From Our Neurons to Yours

Psychedelics, placebo, and anesthetic dreams | Boris Heifets (part 1)

• Wu Tsai Neurosciences Institute, Nicholas Weiler, Boris Heifets • Season 4 • Episode 2

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Psychedelics are a hot topic in psychiatry today.  They’re producing dramatic reversals for patients with severe depression, PTSD, and other mental health conditions. But scientists still have fundamental questions about why these drugs are so effective.

For example, is the "trip" even necessary? Some think it is not and are working to design drugs with similar brain chemistry but no psychoactive effects — “Taking the trip out of the drug.”

Others suspect that many of the benefits of psychedelics can be attributed to hype and expectation: People expect to get better, so they do.

Normally scientists control for placebo using a blinded study where patients don't know if they're getting the real treatment or a sugar pill. But how are you going to do this with mind-altering substances? Patients are probably going to figure out pretty quickly whether they got a sugar cube with or without LSD.

Today's guest, Stanford anesthesiologist Boris Heifets, has come up with a particularly clever strategy to tease apart the psychedelic experience, biochemistry, hype and placebo. 

Listen for the whole story!

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Depression, ketamine & anesthesia:

Anesthetic dreams and trauma recovery:

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Nicholas Weiler:

Psychedelics are an incredibly hot topic in psychiatry today. They're producing dramatic reversals for patients with severe depression, PTSD, and other mental health conditions, but scientists are still debating why they work. Part of the problem, of course, is historical. Research on these substances was banned for decades and is really just getting started again.

On top of that, there are aspects of psychedelics that make them particularly hard to study. For one thing, animal experiments are not super informative. Just try asking a mouse about its experience on magic mushrooms.

This means scientists are still asking fundamental basic questions about psychedelic therapy. For example, is the trip even necessary? Some think it's not, and are working to design drugs with similar brain chemistry, but no psychoactive effects, taking the trip out of the drug. Others suspect that many of the apparent benefits of psychedelics can be attributed to hype and expectation. People expect to get better, so they do. Mental health conditions are notably sensitive to placebo effects and the enthusiasm surrounding psychedelics make that a very real concern.

Normally, scientists control for placebo using a blinded study where patients don't know if they're getting the real treatment or a sugar pill. But again, how are you going to do this with mind-altering substances? Patients are probably going to notice pretty quickly whether they got a sugar cube with or without LSD.

Get ready for a deep dive into the science of psychedelia, the challenges of science, and the importance of meaning in human resilience. This is From Our Neurons to Yours, from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science.

Disentangling the psychedelic experience, the biochemistry, the hype, and the placebo effect is at the heart of understanding the frontiers of today's renaissance in psychedelic therapy. Today's guest is a Stanford anesthesiologist who's come up with some particularly clever strategies to tease these factors apart.

Boris Heifets:

My name is Boris Heifets. I'm an MD PhD, an anesthesiologist, I'm an assistant professor in the Department of Anesthesia, and I have a courtesy appointment in psychiatry because I spend a lot of time working with psychiatrists. My lab studies really psychedelics and other non-ordinary states of consciousness in both animal models and in human subjects research.

Nicholas Weiler:

We love ordinary and non-ordinary states of consciousness here from Our Neurons to Yours. Well, Boris, thank you so much for coming on the show.

Boris Heifets:

Glad to be here.

Nicholas Weiler:

So the reemergence of psychedelics into the mainstream of psychiatry is one of the most talked about topics in mental health these days, I would say. There've been reports of psychedelics treating a wide array of conditions, from depression to post-traumatic stress disorder.

But a lot of that has been covered very extensively. And what I'd love to talk about today is there are some angles that I have not seen covered in depth, which have to do with answering the sort of fundamental questions of do these things really work? What are the effects that we are seeing here?

In medicine, to test whether a treatment is effective, you need to do a controlled trial where some people get the drug and some people don't, and you see what the actual effect of the drug is. But I can imagine it's very hard to do that with psychedelics.

Boris Heifets:

Yeah. I think pretty much everyone knows within an hour of the dosing session whether they're in the placebo group or not. And this is where we get into some real difficulty, right? Because as you laid out, the thing you would typically do is a randomized controlled trial. You'd have a placebo group and an experimental group, and that works great for blood pressure meds, it works great for infectious disease. When the thing that you're trying to manipulate is consciousness itself, that gets a little trickier.

The central kind of vibe, the vibe that you get from a lot of researchers here is that insight into your own condition is a fundamental component of the psychedelic therapy. You get a different view of yourself. What is the central conceit of a randomized controlled trial is that you are blind to what is happening to you. Those things are fundamentally not.

All of that is to say that we need better ways. You can't just do the same sort of placebo controlled trial with psychedelics where you're basically trying to kid people or keep them from having that sort of insight. It fundamentally is not how it works in clinical practice, like how these therapeutics are likely to be used. Does that make sense?

Nicholas Weiler:

Yeah, it does. I like the idea that part of the fundamental goal of psychedelics is insight, and so we need to think about that more. So you did a study where you said, "Well, let's try to separate the effects from this experience of consciousness." So why did you want to do that? And can you tell us what you did in that study?

Boris Heifets:

Sure. So this is where we anesthetize people and then gave them ketamine. The basic idea here is we think about the complexity of psychedelic therapy. I'm not going to rehash all of it, but there's a lot of preparation time, a lot of therapeutic support, a lot of expectation setting. And then there's the day itself, where you spend hours potentially in an altered state of consciousness. And then there's the aftercare, the integration where you make sense of what happens.

Now, there are a lot of things going on there, any number of which might be important to therapy. So the way that we've broken it down is there's the biochemical effects of the drug, think SSRIs, for example, maybe biochemically encoding resilience into your neurons, whether you're aware of it or not. Then there's the trip, the experience itself. Then there's all of the other, the non-drug factors. You can call it hype, you can call it placebo effect, but really we're talking about the drug effect, the experience effect, and the non-drug factors that surround that.

So one of the ways you can get at it is, well, describe the other approach people are taking, which is taking the trip out of the drug. And that's work done by David Olson, Bryan Roth, many other great, great scientists where they're basically re-engineering the psychedelic molecule so it doesn't have those subjective effects. Now, have they succeeded? Well, we won't know until people start taking these drugs.

Nicholas Weiler:

These are all work in progress.

Boris Heifets:

Clinical trials are just started. So we took a little bit of a different approach which says, well, what if we were able to give people a drug, but basically null the effect of the experience? Like if you're unconscious, if you're under general anesthesia, there is no experience to speak of.

When you go in for surgery, you close your eyes, you get put off to sleep, and then you wake up and people will often say like, "Is it over?" Like no time has passed. It's not the same as sleep.

So we took advantage of this actually. Again, I'm an anesthesiologist and that makes anesthesia my hammer and every problem a nail. So we have patients every day that are coming in for surgery, many of whom have unrecognized depression. And we know that ketamine is a drug that's in this broad family of psychedelic class molecules where it's psychoactive, it works fast, and its effects long outlast its lifetime in the body. So the drug is gone, but people are still feeling better. That's what really puts it into this category.

People have really gone back and forth. How much does the trip matter, that dissociative, floaty feeling you get while you're on ketamine, that altered state? There are some evidence both ways, but no one has really been able to get at it. So the way that we approached it is, well, all right, we had depressed patients here for surgery, generally anesthetized, let's give them ketamine or placebo the same way you do in a psychiatry trial and then see how they do.

Nicholas Weiler:

So one quick question, just as a point of clarification to make sure I understand. The people who were coming into this study were people who were coming in for some kind of operation where they already needed to go under general anesthesia, and they also happened to have some sort of significant clinical depression as well. That was your selection criteria for that study, correct?

Boris Heifets:

Yes. These were patients that we screened specifically. They were already scheduled for surgeries like hip replacements, knee replacements, hernias, things like that. And they filled out questionnaires rating their depression symptoms, and then we worked with psychiatrist Laura Heck, who interviewed them, and we got all of our formal measures that way. But these were patients with moderate to severe major depressive disorder, some of whom were treatment resistant.

Nicholas Weiler:

Got it.

Boris Heifets:

And those were the folks that we were looking for.

Nicholas Weiler:

Got it, got it.

Boris Heifets:

So that was the setup.

Nicholas Weiler:

Okay, so now you can do placebo control because neither group is going to experience anything.

Boris Heifets:

And before I say anything about what we found, that is one thing we succeeded in. This may be one of the only, if not the only actual blinded study of a psychedelic class drug. People could not guess what group they're in reliably at all.

Nicholas Weiler:

Exactly, they're unconscious. Now you've successfully taken the trip out of the drug. What did you find about the effects? Did it have any effect without that experience?

Boris Heifets:

Usually, people who have surgery and anesthesia do not get spontaneously better. They have higher rates of heart attacks, strokes, delirium, kidney injury. These are things we worry about in anesthesia. So we were expecting that basically those folks, people wouldn't get better unless maybe they got ketamine and then they would.

So the first part is, well, what happened to the ketamine group? Everyone got better, awesome. By a lot. More than half of the patients had a treatment response, meaning they cut their symptoms in half. And 30% of patients had what we call a treatment remission, where they really had minimal symptoms of major depressive disorder. These are folks with treatment resistant depression in many cases and pretty reasonable severity.

Nicholas Weiler:

And I think I read that that's sort of par for the course on other studies of ketamine, right? You're getting sort of a similar effect.

Boris Heifets:

Exactly. All right, so far so good. Then the placebo, we saw the same thing, exactly. We could not separate placebo from ketamine.

Nicholas Weiler:

Wow.

Boris Heifets:

The placebo group, again, contrary to our expectation that we'd see a flat line for the placebo group, these patients also got better. I remember after one of our patients, such a tough case, she came in without giving too much detail, she was in a bad way. Chronic pain layered on top of depression.

And when she came out of surgery, she was telling me about how, "I'm so glad to have been in this trial. Things happen that were outside of my control, but suddenly I could deal with it. I took all of my nursing exams from my hospital bed." This is as she's suffering a pretty significant complication of surgery. That kind of recovery, at that point, I said, "If she didn't get ketamine, I'm done with medicine. I don't know what..." Or else, I want to know what she got. What-

Nicholas Weiler:

Right. And she was in the placebo group?

Boris Heifets:

She was in the placebo group.

Nicholas Weiler:

Oh my goodness.

Boris Heifets:

It made me crazy. It still does. It's amazing.

Nicholas Weiler:

Okay, so what does that mean? Does that mean that ketamine doesn't do anything? It's all placebo.

Boris Heifets:

That's actually not what I take away from the study. And I got a lot of, let's call it not exactly fan mail.

Nicholas Weiler:

Right, I can imagine.

Boris Heifets:

From a lot of diehard Ketamine fans. But what, if nothing else, again, think about what we were thinking the study would show. We were thinking that just like every other organ system, depression would not get better. And that's what actually people have seen over decades, is that when you monitor mental health in the context of having surgery and anesthesia, patients are not getting better, they're getting worse. Yet we saw this massive improvement in mental health that in many cases was sustained.

So we were able to generate a very large treatment effect on par, with all the Ketamine studies done in the last 15 years, and honestly, on par with the psilocybin studies for major depressive disorder and treatment resistant depression with our placebo effect. What that tells me is that non-drug factors, this stretches even the term of placebo because this is not just, I gave you a pill and tell you to trick yourself. Right?

Nicholas Weiler:

Right.

Boris Heifets:

This is we're setting expectations for the patient. We're consenting them for a therapeutic trial. We're telling them we're interested in their mental health. We're there with them through the stressful journey. There's a big event at the middle. So just think of all of the structure in this study is very similar to what patients go through in a psychedelic trial. They're hearing a lot about it. They'll have to kind of work to get into the study. There's a big event, a psychedelic journey at the middle, and then there's just aftercare. We had a lot of those same elements actually.

Why is it that we attribute, in those psychedelic studies, all of that to the drug and not to just the structure of the trial itself? The overall, I would call experience of being in a highly charged, meaningful clinical trial, meaningful to the patient. To me, that's what our study showed is that if you do placebo right, you can engender hope in people. You give them something to look forward to, a turning point that this is the day that I'm going to turn it around.

Nicholas Weiler:

Right. Well, so what this does suggest is that you don't really need the drug for some of these effects, but you do need the expectation of improvement.

Boris Heifets:

You need the expectation of improvement and you need something. You need something at the middle of it. If I were an FDA regulator, I would say, "Well, you don't need the drug, then you don't need any of it because the other stuff isn't real." And I'm using my air quotes here. It is very real. You're going through something.

Think about if you've ever had anyone in your family or even know anyone who's had a heart attack, people become vegan and kind to their children after a near-death experience in a way that nothing else has been able to do. People have transformative life changes after major experiences, and we inadvertently, in this trial, created that with the trial and the context of surgery and anesthesia.

So to say it's not the drug, I think is kind of understating what is going on. There's ritual involved. It's not new, actually. We've known about the role of these things in mental health and gluing society together for millennia likely. The ritual, the expectation, and then the cohesiveness of that experience is important for transformation.

Nicholas Weiler:

Right, and not everyone who would like to get better from depression then necessarily wants to go through major surgery and go under anesthesia. So having a very intense and potentially meaningful experience that's induced by psychedelic substance in the company of a trained therapist and so on, that's also going to give you this opportunity to reset, opportunity to change, opportunity to believe that you will get better. Is that sort of the way you're thinking about it?

Boris Heifets:

Nick, you hit the nail on the head. For many people, how do you practice mental health care at scale? You can't give a near-death experience to everyone. That's not safe. I don't think the FDA a would approve.

Nicholas Weiler:

It's a science fiction story in there.

Boris Heifets:

You can't jump out planes, you can't send everyone on a vacation to Mexico an, Eat, Pray, Love situation.

Nicholas Weiler:

Right.

Boris Heifets:

But what you can do is give a lot of people a drug with well characterized effects that has little physiological toxicity but generates an intensely meaningful experience. LSD, psilocybin, ketamine, that's the category I put these in. But it leads you, if you buy my chain of reasoning, it leads you to a different place than the startup world around psychedelics is going. Because you could take away from all of these studies that we finally found the switch that makes your neurons resilient and resistant to stress. You don't even need to be there for it, we can just biochemically flip that switch, take this pill every day. I'll see you in a month, you're going to get better. That's like the non-hallucinogenic, psychedelic.

Nicholas Weiler:

Right. So the people who want to take the trip out of the drug biochemically.

Boris Heifets:

Yeah.

Nicholas Weiler:

To make a drug that does something to the brain, but you don't have the psychedelic experience.

Boris Heifets:

And I'll just put a plug. I have kind of an adversarial collaboration with one of the big labs doing this, David Olson's lab. He's founded a company on that basis, Delix. They're testing it in humans. I think it's worth testing. I don't think it's going to work, but empirically, we'll have an answer of whether that approach is viable.

Nicholas Weiler:

I love that idea of adversarial collaboration. That's the way science should be done, right? I don't agree, let's see what happens.

This is so interesting. So you've succeeded, in this first study that we've talked about, in taking the trip out of the drug. But what they have is they've got this expectation, they've got this being part of a trial, being part of this experience and believing that that might make them better. And many of them did, in fact, get better.

Now, you just had another study come out that did sort of the opposite, which took the drug out of the trip. So could you tell us a little bit about that? Was that a similar group of people that you're doing this study where you're giving them a hallucinogenic-like experience but without a psychedelic drug used at all?

Boris Heifets:

This was not a straight path to that result. We were wrapping up, and a lot of credit to Teresa Lee, who is now on faculty here who led the first study, the ketamine and anesthesia study. As we're wrapping that up, I started also working with another anesthesiologist, Harrison Chow.

And Harrison has been doing something interesting in the community before he got back to Stanford. He has been developing this idea that patients coming in for surgery, as long as you're getting lightly anesthetized for these minor procedures, maybe we can induce a dream-like state that some people just find pleasurable. If you talk to people after colonoscopy, some people say it's the best sleep they've had in their life. They'll come out with actual euphoria. And sometimes if you talk to the-

Nicholas Weiler:

Makes it sound nice.

Boris Heifets:

Well, I think it should be a selling point for the GI docs maybe latch onto. But the other thing that happens, if you talk to people right after they emerge from anesthesia, about 20% of them, give or take, will actually tell you about dreams. For the most part, again, anesthesia, our goal is we want you to not remember and not feel anything during surgery. Dreams is really pretty far down on the list. And actually, in some ways, it's a little bit scary. How much do you remember? Were you asleep or were you anesthetized? That's sort of always been in the back of our mind.

Nicholas Weiler:

Because anesthesia is not the same as sleep, right? It's a different brain state.

Boris Heifets:

It is not the same as sleep. One way, depth is kind of not a really complete way to describe it. You can't really think of sleep and anesthesia as just one long road down to the bottom of a hill. But for our purposes, anesthesia is a much deeper state of sedation than sleep. Different brain state, for sure.

But when you talk to people, they'll sometimes say that they dreamed. And what Harrison, again, a lot of credit to Harrison here, he's been inducing this dreamlike state on purpose, as patients come out of anesthesia. It's a nice thing to do if you have the time to do it. And what he found out in the community was, well, patients really seem to, some of them really respond well to it. "I feel better. My anxiety is lifted."

And when we started working together about four or five years ago now, he told me about this and I thought, "I've already been sort of working on psychedelics." This kind of rung true for me. Something was interesting here. And we basically got a team together, psychiatrists, anesthesiologists, basic scientists, EEG experts, and we set out to capture these events. And I'll tell you about a couple cases we found where it's not just people having dreams.

We've done this now hundreds of times just in the context of regular surgery. And by chance, a few of the folks that have come through our operating rooms have had bonafide mental health issues. In particular, there are three patients that we've reported on that had stress disorders, acute stress disorder or post-traumatic stress disorder. I'll tell you briefly about the first case, and this is published already a couple of years ago.

So she was attacked by a family member, pretty intense. And she had defensive injuries in her hand. And she went to the emergency room, they patched her up and they said, "Go to Stanford, get your hand fixed." So Harrison, we encountered her in the pre-op area. She's still basically inconsolable. Harrison says to her, "This is the plan. You're going to have a nerve block in your arm. They're going to fix your hand and you will snooze through this and you might..." Really no cueing here.

And then in the course of surgery. So he's watching the EG, we've gotten this together at time. And what she says when she wakes up, he's identified the state I think is dreaming. And she wakes up and then her heart rate is going like 125 beats a minute, and she's almost in tears like, "It's over." And I think she said those words. And what she related was this dream that she had. And that she had had the same nightmare she'd been having for the last two weeks, this nightmare of being attacked. And just at the moment of the attack, she rockets into consciousness, that's a nightmare.

Except this time, under anesthesia, instead of waking up, she moves past it. She moves past the attack. She dreams of going to the emergency room. She dreams of going to the operating room. She dreams of being back home, using her hand, running errands and being whole again.

Nicholas Weiler:

Wow.

Boris Heifets:

And that was, even at that point, I was thinking, "This is wild. This is an amazing story, but is this going to help this woman long-term?" And we followed her for a day, a week, a month, a year. And she basically no longer has any symptoms. This is someone we would've expected, after an attack like that, to go on to post-traumatic stress disorder, where they don't engage, they can't talk about the event, they have intrusive thoughts. And she's able to recount the event very kind of calmly. She doesn't have nightmares. It's a real recovery.

Nicholas Weiler:

So somehow this dream state created some sort of resilience.

Boris Heifets:

Or, there's a lot of theories about dreaming and memory, that she was finally able to process this traumatic memory, reconsolidate it in a way where she wasn't hyper-excited, hyper-vigilant, just by virtue of the anesthetic that's maintaining her in this state.

And just to bring this back, we already started thinking about, upon seeing these cases, it was very hard to listen to this very intense story and not think about all of this work we're doing with psychedelics where patients are recounting similar sorts of recoveries from PTSD with MDMA-assisted psychotherapy. It's a different sort of thing from a psychedelic, but it's in the same class where they're in a safe place where they can revisit, where they can touch those painful memories and work through them and they're better. Afterwards, they feel some sense of catharsis, relief, reconnection, reintegration.

So this was extremely interesting, we found two more cases. These were published just last month in the American Journal of Psychiatry. Both of these women had actually lost, coincidentally, again, they were coming in for surgery that was unrelated. Parathyroidectomy, a breast biopsy, not related to their trauma, which, in this case, coincidentally, both of them had lost adult children to suicide or overdose. Horribly traumatic.

And what you can see in the linked video, Mare, one of our patients, she told her stories. That she's, during this anesthetic dream, which we're doing on purpose, Harrison is an artist of recognizing these states that we're trying to now formalize. But what she's telling us on awakening, "It's more real than real. I thought that they would be with me in the room. I was reunited." She had a very phantasmagoric experience where she's reliving the birth of her lost son and reunited with him. And together with her family, and they're all together. And what comes through in talking to her is just the joy, the relief, the intensity of just closure, some kind of closure.

And again, we followed her out for a year. She hasn't had nightmares. This is someone who'd had nightmares about her son and trying to save him. Months, months and months and months and months, years. And it's hard to ignore something like that. It's also hard to not see some real connection to all of the importance we're placing in psychedelic therapy on the drug. To me, these stories place human experience at the center of these recoveries. What we're seeing here, again, these are observations. This is not a controlled trial.

Nicholas Weiler:

Sure. This is us trying to understand this very confusing experience.

Boris Heifets:

These are psychedelic-like states. These are, again, a lot of intense emotionally-laden imagery, a lot of stuff coming forth. And some of the neurophysiology is actually, this looks similar too, which we can talk about. But that's all without a psychedelic. There's no ketamine involved, there's no psilocybin, there's no MDMA. It's propofol. Propofol, the anesthetic, which knocks people out.

Nicholas Weiler:

So yeah, it seems like the linking factor here between these studies is, just as you're saying, it's not the drug, it's not the physiology potentially, because people in the first trial we talked about got better just by having the experience of going through the trial itself and going under anesthesia and coming out and thinking they might get better. And in the second study, people had an experience that was, in some ways, dreamlike, like a psychedelic trip, but didn't have a psychedelic drug. They just had these intense anesthesia-related dreams.

It sounds like the common thread here is that the experience of being in a trial or the experience of having this sort of lucid dreamlike state that's induced by anesthesia, it's those experiences themselves that may be therapeutic.

Boris Heifets:

Yeah. And one of them is contained within the context of the anesthetic itself, but one of them is just this broader idea. In one case, these patients are in a trial. In the other, we're just making observations, and they have an internally-generated experience under anesthesia. But if you want to draw a circle around it, all of these things are pointing to experiences that are powerful, that had nothing to do with psychedelics per se.

They check all the boxes for what is happening in these trials, like the experience itself, the expectancy associated with the trial, the big event at the center, whether or not you're there for it. We've basically danced all the way around doing it with the molecule itself.

Nicholas Weiler:

So what does this mean for the field of psychedelic medicine? Should we be doing dream therapy instead? What do you think this means next?

Boris Heifets:

This gets back to any potent therapy, by definition, carries risk. So we don't know enough. If we think that we're doing good, we may also not be doing good, and we need to understand this before we go at scale.

What it does mean, and I think that the lesson here is really a lesson of humanism in that maybe we can't scale psychedelics as quickly as we want where you open a pop-in clinic to take psilocybin and melt your depression away. It has to be couched in some sort of context, like it needs to mean something. There needs to be ritual, there needs to be a context for these powerful experiences that we should not try and chip away at by removing the therapeutic components, by not requiring any of those safeguards, by reducing the intensity of the experience in the hope of making it more palatable somehow, which is absolutely where this field is going.

Nicholas Weiler:

It's the experience itself and the intensity of the experience that may be doing the trick in ways that other things have not for these people. Well, that is a really powerful place for us to end. Just thinking on that, I'd love to have you back on Boris to talk even more about this fascinating topic and what we're learning about the nature of psychedelics and where those experiences are coming from.

Boris Heifets:

Happy to do it. Thanks again, Nick.

Nicholas Weiler:

Thanks again to our guest, Boris Heifets. We'll include links for you to learn more about his work in the show notes. And stay tuned. Next week, we're going to continue the conversation with Boris and talk more about the neuroscience of altered consciousness.

If you're enjoying the show, please subscribe and share with your friends. It helps us grow as a show and bring more listeners to the frontiers of neuroscience. We'd also love to hear from you. Leave us comments or give us a shout out on social media at Stanford Brain.

From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios, with production assistance from Morgan Honecker. I'm Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute. See you next time.