Health
Psychedelics and the Placebo Effect with Dr. Boris Heifets
In this episode of the Science of Perception Box, Dr. Boris Heifets joins hosts Dr. Heather Berlin and Dr. Christophe Koch to explore the intersection of psychedelics, consciousness, and the placebo e...
Psychedelics and the Placebo Effect with Dr. Boris Heifets
Health •
0:00 / 0:00
Interactive Transcript
spk_0
What if you could take the drug out of the trip?
spk_0
In other words, recreate a psychedelic-like experience
spk_0
without reference to a psychedelic drug itself.
spk_0
Hi, I'm Elizabeth Koch.
spk_0
We all live inside our own personal, private perception box.
spk_0
Built by our genes and the physical, social, and cultural environment
spk_0
in which we were born and raised.
spk_0
In this podcast, we explore how although the walls of this mental box
spk_0
are always present, they can't expand and states like,
spk_0
awe, wonder, and curiosity, or contract in response to anxiety, fear, and anger.
spk_0
I'd like to introduce our esteemed hosts to incredible and distinguished minds.
spk_0
Dr. Heather Berlin, professor of psychiatry and neuroscience
spk_0
at the Icon School of Medicine at Mount Sinai in New York City.
spk_0
And Dr. Christophe Koch, chief scientist for the tiny blue dot foundation
spk_0
and the current meritorious investigator and former president
spk_0
of the Allen Institute for Brain Science.
spk_0
Welcome to the Science of Perception Box.
spk_0
Hi, everybody. Welcome to Science of Perception Box.
spk_0
I'm your co-host, Dr. Heather Berlin.
spk_0
I'm your co-host, Dr. Christophe Koch.
spk_0
So every week we feature an aspect of the science of perception box
spk_0
highlighting the latest research together with our expert guest.
spk_0
This week we're exploring the powerful research around psychedelics and dream states
spk_0
in the practice of anesthesiology with a researcher and doctor
spk_0
who has been as fascinated about consciousness as we are.
spk_0
Dr. Boris Haifetz is a board certified anesthesiologist
spk_0
who specializes in providing anesthesia for neurological surgery.
spk_0
He's practiced at Stanford since 2010.
spk_0
In addition to treating patients, Dr. Haifetz also directs clinical research
spk_0
and basic neuroscience.
spk_0
His research group studies how new rapid-acting psychiatric therapies,
spk_0
like ketamine, MDMA, and psilocybin, produce lasting changes
spk_0
in nervous system function, behavior, and therapeutic outcomes.
spk_0
But first we want to share our own connection to psychedelics.
spk_0
So, Christophe, how have psychedelics helped you expand your perception box?
spk_0
They made me lose the sense of self.
spk_0
They made me lose my sense of body of an external world,
spk_0
but there was still consciousness, and they made me lose my fear of death.
spk_0
Well, that's pretty profound.
spk_0
So do you think you're a more relaxed person now?
spk_0
Yes, certainly.
spk_0
You seem very relaxed.
spk_0
Well, Boris, thanks for joining us.
spk_0
Thanks for having me.
spk_0
So, how did you become interested in psychedelics as an anesthesiologist?
spk_0
So, I became interested in psychedelics well before I became an anesthesiologist.
spk_0
Ah, I see.
spk_0
The best is how did I become interested in anesthesiology as a psychedelics explorer?
spk_0
Explore.
spk_0
You mean up psycho note.
spk_0
Well, I've done some research on the topic before we cover you, Dr.
spk_0
when I was towards the end of my PhD training.
spk_0
So, I did an MD in a PhD at Einstein in New York.
spk_0
I had this question of like, well, how am I going to apply this?
spk_0
What we're doing is we're looking at synaptic responses in brain tissue.
spk_0
We're looking at the inner workings of how circuits function in the brain.
spk_0
And I didn't want to lose that, right?
spk_0
And I wanted to pick a specialty that would allow me the most access to that kind of thinking,
spk_0
that kind of environment.
spk_0
And, you know, not to mention this background interest in psychedelics.
spk_0
I think when I started medical school, my mom told me, drop it.
spk_0
You can't have a career.
spk_0
You can't have a career studying psychedelics.
spk_0
It's hippy science.
spk_0
You know, this is in 2000, probably good advice.
spk_0
But when it came time to pick a specialty, I was thinking about psychiatry, neurology, neurosurgery, and anesthesiology.
spk_0
And the closest I could get to applied neuroscience was actually anesthesiology you give.
spk_0
You give a drug and you see its effect on the brain, the body, on consciousness itself.
spk_0
And that to me, it never gets old.
spk_0
How do you know that consciousness is gone as compared to the unable to talk and the unable to signal that they're still there?
spk_0
How do you know they're not present?
spk_0
So we have a lot of interviews with patients after surgery that are, it can attest to that,
spk_0
is that what's kind of remarkable about anesthesia is that it's not like sleep.
spk_0
And when you close your eyes, as you go off to, as you are anesthetized for surgery,
spk_0
when you open them, many patients will feel that no time has passed.
spk_0
It's very different from when you wake up.
spk_0
You kind of have an intuitive sense of how long you may have slept.
spk_0
So that's already one difference, just at the level of what the patient experiences.
spk_0
One of the earliest concerns for anesthesia, as you know, we were developing anesthetic techniques to keep people immobile and pain free and amnestic, right?
spk_0
During surgery is, there's something called the Bryce questionnaire.
spk_0
What's the last thing you remember before going to sleep?
spk_0
What's the first thing you remember when you wake up?
spk_0
And did you have any dreams during anesthesia?
spk_0
Do you recall anything?
spk_0
And that's, you know, that's basically how we set standards for what depth of anesthesia we use.
spk_0
How often does it happen that, I guess, depending on the type of anesthesia and the duration that people do,
spk_0
recall something that does relate in some way to something that did happen in the OR?
spk_0
So it's around one in a thousand.
spk_0
So awareness under general anesthesia, even with EEG monitors.
spk_0
So, you know, we're monitoring brain function.
spk_0
We're getting a sense of the depth, but we're clearly not getting the whole picture because every once in a while,
spk_0
a patient will recall something.
spk_0
Now, I want to put a qualifier on that before, you know, nobody ever has surgery again after listening to this podcast.
spk_0
I've seen one case like this in an elderly woman, not who I would have expected.
spk_0
And though the thing she said was everything was so far away that, you know, I was like,
spk_0
everyone was touching me really softly, but she was recalling conversations in the OR.
spk_0
So there's a deep disconnection, but she was able to maintain some sort of input from the real world.
spk_0
So that, again, that's one in a thousand.
spk_0
And no pain, because she didn't complain of pain.
spk_0
She didn't complain.
spk_0
She didn't complain, you know, it was a little bit distressing to her because she kind of knew what happened.
spk_0
But she wasn't paralyzed.
spk_0
She didn't have, the thing that I was most worried about is, did you feel trapped?
spk_0
And, you know, think how she didn't.
spk_0
And that's again, advances in anesthesia have allowed us to do surgery without paralysis even in some cases.
spk_0
So again, this may be a topic for another, another time, but it's, you know,
spk_0
it's rare complications that we do worry about.
spk_0
And again, that was the early concern of anesthesiologists is that we want to make sure that consciousness is gone.
spk_0
Right.
spk_0
Deep disconnection, disconnected unconsciousness that, you know, that's reversible at the end of surgery.
spk_0
Now, in the last 20 years, you know, anesthesia has gotten a lot safer.
spk_0
We've started innovating things like nerve locks, for example.
spk_0
So now we have a little bit more room to think about, you know, how much do I want to sedate this patient?
spk_0
What kind of experience do I want to provide?
spk_0
And that's where things start to get a little bit interesting.
spk_0
So, so before we get into the research, can you tell us a little bit about how psychedelics work in the brain?
spk_0
And how they can be used as a therapeutic intervention?
spk_0
Sure. So this is a very hot topic right now.
spk_0
And, you know, when we talk about psychedelics, what are we talking about?
spk_0
There's the classic psychedelics, LSD, psilocyte.
spk_0
The classics.
spk_0
The classics, the greatest hits.
spk_0
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.
spk_0
Drugs like MDMA, which is nearing approval potentially for PTSD.
spk_0
Catamy.
spk_0
Acisted therapy.
spk_0
Yes.
spk_0
MDMA assisted therapy, which we're going to return to that point, I hope.
spk_0
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.
spk_0
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.
spk_0
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.
spk_0
You know, whether it be like, what is going on in my body?
spk_0
Why, where is this pain coming from?
spk_0
Or, you know, who is this person who's, you know, always depressed and, you know, pessimistic all this perspective shift is something that people across these drug classes will talk about.
spk_0
And to me, that's what defines this broad class.
spk_0
They're acutely psychoactive, powerfully so.
spk_0
Their effects are rapid, that perspective shift or however you want to call it, it's rapid.
spk_0
Change an perception box.
spk_0
You can put it that way as well. And finally, the effects are durable.
spk_0
This is very different from modern mental health care.
spk_0
You don't need to take, you don't take these drugs every day.
spk_0
You have long after the ketamine or the MDMA or the psilocybin has cleared your bloodstream, you are still feeling those positive effects.
spk_0
This is a sea change in how therapy is delivered.
spk_0
And I want to emphasize again, it is far more complex than just giving someone a drug, putting them in a room while they have their experience.
spk_0
So it's the synergistic effect between the actual, you know, physical effects of the drug and the brains and this psychological effect.
spk_0
I'm going to challenge that.
spk_0
I think that's actually one of the biggest debates right now is, and it has implications.
spk_0
Is it the drug or the trip that's responsible for these therapeutic benefits?
spk_0
Right, because you get the same benefits.
spk_0
Assuming that conceptually, A and B, empirically, experimentally, you can separate those two.
spk_0
That's exactly it. Right? That's why there's the debate.
spk_0
It is right now all we're looking at is correlation.
spk_0
So tell us more about this debate.
spk_0
If it boils down to this, is you can think of the complexity of psychotherapy, you can simplify into three basic stages.
spk_0
There's preparation, which involves setting expectations, building rapport.
spk_0
There's the drug experience itself that possibly eight hour extravaganza sometimes.
spk_0
24 hours.
spk_0
Or 48, it depends, you know, the dose is everything.
spk_0
And then there's the integration, making sense of what happens and trying to incorporate those changes into your life.
spk_0
Which can take weeks.
spk_0
And in trials, that's how long it takes is that you have weeks of apathy therapy.
spk_0
So, you know, the inclination, you know, based on decades of experience, you know, pharma,
spk_0
is well, it's got to be that little crystal and entity in the middle of all of this that's driving these effects.
spk_0
But in reality, as you pointed out, you cannot possibly attribute to one factor with therapeutic change,
spk_0
unless you can independently manipulate them.
spk_0
Right? And this is where the science comes in.
spk_0
I'm going to put it in a brief plug for why any of this matters.
spk_0
There are people who, you know, believe not without cause that it's enough that it works.
spk_0
Why do we, why gets a vent out of shape about how it works?
spk_0
It's just enough that it does work.
spk_0
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.
spk_0
And when I see, you know, one of the most magical moments in residency, I don't need to gross you without,
spk_0
but watching a transplanted heart get put into someone's chest,
spk_0
bibrillate, and then convert to sinus rhythm.
spk_0
Great.
spk_0
It's like watching birth, like, or the earth being born or a total eclipse.
spk_0
It was, it was, it was just awe inspiring.
spk_0
How did we get from someone living for 50 hours in the 60s after a heart transplant
spk_0
to let, you know, 80% at five years,
spk_0
to the amazing, it's by understanding the risk and understanding the mechanism.
spk_0
Mechanism, I mean, science.
spk_0
Yes.
spk_0
That's what science works.
spk_0
And so that to me is the question, if a therapy is truly potent by definition, if carries risk.
spk_0
spk_0
And when you think about the early days of chemotherapy, chemotherapy in 1975 was almost a death sentence in itself.
spk_0
30 years later, you have the first rationally designed chinesinhibitor.
spk_0
That blew my mind in 1999, Gleeveck.
spk_0
That cured leukemia.
spk_0
And, you know, what, again, that's, you take something that has, it's a powerful chemotherapy.
spk_0
It was powerful and crude, and we were in something and innovated and distilled it down to something,
spk_0
something highly effective in targeting.
spk_0
I'm not sure that CNS, you know, that psychedelics are going to go that way.
spk_0
But there's a pretty strong track record in every other field of medicine for this approach.
spk_0
They're also strong motives in the industry to pursue that.
spk_0
Because that's what the entire medical system is based on.
spk_0
You give one little therapeutic intervention that the FDA proves that you can then, you know, sell to everyone that works.
spk_0
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.
spk_0
And I seriously doubt having studied my entire life that anyone drug will be a magic bullet that cures whatever existential problems that brain or that mind has.
spk_0
I'm going to turn that on its head in that I completely agree with you.
spk_0
But how do you, without demonstrating the centrality of my, my overall overwhelming sense from all the work I've done is that we need to center the experience.
spk_0
My biggest question is whether it's the molecule itself or you need this cycle of psychological experience.
spk_0
And can you isolate this like a logical experience so they don't have to even take the drug or there are other ways to get to that transformative experience?
spk_0
Yeah. That's what we are trying to develop is that psychedelics pose really fundamental challenges for, you know, randomized controlled trials.
spk_0
That's sorry with that for a second.
spk_0
Right. Because you don't, you know, you're on the drug once you're on it.
spk_0
And so why would that be a complication?
spk_0
So it introduces all kinds of biases in that, you know, the randomized placebo controlled trial was designed for antibiotics and one pressure medication.
spk_0
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 drug can have just thinking you've taken the drug that can have an effect.
spk_0
Probably not for TB or that's see.
spk_0
Yeah, there are some things where placebo effect, you know, we should be so lucky to have a cancer placebo effect.
spk_0
Right. Right.
spk_0
People don't spontaneously often do not often spontaneously remit, you know, just on the strength of their belief, although, you know, they're all kinds of stories.
spk_0
But it's important because you know, think about it from a patient's point of view.
spk_0
You have read Michael Pollan's book.
spk_0
You are fascinated at the potential of still a siphon.
spk_0
You have out competed a thousand other applicants to be in the study on depression.
spk_0
You have already won lottery. Right.
spk_0
Now you go into the finale and you've already done to fail to other trials.
spk_0
You've already failed to other trials.
spk_0
I think this is going to be it.
spk_0
And so you have an expectation.
spk_0
It's obvious that if I get the drug, I'm likely to improve because look at what all of these smart people say.
spk_0
And now comes the moment, the moment of truth.
spk_0
You're your boyfriend, your girlfriend drives you.
spk_0
Maybe you fight about it because you've been so persistent in your pursuit.
spk_0
You go through a lot of trouble to get to that room, to that therapist room.
spk_0
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 have a bit in a psilocybin trial or a moment of betrayal.
spk_0
Where why did I spend all of this effort to be in the placebo group because nothing happens because it's obvious.
spk_0
It's to most I mean, it's such an obvious like a lack of effect.
spk_0
So, you know, if you just it's like it's like winning the lottery.
spk_0
What is the effect of winning the lottery and you tell me, what does that have to do with depression?
spk_0
Like I guess like winning the lottery could be a short term added, a press.
spk_0
But that's that's sort of the heart of it.
spk_0
Because they've been told near end that these are wonderful drugs.
spk_0
They were less likely to be depressed afterwards.
spk_0
That's what you're saying.
spk_0
Yeah, that's what the placebo effect would be.
spk_0
Exactly.
spk_0
But because they know if they're on the placebo or not with psychedelics, it's very hard to control for that.
spk_0
So, do you have a way that you're trying to get around this?
spk_0
So, again, if that's one of the biggest problems facing psychedelic medicine is identifying a drug specific effect,
spk_0
it requires some innovative solutions.
spk_0
And I want to talk about a couple.
spk_0
One is efforts by David Olsen and Brian Roth.
spk_0
Two great chemists and many others who are reengineering the molecule itself.
spk_0
They're basically trying to take the trip out of the drug.
spk_0
Christophe, I'm thinking that's no fun.
spk_0
I already know.
spk_0
But they want to take the fun.
spk_0
I mean, I can't even remind you.
spk_0
This is the sign.
spk_0
That's the sign.
spk_0
That to me, it's cool.
spk_0
Exactly.
spk_0
spk_0
Like you have to test.
spk_0
How can you know?
spk_0
Let's just say for a minute it's possible.
spk_0
You will get some answer there.
spk_0
Is can you just encode resilience, you know, biochemically without anybody noticing?
spk_0
What about giving the psychedelic wall somebody's under anesthesia?
spk_0
Well, it's a lot of different approaches.
spk_0
This is the one we took.
spk_0
Now, I'm an anesthesiologist.
spk_0
And one, you know, it's hard to escape the idea that you have all these people that come in from all walks of life.
spk_0
Many with pre-existing depression PTSD, that's usually not what we're focused on.
spk_0
We're usually focusing on getting them through surgery.
spk_0
And we saw this as an opportunity.
spk_0
Is that patients are put under general anesthesia.
spk_0
And while they're anesthetized, there's no there there.
spk_0
They're not there for it.
spk_0
That's kind of the goal.
spk_0
So what if we gave a psychedelic class drug like ketamine during anesthesia?
spk_0
So it's important to know that this is on a background of general anesthesia with not not using ketamine as an anesthetic.
spk_0
We're using drugs like propyl, drugs like sebum fluorine.
spk_0
These are standard anesthetic cocktails.
spk_0
And we're getting everyone to pretty even cruising depth of anesthesia before we give them either ketamine or placebo.
spk_0
So they're deep.
spk_0
So if you do a surgical cocktail on that's the goal.
spk_0
They're there for surgery.
spk_0
Now part of how we were easily able to get approval for this is that ketamine is an anesthetic.
spk_0
It's an anesthetic adjunct.
spk_0
So we were in patients for whom there's what we call equipoids about ketamine is kind of giver.
spk_0
You don't need to give it.
spk_0
It's just something in the case that screams out this patient should definitely get ketamine.
spk_0
We were able to do this trial.
spk_0
And we ran it like a psychiatry trial.
spk_0
This is with actual psychiatrist like Laura Hack and Alan Chasfer who helped quite a bit on this study.
spk_0
But we ran a psychiatry trial in the operating room.
spk_0
They give half a milligram per kilogram over 40 minutes to minimize the psychoactive effects.
spk_0
But in a regular wake person there would be strong psychoactive effects.
spk_0
Was this dose, right?
spk_0
Yes. And that's what we've seen.
spk_0
We've done other work done a trial of no one Williams where we're giving ketamine to awake patients.
spk_0
At this dose.
spk_0
At this dose.
spk_0
And patients will have what's called, you know, build dissociate.
spk_0
They'll get into a dreamy state.
spk_0
You know, they might hallucinate the if you listen to what they say.
spk_0
So it's there is a lot of overlap with psychedelic like effects.
spk_0
And let's put that on pause for a minute.
spk_0
But that's that's the trip of ketamine that we're actually trying to see.
spk_0
Like, do you need that in order to benefit from ketamine?
spk_0
So now you give them this dose, which normally in a wakeful person they would have a sort of psychedelic effect.
spk_0
But they're under anesthesia and you have it placebo controlled meaning you're going to give them another substance.
spk_0
That's not going to give them no.
spk_0
We just give them normal sailing.
spk_0
Okay.
spk_0
If that's, you know, fluid with the same volume and I guarantee you the patients were not aware.
spk_0
Everyone was blinded in the study.
spk_0
So they wake up and what's the measurement?
spk_0
What do you assess?
spk_0
So again, we want to copy what's been done before when I reinventing anything.
spk_0
We're using a standard scale of depression called the Montgomery Asberg Depression rating scale.
spk_0
It's a clinician rated scale meaning I, 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?
spk_0
And there's kind of standard degrees of severity.
spk_0
But you're expecting there to be an impact effect right away right after the surgery.
spk_0
That's the beauty of ketamine.
spk_0
As I said, you give a patient and maybe six weeks later they say you'll feel something maybe.
spk_0
And it's very hard to like make the connection between the drug and the impact.
spk_0
But with ketamine, they give it in the psych ER and it really can knock out suicidality.
spk_0
And there's new ones to everything.
spk_0
But essentially yes.
spk_0
That's the design of this therapy is that it's rapid acting antidepressant.
spk_0
So you give them this measure of depression right when they come out of surgery.
spk_0
You don't know who's had it and who was it.
spk_0
So we waited a day.
spk_0
There's a lot of things that happen right after surgery.
spk_0
Yeah, 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.
spk_0
Long after the drug has gone, because you know where we started this description.
spk_0
And that's where we're taking our primary measure.
spk_0
It's looking at depression scores in the one to three days post-infusion post-surgery.
spk_0
And what you found was?
spk_0
Well, all of the patients who got ketamine did great.
spk_0
They, you know, 50% response, 30% remission from patients many of whom had treatment resistant depression.
spk_0
So what about the other patients?
spk_0
Well, so the placebo group also did great.
spk_0
50% response, 30% remission.
spk_0
So it's remarkable.
spk_0
So you're saying whether or not they got the ketamine both groups on average showed the same degree of improvement.
spk_0
You could not separate them.
spk_0
The key here is that both were massive, massive improvements.
spk_0
And there's a couple of fine points here because I got a lot of, you know,
spk_0
well, it's actually a family about the study, but people who looked at the study say,
spk_0
are you saying ketamine doesn't work?
spk_0
And there are a couple of points to bring out about this.
spk_0
And the first point is what was the patient experience like?
spk_0
And you'll see how this is important in a minute, I think.
spk_0
And again, keep in mind this very large placebo effect that we saw that we were absolutely not expecting.
spk_0
From a patient, let's say you're coming in for surgery.
spk_0
For 20 years, you've been dealing with a lot of trauma, the holdovers from a rough childhood, et cetera.
spk_0
And now you go see your surgeon.
spk_0
And do you think your surgeon is going to ask you about your mood?
spk_0
We can venture, I guess, to say usually not.
spk_0
It's the rare surgeon that has time because the priorities, there are other priorities.
spk_0
So from your point of view, you're getting something in your email saying,
spk_0
we care about your mental health and recovery after surgery.
spk_0
You know, would you be willing to fill out the survey and talk to us?
spk_0
That's our first contact with the patient a few weeks before surgery.
spk_0
And then you come in, you get a consent.
spk_0
It's about an hour long where you hear all about the study.
spk_0
And can't imagine, we think it's an antidepressant in other circumstances.
spk_0
We're wondering whether this has therapeutic value during surgery.
spk_0
Now you come in for a two-hour interview with four of us, a nurse, myself, a research coordinator.
spk_0
Two alternatives.
spk_0
Just as part of the work of the study.
spk_0
Yeah, this we want to know everything, you know, and from a patient's perspective.
spk_0
First of all, they're getting more attention.
spk_0
You're talking about their mood.
spk_0
You're giving in, you're priming them to this drug might really help your depression.
spk_0
Exactly.
spk_0
And there have been studies of depression during surgery before.
spk_0
And I don't think they went out all out like this.
spk_0
We were looking for a particular type of patient.
spk_0
I was so happy to get each one of them, each of these 40, that, you know, we really,
spk_0
we learned a lot about all of them.
spk_0
And so two hours where, you know, we heard about their trauma, their mental health history,
spk_0
their physical, you know, their physical history.
spk_0
And then, you know, the morning of surgery, I, again, I wanted to make sure things go up without a hitch.
spk_0
In many cases, I held their hands as they went off to sleep.
spk_0
Right? I mean, these patients were precious to me.
spk_0
And I was not at all thinking of the time, my God, what kind of placebo effect I'm in gendering.
spk_0
And let me stop there for a second.
spk_0
Why was I so, uh, lively, unaware of the possibility that we might induce this massive placebo effect?
spk_0
It's because I think the broader context is surgical anesthesia.
spk_0
Surgery and anesthesia are associated with the higher risk of heart attack, stroke, cognitive dysfunction, kidney injury, lung injury.
spk_0
Actually, all of our literature points to all these things getting worse after surgery.
spk_0
Nice.
spk_0
And putting people at risk for opioid use disorder.
spk_0
So that's what I came in with.
spk_0
I was not thinking that placebo would be a problem or that this study would even be about placebo.
spk_0
To the placebo was really a surprise to you.
spk_0
It was a big surprise.
spk_0
Well, this is like question.
spk_0
I mean, what does the takeaway here?
spk_0
Is the takeaway that for the effects of ketamine, you don't need the psychedelic effective ketamine for there to be an improvement?
spk_0
The takeaway is this.
spk_0
It's in the placebo effect.
spk_0
We can't, we can't say much about ketamine in this trial.
spk_0
But what I think we can say something about is full of the trials going on in the psychedelic space.
spk_0
Again, I painted that picture for you of winning the clinical trial lottery, right?
spk_0
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.
spk_0
So inadvertently, just the structure of this trial with preparation, a big central event, surgery and anesthesia.
spk_0
And then close follow up in the aftermath, we had replicated a lot of the key elements of most psychedelic studies and driven a placebo effect that is enormous.
spk_0
In some ways, this is really good news.
spk_0
I mean, first of all, where is this published, this paper in nature, mental health.
spk_0
Okay.
spk_0
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 psychedelics studies in a different way.
spk_0
However, it's really positive to say that, like, for instance,
spk_0
your mind can change your body.
spk_0
Yes. So we don't need the drugs.
spk_0
We need something. These patients went through something. I think that's a key part of this.
spk_0
An experience, though. It was an experience.
spk_0
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...
spk_0
But it's got to be... You can't just tell them. You need good placebo.
spk_0
We had really good placebo. We had the best placebo.
spk_0
Tell me, what about the... That's 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?
spk_0
And how does that affect?
spk_0
So, you know, they said we weren't expecting this massive placebo effect.
spk_0
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.
spk_0
So we didn't ask people until the very end of the study, which group did you think you were in?
spk_0
I will say this is like one of the only... Maybe the only truly blinded study of a psychedelic eye's drug, so that was a small victory.
spk_0
But when we asked them what they thought they got, so nobody knew, first of all.
spk_0
But what in talking to them, they're... You know, in my conversations with these patients, if they got better, they attributed it to the ketamine.
spk_0
They said, why must have been in the ketamine group because I feel better, which suggests that they had some prior belief.
spk_0
Right? You wouldn't say that you got ketamine unless you believe the ketamine is their...
spk_0
But surely there must have been some people who believe it, or maybe not, they will believe they were on the placebo.
spk_0
And those are the... Yeah, because they didn't get better. They didn't get better.
spk_0
And they're like, well, I must have been in the placebo group.
spk_0
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 potential for therapeutic benefit.
spk_0
And I think that's how you conclude in the last paragraph of the paper. This is called conventionally the...
spk_0
The shop name of this is Hope.
spk_0
Yes. So there is a dangerous side to that, not dangerous, but we can draw some of the wrong conclusions from this work.
spk_0
One is that, you know, the convention... What placebo is an old word, and, you know, literally means like, I please.
spk_0
To see. 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,
spk_0
it's more than a little awkward. They're like, well, all that stuff I said, well, in the throws of placebo, was that all...
spk_0
It wasn't real, right? And so it's very... You know, people need to feel seen, need to feel heard, and that idea that placebo is just something that you trick children with.
spk_0
We have to dispense with that idea.
spk_0
I think we need to harness the placebo. I've always said, as harness the placebo effect, and use it in medicine.
spk_0
Yes.
spk_0
Exploite the placebo effect. Well, good doctors do it.
spk_0
Yeah.
spk_0
And the real insight... That's why you have white coats, that's why you have Dr. Bowers high-sense.
spk_0
Well, because if I believe you, just like a shaman, if I believe you are the shaman, then I'm more likely...
spk_0
That has to be part of it, and there has to be a strong experience at the center.
spk_0
I had a barmas for when I was 13.
spk_0
My father said, today, my son, you're a man, and I can tell you, my voice did not drop, but I felt different.
spk_0
People looked to be different, they treated me differently.
spk_0
And how does that happen? It's not a person in isolation.
spk_0
It's certainly not a drug effect. It's a door that you walk through that is held up by the collective understanding of the community that surrounds it.
spk_0
And that is a very devilishly hard thing to study with conventional scientific methods.
spk_0
A lot of it is the power of suggestion.
spk_0
If they come in and they're depressed, and they're low, I'm never going to meet anybody, I'm never going to find anyone.
spk_0
You give them the sort of hope.
spk_0
And they believe you because you have all these credentials and stuff, rather than me just giving my friends some good advice and pot.
spk_0
They take your... I really feel like you're going to meet someone.
spk_0
I trust that. And then they start to believe it, because someone in a sort of authority position gives them that hope.
spk_0
It's not a balky SSRI they're taking, but studies do show in conjunction.
spk_0
You get some powerful effects from the SSRI, some from therapy.
spk_0
When they work together, you get this synergistic effect.
spk_0
But I want to just talk about, because I know there's other research you do in terms of dreams.
spk_0
And sort of inducing dream-like states within anesthesia that I really want to...
spk_0
So going with this theme of experience, in this study that we're just wrapping up the experience, they all went through something.
spk_0
It's not the experience on drug, but it's the larger experience of being in the study and going through a door.
spk_0
Having surgery and coming through the other side.
spk_0
Is there any therapy afterwards?
spk_0
No.
spk_0
Like every other Academy study.
spk_0
You take good enough therapy.
spk_0
And how long did you...
spk_0
Two weeks.
spk_0
And so you didn't track these people still?
spk_0
Not formally.
spk_0
I mean, I kept up with some of them and some of the stories.
spk_0
I'd love to share some of them.
spk_0
It really may be question whether I should be in science or not.
spk_0
When I couldn't tell, is this woman in the Academy group?
spk_0
Because how do you get that kind of transformation without something to account for it?
spk_0
Of course, she's in the placebo group.
spk_0
So there's another way to look at this.
spk_0
We're coming back to this theme of preparation and the day of the dosing,
spk_0
the drug and the trip and then integration and really focusing on the drug and the trip.
spk_0
Which you can either take the trip out of the drug and we've now talked about a couple of ways to do that.
spk_0
What if you could take the drug out of the trip?
spk_0
In other words, recreate a psychedelic-like experience without reference to a psychedelic drug itself.
spk_0
That would be a pretty interesting way to test this idea of how special is the serotonin to a receptor.
spk_0
There's just some very exciting research.
spk_0
Now we're talking about how do you create a hallucination without the psychedelic.
spk_0
Wouldn't it be an interesting past if we could induce a psychedelic-like state without a psychedelic
spk_0
and get some of the same physiology, descriptions of experience and therapeutic effects?
spk_0
Would that maybe turn on its head the idea that there's a powder at the center of all of these therapeutic effects?
spk_0
That's almost by accident what we've stumbled upon working with anesthesia and dreams.
spk_0
I have a colleague, Harrison Chow.
spk_0
I was going to say an artist. He's an anesthesiologist.
spk_0
This is the fart of medicine.
spk_0
He's been many years in private practice.
spk_0
Minor procedures.
spk_0
Patients would come in for hernias or doscopies, minor stuff.
spk_0
He would try and make the experience as pleasant as possible.
spk_0
He would do this thing where he would watch the EEG monitor and look for what he thought was dreaming.
spk_0
Patients would wake up and say, I had the best dream.
spk_0
I had the best sleep I've ever had.
spk_0
But as you emerge, one of the things that you can notice if you really pay close attention to the EEG,
spk_0
this is brain state monitoring.
spk_0
You're watching them as they come out of anesthesia and the waves start speeding up
spk_0
and they're getting higher frequency.
spk_0
When he came to Stanford, my chair put him together with me because he knew I was a psycho-naud drug nerd
spk_0
into non-ordinary states of consciousness and you should talk to each other and maybe figure something out.
spk_0
It was a great partnership.
spk_0
Harrison is really into the idea of making anesthesia more pleasant.
spk_0
I'm a little bit more scientific and I was very skeptical at first.
spk_0
We agree that we're going to get a portable EEG, a sublime, the same kind of couple leads.
spk_0
We have a team that includes a psychiatrist.
spk_0
We are going to do interviews, diagnostics, and we're going to follow these patients.
spk_0
I want to know is what you're saying? Are you both cheating me?
spk_0
Or is it real? Is there something there?
spk_0
And not long after, we had our first case.
spk_0
This is a case of a woman. This is published in 2022 where this woman,
spk_0
she had been attacked at close quarters by a relative with a knife horrifying.
spk_0
As you might imagine, she had nightmares.
spk_0
She went to the emergency room and they said go to Stanford, get your hand fixed.
spk_0
In the intervening time.
spk_0
The hand got injured.
spk_0
Yeah, exactly.
spk_0
To the surgery was for her hand.
spk_0
In the intervening two weeks, she's basically a non-functional human.
spk_0
She's hypervisual and she's having difficulty.
spk_0
She has to be a beauty.
spk_0
Due to the time frame, we call it acute stress disorder.
spk_0
This is somebody who would be more likely than not.
spk_0
We would be worried she would go on to develop PTSD.
spk_0
She's in the pre-op area.
spk_0
She's here for her hand.
spk_0
In Harrison finds her again, she's still...
spk_0
All she can talk about, and she's really hard to reach.
spk_0
Again, talking about innovations in anesthesia, they put her arm to sleep.
spk_0
She gets a nerve block.
spk_0
And Harrison does a dream thing.
spk_0
Wait, is her arm anesthetized?
spk_0
Yes, her arm is anesthetized.
spk_0
So she doesn't need to be so deeply anesthetized that she can't feel well.
spk_0
When you say the dream thing, it's just that you're controlling the amount of profile.
spk_0
And watching the eGee and getting her into the sort of sweet spot where he knows that the dreams occur.
spk_0
How long is this state of dreaming in this patient?
spk_0
About 10 minutes.
spk_0
We're very brief.
spk_0
Relatively brief, but there's a lifetime in 10 minutes.
spk_0
Yeah.
spk_0
So what she says immediately upon waking is the nightmare.
spk_0
It was there again.
spk_0
I had the nightmare again.
spk_0
And it was looping just like it always does.
spk_0
But instead of rocketing her into consciousness,
spk_0
which is what a nightmare is, by virtue of this anesthetic suppression,
spk_0
she stays in that state and she actually in her dream moves past the attack.
spk_0
She in her dream goes to the emergency room, goes to the operating room.
spk_0
She's back home running errands with her hand.
spk_0
All in 10 minutes.
spk_0
All in 10 minutes, a lifetime in 10 minutes.
spk_0
Just to go back for a second, it's just because in terms of therapy,
spk_0
you know, often like I'm working with traumatic with patients to fat trauma.
spk_0
And the idea is to help them, you know, work through the emotions,
spk_0
is to sit with the thing that makes them anxious or uncomfortable long enough.
spk_0
For sure.
spk_0
Yeah, exposure long enough to get through it and resolve it and then move on.
spk_0
But often when people as soon as they get, you know, the cortisol comes or whatever,
spk_0
they want to avoid it and they never get through that.
spk_0
So maybe that being in the stream state allowed her to get past the anxiety part of it,
spk_0
enough so that her brain was able to pass us.
spk_0
We're thinking along similar lines.
spk_0
So first of all, we followed her for a day, a week, a month, the year.
spk_0
And what is still remarkable to me is she's able to just talk about this attack.
spk_0
No nightmares, like, you know, she's basically, she's functional.
spk_0
She's a functional person who is recovered from trauma.
spk_0
You're seeing you to a 10 minute dream.
spk_0
Well, we've done it now about 600 times.
spk_0
And patients.
spk_0
So we've been, this is clinical care.
spk_0
This is gentle clinical care that now we've added, you know, an observational study
spk_0
on top of the, just seeing what happens when we do this at scale.
spk_0
And, you know, the technique isn't perfect.
spk_0
We have, you know, somewhere between 60 and 85% hit rate for getting patients to have these vivid dreams.
spk_0
And I can tell you, you know, the things that patients say upon awakening,
spk_0
you know, this was more real than real.
spk_0
I expected to be somewhere else.
spk_0
Patients are having a very powerful experience.
spk_0
It's more than just regular dreaming.
spk_0
And do you find that they're less anxious after or less?
spk_0
Well, so what we actually, the real clincher, or what was so surprising is, you know,
spk_0
just by chance, two patients that came through the Stanford operating rooms had bona fide PTSD.
spk_0
In both cases, coincidentally, it was the loss of a child.
spk_0
An adult, an adult child, either due to drug overdose or suicide.
spk_0
You know, again, a horrible thing to live with for years.
spk_0
And, you know, as you can imagine, nightmares about trying to save your child, like it's really,
spk_0
we didn't know this before they went to sleep.
spk_0
This all came up in the immediate aftermath, where putting them into these states for 10 to 15 minutes,
spk_0
they emerge one of our patients, mayor, and she's, there's a story on the Stanford Med School blog now, detailing her experience.
spk_0
She dreamt, you know, she re-experienced the birth of her son instead of being a traumatic birth.
spk_0
It was joyful.
spk_0
She was reunited with her son and with her family.
spk_0
And they were, and listening, we have a video also on our, on my lab website.
spk_0
It still gives me chills actually to even listen to, and that she said, thank you for this, you know, being able to have that experience.
spk_0
And, you know, mayor, you know, and the, and the, and the patients who tell us these things have invigorated,
spk_0
and, you know, a small army of people in the operating rooms who are now like trying, you know, they want to do this.
spk_0
But then it's transformative. After the fact, then there was a set about these traumatic events.
spk_0
She's had nightmares her entire life, and especially after this, you know, this traumatic event.
spk_0
And now, you know, what she's telling us, a year later, is that she had not had nightmares.
spk_0
So what, I mean, what this tells me is that, you know, however you get to these transformative experiences,
spk_0
whether it's, you take MDMA, and that allows you to sit with the trauma and work through it and process it,
spk_0
you in this sort of drug-induced dream state that allows you to sit with the trauma and process it,
spk_0
or the psychedelic experiences, and even these intense placebo experiences,
spk_0
there is something about the psychological effect of sitting with things, I even working through it,
spk_0
and however you can, psychedelics are way to get there, but they're not the only way.
spk_0
This woman, that sounds wonderful, but it's just one other thing.
spk_0
You said there's several hundred, or it's most patients, or most patients.
spk_0
So most patients, so again, this is, we're doing this in the, on the background of providing clinical care.
spk_0
So these patients...
spk_0
They all come in again for other types of surgery.
spk_0
Yeah, they're coming in for, you know, thyroid surgery, you know, plastic surgery, you know,
spk_0
all of the breast-pastures.
spk_0
So they get, and it's a cocktail, but the goal is always the same.
spk_0
It's during emergence, we are targeting a state, right?
spk_0
In the, whether we see, we've had patients report this with sevalp foreign, with propylfall,
spk_0
with propylfall and Remy Fenteno.
spk_0
This again, this hits at the point, it's not the drug itself.
spk_0
It's not the drug itself.
spk_0
So that being said, in terms of what we're starting to learn from the science and from these experiments,
spk_0
is that it's not necessarily the chemical molecule itself that's having the impact on transforming these patients
spk_0
or people who have anxiety and mood disorders.
spk_0
It's the psychological experience that seems to be the most impactful therapeutic here.
spk_0
And trying to understand what are the bounds, like how do we define that?
spk_0
Like, what are the characteristics that need to be present?
spk_0
In order for it to be transformative.
spk_0
At the end of every episode, we ask a perception marks question.
spk_0
And our question today is, what aspects of yourself are you now grateful for that in the past you struggled with or hated?
spk_0
I can give, I can speak up.
spk_0
I used to start as a little child, and I went to a local therapy for like six weeks, and I was, you know, I just couldn't.
spk_0
So, 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 a situation where I needed to control my language.
spk_0
And I don't know because it was when I was nine in ten and eleven, I did the sort of mindfulness training, et cetera.
spk_0
Then I managed to overcome that, and you said, as a way to learn how to give talks and how to convince people.
spk_0
So I think this has turned to benefit.
spk_0
Might even over compensate it.
spk_0
Sorry, really.
spk_0
Thank you.
spk_0
Injust.
spk_0
So what, one of the things, you know, I have younger brothers, ten years younger, but so for ten years I was an only child, and I developed, you know,
spk_0
ten years, I was very, you know, in my own world.
spk_0
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 they would marinate and stew, and one day, you know, during my PhD, something clicked, something clicked being in a lab in my mentor,
spk_0
or Pablo Castillo really nailed this for me in the arguing, the joy of, you know, exposing yourself and your ideas.
spk_0
It takes a certain amount of courage or a jump.
spk_0
It's, you know, 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.
spk_0
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, you know, some of them didn't survive.
spk_0
But, you know, we have the same 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.
spk_0
That's the power of discourse, which I think we're losing now.
spk_0
A lot of people are, you know, trigger warnings and safe spaces and whatever, but that's actually be able to have, you know, arguments and discourse.
spk_0
It's also deeply enjoyable. I can engage in this community of people.
spk_0
Yeah, absolutely.
spk_0
And it shifts your perspective and your ideas.
spk_0
So, so my, I think, I don't know if 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.
spk_0
I, a lot of the time, and this was like, you know, in the 90s and the early 2000s just wasn't taken seriously.
spk_0
If I was too feminine, like wearing makeup, dress, whatever.
spk_0
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.
spk_0
I placed those life-offs for it and Harvard and all the, and there was this unconscious bias and stereotype.
spk_0
And if I would walk in to give like a lecture or a keynote, immediately expectations were lower.
spk_0
If I was more, let's say, feminized.
spk_0
And so I really tried to like hide that aspect of myself.
spk_0
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.
spk_0
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 of I come in like, oh, you're the keynote.
spk_0
And then they have lower expectations.
spk_0
For other, some of like crystal comes with the German acts whenever they're expecting to say something very intelligence.
spk_0
But it doesn't.
spk_0
And then it doesn't, and it's a big disappointment.
spk_0
Whereas I have this free advantage where I, they have lower expectations and then I can, you know, show what I want.
spk_0
But I know so I'm very grateful now for that.
spk_0
But that was a part of myself that I used to kind of try to downplay and so yeah.
spk_0
That's mine.
spk_0
It's superficial, but I think still meaningful.
spk_0
That's that that's pretty deep.
spk_0
spk_0
Well, I want to thank you, Boris, for being here with us today.
spk_0
Thank you.
spk_0
Thanks for having me.
spk_0
This is a lot of fun.
spk_0
Fascinating conversation.
spk_0
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 your guests.
spk_0
And check out other questions on the website at unlikelyflaborators.com.
spk_0
You could also subscribe to our YouTube channel and watch the show or listen wherever you get your podcasts.
spk_0
This has been Science of Perception Box created by unlikely collaborators in partnership with pod people.
spk_0
I'm Dr. Heather Berlin.
spk_0
I'm Dr. Christoff Kohl.
spk_0
Thank you very much.
spk_0
You
Topics Covered
psychedelic experience
anesthesia and consciousness
psychedelics research
therapeutic psychedelics
ketamine therapy
MDMA for PTSD
neuroscience of perception
perspective shift in therapy
psychoactive drugs
deep disconnection in anesthesia
anesthesiology and psychedelics
mental health therapy
psychedelic-assisted therapy
neuroscience and psychiatry
consciousness and anesthesia