursday. Follow the show on YouTube, Spotify, Apple Podcasts, Amazon Music, or wherever podcasts are found. Love the show? Write us a review on your podcast app, or tell a friend about the show. Visit unlikelycollaborators.com for more information. Episode Chapters: (00:00) - Introduction (01:34) - Exploring Psychedelics and Anesthesiology (02:53) - Dr. Boris Heifetz's Background (04:32) - Understanding Anesthesia and Consciousness (07:56) - The Therapeutic Potential of Psychedelics (10:48) - Challenges in Psychedelic Research (18:00) - Innovative Approaches in Psychedelic Medicine (24:35) - Introduction to the Study and Consent Process (24:50) - Patient Interviews and Priming for Ketamine (25:33) - Surgical Anesthesia and Placebo Effect (26:28) - Unexpected Placebo Findings (26:45) - Implications for Psychedelic Studies (27:32) - Harnessing the Placebo Effect (31:47) - Dream States and Anesthesia (38:22) - Transformative Experiences in Clinical Care (42:53) - Personal Reflections and Gratitude (47:07) - Conclusion and Final Thoughts

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

  What if you could take the drug out of the trip? In other words, recreate a psychedelic-like experience without reference to a psychedelic drug itself?

• 0:12Speaker 01

  Hi, I'm Elizabeth Koch. We all live inside our own personal, private perception box, built by our genes and the physical, social, and cultural environment in which we were born and raised. In this podcast, we explore how although the walls of this mental box are always present, they can expand in states like awe, wonder, and curiosity, or contract in response to anxiety, fear, and anger. I'd like to introduce our esteemed hosts to incredible and distinguished minds. Dr. Heather Berlin, professor of psychiatry and neuroscience at the Icahn School of Medicine

• 0:57Speaker 01

  at Mount Sinai in New York City, and Dr. Kristof Koch, chief scientist for the Tiny Blue Dot Foundation and the current meritorious investigator and former president of the Allen Institute for Brain Science. Welcome to the Science of Perception Box.

• 1:18Heather Berlin?

  Hi, everybody. Welcome to Science of Perception Box. I'm your co-host, Dr. Heather Berlin.

• 1:23Speaker 03

  And I'm your co-host, Dr. Kristof Koch.

• 1:27Heather Berlin?

  So every week, we feature an aspect of the Science of Perception Box, highlighting the latest research together with our expert guests. This week, we're exploring the powerful research around psychedelics and dream states in the practice of anesthesiology with a researcher and doctor who has been as fascinated about consciousness as we are. Dr. Boris Hyfitz is a board-certified anesthesiologist who specializes in providing anesthesia for neurological surgery. He's practiced at Stanford since 2010. In addition to treating patients, Dr. Hyfitz also directs clinical research and basic neuroscience. His research group studies how new, rapid-acting psychiatric therapies like ketamine, MDMA,

• 2:10Heather Berlin?

  and psilocybin produce lasting changes in nervous system function, behavior, and therapeutic outcomes. But first, we want to share our own connection to psychedelics. So Kristof, how have psychedelics helped you expand your perception box?

• 2:29Speaker 03

  They made me lose a sense of self. They made me lose my sense of body of an external world, but there was still consciousness. And they made me lose my fear of death.

• 2:41Heather Berlin?

  Well, that's pretty profound.

• 2:42Speaker 03

  Yeah.

• 2:43Heather Berlin?

  So do you think you're a more relaxed person now?

• 2:46Speaker 03

  Yes, certainly.

• 2:48Heather Berlin?

  You seem very relaxed. Well, Boris, thanks for joining us.

• 2:52Speaker 00

  Thanks for having me.

• 2:54Heather Berlin?

  So how did you become interested in psychedelics as an anesthesiologist?

• 3:01Speaker 00

  So I became interested in psychedelics well before I became an anesthesiologist.

• 3:06Heather Berlin?

  Ah, I see.

• 3:06Speaker 00

  The question is, how did I become interested in anesthesiology as a psychedelics?

• 3:11Heather Berlin?

  Explorer.

• 3:11Speaker 00

  Explorer.

• 3:13Speaker 03

  You mean a psychonaut?

• 3:14Speaker 00

  Well, I've done some research on the topic before becoming a doctor. When I was towards the end of my PhD training, so I did an MD and a PhD at Einstein in New York, I had this question of like, well, how am I going to apply this? What we're doing is we're looking at synaptic responses in brain tissue. We're looking at the inner workings of how circuits function in the brain. And I didn't want to lose that, right? And I wanted to pick a specialty that would allow me the most access to that kind of thinking, that kind of environment. And, you know, not to mention this background interest in psychedelics. I think when I started medical school, my mom told me, drop it.

• 3:58Speaker 00

  Drop it. You can't have a career. You can't have a career studying psychedelics. It's hippie science. You know, this is in 2000, probably good advice. But when it came time to pick a specialty, I was thinking about psychiatry, neurology, neurosurgery and anesthesiology. And the most, the closest I could get to applied neuroscience was actually anesthesiology. You give, you give a drug and you see its effect on the brain, the body, on consciousness itself. And that, to me, it never gets old.

• 4:32Speaker 03

  How do you know their consciousness is gone as compared to they're unable to talk and they're unable to signal that they're still there? How do you know they're not present?

• 4:41Speaker 00

  So we have a lot of interviews with patients after surgery that, you know, can attest to that is that what's kind of remarkable about anesthesia is that it's not like sleep. And when you close your, when you close your eyes as you go off to, as you are anesthetized for surgery, when you open them, many patients will feel that no time has passed. It's very different from when you wake up. You kind of have an intuitive sense of how long you may have slept. So that's already one difference, just at the level of what the patient experience is. One of the earliest concerns for anesthesia, as you know, we were developing anesthetic

• 5:20Speaker 00

  techniques to keep people immobile and pain-free and amnestic, right? During surgery is there's something called the Brice questionnaire. What's the last thing you remember before going to sleep? What's the first thing you remember when you wake up? And did you have any dreams during anesthesia? Do you recall anything? And that's, you know, that's basically how we set standards for what depth of anesthesia we use.

• 5:45Speaker 03

  So how often does it happen that, I guess, depending on the type of anesthesia and the duration, that people do recall something that does relate in some way to something that did happen in the OR?

• 5:57Speaker 00

  So it's around one in a thousand. So awareness under general anesthesia, even with EEG monitors. So, you know, we're monitoring brain function. We're getting a sense of the depth, but we're clearly not getting the whole picture because every once in a while, a patient will recall something. Now, I want to put a qualifier on that before, you know, nobody ever has surgery again after listening to this podcast. I've seen one case like this and in an elderly woman, not who I would have expected. And though the thing she said was, everything was so far away that every, you know, I was like, everyone was touching me really softly, every, but she was recalling conversations in the OR.

• 6:41Speaker 00

  So there's a deep disconnection, but she was able to maintain some sort of input from the real world. So that, again, that's, that's one in a thousand.

• 6:51Speaker 03

  And no pain, right? Because pain is controlled separately.

• 6:53Speaker 00

  She didn't complain of pain. She didn't complain, you know, it was a little bit distressing to her because she kind of, she knew what happened, but she wasn't paralyzed. She didn't, she, the thing that I was most worried about is, did you feel trapped? And, you know, thank God she didn't. And that's again, advances in anesthesia have allowed us to do surgery without paralysis even, in some cases. So again, that's maybe a topic for another, another time, but it's, you know, it's a rare complication that we do worry about. And again, that was the early concern of, of anesthesiologists is that we want to make sure that consciousness is gone, right? Deep disconnection, disconnected unconsciousness that, you know, that's reversible at the end of surgery.

• 7:36Speaker 00

  Now, in the last 20 years, you know, anesthesia has gotten a lot safer. We've started innovating things like nerve blocks, for example. So now we have a little bit more room to think about, you know, how much do I want to sedate this patient? What kind of experience do I want to provide? And that's where things start to get a little bit interesting.

• 7:56Heather Berlin?

  So, so before we get into the research, can you tell us a little bit about how psychedelics work in the brain and how they can be used as a therapeutic intervention?

• 8:09Speaker 00

  Sure. So this is a very hot topic right now. And, you know, when we talk about psychedelics, what do we talk about? There's the classic psychedelics, LSD, psilocybin.

• 8:19Heather Berlin?

  The classics.

• 8:20Speaker 00

  The classics, the greatest hits. And then there are other drugs that are, I would say psychedelic adjacent, that a lot of people will identify psychedelic-like properties in these drugs, drugs like MDMA, which is nearing approval potentially for PTSD, ketamine.

• 8:38Speaker 03

  Assisted therapy.

• 8:40Speaker 00

  Yes. MDMA assisted therapy, which we're going to return to that point, I hope. So, and these drugs are not, you know, they don't have the same perceptual effect, but they clearly are, you know, they are acutely psychoactive in a profound way that is very memorable and unmistakable. And what ties all of these together? And what has led to this explosion of research and excitement is that when you provide a space for people to have a powerful psychoactive drug in a safe setting and just let them, you know, let their mind wander, things come out, things that, you know, if you have PTSD, if you have painful memories, if there are things that you haven't been

• 9:24Speaker 00

  able to resolve in your life, what people talk about is getting a new perspective. You know, whether it be like, what is going on in my body? Why? Where is this pain coming from? Or, you know, who is this person who's, you know, always depressed and, you know, pessimistic? All, you know, this perspective shift is something that people across these drug classes will, will, will, will talk about. And to me, that's what defines this broad class. They're acutely psychoactive, powerfully so. Their effects are rapid, that perspective shift, or however you want to call it, it's rapid.

• 10:01Speaker 03

  Change in a perception box.

• 10:03Speaker 00

  You could put it that way as well. And, and finally, the effects are durable. This is very different from modern mental health care. You don't need to take, you don't take these drugs every day. You have, long after the ketamine or the MDMA or the psilocybin has cleared your bloodstream, you're still feeling those positive effects. This is a sea change in, in how therapy is delivered. And I want to emphasize again, it is far more complex than just giving someone a drug, putting them in a room, you know, while they, you know, have it have their experience.

• 10:39Heather Berlin?

  So it's the synergistic effect between the actual, you know, physical effects of the drug in the brains and this psychological.

• 10:47Speaker 00

  Well, I'm going to challenge, challenge that. I think that's actually one of the biggest debates right now is, and it has implications, is, is it the drug or the trip that's responsible for these therapeutic benefits?

• 11:00Heather Berlin?

  Right, like you get the same benefits without.

• 11:02Speaker 03

  Assuming that conceptually, A and B empirically, experimentally, you can separate those two.

• 11:07Speaker 00

  That's exactly it, right? That's why there's the debate is right. Right now, all we're looking at is correlation.

• 11:12Speaker 03

  And so tell us more about this debate.

• 11:14Speaker 00

  It boils down to this, is you can think of, you know, the complexity of psychotherapy, you can simplify into three basic stages. There's preparation, which involves, you know, setting expectations, building rapport. There's the drug experience itself, possibly eight-hour extravaganza sometimes.

• 11:34Speaker 03

  Twenty-four hours.

• 11:35Speaker 00

  Or forty-eight, it depends, you know, the dose is everything. And then there's the integration, making sense of what happens and trying to incorporate those changes into your life.

• 11:45Speaker 03

  Which can take weeks.

• 11:46Speaker 00

  And in trials, that's how long it takes, is that you have weeks of after-therapy. So, you know, the inclination, you know, based on decades of experience in, you know, pharma, is, well, it's gotta be that little crystalline entity in the middle of all of this that's driving these effects. But in reality, as you pointed out, you cannot possibly attribute to one factor the therapeutic change unless you can independently manipulate them, right? And this is where the science comes in. I'm gonna put in a brief plug for why any of this matters. There are people who, you know, believe, not without cause, that it's enough that it works. Why do we, why get so bent out of shape about how it worked? It's just enough that it does work.

• 12:32Speaker 00

  And I would answer to that is, you know, one thing that anesthesia has brought me in contact with is some of the most advanced medicine on earth. And when I see, you know, one of the most magical moments in residency, and I don't mean to gross you out, but watching a transplanted heart get put into someone's chest, fibrillate, and then convert to sinus rhythm. It's like watching birth, like, or the earth being born, or a total eclipse. It was, it was just awe-inspiring. How did we get from someone living for fifty hours in the sixties after a heart transplant to, you know, eighty percent at five years? This is amazing. It's by understanding the risk and understanding the mechanism.

• 13:15Speaker 03

  Mechanism, I mean, science, this is how science works.

• 13:18Speaker 00

  And so that, to me, is the question. If a therapy is truly potent. By definition, it carries risk, right? And when you think about the early days of chemotherapy, chemotherapy in 1975 was almost a death sentence in itself. Thirty years later, you have the first rationally designed kinase inhibitor. That blew my mind in 1999, Gleevec. That cured leukemia. And, you know, what, again, that's, you take something that has, it's a powerful, chemotherapy, you know, was powerful and crude. And we learned something and innovated and distilled it down to something, something highly effective and targeted.

• 14:01Speaker 00

  I'm not sure that CNS, you know, that psychedelics are going to go that way. But there's a pretty strong track record in every other field of medicine for this approach.

• 14:12Speaker 03

  There are also strong motives in the industry to pursue that. Because that's what the entire medical system is based on. You give one little therapeutic intervention that the FDA proves that you can then, you know, sell to everyone that works. But in this case, because this is the most complex, you're talking to the most complex piece of active matter in the known universe. And I seriously doubt, having studied my entire life, that any one drug will be a magic bullet that cures whatever existential problems that brain or that mind has.

• 14:45Speaker 00

  I'm going to turn that on its head in that I completely agree with you. But how do you, without demonstrating the centrality of like, my, my overall overwhelming sense from all the work I've done is that we need to center the experience.

• 15:02Heather Berlin?

  My biggest question is whether it's the molecule itself or you need the psychological experience. And can you isolate the psychological experience? So they don't have to even take the drug? Are there other ways to get to that transformative experience?

• 15:14Speaker 00

  Yeah, that's what we're trying to develop is that psychedelics pose really fundamental challenges for randomized controlled trials. Let's start with that for a second.

• 15:24Heather Berlin?

  Right, because you don't, you know, you're on the drug once you're on it.

• 15:27Speaker 03

  And so why would that be a complication?

• 15:29Speaker 00

  So it introduces all kinds of biases in that, you know, the Randomized placebo controlled trial was designed for antibiotics and blood pressure medication.

• 15:39Heather Berlin?

  But the power of not knowing whether you're on the drug or not is really to get around the placebo effect thing is if there's a certain amount of impact that the that the drug can have, just thinking you've taken the drug, that can have an effect.

• 15:52Speaker 03

  But probably not for TD, that's the logic behind it.

• 15:55Speaker 00

  Yeah, there's some things where placebo effect, you know, we should be so lucky to have a cancer placebo effect, right?

• 16:01Heather Berlin?

  Right.

• 16:01Speaker 00

  You know, people don't spontaneously, often do not often spontaneously remit, you know, just on the strength of their belief. Although, you know, there are all kinds of stories. But it's important because, you know, think about it from a patient's point of view. You have read Michael Pollan's book. You are fascinated at the potential of psilocybin. You have outcompeted a thousand other applicants to be in the study on depression. You have already won a lottery, right? Now you go into the finale.

• 16:30Speaker 03

  And you've already done two failed two other trials.

• 16:33Speaker 00

  You've already failed two other trials and like, I think this is gonna be it. And so you have an expectation. It's, you know, it's obvious that if I'm, if I get the drug, I'm likely to improve. Because look at what all of these smart people say. And now comes the moment, the moment of truth. You're in, you know, your boyfriend, your girlfriend drives you, you know, maybe you fight about it because you've been so kind of persistent in your, in your pursuit. You go through a lot of trouble to get to that room, to that therapist's room. And then you take the drug and an hour later, there's either a moment of confirmation and acceptance and being seen and being in an elite group of people on earth

• 17:13Speaker 00

  who've been in a psilocybin trial, or a moment of betrayal, where why did I spend all of this effort to be in the placebo group?

• 17:21Speaker 03

  Because nothing happens to your mind.

• 17:21Speaker 00

  Because it's obvious, it's to most, I mean, it's such an obvious psychoactive effect. So, you know, if you just, it's like, it's like winning the lottery. What is the effect of winning the lottery? And you tell me, does that, what does that have to do with depression? Like, I guess like winning the lottery could be a short term antidepressant, but that's, that's sort of the heart of it.

• 17:40Speaker 03

  And so because they've been told and they read that these are wonderful drugs, they were less likely to be depressed afterwards. That's what you're saying, that's what the placebo factor is.

• 17:49Speaker 00

  Exactly.

• 17:50Heather Berlin?

  But because they know if they're on the placebo or not with psychedelics, it's very hard to control for that. So do you have a way that you're trying to get around this?

• 18:00Speaker 00

  So again, if that's one of the biggest problems facing psychedelic medicine is identifying a drug-specific effect, it requires some innovative solutions. And I want to talk about a couple. One is efforts by David Olson and Brian Roth, you know, two great chemists and many others who are re-engineering the molecule itself. They're basically trying to take the trip out of the drug.

• 18:26Heather Berlin?

  Kristoff's thinking, that's no fun. Where's the fun in that?

• 18:29Speaker 03

  They want to take the fun out of everything.

• 18:31Speaker 00

  This is the science. That's the, that to me, it's crucial, right? Like you have to test. How can you not?

• 18:37Speaker 03

  Assuming you can do that.

• 18:38Speaker 00

  Let's just say for a minute it's possible. You, you will get some answer there is can you just encode resilience, you know, through biochemically without anybody noticing, right?

• 18:48Heather Berlin?

  What about giving the psychedelic while somebody's under anesthesia? And they have no experience.

• 18:52Speaker 00

  Well, Heather, that happens to be what we did. I'm so glad you asked. So it requires a lot of different approaches. And this is the one we took. Now, I'm an anesthesiologist and one, you know, it's hard to escape the idea that, you know, you have all these people that come in from all walks of life, many with pre-existing depression, PTSD. That's usually not what we're focused on. We're usually focused on getting them through surgery. And we, you know, we saw this as an opportunity is that patients are put on, you know, they're, they're put under general anesthesia. And while they're anesthetized, like there's, you know, there's no there there. They're not there for it, right? That's kind of the goal. So what if we gave a psychedelic class drug like ketamine during anesthesia?

• 19:36Speaker 00

  So it's important to know that this is on a background of general anesthesia with not, not using ketamine as an anesthetic. We're using drugs like propofol, drugs like sevoflurane. These are standard anesthetic cocktails. And we're getting everyone to a pretty even cruising depth of anesthesia before we give them either ketamine or placebo.

• 19:57Speaker 03

  So they're deep. So if you do surgical, cut it on?

• 19:59Speaker 00

  That's the goal. They are there for surgery. Now, part of how we were easily able to get approval for this is that ketamine is an anesthetic. It's an anesthetic adjunct. So we were, you know, in patients for whom there's what we would call equipoise about, you know, ketamine is kind of give it, you don't need to give it. It's there's nothing in the case that screams out, this patient should definitely get ketamine. We were able to do this trial and we ran it like a psychiatry trial. And this is with actual psychiatrists like Laura Hack and Alan Chasberg, who helped quite a bit on the study. But we ran a psychiatry trial in the operating room. They give half a milligram per kilogram over 40 minutes to minimize the psychoactive effects.

• 20:39Speaker 03

  But in a regular awake person, there would be strong psychoactive effects with this dose, right?

• 20:44Speaker 00

  Yes, and that's what we've seen. We've done other, worked on a trial with Nolan Williams, where we're giving ketamine to awake patients.

• 20:51Speaker 03

  At this dose?

• 20:52Speaker 00

  At this dose. And patients will, they'll have what's called, you know, they'll dissociate. They'll get into a dreamy state, you know, they might, they might hallucinate. They, if you listen to what they say, it's, there is a lot of overlap with psychedelic like effects. And let's put that on pause for a minute. But that's, that's the trip of ketamine that we're actually trying to see. Like, do you need that in order to benefit from ketamine?

• 21:17Heather Berlin?

  So now you give them this dose, which normally in an awake full person, they would have a sort of psychedelic effect. But they're under anesthesia and you have it placebo controlled, meaning you're going to give them another substance that's not ketamine? You just give them no ketamine?

• 21:30Speaker 00

  We just give them normal saline.

• 21:32Heather Berlin?

  Okay.

• 21:32Speaker 00

  If that's, you know, a fluid with the same volume. And I guarantee you, the patients were not aware. Everyone was blinded in the study.

• 21:40Heather Berlin?

  So they wake up and what's the measurement? What do you assess?

• 21:43Speaker 00

  So again, we want to copy what's been done before. We're not reinventing anything. We're using a standard scale of depression called the Montgomery Asperg Depression Rating Scale. It's a clinician rated scale, meaning I, if let's say you're my patient, I'll ask you questions about, you know, tell me about your fatigue levels or, you know, how's your appetite? And there's kind of standard degrees of.

• 22:04Heather Berlin?

  Of severity, but you're expecting there to be an effect right away, right after the surgery?

• 22:08Speaker 00

  That's the beauty of ketamine.

• 22:10Heather Berlin?

  Give a patient and maybe six weeks later, they say you'll feel something maybe. And it's very hard to like make the connection between the drug and the impact. But with ketamine, they give it in the psych ER and it really can knock out suicidality.

• 22:21Speaker 00

  And there's nuance to everything, but essentially, yes. That's, that's the, the, the design of this therapy is that it's rapid acting antidepressant.

• 22:30Heather Berlin?

  So you give them this measure of depression right when they come out of surgery. You don't know who's had it and who hasn't.

• 22:34Speaker 00

  We waited a day. There's a lot of things that happen right after surgery. And again, we're copying other studies where you have the, the peak effect, the peak antidepressant effect of ketamine is one to three days after infusion, long after the drug is gone. Which is, you know, where we started this description. And, and that's where we're taking our primary measure is looking at depression scores in the one to three days post infusion, post surgery.

• 22:59Heather Berlin?

  And what you found was?

• 23:00Speaker 00

  Well, all of the patients who got ketamine did great. They, you know, 50% response, 30% remission from patients, many of whom had treatment resistant depression.

• 23:10Speaker 03

  So what about the other patients?

• 23:12Speaker 00

  Well, so the placebo group also did great. 50% response, 30% remission.

• 23:18Speaker 03

  So it's remarkable. So you're saying whether or not they got the ketamine, both?

• 23:23Speaker 00

  Both groups on average showed the same degree of improvement. They, you could not separate them. The key here is that both were massive, massive improvements. And there's a couple of fine points here because I got a lot of, you know, wasn't exactly fan mail about the study, but people who looked at the study say, are you saying ketamine doesn't work? And there are a couple of points to bring out about this. And the, the first point is what was the patient experience like? And this, you'll see how this is important in a minute, I think. And again, keep in mind this very large placebo effect that we saw that we were absolutely not expecting. From a patient, let's say you're coming in for surgery. For 20 years, you've been dealing with a lot of trauma, the holdovers from a rough childhood, et cetera.

• 24:08Speaker 00

  And now you're, you know, you go see your surgeon and do you think your surgeon is going to ask you about your mood? We can venture a guess to say usually not. It's the rare surgery that has time because the priorities, there are other priorities. So from your point of view, you're getting something in your email saying, we care about your mental health and recovery after surgery. You know, would you be willing to fill out the survey and talk to us? That's our first contact with the patient a few weeks before surgery. And then you, you come in, you get a consent. It's about an hour long where you hear all about the study. Ketamine, we think it's, it's an antidepressant. In other circumstances, we're wondering whether this has therapeutic value during surgery.

• 24:50Speaker 00

  Now you come in for a two hour interview with, you know, four of us, a nurse, myself, a research coordinator.

• 24:56Speaker 03

  Two hours interview, just as part of the work of this study.

• 24:58Speaker 00

  Yeah, this, we want to know everything, you know, and from a patient's.

• 25:01Heather Berlin?

  So you're sort of priming, first of all, they're getting more attention. You're talking about their mood, you're giving, and you're priming them to this drug might really help your depression.

• 25:10Speaker 00

  Exactly. And there have been studies of depression during surgery before, and I don't think they went out all out like this. We were looking for a particular type of patient. I was so happy to get each one of them, each of these 40, that, you know, we really, we, we learned a lot about all of them. And so two hours where, you know, we heard about their trauma, their mental health history, their physical, you know, their, the physical history. And then, you know, the morning of surgery, I, again, I wanted to make sure things go off without a hitch. In many cases, I held their hands as they went off to sleep. Right? I mean, the, I, these patients were precious to me and I was not at all thinking at the time, my God, what kind of placebo effect I'm engendering. And let me stop there for a second.

• 25:51Speaker 00

  Why was I so blithely unaware of the possibility that we might induce this massive placebo effect? It's because, think the broader context is surgical anesthesia. Surgery and anesthesia are associated with a higher risk of heart attack, stroke, cognitive dysfunction, kidney injury, lung injury. Actually, all of our literature points to all these things getting worse after surgery.

• 26:17Heather Berlin?

  Nice.

• 26:17Speaker 00

  That, and, and putting people at risk for opioid use disorder. So that's what I came in with, all right? I, I was not thinking that placebo would be a problem or that the study would even be about placebo.

• 26:28Speaker 03

  The placebo was really a surprise to you.

• 26:30Speaker 00

  It was a big surprise.

• 26:31Heather Berlin?

  Well, this is my question. I mean, what is the takeaway here? Is the takeaway that? For the effects of ketamine, you don't need the psychedelic effect of ketamine for there to be an improvement.

• 26:42Speaker 00

  The takeaway is this, it's in the placebo effect. We can't, we can't say much about ketamine in this trial, but what I think we can say something about is all of the trials going on in the psychedelic space. Again, I painted that picture for you of winning the clinical trial lottery, right, and going through that process and all the confirmation bias that might go along with it. There are a lot of non-drug factors there. So inadvertently, just the structure of this trial with preparation, a big central event, surgery and anesthesia, and then, you know, close follow-up in the aftermath. We had, you know, we had replicated a lot of the key elements of most psychedelic studies and driven a placebo effect that is enormous.

• 27:26Heather Berlin?

  Well, in some ways, this is really good news. I mean, first of all, well, where is this published, this paper?

• 27:30Speaker 00

  Uh, Nature Mental Health.

• 27:32Heather Berlin?

  Okay, so I think everyone should take a look at the paper, but it's a warning to say, look, we really need to structure these psychedelic studies in a different way. However, it's really positive to say that, like, for instance.

• 27:43Speaker 03

  Your mind can change your body.

• 27:45Heather Berlin?

  Yes, so we don't need the drugs.

• 27:49Speaker 00

  We need something. These patients went through something, and I think that's a key part of this.

• 27:53Heather Berlin?

  An experience, though, it was an experience.

• 27:55Speaker 03

  Yeah, but they need this belief. If they don't have this belief, so you have to tell them that this thing is magical, whether it's a ceremony, or a dance, or a beauty, or a molecule.

• 28:05Speaker 00

  You need good placebo. We had really good placebo, we had the best placebo.

• 28:10Speaker 03

  Tell me, what about the, does the belief that the patient, because you must have asked the patient, did you think you got it? Or did you think you were in the placebo? And how does that affect?

• 28:18Speaker 00

  So, you know, as I said, we weren't expecting this massive placebo effect. So, and this was in, you know, we started the study in 2019, when before a lot of the writing about expectancy had come up. So we didn't ask people until the very end of the study, which group did you think you were in? I will say, this is like one of the only, maybe the only truly blinded study of a psychedelic class drug, so that was a small victory. Um, but when we asked them what they thought, they got it. So nobody knew, first of all, but what in talking to them, they're, you know, in my conversations with these patients, if they got better, they attribute it to the ketamine. They said, well, I must have been in the ketamine group because I feel better,

• 28:57Speaker 00

  which suggests that they had some prior belief, right? They, if you wouldn't say that you got ketamine unless you believe that ketamine.

• 29:05Speaker 03

  But surely there must have been some people who believe, or maybe not, who believe they were on the placebo.

• 29:10Speaker 00

  And those are the, yeah, because they didn't get better. They didn't get better. And they're like, well, I must have been in the placebo group. So what that shows, if anything, is that we did a job unwittingly or not, a good job of instilling a sense of hope, that this is, this has a potential for therapeutic benefit.

• 29:26Speaker 03

  And I think that's how you conclude in the last paragraph of the paper. This is called conventionally, the shop name of this is hope.

• 29:33Speaker 00

  Yes. So there is a dangerous side to it, not dangerous, but we can draw some of the wrong conclusions from this work. One is that, you know, the convention, placebo is an old, an old word and, you know, it literally means like, I please.

• 29:46Speaker 03

  To please.

• 29:47Speaker 00

  Right? So one of the kind of awkward things is if someone gets better after getting placebo and then you tell them they got placebo, it's more than a little awkward. They're like, well, all that stuff I said, well, in the throes of placebo, like, was that all, like, it wasn't real. Right? And so it's very, you know, it's, people need to feel seen, need to feel heard. And, you know, that, that idea that placebo is just something that you trick children with, right? We have to dispense with that idea.

• 30:16Heather Berlin?

  I think we need to harness the placebo. I've always said this, harness the placebo effect and use it in medicine.

• 30:21Speaker 03

  Yes.

• 30:21Heather Berlin?

  Exploit the placebo effect.

• 30:23Speaker 00

  Good doctors do it and real and psychedelic therapy.

• 30:25Speaker 03

  That's why you have white coats. That's why you have Dr. Boris Heisenfeld. Well, because if I believe you just like a shaman, if I believe you are the shaman, then I'm more likely.

• 30:36Speaker 00

  That's, that has to be part of it. And there has to be a strong experience at the center. I had a bar mitzvah when I was 13. My father said, today, my son, you're a man. And I could tell you, my voice did not drop, but I felt different. People looked at me differently, treated me differently. And that's right. I mean, and how does that happen? It's not a person in isolation. It's certainly not a drug effect. It's a door that you walk through that is held up by, you know, the collective understanding of the community that surrounds it. And that is a very devilishly hard thing to study with, you know, conventional scientific methods.

• 31:12Heather Berlin?

  A lot of it is the power of suggestion. Right? If they come in and they're depressed and, you know, or they're low, I'm never going to meet anybody, I'm never going to find anyone. You give them the sort of hope and they believe you because you have all these credentials and stuff. Like rather than me just giving my friends, you know, some good advice and, you know, they take your, I really feel like you're going to meet someone. I really have, you know, I trust that that's. And then they start to believe it because someone in a sort of authority position gives them that hope. It's not about the SSRI they're taking, but in, but studies do show in conjunction, you know, you get some powerful effects from the SSRI, some from therapy. When they work together, you get this synergistic effect. But I want to just talk about, because I know there's other research you do in terms of dreams

• 31:54Heather Berlin?

  and, and sort of inducing dream like states with anesthesia that I really want to.

• 31:59Speaker 00

  So going, going with this theme of experience, you know, in this study that we're just, you know, wrapping up, the experience, they all went through something. It's not the experience on drug, but it's the larger experience of being in the study and going, going through a door, right? Having, uh, having surgery and coming through the other side.

• 32:17Speaker 03

  And so any therapy afterwards?

• 32:19Speaker 00

  No, that's we, like every other ketamine study, including no therapy.

• 32:24Speaker 03

  And how long did you, how long did you?

• 32:27Speaker 00

  Two weeks.

• 32:28Speaker 03

  And so you didn't track the, are these people still?

• 32:31Speaker 00

  Not, not formally. I mean, I kept up with some of them and some of the stories, you know, I'd love to share some of them. It really made me question whether I should be in science or not when I couldn't tell like, is this woman in the ketamine group? Because how do you get that kind of transformation without something to account for it? Of course she's in the placebo group. So there's another way to, to look at this and, you know, we've, coming back to this theme of, you know, preparation and the drug, you know, the day of the dosing, the drug and the trip, and then integration and really focusing on the drug and the trip. Which you can either take the trip out of the drug, and we've now talked about a couple of ways to do that. What if you could take the drug out of the trip?

• 33:14Speaker 00

  In other words, recreate a psychedelic-like experience without reference to a psychedelic drug itself? That would be a pretty interesting way to test this idea of how special is the serotonin to a receptor, right? And there's a, just some very exciting research.

• 33:32Heather Berlin?

  But now we're talking about how do you create

• 33:34Speaker 00

  Well, how do you regenerate?

• 33:35Heather Berlin?

  Hallucinations without the psychedelics.

• 33:38Speaker 00

  So wouldn't it be an interesting test if like, we could induce a psychedelic-like state without a psychedelic and get some of the same physiology, descriptions of experience, and therapeutic effects? Would that maybe turn on its head the idea that there is a, you know, a powder at the center of all of these therapeutic effects? And that's almost by accident what we've, what we've stumbled upon, working with anesthesia in dreams. And I have a colleague, Harrison Chow. He's a, I was gonna say an artist. He's an anesthesiologist, but he is, you know, this is the art of medicine. He spent many years in private practice. You know, minor procedures. Patients would come in for, you know, hernias or, you know, endoscopies, minor, minor stuff. And he would, you know, he would try and make

• 34:23Speaker 00

  the experience as pleasant as possible. So he, and he would do, do this thing where he would watch the EEG monitor and look for what he thought was dreaming. And then patients would wake up and say, I had the best dream. I had the best sleep I've ever had. But as you emerge, you know, one of the things that you can notice if you really pay close attention to the EEG, right, this is brain state monitoring.

• 34:45Heather Berlin?

  So you're watching them as they calm out of anesthesia and the wave starts speeding up and they're getting higher frequency.

• 34:52Speaker 00

  Yep. So when he came to Stanford, you know, my chair put him together with me because he knew I was like a psychonaut drug nerd into non-ordinary states of consciousness. And if you should talk to each other and like, maybe figure something out. It was a great, great partnership. Harrison is really like into the idea of making anesthesia more pleasant. I'm, you know, a little bit more a scientist. I was very skeptical at first. So we agreed we're going to get a portable EEG, a sideline, the same, you know, a kind of couple leads. We have a team, you know, includes a psychiatrist. We are going to do, you know, interviews, diagnostic interviews, and we're going to follow these patients. I want to know is what you're saying, are you bullshitting me or is it's real?

• 35:36Speaker 00

  Is there something there? And not long after we had our first, our first case. And this is a case of a woman that's published 2022 where this woman, she, she had been attacked at close quarters by a relative with a knife. Horrifying. As you might imagine, she had nightmares, right? She went to the emergency room and they said, go to Stanford, get your hand fixed. And, you know, in the intervening time.

• 36:03Speaker 03

  The hand got injured.

• 36:04Speaker 00

  Yeah.

• 36:04Speaker 03

  Defending herself. So the surgery was to.

• 36:07Speaker 00

  Was. Yeah, the surgery, the surgery was for her hand. And she, you know, in the intervening two weeks, she's basically a non-functional human, right? She is hyper visual and she is, you know, having difficulty.

• 36:21Speaker 03

  She is severe.

• 36:21Speaker 00

  So due to the timeframe, we call it acute stress disorder. But this is somebody who would bear more likely than not, we would be worried she would go on to develop PTSD. So she's in the pre-op area, right? She's just, she's here, there for her hands. You know, and Harrison finds her again, still, you know, that's all she can talk about. And then she's really, you know, hard to reach. And they, again, talking about like innovations in anesthesia, they put her arm to sleep. She gets a nerve block and Harrison does a dream thing.

• 36:51Speaker 03

  Wait, so is her arm anesthetized?

• 36:53Speaker 00

  Yeah, her arm is anesthetized. So she doesn't need to be so deeply anesthetized that she can't feel.

• 37:00Heather Berlin?

  When you say the dream thing, it's just that you're controlling the amount of propofol.

• 37:04Speaker 00

  And watching.

• 37:05Heather Berlin?

  And watching the EEG and getting her into the sort of sweet spot where he knows that the dreams occur.

• 37:10Speaker 00

  Yeah.

• 37:10Speaker 03

  How long is this state of dreaming in this patient?

• 37:13Speaker 00

  About 10 minutes.

• 37:14Speaker 03

  Oh, very brief.

• 37:15Speaker 00

  Relatively brief, but there's a lifetime in 10 minutes.

• 37:18Heather Berlin?

  Yeah.

• 37:19Speaker 00

  So what she, you know, what she says immediately upon waking is the nightmare, it was, it was there again. I had the nightmare again, and it was looping just like it always does. But instead of rocketing her into consciousness, right? Which is what a nightmare is. Um, by virtue of this anesthetic suppression, she stays in that state and she actually, in her dream, moves past the attack. She, in her dream, goes to the emergency room, goes to the operating room. She is back home running errands with her hand healed.

• 37:50Speaker 03

  All in this 10 minutes.

• 37:50Speaker 00

  All in 10 minutes, a lifetime in 10 minutes.

• 37:52Heather Berlin?

  Just to go back for a second, just because in terms of therapy, you know, often like I'm working with traumatic, with patients who've had trauma. And the idea is to help them, you know, work through the emotions is to sit with the thing that makes them anxious or uncomfortable long enough. Yeah, exposure, long enough to get through it and resolve it and then move on. But often when people, as soon as they get, you know, the cortisol comes or whatever, they, they want to avoid it. And they never get through that. So maybe that being in this dream state allowed her to get past the anxiety part of it enough so that her brain was able to kind of process it.

• 38:23Speaker 00

  We're thinking along similar lines. And so first of all, we followed her for a day, a week, a month, a year. And what is still remarkable to me is she's able to just talk about this attack. No nightmares, like, you know, she's basically, she's, she's functional. She's a functional person who has recovered from trauma.

• 38:39Speaker 03

  You're saying due to a 10 minute dream?

• 38:42Speaker 00

  Well, we've done it now about 600 times.

• 38:45Heather Berlin?

  And?

• 38:45Speaker 00

  Patients. So we've, we've, we've been, this is clinical care. This is gentle clinical care. But now we've added, you know, an observational study on top of this, just seeing what happens when we do this at, at scale. And, you know, the technique isn't perfect. We have, you know, somewhere between 60 and 85% hit rate for getting patients to have these vivid dreams. And I can tell you, you know, the things that patients say upon awakening, you know, this was more real than real. I expected to be somewhere else. Patients are having a very powerful experience.

• 39:17Heather Berlin?

  It's more than just regular dreaming. And do you find that they're less anxious after or less?

• 39:22Speaker 00

  Well, so what we actually, the, the real clinch- Or what was so surprising is, you know, just by chance, two patients that came through Stanford operating rooms had bona fide PTSD. In both cases, coincidentally, it was the loss of a child, an adult's, an adult child, either due to drug overdose or suicide. You know, again, a horrible thing to live with for years. And, you know, as you can imagine, nightmares about trying to save your child, like, it's really, we didn't know this before they went to sleep. This all came up in the immediate aftermath, where putting them into these states for 10 to 15 minutes, they emerge, one of our patients, Mare, and she's, there's a

• 40:07Speaker 00

  story on the Stanford Med School blog now detailing her experience. She dreamt, you know, she, she re-experienced the birth of her son. Instead of being a traumatic birth, it was, it was joyful. She was reunited with her, with her son and with her family and they were in, and listening, we have a video also on our, my lab website. It's, it's, it still gives me chills, actually, to even listen to, that she says, "Thank you for, for this, you know, being able to have that experience." And, you know, Mare, you know, and Edie and the patients who tell us these things have invigorated, you know, a small army of people in the operating rooms who are now, like, trying, you know, they want to do this.

• 40:51Heather Berlin?

  But then it's transformative. After the fact, then they're less upset about these traumatic events.

• 40:55Speaker 00

  She's had nightmares her entire life, and especially after this, you know, this traumatic event. And now, you know, what she's telling us, a year later, is that she has not had nightmares.

• 41:04Heather Berlin?

  So what, I mean, what this tells me is that, you know, however you get to these transformative experiences, whether it's you take MDMA, and that allows you to sit with the trauma and work through it and process it, you in this sort of drug-induced dream state that allows you to sit with the trauma and process it, or the psychedelic experiences, and even these intense placebo experiences, there is something about the psychological effect of sitting with the anxiety, working through it, and however you can, psychedelics are a way to get But they're not the only way.

• 41:36Speaker 03

  This woman, it sounds wonderful, but it's just one of the three. You said there's several hundred. Or is most patients?

• 41:43Speaker 00

  So most patients, so again, this is, we're doing this in the, on the background of providing clinical care. So these patients-

• 41:50Speaker 03

  They all come in again for other types of surgery.

• 41:52Speaker 00

  Yeah, they're coming in for, you know, thyroid surgeries, you know, plastic surgery, you know.

• 41:55Speaker 03

  But they now always get propofol.

• 41:58Speaker 00

  So they get, and it's a cocktail, but the, the goal is always the same is during emergence, we are targeting a state, right? Whether we see, we've had patients report this with sevoforine, with propofol, with propofol and remifentanil. This, again, this hits at the point, it's not the drug.

• 42:15Heather Berlin?

  It's not the drug itself. So that being said, though, what, in terms of what we're starting to learn from the science and from these experiments, is that it's not necessarily the chemical molecule itself that's having the impact on transforming these patients or people who have anxiety and mood disorders. It's the psychological experience that seems to be the most impactful therapeutic here.

• 42:38Speaker 00

  And, and trying to understand what are the bounds, like, how do we define that? Like, what are the characteristics that need to be present in order for it to be transformative?

• 42:53Heather Berlin?

  At the end of every episode, we ask a Perception Box question. And our question today is, what aspect of yourself are you now grateful for that in the past you struggled with or hated?

• 43:07Speaker 03

  I can, I can give, I can speak up. I, I used to stutter as a little child and I, I went to logotherapy for like six weeks and I, I was, you know, I, I just couldn't, particularly when people were looking at me, like in this scenario. But then I sort of challenged myself and did this on purpose to, to, to get into a situation where I needed to control my, my language. And I don't know, because it was when I was nine and 10 and 11. I did the sort of mindfulness training, et cetera. Then I managed to over, to overcome that and, and use that as a way to learn how to give talks and how to convince people. So I think that this has turned to benefit.

• 43:49Heather Berlin?

  I might even overcompensated.

• 43:55Speaker 03

  Injust.

• 43:57Speaker 00

  So what, one of the things, you know, I have younger brothers, 10 years younger, but so for 10 years I was an only child and I developed, you know, tend to, I was very, you know, in, in my own world and for many years, um, I would kind of hold ideas and I would not, I didn't want to share them until they were perfect and they would marinate and stew and one day, you know, during my PhD, something clicked, something clicked being in, in, in a lab and my mentor, Pablo Castillo, really nailed this for me, um, in, in the arguing, the, the joy of, you know, exposing yourself and your ideas. It takes a certain amount of courage or a jump.

• 44:38Speaker 00

  It's, you know, these are things like my, my ideas, my dreams, like, these are things that are really deeply special to me that, you know, I want to hold on to and I want to kind of protect. But what I found very quickly is that by exposing them and talking, you know, and really just tearing them apart in a way, they be, you know, they, some of them didn't survive. But, you know, we, we have the saying in my lab now that, you know, if an idea can survive this room, my office, and after talking about it for three hours, there might be something there.

• 45:09Heather Berlin?

  That's the power of, of discourse, which I think we're losing now. A lot of people are, you know, trigger warnings and safe spaces and whatever, but to actually be able to have, you know, arguments and discourse.

• 45:19Speaker 03

  So it's deeply enjoyable. I engage in this community of people.

• 45:23Speaker 00

  Yeah, absolutely.

• 45:24Heather Berlin?

  And it shifts your perspective and your ideas. So, so my, I think, I don't know if it's, it's more superficial or not, but the first thing that came to my mind is, you know, I used to, um, you know, being an academic and, and, um, being a woman, I, a lot of the time, and this was like, you know, in the nineties and the early 2000s, just wasn't taken seriously. If I was too feminine, like, wearing makeup, dress, whatever. So I used to like, Dislike my femininity and dress down and not wear makeup and wear baggy clothes and whatever, to be taken seriously at places like Oxford and Harvard and all the... And there was this unconscious bias and stereotype. And if I would walk in to give like a lecture or keynote, immediately expectations were

• 46:08Heather Berlin?

  lower if I was more, let's say feminized. And so I really tried to like hide that aspect of myself. And then I, as the time went on and I got more confident and like, you know, I know what I know and I know the science and I had confidence, I didn't have to like pretend anymore that I wasn't feminine and I could wear makeup and dress the way I want to, whatever, and still be taken seriously and actually take advantage of those lower expectations. Because if I come in like, oh, you're the keynote. And then they have lower... Rather, if someone like Kristoff comes up with a German accent, whatever, they're expecting him to say something very intelligent.

• 46:42Speaker 03

  He doesn't.

• 46:43Heather Berlin?

  And then he doesn't, and it's a big disappointment. Whereas I have this great advantage where I, they have lower expectations and then I can, you know, show what I know. So I'm very grateful now for that, but that was a part of myself that I used to kind of try to downplay. And so, yeah, that's mine. It's a bit superficial, but I think still meaningful. That runs pretty deep.

• 47:06Speaker 03

  Yeah.

• 47:07Heather Berlin?

  Well, I want to thank you, Boris, for being here with us today.

• 47:11Speaker 03

  Thank you very much for being with us.

• 47:12Heather Berlin?

  Thank you. Thanks for having me. This was a lot of fun. Fascinating conversation. So if you'd like to learn more about your own Perception Box, spend some time this week answering the same Perception Box questions that we asked our guests, and check out other questions on the website at unlikelycollaborators.com. You could also subscribe to our YouTube channel and watch the show or listen wherever you get your podcasts. This has been Science of Perception Box, created by Unlikely Collaborators in partnership with Podpeople. I'm Dr. Heather Berlin.

• 47:43Speaker 03

  And I'm Dr. Kristoff Koch. Thank you very much. [music]