← Science of Perception Box
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- [00:00]
Dr. Boris Heifetz
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.
- [00:12]
Elizabeth Koch
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, two incredible and distinguished minds. Dr. Heather Berlin, professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai, New York City. And Dr. Christoph 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. Hi everybody. Welcome to Science of Perception Box. I'm your co host, Dr. Heather Burlev.
- [01:24]
Dr. Christoph Koch
And I'm your co host, Dr. Christoph Koch.
- [01:27]
Elizabeth Koch
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 Heifetz 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. Heifetz also directs 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. But first, we want to share our own connection to psychedelics. So Kristof, how have psychedelics helped you expand your perception box?
- [02:29]
Dr. Christoph Koch
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.
- [02:41]
Elizabeth Koch
Well, that's pretty profound.
- [02:43]
Dr. Christoph Koch
Yeah.
- [02:44]
Elizabeth Koch
So do you think you're a more relaxed person though?
- [02:46]
Dr. Christoph Koch
Yes.
- [02:47]
Elizabeth Koch
Suddenly you seem very relaxed. Well, Boris, thanks for joining us.
- [02:53]
Dr. Boris Heifetz
Thanks for having me.
- [02:55]
Elizabeth Koch
So how did you become interested in psychedelics as an anesthesiologist?
- [03:01]
Dr. Boris Heifetz
So I became interested in psychedelics well before I became an anesthesiologist. The question is, how did I become interested in anesthesiology as a psychedelics explorer? Explorer?
- [03:13]
Dr. Christoph Koch
Give me a psychonaut.
- [03:15]
Dr. Boris Heifetz
Well, I've done some research on the topic before. 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 and 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. You can't have a career. You can't have a career studying psychedelics. It's hippie science. 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 a drug and you see its effect on the brain, the body, on consciousness itself. And that to me, it never gets old.
- [04:32]
Dr. Christoph Koch
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?
- [04:42]
Dr. Boris Heifetz
So we have a lot of interviews with patients after surgery that 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 eyes as you go off to sleep, 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 experiences. One of the earliest concerns for anesthesia, as we were developing anesthetic techniques to keep people immobile and pain pain free and amnestic, right. During surgery, is there's something called the Bryce 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 basically how we set standards for what depth of anesthesia we use.
- [05:47]
Dr. Christoph Koch
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.
- [05:57]
Dr. Boris Heifetz
In the or 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. 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.
- [06:51]
Dr. Christoph Koch
And no pain, because. Pain.
- [06:53]
Dr. Boris Heifetz
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 was, you know, 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. 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.
- [07:57]
Elizabeth Koch
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?
- [08:09]
Dr. Boris Heifetz
Sure. So this is a very hot topic right now. And, you know, when we talk about psychedelics, what are we talking about? There's the classic psychedelics, lsd, psilocybin, the classics. 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 Assisted therapy. 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, you know, 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 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. 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.
- [10:01]
Dr. Christoph Koch
To call it, it's rapid change in the perception box.
- [10:03]
Dr. Boris Heifetz
You can put it that way as well. 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 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.
- [10:39]
Elizabeth Koch
So it's the synergistic effect between the actual, you know, physical effects of the drug in the brain and this psychological effect.
- [10:49]
Dr. Boris Heifetz
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. Or the TRP that's responsible for these therapeutic benefits?
- [11:01]
Elizabeth Koch
Right. Because you get the same benefits out.
- [11:03]
Dr. Christoph Koch
Conceptually, A and B, empirically, experimentally, you can separate those two.
- [11:07]
Dr. Boris Heifetz
That's exactly it. Right. That's why there's. The debate is right now all we're looking at is correlation.
- [11:13]
Dr. Christoph Koch
And so tell us more about this.
- [11:14]
Dr. Boris Heifetz
Debate 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 setting expectations, building rapport. There's the drug experience itself, possibly eight hour extravaganza, sometimes 24 hours or 48, it depends the doses, everything. And then there's the integration, making sense of what happens and trying to incorporate those changes into your life, which can take weeks. And in trials, that's how long it takes, is that you have weeks of after therapy. So, you know, the, the inclination, you know, based on decades of experience in, you know, pharma is, well, it's got to be that little crystalline entity in the middle of all of this that's, that's driving these effects. But in reality, as, 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 want to 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 works? It's just enough that it does work. 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 or the earth being born or a total eclipse. It was just awe inspiring. How did we get from someone living for 50 hours in the 60s after heart transplant to 80% at five years, this is amazing. It's by understanding the risk and understanding the mechanism.
- [13:16]
Dr. Christoph Koch
Mechanism, I mean, science. This is how science works.
- [13:19]
Dr. Boris Heifetz
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 was powerful and crude. And we learned something and innovated and distilled it down to something highly effective and targeted. I'm not sure that cns 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.
- [14:12]
Dr. Christoph Koch
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 approves 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.
- [14:45]
Dr. Boris Heifetz
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.
- [15:02]
Elizabeth Koch
My biggest question is whether it's the molecule itself or you need the psycholife 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?
- [15:15]
Dr. Boris Heifetz
Yeah, that's what we are trying to develop is that psychedelics pose really fundamental challenges for, you know, randomized controlled trials. Let's start with that for a second.
- [15:25]
Elizabeth Koch
Right. Cause you don't, you know, you're on the drug once you're on it, and.
- [15:27]
Dr. Christoph Koch
So why would that be a complication?
- [15:29]
Dr. Boris Heifetz
So it introduces all kinds of biases in that, you know, the randomized placebo controlled trial was designed for antibiotics and blood pressure medication.
- [15:39]
Elizabeth Koch
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.
- [15:52]
Dr. Christoph Koch
And so probably not for tb. Right. That's the logic.
- [15:56]
Dr. Boris Heifetz
There are some things where placebo effect, you know, we should be so lucky to have a cancer. Placebo effect.
- [16:01]
Elizabeth Koch
Right, right.
- [16:02]
Dr. Boris Heifetz
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 patients point of view. You have read Michael Pollan's book. You are fascinated at the potential of psilocybin. You have out competed a thousand other applicants to be in the study on depression. You have already won a lottery. Right. Now you go into the finale and.
- [16:31]
Dr. Christoph Koch
You'Ve already done two, failed two other trials.
- [16:34]
Dr. Boris Heifetz
You've Already failed two other trials. And like I think this is going to 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 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 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?
- [17:21]
Dr. Christoph Koch
Because nothing happens.
- [17:22]
Dr. Boris Heifetz
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.
- [17:41]
Dr. Christoph Koch
And so because they've been told in the red that these are wonderful drugs, they were less likely to be depressed afterwards. That's what you're saying, that's what the placebo effect is.
- [17:50]
Dr. Boris Heifetz
Exactly.
- [17:51]
Elizabeth Koch
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?
- [18:00]
Dr. Boris Heifetz
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'll 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.
- [18:26]
Elizabeth Koch
Kristoff's are thinking that's no fun. Where's the fun in that? They want to take your mind.
- [18:31]
Dr. Boris Heifetz
This is the science that to me it's crucial.
- [18:35]
Dr. Christoph Koch
Right.
- [18:35]
Dr. Boris Heifetz
Like you have to test, how can.
- [18:37]
Dr. Christoph Koch
You, assuming you can do that, let's.
- [18:38]
Dr. Boris Heifetz
Just say for a minute it's possible you will get some answer. There is. Can you just encode resilience, you know, through biochemically without anybody noticing. Right.
- [18:48]
Elizabeth Koch
What about giving the psychedelic while somebody's under anesthesia and they have no experience?
- [18:53]
Dr. Boris Heifetz
That happens to be related to us. Absolutely. Oh, 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, their 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? 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 Sivaflurine. 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.
- [19:57]
Dr. Christoph Koch
So they're deep. So if you do surgical cut, they don't.
- [20:00]
Dr. Boris Heifetz
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'd call equipoise about, you know, ketamine is kind of giver. You don't need to give it. There's nothing in the case that screams out, this patient should definitely get ketamine. We're able to do this trial and we ran it like a psychiatry trial. And this is with actual psychiatrists like Laura Hack and Alan Shasper, who helped, you know, quite a bit on this study. But we ran a psychiatry trial in the operating room and they give half a milligram per kilogram over 40 minutes to minimize the psychoactive effects.
- [20:39]
Dr. Christoph Koch
But in a regular weak person, there would be strong psychoactive effect with this dose, right?
- [20:44]
Dr. Boris Heifetz
Yes. And that's what we've seen. We've done other. Worked on a trial with no. 1 Williams, where we are giving ketamine.
- [20:50]
Dr. Christoph Koch
To awake patients at this dose, at.
- [20:52]
Dr. Boris Heifetz
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?
- [21:17]
Elizabeth Koch
So now you give them this do dose which normally in a wakeful person they would have a sort of psychedelic effect, but they're under anesthesia and you have a placebo controlled, meaning you're going to give them another substance that's not ketamine or just give them no ketamine.
- [21:31]
Dr. Boris Heifetz
We just give them normal saline.
- [21:32]
Elizabeth Koch
Okay.
- [21:33]
Dr. Boris Heifetz
If that's, you know, fluid with the same volume. And I guarantee you the patients were not aware everyone was blinded in the study.
- [21:41]
Elizabeth Koch
So they wake up and what's the measurement? What do you assess?
- [21:44]
Dr. Boris Heifetz
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 Asberg 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 is your appetite and there's kind of standard degrees of, of severity.
- [22:05]
Elizabeth Koch
But you're expecting there to be an effect right away, right after the surgery.
- [22:09]
Dr. Boris Heifetz
That's the beauty of ketamine.
- [22:10]
Elizabeth Koch
SSRIs you 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 and there's nuance to everything.
- [22:23]
Dr. Boris Heifetz
But essentially yes, that's, that's the design of this therapy is that it's rapid acting antidepressant.
- [22:30]
Elizabeth Koch
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.
- [22:34]
Dr. Boris Heifetz
So 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 peak effect. The peak antidepressant effect of ketamine is one to three days after infusion, long after the drug is gone. Just where we started this Description. And that's where we were taking. Our primary measure is looking at depression scores in the one to three days post infusion, post surgery.
- [22:59]
Elizabeth Koch
And what you found was, well, all.
- [23:01]
Dr. Boris Heifetz
Of the patients who got ketamine did great. 50% response, 30% remission from patients, many of whom had treatment resistant depression.
- [23:10]
Dr. Christoph Koch
So what is, what about the other patients?
- [23:12]
Dr. Boris Heifetz
Well, so the placebo group also did great, 50% response, 30% remissions.
- [23:18]
Dr. Christoph Koch
So it's remarkable. So you think whether or not they.
- [23:21]
Dr. Boris Heifetz
Got the ketamine, both, 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 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 points to bring out about this. And 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. 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 surgeon 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 come in, you get a consent, it's about an hour long, where you hear all about the study. Ketamine. We think it's an antidepressant. In other circumstances, we're wondering whether this has therapeutic value during surgery. Now you come in for a two hour interview with, you know, four of us, a nurse, myself, a research coordinator.
- [24:57]
Dr. Christoph Koch
Just as part of the work.
- [24:58]
Dr. Boris Heifetz
Yeah, we want to know everything you know and from a patient.
- [25:01]
Elizabeth Koch
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.
- [25:10]
Dr. Boris Heifetz
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, 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 physical history. And then, you know, the morning of surgery, I again, I wanted to make sure things go off without a hitch. I, in many cases, I held their hands as they went off to sleep. Right. I mean, 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. 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. Nice. And putting people at risk for opioid use disorder. So that's what I came in with. I was not thinking that placebo would be a problem or that this study would even be about placebo.
- [26:28]
Dr. Christoph Koch
Placebo was really a surprise to you?
- [26:30]
Dr. Boris Heifetz
It was a big surprise.
- [26:31]
Elizabeth Koch
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.
- [26:43]
Dr. Boris Heifetz
The takeaway is this. It's in the placebo effect. 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.
- [27:26]
Elizabeth Koch
Well, I think in some ways this is really good news. I mean, first of all, well, where is this published, this paper in Nature Mental Health? 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.
- [27:43]
Dr. Boris Heifetz
Like, for instance, your mind can change your body.
- [27:46]
Elizabeth Koch
Yes. So we don't need the drugs.
- [27:49]
Dr. Boris Heifetz
We need something. These patients went through something, and I.
- [27:52]
Elizabeth Koch
Think that's a key part of this experience, though. It was an experience.
- [27:56]
Dr. Christoph Koch
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 dance or.
- [28:04]
Dr. Boris Heifetz
But it's got to be. You can't just tell them you need good placebo. We had really good placebo. We had the best place.
- [28:10]
Dr. Christoph Koch
Tell me, what about the. Just a 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.
- [28:19]
Dr. Boris Heifetz
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. But when we asked them what they thought they got. So nobody knew, first of all. But what, in talking to them, 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. Which suggests that they had some prior belief. Right. You wouldn't say that you got ketamine unless you believe the ketamine.
- [29:05]
Dr. Christoph Koch
But it's therapeutic. Surely There must have been some people who believe it, or maybe not, who believe they were on the placebo.
- [29:10]
Dr. Boris Heifetz
And those are the ones. 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 has the potential for therapeutic benefit.
- [29:27]
Dr. Christoph Koch
And I think that's how you conclude in the last paragraph of the paper. This is called conventionally fit. The short name of this is hope.
- [29:33]
Dr. Boris Heifetz
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 to please. 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. It. 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.
- [30:16]
Elizabeth Koch
I think we need to harness the placebo. I've always said this. Harness the placebo effect and use it in medicine.
- [30:21]
Dr. Christoph Koch
Yes.
- [30:22]
Elizabeth Koch
Exploit the placebo effect.
- [30:23]
Dr. Boris Heifetz
Good doctors do it. And real and psychedelic white coats.
- [30:27]
Dr. Christoph Koch
That's why you have Dr. Bowers Heisen. Well, because if I believe you, just like a shaman, if I believe you are the shaman, then I'm more likely that's who.
- [30:37]
Dr. Boris Heifetz
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 can tell you my voice did not drop. But I felt different. People looked at me different, they 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. That surrounds it. And that is a very devilishly hard thing to study with. With, you know, conventional scientific methods.
- [31:12]
Elizabeth Koch
A lot of it is the power of suggestion.
- [31:14]
Dr. Boris Heifetz
Right.
- [31:14]
Elizabeth Koch
If they come in and they're depressed and, you know, 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. And they believe you because you have all these credentials and stuff. Like, rather than me just giving my friend, you know, some good advice and you. They take your. I really feel like you're gonna 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. 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 wanna just talk about. Cause I know there's Other research you do in terms of dreams and sort of inducing dreamlike states with anesthesia, that.
- [31:59]
Dr. Boris Heifetz
I really wanna 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. Having surgery and coming through the other side.
- [32:18]
Dr. Christoph Koch
Was there any therapy afterwards?
- [32:20]
Dr. Boris Heifetz
No, that's. We, like every other ketamine study included no therapy.
- [32:25]
Dr. Christoph Koch
And how long did you. How long did you.
- [32:28]
Dr. Boris Heifetz
Two weeks.
- [32:29]
Dr. Christoph Koch
And so you didn't track the. Are these people still.
- [32:31]
Dr. Boris Heifetz
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're 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 could either take the trip out of the drug. And we've now talked about a couple ways to do that. 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? That would be a pretty interesting way to test this idea of how special is the serotonin 2A receptor. Right. And there's a. Just some very exciting research.
- [33:33]
Elizabeth Koch
But now we're talking about how do you create. Well, how do you regenerate exactly, hallucinations without the psychedelics.
- [33:38]
Dr. Boris Heifetz
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's 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 stumbled upon working with anesthesia and dreams. And I have a colleague, Harrison Chow, he's a. I was going to say an artist. He's an anesthesiologist, but he's, 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 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.
- [34:46]
Elizabeth Koch
So you're watching them as they calm out of anesthesia and the waves start speeding up and they're getting higher frequency.
- [34:52]
Dr. Boris Heifetz
Yeah. 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 you two 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 scientific. And I was very skeptical at first. So we agreed we're going to get a portable eeg, a sedline, the same, you know, 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 this real? Is there something there? And not long after, we had our first, our first case. And this is a case of a woman, this is published 2022, where this woman, 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 in the intervening time the hand got injured. Yeah, defending herself.
- [36:06]
Dr. Christoph Koch
So the surgery was to.
- [36:07]
Dr. Boris Heifetz
Was 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's hypervigilant, she's, you know, having difficulty.
- [36:21]
Dr. Christoph Koch
She has severe.
- [36:22]
Dr. Boris Heifetz
So due to the time frame, we call it acute stress disorder. But this is somebody who would, 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, it's all she can talk about. And 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 blocked and Harrison does his dream thing.
- [36:52]
Dr. Christoph Koch
Wait, so is her arm anesthetized?
- [36:54]
Dr. Boris Heifetz
Yeah, her arm is anesthetized. So she doesn't need to be so deeply anesthetized that she can't feel.
- [37:01]
Elizabeth Koch
When you say the stream thing, it's just that you're controlling the amount of propofol and watching, and watching the EEG and getting her into this sort of sweet spot where he knows that the dreams occur.
- [37:10]
Dr. Christoph Koch
Yeah. How long is this state of dreaming in this patient?
- [37:13]
Dr. Boris Heifetz
About 10 minutes.
- [37:14]
Dr. Christoph Koch
Very brief.
- [37:16]
Dr. Boris Heifetz
Relatively brief. But there's a lifetime in 10 minutes.
- [37:19]
Elizabeth Koch
Yeah.
- [37:19]
Dr. Boris Heifetz
So what she, you know, what she says immediately upon waking is the nightmare. 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 what a nightmare is 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's back home running errands with her hand. This 10 minutes, all in 10 minutes. A lifetime in 10 minutes.
- [37:53]
Elizabeth Koch
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 exposure. Yeah, exposure. Long enough to get through it and resolve it and then move on. But often 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 the stream state allowed her to get past the anxiety part of it, enough so that her brain was able to kind of process it.
- [38:23]
Dr. Boris Heifetz
Well, 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.
- [38:39]
Dr. Christoph Koch
From trauma, you think, due to a ten minute dream.
- [38:42]
Dr. Boris Heifetz
Well, we've done it now about 600 times. And patients. So we've been. This is clinical care, this is gentle clinical care that now we've added an observational study on top of just seeing what happens when we do this at scale. And the technique isn't perfect. We have somewhere between 60 and 85% hit rate for getting patients to have these vivid dreams. And I can tell you 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.
- [39:18]
Elizabeth Koch
It's more than just regular dreaming. And do you find that they're less anxious after or less.
- [39:23]
Dr. Boris Heifetz
Well, so what we actually, the real clincher or what was so surprising is, you know, just by chance, two patients that came through Stanford operating rooms had bonafide ptsd. In both cases, coincidentally, it was the loss of a child, an adult child, either due to drug overdose or suicide. Again, horrible thing to live with for years. And as you can imagine, nightmares about trying to save your child. 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 story on the Stanford Med school blog now detailing her experience. She dreamt, you know, she re experienced the birth of her son. Instead of being a traumatic birth, it was joyful. She was reunited with her son and with her family and they were. And listening. We have a video also on our, on my lab website. Um, 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, Merritt, you know, and, and Edie and are 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.
- [40:51]
Elizabeth Koch
This, they do, but then it's transformative after the fact, then they're less upset about these traumatic events.
- [40:56]
Dr. Boris Heifetz
She's had nightmares her entire life. And especially after this, you know, this traumatic event and now, you know, what she's a year later is that she has not had nightmares.
- [41:05]
Elizabeth Koch
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 in however way you can. Psychedelics are a way to get there, but they're not the only way.
- [41:37]
Dr. Christoph Koch
This woman sounds wonderful, but it's Just one out of three. You said there's several hundred. Or it's most patients.
- [41:43]
Dr. Boris Heifetz
So most patients. So again, this is. We're doing this in the. On the background of providing clinical care. So these patients, they all come in.
- [41:51]
Dr. Christoph Koch
Again for other types of surgery.
- [41:52]
Dr. Boris Heifetz
Yeah, they're coming in for, you know, thyroid surgeries, you know, plastic surgery, you.
- [41:56]
Dr. Christoph Koch
Know.
- [41:58]
Dr. Boris Heifetz
So they get. And it's a cocktail. But the goal is always the same, is during emergence, we are targeting a state. Right. Whether we use. We've had patients report this with sevoflurane, with propofol, with propofol and remifentanil. This, again, this hits at the point it's not the drug.
- [42:15]
Elizabeth Koch
It's not the drug itself. So that being said, though, 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 and.
- [42:39]
Dr. Boris Heifetz
Trying to understand what are the bounds, like, how do we define that? What are the characteristics that need to be present in order for it to be transformative?
- [42:54]
Elizabeth Koch
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?
- [43:07]
Dr. Christoph Koch
I can. I can give. I can speak up. I. I used to stutter as a little child, and I went to logotherapy for like six weeks. And I. I was, you know, 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 get into situation where I needed to control my language. And I don't know, because it was When I was 9 and 10 and 11, I did the sort of mindfulness training, et cetera. Then I managed to overcome that 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.
- [43:50]
Elizabeth Koch
Am I even overcompensated? Thank you. Ingest.
- [43:58]
Dr. Boris Heifetz
So one of the things, you know, I have a younger brother who's 10 years younger, but so for 10 years I was an only child, and I developed, you know, tended. I was very, you know, in. In my own world. And for many years I would kind of hold ideas and I would not. I didn't want to share them until they were perfect. And it would marinate and stew. And one day, you know, during my PhD, something clicked. Something clicked, being in a lab. And my mentor, Pablo Castillo, really nailed this for me in the arguing. The joy of, you know, exposing yourself and your ideas, it takes a certain amount of courage or a jump. It's, you know, these are things that, like, my idea, my ideas, my dreams. Like, these are things that are really deeply special to me that 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 some of them didn't survive. But we have the saying in my lab now that if an idea can survive this room, my office, after talking about it for three hours, there might be something there.
- [45:10]
Elizabeth Koch
That's the power 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, deeply enjoyable.
- [45:21]
Dr. Christoph Koch
Are you engaged in this community of people?
- [45:23]
Dr. Boris Heifetz
Yeah, absolutely.
- [45:24]
Elizabeth Koch
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, you know, being an academic and being a woman, I. A lot of the time, and this was like, you know, in the 90s 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. A lecture or a keynote, immediately expectations were 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 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 wanted, 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 Crystal comes in with the German acts, whatever, they're expecting him to say something very intelligent, and he doesn't. And then he doesn't, and it's a big disappointment. Whereas I have this great advantage where 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.
- [47:05]
Dr. Boris Heifetz
That runs pretty deep.
- [47:06]
Elizabeth Koch
Yeah. Well, I want to thank you, Boris, for being here with us today.
- [47:12]
Dr. Boris Heifetz
Thank you. Thanks for having me.
- [47:13]
Elizabeth Koch
This is 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@ unlikely collaborators.com youm 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 Pod People. I'm Dr. Heather Berlin.
- [47:42]
Dr. Christoph Koch
And I'm Dr. Christoph Koch. Thank you very much.