Plain English with Derek Thompson - The Truth About Ketamine: Depression Cure, Health Fad, or Placebo?

Episode Date: December 22, 2023

One week ago, Matthew Perry’s autopsy report came back, finding that the ‘Friends’ actor died from the acute effects of ketamine overdose. His death has sharpened focus on the popular and controversial drug. Ketamine has been hailed as a miracle cure for depression and anxiety, criticized as a VC-fueled fad, and investigated as a placebo. But what is ketamine, what is its history, what do we know about how and why it works, and how could it help hundreds of millions of people with depression and anxiety? Today’s guest is Boris Heifets. He is an assistant professor of anesthesiology at Stanford University and the author of a much talked about and utterly fascinating study on ketamine that came up with a brilliant way to test the effects of ketamine. The study's surprising results raise big questions about not only ketamine, but the curative power of belief. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Boris Heifets Producer: Devon Baroldi Learn more about your ad choices. Visit podcastchoices.com/adchoices

Galaxy Lights, Coachella, Lightning Bolt Necklaces. 20203 was the year of Scandival. On March 3rd, one cheating scandal launched a reality TV investigation that generated hundreds of conspiracy theories, thousands of podcast episodes, and millions of dollars in revenue. I'm Jody Walker, host of an American Scandival. One retrospective story told in three salacious parts. Listen, December 26th, on the Ringer Reality Feudel. feed. Today's episode is about one of the most promising and profitable treatments for anxiety and

depression, which is firmly in the news cycle today. One week ago, the actor Matthew Perry's autopsy report came back, finding that the actor from friends died from the acute effects of ketamine. He was discovered unresponsive in a pool at his L.A. home in October. Perry died at the age of 54. Matthew Perry was open about his substance abuse issues. He had reported, orderly been sober for 19 months and was receiving ketamine infusion therapy for depression and anxiety. The amount of ketamine in his system, however, was extreme, far more than the typical therapeutic dose and even more than many patients get under anesthesia. Before long, several news outlets I saw, including the Wall Street Journal, used Perry's death as a newspeg to run stories about how his

demise darkened the glow of ketamine, the head of Yale's depression, research programs said in the journal, quote, this is a wake-up call for ketamine use. As someone who reports about happiness and well-being and anxiety and medicine, ketamine has always been fascinating to me. Originally synthesized in 1962, ketamine is a powerful short-term anesthetic. It was used to treat soldiers in the Vietnam War and later approved by the FDA for broad use in pain management. For years, it's been popular as a club drug. In 2000, a Yale University study confirmed that ketamine had a significant effect on reducing depression, the first of several studies suggesting that it holds incredible promise for mental health.

In the last few years, it's been hard to think of another drug, except maybe these GLP-1s I've been going on about in the show, that has bloomed into public view quite like this one. In 2019, according to the journal, there were only about 20 ketamine clinics in the country. Today, there are 400. Revenue from treatments has grown in that time from about $10 million to almost $200 million. VC money is flowing in for several kinds of business, small practices, large wellness centers,

even virtual clinics which ship ketamine to patients after a consultation with a doctor. In many corners, ketamine is the most promising treatment for, anxiety, depression, and suicidal thinking. That is a big deal in the country where anxiety among American teens has never been higher, where suicides are rising, where 15 million Americans have one major depressive episode a year. And to be clear, from the onset, I am absolutely unreservedly rooting for ketamine to prove miraculous. But extraordinary drugs with extraordinary claims deserve extraordinary evidence. There are small studies and medical.

analyses that prove ketamine works for many, many people, but what's less clear is why? And how? Does ketamine work because of the drug itself or because of the experience that comes with the drug? In this way, you could say it's similar to other trendy drugs like magic mushrooms, psilocybin, or MDMA, ecstasy, both of which have been shown to reduce depressive symptoms for weeks or even months. All of these drugs, K, magic muisance, mushroom, ecstasy, are taken recreationally because they aren't merely this weird skeleton key for anxiety. For many people, they're just plain fun, even profound, transformational. They break the surly bonds of normal human experience. But again, that's the deep question. Do these

drugs work for anxiety and depression because of the experience they offer, in which case we could theoretically enjoy the experience without the drug? Or do they work because of the, the molecule itself, which we could theoretically design to deliver all these benefits without any kind of high. You could take the drug and still drive a car. Today's guest is working hard to answer all these questions. His name is Boris Hyphitz. He is an assistant professor of anesthesiology at Stanford University and the author of a much-talked-about, somewhat controversial and I think utterly fascinating study on ketamine that came up with a brilliant way to test this profound question, is it the drug or is it the experience? He and his team gave ketamine to people

under general anesthesia. They couldn't have a waking experience of the drug even if they tried. And the results of this study take us deep into not only the question of does ketamine work, but the bigger question of placebo effects and the incredible power of belief in science and medicine. I'm Derek Thompson. This is plain English. Dr. Boris Haifitz, welcome to the show. Thanks, Derek. Nice to be here.

So the death of Matthew Perry and the news of his ketamine overdose has cracked open a ton of questions about ketamine in the news media, and it has really reinvigorated my interest in this subject as someone who's reported on anxiety and depression and the frontier of medicine. I want to begin with an extremely 101 question. What is ketamine? How would you? define it as a scientist and why do you think it has exploded in popularity in the last few years?

Ketamine is a synthetic drug. It is synthesized about 60 years ago and it's been in medical practice for over 50 years now. It was first approved in 1970 as an anesthetic. But the real advance was with ketamine as a anesthetic drug was that when you would give it to people, they would, still breathe, right? So you wouldn't have this issue with a lot of early surgical anesthetics where you give anesthesia and then not only does the patient become insensate, they also stop breathing and you have to support their vital functions. So it got a lot of use, right? So this is right before the Vietnam War, as a battlefield anesthetic. Again, extremely useful where you can help, you know, folks who have life-threatening injuries, give them some relief, and also,

you know, allow them to maintain their vital status, breathing, heart beating, all that stuff. So we've got this anesthetic that we've used in the battlefield that keeps people awake. Now, fold that into the story of how it became one of the most promising anti-depression drugs. You know, the history of mental health, looking for mental health treatments in medicine, is mostly been accident and happenstance, and ketamine is no different. And what researchers were looking for 20, 25 years ago was something that would mimic the effects of schizophrenia. And what they found was something that, for some reason, these people who are taking ketamine feel better immediately from depression.

It has nothing, and it didn't seem to have anything to do with schizophrenia in particular. And that really set it apart. The first thing that people noticed about ketamine was that it works fast. And one of the ongoing complaints about drugs like Prozac, Axel, SSRI-type drugs, is that they take a long time to kick in, right? Is that you start taking it and then you sort of have to ask yourself, like, is it working it? And after three or four weeks, eventually you start feeling better. Some patients, not everyone. a lot of people don't respond to SSRI-type drugs.

That was the other thing about ketamine in these early studies. Everyone seemed to be getting better. Not everyone, but like 60% of patients, big numbers, big numbers, meaning 60% of people with treatment-resistant depression, meaning they've already been failed by many conventional treatments. And then they take ketamine, and then they have a 60% chance of, cutting their symptoms in half, right?

Those are big numbers. And that got a lot of people's attention. And the first, I'd say, 10, 15 years of studies on ketamine, this is basically from 2000 to 2015, is that people just reproducing this thing. And this really, it starts looking like a revolution and that we've never seen this before. This is not usually how mental health treatment works.

And it starts looking much more like something we see, for example, in surgery, which is where I spend most of my time in an operating room, where, you know, you see a problem and you're basically able to see the result immediately, which is, you know, again, not something that we're used to seeing in mental health. Before we go deeper into ketamine, I want to bring in a few other drugs where there's this question of, is it the drug, is it the experience? There's ketamine, there's psilocybin, magic mushrooms, There's MDMA, Ecstasy. I feel like this is an interesting trio of drugs

where we want to understand why does it seem like they have this effect on depression on top of this experience they're delivering. It is really hard to miss the thing that binds these together, which is, again, different from pretty much everything that's come before in mental health treatment, which is that they are profoundly psychoactive. They work fast, as in people will see,

say that they feel better and less depressed within hours or a day. And the other thing is that you don't need to keep taking them. And that as soon as the drug is worn off, you're still feeling, you're still feeling better. Ketamine has left your system, you know, in a matter of hours. But a week later, you're still getting profound relief from suicidal ideation, from depression, from anxiety. And the same is true for psilocybin and MDMA. That's really what binds them together is this time course that is unlike anything else we've seen, where you have this rapid action and this duration of effect that, you know, we don't actually know how long some of these things last. Kind of mean we have a pretty good idea. One dose will last about one

week on average. Cilocybin, it could be like a single dose, a single mind-bending trip in the therapist's office with psychological support. That could give people relief. for weeks, months. MDMA, you know, the earliest studies were following people out four years after a single treatment of MDMA for post-traumatic stress disorder, and people were still reporting there better.

Now, if you report something like that, if you put something like that in a medical journal, it is hard not to get excited. Let me ask the obvious stupid question here. If psilocybin has an effect size at last months, and MDMA has been shown to reduce the symptoms of PTSD for months or even years. And I read in the research for this episode one meta-analysis in the Cambridge University press that found that the effect size of ketamine is significantly larger than many SSRIs,

okay, well, why don't we just say let a rip and just approve all of these things for mass use with the understanding that there's 15 million Americans with major depressive episodes every year and tens of millions of Americans with anxiety, what is the reasonable answer to the question, well, let's just approve all these drugs and help Americans feel great again? So there are a couple different issues there, and I want to be really clear that there is a very different conversation about decriminalization and the legal status of these drugs, that you can be put in jail for using, selling, distributing MDMA and psilocybin in 2023. And in my own opinion, I think that is a horrible use of law enforcement resources.

That is a different, different question because what we're talking about is medicine, right? We are calling these things medicine. There are a lot of reasons. Some of them are interesting, some less so, about how it is that these drugs, psilocybin, MDMA, ketamine, are being put in a medical container, meaning they're being deployed as treatments for a specific disease. So to your question, why don't, you know, they work. So what's the big deal? You know, that if there wasn't so much need in this country, you know, mental health need,

this would be a lot, a much easier conversation to have, right? But part of it is the urgency and that I think is driving this. But the bottom line is that let's say just for a second that all of the effect of MDMA, right, which is an amphetamine derivative, was all basically a sort of a placebo-like effect where people want to get better and then they take this amphetamine drug, it makes it feel great, and then they come down and they tell, you know, there are no objective symptoms, really, of whether your PTSD got better other than what you tell the, you know, the guy with the clipboard, right? So if let's just say for a minute, none of it is like, quote unquote, real, then what you're doing is, and let's say you approve the drug on that basis.

There are 50 million people in the U.S. that would meet criteria for PTSD that could get MDMA. So from a public health perspective, we're saying that like let's just like give people a high dose amphetamine, you know, that can cause substance use issues. Certainly is related to, you know, people miss you. use MDMA ecstasy all the time. That's why it's so popular. That's why it hasn't got away. I knew about it. It was called ecstasy, right? This drug has been a round time, a long around time. So the point is that there is, you know, if there's a harm associated with a drug and any drug that is potent automatically has harm associated with it, otherwise it wouldn't be potent, right? Think about that. So there's the benefit and the harm. And this idea that like, well,

It works, so let's just use it, is completely missing the risk part of the risk-benefit calculation. Everything we do in medicine is a risk-benefit calculation. Why should we be treating these drugs any differently? Once the sheen wears off, and we're 10 years into this, we're going to be looking back with a lot of misgivings about why did we just ignore all of these red flags and just move forward. So to summarize my understanding of ketamine, this is a drug that has a drug that has, been in our lives collectively for about 60 years, first used as an anesthetic that was good at keeping people alert and breathing, very important for an anesthetic, was later discovered about

20 years ago to be useful for people with anxiety and depression. Its use has skyrocketed, especially in the last three years. A lot of media attention has flowed to it. A lot of VC funds have flowed to it. But there's still this open question, I think, of what exactly, exactly is ketamine doing? How does it actually work? And you helped to publish a study earlier this year that got a lot of really interesting attention in the community of people who want to know more about ketamine. Tell me about this study that you published. What was the question you were asking and why were you asking that question in this study? So part of understanding the risk benefit, right, is you want to know how these drugs work. If you know how they work,

then you can refine them, right? If you think about the first versions of chemotherapy and then what we have now where we're literally curing some cancers, that's amazing. And that's because we understand how drugs work. Ketamine is no different in that regard. If we understand how it works, then we can refine it, make it better, faster, cheaper, safer, all of the, all the good things. So, uh, so how does it work? We have no, I mean, still, still I could safely say we have very little idea. And part of the problem, part of the problem is this, is that when we give it to people, right, we're not usually doing the kinds of experiments that would tell us how a drug works. if you really know how a drug works, you should be able to block it somehow, right?

You should use another drug to block it. Or you should be able to mimic it with a similar drug, saying we know that it buys to this receptor, the NMDA receptor, which is what ketamine, you know, the most prominent idea right now is that ketamine works because of its affinity for one type of receptor in the brain called the NMDA, not MDMA, but NMDA, receptor that's expressed, you know, broadly throughout the brain. Now, that's a cool idea. There's been, you know, an empire of mouse studies on this. But what's a little bit weird is, you know, there's about a billion dollars worth of failed drugs that try and basically

repeat the magic of ketamine that also hit this same receptor, but they do not do what ketamine does. They don't have that rapid, persistent antidepressant effect. So that suggests that we have the idea wrong. And that brings up this question. Well, is it just the experience? Is it the drug or the trip? Right? If you need, is there something that ketamine is doing, however it does it that puts people in this state, this trip-like state like psilocybin, maybe like MDMA. We don't, you know, there's a lot of questions there. Um, that is. that's the part that's important. And maybe it doesn't even matter how you get there

as long as you get that trip aspect. Or is it the drug? Is it something that, as some people would believe, you can make non-holucidogenic versions of these, and we think we can, and you can give them to people in theory, and the dendrites of their neurons, a thousand dendrites would bloom

while they're sleeping or, you know, doing the laundry, and encode resilience somehow. and they would never even, there's no, you know, there's no trip there. It's all drug, right? That's what we think about as like a biochemical effect. Tell me if this is a wrong way to restate what you're saying. It seems like some of these drugs have a dissociative effect or they produce an extreme experience. They also, however, seem to do stuff like under the hood in our neurons. And we want to know if there's a way to

deliver the benefits of these drugs without the high. Like, could we decode the ketamine mechanism and deliver a ketamine-based drug with no high whatsoever. So, like, you could take this while driving, you could take it while babysitting a nephew. It just works as well on depression and anxiety without any kind of psychedelic experience. Is that basically it? I want to put a little bit of a finer point on it. There are a couple distinctions here. One is, so ketamine has another name, is a dissociative anesthetic, right? And that, that you get that, like, real, like, I'm not in my body right now, which is a little bit different from psilocybin and MDMA. But the idea is similar, that you're clearly having a profound psychoactive effect, right,

with these drugs, and that you're getting some space, some perspective from your life, right? I think that part is most certainly common to all three of them, that people will talk about when they're people that I've treated with ketamine for suicidality and depression, they'll say things like, I could see my depressed self and then my real self, and I could, you know, I could see ways where I didn't have to be like her, right?

Things like that where you get some sort of space or, you know, and you hear stories with that same kind of arc of, you know, I finally, I can see my life in a different light. Like I have this distance, this space, this, you know, a new sense of connection and disconnection. even from the events by life. The other is, you know, how do we think about, like, what, what's accounting for these

effects? And you pinpointed a couple of things. One is, is it the trip, right? Number two, is it just the drug? You know, you can, and when we say, is it just the drug, we're really thinking this is just like all of the medicines and the rest of medicine, that they do their thing and you don't even know you're taking blood pressure medicine. It just sort of works, right?

And that's sort of a very reductionist view of how mental health works. And then, so there's the drug, there's the trip. And then there's all of this other stuff, the set and setting, right? That's a term from Timothy Leary. The things that you bring in to a drug experience like expectations, hopes, dreams. And then there is the aftermath, right? All of the stuff around that drug experience that we have this general sense, will shape the course of your trajectory.

Like, you know, how do you make sense of what happened? You go out, you have this big experience, and how do you integrate those changes into your life and make changes? Okay, let's finally talk about this study. What did you do? So in order to get at this question of, is it the drug or the trip? There aren't a lot of good ways to do that.

Except, well, what if you gave, the drug to people who were under general anesthesia. They don't know what drug they're getting. They don't know if they're getting placebo. They don't know whether they're getting ketamine. And that's one way to answer this question of is it the drug or the trip? What we did was, again, I'm an anesthesiologist, and so we use the tools available to us. We have patients coming through our hospital at Stanford all the time with disabling degrees of depression. right? So what we set out to do is basically run a psychiatry trial in an operating room. We screen patients who were reported symptoms of moderate or severe depression prior to surgery.

And while they're anesthetized, we would give them an antidepressant dose of ketamine, very well-studied dose of ketamine. That's been used in a dozen studies over the years. And then we would wake up. up. The ketamine would be long gone. And then after they woke up for the next days in the days after, we would ask these standard questions about their mood. So you administer ketamine to knocked out patients who have no way of tripping, no way of knowing with any kind of waking experience whether they're having a high. And were you surprised by what you found? So I was really surprised when I unblinded the study for our team, because everyone seemed to be getting better,

not just better, but a lot better, and there was no difference between ketamine and placebo. So this is confusing on a number of levels, actually. This is not, again, not straightforward. But the first point is, what do we expect, you know, again, I mean, we deal with patients all the time coming for surgery, and they don't generally get better if they're depressed. If anything, we worry about people getting worse with anesthesia and surgeries. What's the biggest risk factor for getting worse on mental health measures is stressors, right?

A big stress like surgery, like study after study shows how patients generally, you know, we worry, like, how do we prevent these, you know, the rise in opioid use after surgery? because, again, people have spikes in mood symptoms and pain after surgery. That's what we were expecting. We were expecting the placebo group to be just like most of these other patients in that they're not getting better and they're basically staying at a flat line. What we saw is even so the ketamine, the people who got ketamine got better, but the placebo group also got better.

And the degree they got better was surprising. About 30% of patients went into remission. from severe depression. So this is a Rorschach test for what people believe in ketamine, right? Is it real or is it bullshit? This study got a lot of attention in the psychiatry world. What do you think that people reading this study missed? The most interesting part of the study was the size of the placebo effect we were able to drive

in a patient population that does not typically see these types of placebo effects. And what does that say, moreover, about all of these studies, ketamine, psilocybin, MDMA, where at the heart of the study, you're taking a drug that puts you in an elite class of patients around the world for a drug like psilocybin. There are maybe a thousand patients in the world that have been in a clinical trial for psilocybin. And suddenly, you're either in the club or you're not when you're on that couch and you know whether you got placebo or psilocybin. And it raises a big issue, is how much of the effect that you get, right, in the aftermath of that experience, how much of the effect you get was just from knowing that you were in, like, which group you were in, right?

This idea that, like, you're in the good group, you won the lottery, the clinical trial lottery, so to speak. And, you know, and that's what's driving the results. These patients were unconscious, though. What would be the placebo effect? in this case our patients you know when we think about how we did this study we message them for weeks before surgery we told that we sent them an email we said we care about your mental health right we're already sort of putting the expectation in their in their minds and then we spend a few

hours with these patients really going through in detail all of the things that led them to this moment in their mental health state right this is just this is part of our intake and there's the consent process. And when you think about the consent, what are we doing in the consent process? Ketamine is this amazing therapy. It might help your depression. We don't know, but it might. So even if we're not explicitly saying, you know, ketamine is setting an expectation that ketamine will cure you, we're clearly introducing this in a context where it may be helpful. Just tell me very clearly one more time. What did you tell these people that might have triggered this expectation?

We told them in the consent process that you may get ketamine or you might get placebo. We're studying this because we think ketamine might help with depression. So that's the important point, is that all of these patients were informed as part of the consent process. The thing they know about ketamine now is that ketamine can have a beneficial effect in mental health. and while they don't know which group they're going to be in, it sets this expectation that if they get ketamine,

they may get better. Yes, I got it. Okay, so it seems like we have to talk about two possible explanations. I guess there's three possible explanations for this really interesting study. One is that this is a study that just won't replicate. Like, you might try this again, and it turns out that, like, there's a huge effect of ketamine and no effect for the non-cetamine.

group and maybe you run the study seven times and this turns out to be the outlier. Like I'm not predicting that's the case, but of course, you know, it's one study and maybe it is the case. The second possible explanation is that what we're dealing with here is a really, really powerful placebo effect. And there really are like powerful, like treatment effects in belief. In a presentation that I saw you give to Stanford, you talked a little bit about like the, I love the way you framed this question. You said, what's inside of a placebo effect? when we talk about placebos, what's actually happening? And you said that both positive expectations and negative expectations can have an effect.

Talk a little bit more about that. All of these studies, ketamine, psilocybin, etc., they have the same problem in that you can't really do a double-blind study with them because people immediately know the group that they're in, right? It's very hard to mask this powerful psychoactive effect. So that's, and that gives rise to. a couple things, right? If you come in with expectations that I spent so much time getting, you know, trying to get

into this trial and now I'm here and I got the placebo group, like I'm done, right? Like, it's, there's a lot of disappointment. We've talked to patients who've expressed that. And on the flip side, there's also this like confirmation. Like, I was in the right group. Like I, these, whatever happens next is has to be because of the drug. And so then you attribute these things to the drug, and that's one part of placebo. There are a whole bunch of other things happening.

One is the condition response. Every time you go to the doctor's office and they do a physical exam, that ritual, right? That ritual is sort of that also that has a healing effect. We know that. There's other types of placebo effects that beyond just instruction where I tell you what might happen, beyond just this idea of a condition response to being in a treatment environment is that just paying attention to people, right? Being in a study can have beneficial effects.

All of these things are sort of grouped in what we call placebo, but they really are different things. And it's a little bit of a disservice, actually, to just say it's just placebo. This is one of the things that has really started grinding my gears about the study is that people say it's just placebo. It's just placebo is the most reproducible effect in medicine, right? Like trial after trial, we don't, drugs work, they don't work. But placebo works really, really well a lot of the time.

You had an amazing story that you told about a woman with knife attack trauma that underwent, that was sedated. Fold that story into the picture, because that really blew my mind. I have to give a lot of credit to my colleague Harrison Chow. who's been doing this for years in private practice anesthesia, and then we finally were able to study it in a real way. What happened was we had this woman come to us for repair of her hand. Now, she'd been attacked by a relative, a couple weeks prior,

knife attack, close quarters, defensive wounds, awful, awful thing to have happened to you. And as you might expect, in the intervening two weeks between the attack and the time we saw her, she has nightmares, she's unable to live her life. It's just the event just loops over and over and over again. And she's not able to get any relief from it. And when Harrison sees her in the pre-op area, she's still, she's basically inconsolable.

And what we've been doing in the background here is we've been doing this type of anesthesia. So anesthesia's changed since the 90s. And that now you can do nerve blocks and you sedent. patients. You don't put them all the way to sleep. And so what we've been playing with is this idea that you can put patients in a state where they're dreaming. And this woman wakes up. Her heart rate goes to 150 and now she's telling the story, a mile a minute, that she's had the same nightmare. She just had the same nightmare that she'd had every night for the last two weeks. And as it comes to a quote every time

instead of ending with the attack and instead of rocketing her into conscious awareness, which is what nightmares do, instead she moves past it. In her dream, she goes to the emergency room. She goes to the operating room. She's home, running

errands looking at her healed hand, completely done. And now she's awake in the operating room in actual reality saying it's over. And we were surprised. We followed up with her. We hooked her up with the psychiatrist. We did all the formal diagnostics.

We followed her for a year. And she's, it's done. There are no nightmares. She's able to talk like, you know, just normal conversation about this like awful thing that happened to her. This is someone who would have gone on to develop PTSD, right? That's usually how these things go. And so this is like, this is an amazing thing to us because number one is, this is experience.

There's no, like there are drugs involved. There's propophol. You know, this is like Michael Jackson's favorite drug. Something that, you know, when used in this way, like, you can induce these dream states, there's no ketamine, there's no psilocybin. There's no psychedelic. But the things she's describing are so reminiscent of what we hear in these psychedelic trials of patients, you know, getting re, kind of reimagining, you know, events in their lives,

getting some sort of distance, new perspective. that it really has changed the way I thought about this. And again, if you think, you know, just going back a little bit, thinking about is it the drug, is it the experience, is it all of the other stuff around these studies? Well, each of these stories sort of gets at a different piece, and this story in particular really puts subjective experience right at the center, having a big transformational moment.

Think for a minute about what it takes. the stories that you may have heard in your own life about when people make big changes, having a heart attack, having a near-death experience, right, going on a big trip, people can often point to the date and time of their transformation, right? And again, a lot of this is bound up in ritual and intensity and having something that's sort of a central event. And in a way, that's sort of what we're creating here. with all of these different treatments,

whether it be ketamine, psilocybin, or even just this profound dream state that allows people to re-experience trauma in a safe way. So I want you to, at the end of this interview, help me resolve my own feelings about this drug, about ketamine specifically. So I think that I think a few things. One, I do think that ketamine does something

at the molecular level. People are told that SSRIs, work. They're told that benzos work. They're told that lots of drugs work for mental health. But ketamine just seems in a lot of these meta-analyses to have a different sized effect on people's mental health. So I do hold on to this idea that ketamine does something at the molecular level that is distinct from other drugs in this class. The second thing I think is that ketamine, like psilocybin, MDMA, seem to deliver a therapeutic, or you've called it even transformational experience. It changes people's minds.

And there seems to be something about that experience phenomenologically, that reorientation of subjective experience that is having its own effect, maybe separately from whatever receptor this chemical is binding to in the brain. The third thing, I think, is your study suggests that anesthesia, for some reason, creates a sensitive window for potential transformations. And I'm not sure why that would be the case. Surely, if it were that obvious, people with depression could just be cured by getting major surgery. It'd be like, are you anxious?

Tear your ACL, get wisdom teeth surgery. Like, it's obviously not that simple. But maybe there is something about anesthesia that creates a sensitive window for a profound experience. How do you feel about those general conclusions? So I like the way you frame that. And, you know, the truth that, like, how do these drugs work as much as we want it to be clean categories? it never will be. You know, the things that we keep finding out about old drugs and how old treatments work,

there's always can always go deeper. And, you know, biology doesn't lend itself to simplicity as much as we wanted to. And just to, you know, to kind of hit each of these points, they're really, I would, put this into three big buckets. And number one is really this biochemical-like effect. And, you know, that's, there is probably something there. Proving it is the challenge, right? Dissociating.

How do you separate out this drug-specific effect from expectancy and from the experience? That is a, that's science. That's what the science is for. And what our study, this study shows is that the non-drug factors are very, are just as capable of driving this type of effect as the drug itself. Now, whether or not, you know, if we remove all of those not drug factors, can we still get the same effect? We don't know.

There's actually some interesting other studies in China that suggests that, yes, they did very similar types of experiments under anesthesia, and they are seeing an effect of just the drug of ketamine. Why is that? It's interesting. The way that China views ketamine is very different from the, you know, hearts and rainbows and unicorns in the U.S. And that it's, you know, when you look at, if you, Theresa Lee, the first off of her study, she went to Baidu, the search engine that in China and put in ketamine. What does she get is Elon Musk a zombie?

I took ketamine and now like my bladder doesn't work and I need to use this bag. Ketamine is, you know, a toxin, right? The messaging around Ketamete is so vastly different. So all of that's to say is that these not, like, expectation clearly plays some role, this placebo response, all of these things that we keep trying to get rid of in clinical trials, but actually make use of in clinical care. They're actually really important. So there's the drug, there's this non-drug factor, and then there's the experience itself.

Boris Heifetz, thank you very much. That was utterly fascinating. And yeah, we'll be watching Kedamine News for Allo 2024 as well. Thank you. Thank you. Thank you for listening. Plain English is produced by Devin Beraldi. Our holiday schedule will be a little bit different than typical. We'll be coming at you once a week on Wednesdays. Happy holidays and we will see you soon.