From Our Neurons to Yours

The power of psychedelics meets the power of placebo: ketamine, opioids, and hope in depression treatment | Boris Heifets & Theresa Lii

• Wu Tsai Neurosciences Institute at Stanford University, Nicholas Weiler • Season 6 • Episode 6

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Join us as we dive back into the world of psychedelic medicine with anesthesiologists Boris Heifets and Theresa Lii, who share intriguing new data that sheds light on how ketamine and placebo effects may interact in treating depression.

We explore provocative questions like: How much of ketamine's antidepressant effect comes from the drug itself versus the excitement of being in a psychedelics trial? What do we know about how placebo actually works in the brain? And should we view the placebo effect as a feature rather than a bug in psychiatric treatment?

Join us as we examine the complex interplay between psychoactive drugs, the brain's own opioid system, and the healing power of hope in mental health care.

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Nicholas Weiler (00:00):

Hey everyone. Nicholas Weiler here. A quick note before we get into this week's episode. We're still collecting listener feedback to inform the next phase of the show. And if you'd be willing to help out, we'd love it if you could send us a short note, and we'll be in touch. We are at neuronspodcast@stanford.edu, and you can find that address in the show notes. Thanks so much. Now, let's get to this week's conversation on psychedelics and the nature of the placebo effect.

(00:30):

This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science. 

As we shared a few weeks ago, our show recently won a 2024 Signal Award for Best Science Podcast. One of the episodes that caught the attention of the judges was our conversation with Boris Heifets on psychedelic medicine, anesthesia, and the power of placebo. So we thought that today we'd circle back with Boris to follow up on that research.

(01:11):

In our original conversation with Boris, we talked about the growing excitement in medicine, about using psychedelics like psilocybin, MDMA, ketamine to treat disorders like depression and PTSD. Now, Boris is an anesthesiologist, which allowed him to take a unique approach to this research. In our first conversation, he told us about an experiment he conducted where his team gave ketamine to patients with depression while they were under general anesthesia.

(01:42):

In a nutshell, the goal of this experiment was to separate out the drug from the experience of the psychedelic trip. No one will experience a trip under anesthesia. The results were a big surprise. Patients who got ketamine showed improvements in their depression, but patients who did not get ketamine also showed similar benefits. These results raised important questions about the power of the placebo effect in psychedelic medicine.

(02:11):

So today, we're back with Boris and his colleague Theresa Lii, who have new data that take us even deeper into the neuroscience of placebo. The question at the core of our conversation goes beyond psychedelics and treatment-resistant depression. How is it that the belief that you will get better can actually make you better? And what are the implications for how we do medicine? 

Boris and Theresa, welcome to From Our Neurons to Yours.

Theresa Lii (02:39):

Great. Thank you for the warm welcome.

Boris Heifets (02:41):

Thanks for having me back.

Nicholas Weiler (02:42):

So earlier this year, we had a really interesting conversation about a study that the two of you did to try to address a problem with clinical trials that are trying to assess whether psychedelic and psychoactive drugs, MDMA, psilocybin, ketamine and so on, could be used to treat psychiatric conditions like PTSD and depression.

(03:04):

And I'm really excited to talk about some new research your team is doing as an update on that research. But first, Boris, I wonder if you could briefly recap for us the excitement around using drugs like ketamine in psychiatry and the big problem the field has faced so far with conducting high-quality placebo-controlled clinical trials with psychoactive substances like these.

Boris Heifets (03:27):

Sure. Only a little bit controversial. So there has been a big change in ideas about how mental health care can be delivered and what our options are. As you're probably aware, if you live through the 90s, that's the era that a lot of us grew up in, where SSRIs, SNRIs, drugs like that were really the next big thing. The challenge with them, which became very evident over many years, was they take a long time to kick in. They don't work for everybody.

(03:58):

And around 2000, the first study in the US showed that ketamine, which is previously an anesthetic, was repurposed. And when given in a infusion, a single dose could relieve symptoms of depression for about a week. So long after the drug is gone, they're still feeling better. And it worked within hours. That was a remarkable difference. That research has gone on over the last 25 years now. This is where a lot of the excitement around ketamine comes from. It acts quickly, and it seems to be durable. At least you don't need to be on it all the time.

Nicholas Weiler (04:36):

Right. In contrast to SSRIs, which can take weeks or months to get active.

Boris Heifets (04:41):

Exactly. So one drug is actually approved on that basis. That's called Spravato, which is a version of ketamine that it's a nasal spray and you have to keep going in for boosters, it seems like. But the point is that you take a dose and then you're better for a while.

Nicholas Weiler (04:58):

And this is for depression.

Boris Heifets (04:59):

That's for depression, yes. A much more, I would say, radical version of this or thinking in this sort of framework about things that act fast, things that are psychoactive, right. So ketamine, Spravato, these things that are not... it's not just taking a pill, it's a trip. Pretty much everyone would agree that taking one of these drugs in a clinic, you have to be supervised because you shouldn't be operating heavy machinery. Let's leave it at that for now.

(05:24):

So, in that context, psychedelics are a little easier to understand. They're very much a disruptive force in mental healthcare because it's an even more extreme version of what we've seen with ketamine in that they're powerfully psychoactive, more so arguably, right. If you take psilocybin, the active ingredient of magic mushrooms, you will be altered for hours. It's a profound experience. Some people would call it one of the most meaningful experiences of their lives. We can talk about that, I think, a little bit later, but it's a big experience.

Nicholas Weiler (05:58):

Right.

Boris Heifets (05:59):

And the effects in trials for depression last at least six weeks, maybe longer, maybe months. Some people think years. So it's a single dose. It acts quickly and it lasts for a long time, and it is definitely psychoactive. And this is a big change from traditional antidepressant medications like SSRIs.

Nicholas Weiler (06:22):

Right. Which you barely even notice until it starts-

Boris Heifets (06:25):

Yes.

Nicholas Weiler (06:25):

... gradually starts to work.

Boris Heifets (06:26):

You barely notice the antidepressant effect, but I think they do work for people. So why are people getting so bent out of shape about do these really work? I just told you that they seem to work. There's a big asterisk there in that unlike antibiotics or blood pressure medication, which you can give two groups of people at random, one gets a blood pressure med, one gets a placebo, and you can tell by looking at their blood pressure whether the drug does the thing that you think it does.

(06:57):

Is this a blood pressure medication that reduces blood pressure? Yes. And your opinion on it when you get it doesn't really matter. So to sum up. In a nutshell, the blinding issue is very difficult to deal with psychedelics. The minute you take a psychedelic, not the minute, but maybe 30 minutes later, something starts to happen. You go somewhere, right.

Nicholas Weiler (07:19):

Right.

Boris Heifets (07:19):

You're not yourself. You know whether you're in the placebo group or whether you're in the psychedelic group. And knowing all of the cultural context around these things, knowing what people have written about, like Michael Pollan, fabulous author at Berkeley, How to Change Your Mind, this has really changed a lot of people's perception of what psychedelics are, what they can do.

(07:41):

And so they go into these clinical trials with a very strong preconception of what the experience is going to net them. And if they have the experience, it's like they won the lottery, right. These trials, like with psilocybin, there are still maybe a thousand people that have been treated in these trials in the world, maybe a little bit more now, but it's a very select group. And getting into one of these trials is very difficult from a patient perspective.

Nicholas Weiler (08:10):

Right. So, patients who start feeling the trip, they're like, "Yes, I got the active ingredient. I'm going to get better. This is great."

Boris Heifets (08:16):

"One, I'm going to tell my friends." And then you got to think also, are you motivated to maybe overestimate the effect it has on your depression? You know you're in a group, you know what the drug is supposed to do, and now you also have a little bit, maybe there's some social capital tied up in whether the drug works for you or not.

Nicholas Weiler (08:34):

Mm-hmm.

Boris Heifets (08:35):

There isn't community expectations. It's actually pretty complicated. And the flip side, let's say you didn't get the drug. Maybe there's a little disappointment now you're on the couch for five hours in tightly monitored setting, having taken a placebo, and you know it. And what does that do?

Nicholas Weiler (08:50):

Right. It would be a bummer, right. You're like, "Oh, I did this whole trial. I spent all this time trying to get into this trial, and now I'm in the placebo group. Great."

Boris Heifets (08:57):

And you put a lot of effort into this stuff, and it doesn't work. And the point is, this is a good illustration of why it's difficult to test these things in a truly dispassionate objective, and I'm using air quotes here, way because, basically, you can't untangle the effects of anti-depression effects from expectations.

Nicholas Weiler (09:22):

Right.

Boris Heifets (09:22):

Right.

Nicholas Weiler (09:23):

And we know that particularly in areas like depression, that the placebo effect, the effect of expectation can be really strong. I mean, expecting to get better is essentially a form of hope. And hope is a really great treatment for depression.

Boris Heifets (09:35):

And why would we want to get rid of that? That's...

Nicholas Weiler (09:38):

Right, right. But it does make it hard to interpret your results.

Boris Heifets (09:41):

Yeah.

Nicholas Weiler (09:42):

So this is when the two of you, so you're anesthesiologists, and so you came up with a clever experiment that under general anesthesia, there's no consciousness, there's no dreams, there's no experience at all, right. And Theresa maybe-

Boris Heifets (10:00):

For the most part.

Nicholas Weiler (10:00):

For the most part. And so, Theresa, can you tell me a little bit about what the thought was of how you could assess the effects of ketamine while under anesthesia?

Theresa Lii (10:09):

Yeah, so part of what made this almost like a natural extension of our work as anesthesiologists is that we give ketamine day in day out. It's a very routine anesthetic. Here at Stanford, we mix in ketamine with other anesthetics. It has nice pain-relieving features.

(10:27):

So it's a very commonly used drug. And what we wanted to find out was whether or not the longer-lasting antidepressant effects could still be detected in patients who received ketamine during their surgical anesthesia compared to patients who didn't. And what we wanted to study was specifically patients who met clinical criteria for major depressive disorder. And one, we were curious about whether or not surgical anesthesia would be effective at blinding.

(10:59):

We suspected that it would be, but it takes a clinical trial to really prove that. And the other thing we really also looked at was whether or not this could be a perioperative intervention to help patients have improved recovery after surgery. This is actually our primary motivation when we first set out to design this study. And then, later on, we were like, "This is actually a fantastic way of blinding any kind of psychoactive substance."

Nicholas Weiler (11:24):

Interesting. So you... first, you wanted to know, does ketamine help people recover from surgery better since it seems to have these antidepressant effects and so on?

Theresa Lii (11:32):

Yeah.

Nicholas Weiler (11:32):

And then you thought, "Well, actually, if we're giving ketamine when people are under, then we no longer have this big issue that's been challenging the field." Neither the people in the ketamine arm of the trial or in the placebo arm neither of them have any experience at all because they're under anesthesia. So they don't know if they got ketamine or if they didn't.

Theresa Lii (11:53):

Right.

Nicholas Weiler (11:53):

And now you can maybe disentangle this question like, are people getting better because they expect to get better? Or is ketamine actually doing something in the brain? And I think this is also interesting because it gets at this whole other question in the field where doing treatments with psychoactive substances, with psychedelics, is tricky, right. You generally have to be supervised. There's often a therapeutic component, which can be expensive.

(12:20):

It can be hard for people to access, and there's side effects to some of these compounds. There's potential addictive effects of some types of compounds. People have been wondering like, "Well, is the trip part, is that really necessary? Or is there something that these drugs are doing in the brain separate from the experience that is helping people with depression or with other psychiatric conditions?"

(12:41):

So it's kind of cool because you got to sort of test both of those things at the same time. So if I remember correctly, you had about 40 patients with clinical depression who happened to be undergoing routine surgery. You gave half of them ketamine while they were under anesthesia, and the other half didn't get ketamine. And the results when you analyzed them were pretty surprising. Theresa, can you remind us what you found?

Theresa Lii (13:06):

Yeah, so what we expected to see, which was not what we saw, was that perhaps the group that received placebo wouldn't really show a decrease in their depression symptoms. And the group that received ketamine would show a big decrease in depression symptoms.

Nicholas Weiler (13:23):

That would suggest that the ketamine is doing the job and not the placebo.

Theresa Lii (13:27):

Yeah, exactly. Instead, what we saw was that both groups had a huge antidepressant effect, and the effect that we saw was similar in size as previously published ketamine studies done in awake patients.

Nicholas Weiler (13:40):

Right. It raises the question of how do you interpret this. How much of the ketamine benefit has to do with placebo, and how much of it has to do with the compound?

Theresa Lii (13:50):

Yeah, yeah. So our study, unfortunately, was not set up to answer that very important and very interesting question. This study actually kind of caught us off guard. In retrospect, I think if we had to redo this study. One of the things that we would change is that we would ask participants early on what they expected from their treatment.

(14:11):

We did ask participants at the end of their outcomes assessment period, which is two weeks, to guess what they thought they got before we revealed their actual treatment. And what we found was that participants who had greater decreases in depression symptoms throughout the study were more likely to guess ketamine than those who had more moderate or smaller improvements in their depression.

(14:39):

Now, the issue with asking them at the end of the study is that they've already experienced the effect of their treatment regardless of whether or not they got ketamine or not. So there's a bit of a look-back bias. Would've been more powerful is that if we had asked what they expected perhaps right when they woke up from the anesthesia or just a day after, we could probably key in on how much expectations would drive the remaining two weeks of depression symptoms.

Nicholas Weiler (15:09):

Okay. So you're left with this puzzle that patients who got ketamine under anesthesia did show similar improvements to other studies of ketamine and depression. They got an antidepressant effect. And patients who did not get ketamine under anesthesia also showed the same effect, and all they got was being part of a trial and going through anesthesia under surgery. So...

Theresa Lii (15:36):

So I was going to say the phrasing of all they got, I think, maybe underplays how much being part of a study is a huge change from their daily routine. The all they got actually could lead us into another long, lengthy discussion of why we think participants in clinical trials do so well.

Nicholas Weiler (15:55):

Exactly. And yeah, we got into a little bit of this in our previous conversation with Boris about maybe it's this experience of being in a trial of the focus of the trial of going through this whole experience, but I'm eager to get to your new study, which tries-

Theresa Lii (16:07):

Yeah.

Nicholas Weiler (16:08):

... to address some of the puzzle that's leftover from this research. But before we get into it, it sort of brings up a question that we've been circling around and that I'm really interested in, and maybe Boris, you can take a stab at this one. What is the placebo effect? What do we know about what's going on in the brain when people experience these benefits from something that, as far as we know, is not directly active on the biology of interest?

Boris Heifets (16:35):

So placebo is an old, old idea. And actually, not to get too Latin about it, but I think literal means placebo means I will please in Latin, right. So there's this underlying assumption that a placebo response is something that happens when we're trying to placate a patient, basically.

(16:55):

We're giving them something that doesn't really have an active ingredient but does fulfill some other social or psychological need so that it's not specific in any way. And it's sort of when we talk about placebo effects is typically used to impugn the patient to a small degree. Let's just... It's all placebo.

Nicholas Weiler (17:15):

We'll give them a sugar pill, and they'll think that they're going to get better.

Boris Heifets (17:18):

And they'll think that they're going to [inaudible 00:17:20] better. The implication being that, number one, that they're going to get better for no reason other than it's all in your head, quote, unquote. And the other is that if you got better from a placebo, there was nothing wrong with you to begin with. That's a very, I think, pernicious way of thinking about the social and psychological dimensions of mental health care.

(17:39):

If you really want to push this analogy to it's an extreme, psychotherapy is placebo. Tell me [inaudible 00:17:47] the active ingredient, is very hard. You talk to people who've been through psychotherapy, and I have a therapist. Everyone in my family has a therapist, and there is a real therapeutic process that happens there, but there isn't a drug that's involved. And yet, somehow, we went through this dualistic approach to, "Well, that's somehow different from drug therapy." Let me put it to you a little bit differently.

(18:08):

The most targeted drug I could ever hope to design in a Stanford lab is something that has the same power as the words that I use from my mouth that tell you something that you need to hear at a particular moment. That is a very specific targeted mechanism that we're approximating with drugs. I'm framing it in this way because I think it's important to think about therapeutic mechanism more broadly. And when we say placebo, it's actually a pretty complex set of responses. There's real biology there, and we can harness that biology to get people better.

Nicholas Weiler (18:46):

And then I think that's sort of at the heart of what I'm curious about to set up your new study, which is what are we learning about the biology of what's happening in the brain when someone is getting this so-called sugar pill and then experiencing some significant improvements.

Boris Heifets (19:02):

So I want to say just a little bit about what we do know actually about how placebo works. For about almost 40 years now, there's been a body of literature into placebo mechanisms. How does placebo work in your brain when you get a sugar pill? Why is that do anything? And one of the areas where this has been most well-established is placebo analgesia.

Nicholas Weiler (19:25):

So pain effects.

Boris Heifets (19:26):

Yeah, pain. So I give you a sugar pill, and your pain gets better. Anyone who has kids knows that this totally works, right.

Nicholas Weiler (19:33):

Right. You can kiss it better.

Boris Heifets (19:34):

Exactly. So one of the coolest early studies that were done in patients who were having dental surgery, so what they did is, after surgery, they would either give them, instead of morphine, they would give them a placebo, or they would give them placebo with a drug that blocks opioid receptors called naloxone. And the surprising thing they found is that placebo works. As we expect, patients would say, "Oh, thank you, that feels much better."

(20:02):

But when we gave them naloxone, when they gave them naloxone, the opioid blocker, suddenly placebo didn't work, or it was much less effective. So that hints at an interaction between your expectations about pain relief and maybe opioids being released in your own brain, right. Endorphins, this is something that we've kind of heard about in the lay culture for a long time. Things that happen when you exercise, like things that make you feel good, that same system seems to be involved in the opioid or the placebo analgesia response.

Nicholas Weiler (20:37):

So I think this is an important point to dwell on for just a moment. I'm sure many people have heard of endorphins, but I don't know how many people know that that is what we would call in neuroscience an endogenous opioid. We talked on an episode recently with Ivan Soltesz about endogenous cannabinoids, the endocannabinoid system, that there are these molecules in your brain and there are receptors, and that the drug comes in and kind of hijacks that system.

(21:02):

And the same thing goes on with opioids. Your brain uses what we call opioid receptors, and they're called that because the extract of the poppy plant hijacks that system, acts on that system, mimics that system. And so I also find that finding that blocking the internal opioid system can significantly reduce or block the placebo effect is really thought-provoking. I mean, so that suggests that when you kiss it better, you're sort of giving a little mini opioid dose to act as a painkiller in the brain.

Boris Heifets (21:39):

That is what we think is happening. And one of the questions that we don't really have a good handle on is how far does that go. We use placebo in a lot of different ways. There's placebo analgesia with pain relief. There's also the placebo antidepressant response, which is what we saw in our trial, a massive Placebo antidepressant response.

(22:03):

This research is ongoing. I think it's a hot topic, but there's still a lot we don't know. And one of the things we don't know is is this system is this endogenous internal opioid system where you make your own, basically, is that hope? Is that what... It's like, do we experience that the same way?

(22:21):

Is that the thing that you engage when you go into a doctor's office, you see the white coat, you take the pill, you get a lecture about, "This is how the treatment's going to work," and you can draw a line. There you see yourself going through the process that the doctor is laying out. That's basically what, when you do a placebo right, all of those processes are engaged.

Nicholas Weiler (22:43):

Mm-hmm.

Boris Heifets (22:44):

And the question that we're asking is, even beyond just pain relief, is this what opioids in your own body do?

Nicholas Weiler (22:51):

Mm-hmm. So Theresa, maybe you can take us into your new study. How did you start to pick apart this question of placebo versus ketamine and whether there's this opioid-mediated placebo for anti... the antidepressant effects that you were seeing? How did you pick that apart?

Theresa Lii (23:08):

Yeah, so a little bit of the background that led to my secondary analysis. There's already some good existing research and literature strongly suggesting that the placebo antidepressant effect also depends on the endogenous opioid system. There was also another study done by Boris and our psychiatry colleagues here at Stanford showing that ketamine's antidepressant effect was also blocked by a different opioid blocker called naltrexone.

(23:36):

So lots of evidence swirling about, strongly suggesting that the antidepressant effect of ketamine, but also placebo effect, could both be dependent on the endogenous opioid system. So I was looking at my data and knowing that our patient population was a surgical population, I had thought, "Wait, some of these folks are taking opioids chronically on a day-to-day basis. Some of them aren't."

(24:04):

We know chronic pain patients and patients who have opioid use disorder who are exposed to opioids every day, we know that their endogenous opioid system is not normal. What do I mean by that? It's basically the act of exposing your endogenous opioid system to an outside opioid, an exogenous opioid such as opioid drugs, or drugs such as heroin or fentanyl. Chronic exposure to the exogenous opioid system leads to changes in the endogenous opioids that blunt your own responses to your own opioids.

Nicholas Weiler (24:41):

Right. So it basically makes the internal opioid system less sensitive, sort of turns down the volume, so to speak.

Theresa Lii (24:48):

Exactly. In many ways, it's the system becomes less sensitive. Your body decides... Not decides, but your body just ends up making less opioids because you have so much constant exposure to exogenous opioids. And so I thought, okay, this is actually an interesting question that I can address because I have a population of patients who were on chronic opioids taking them for pain, and then I have a population who was not taking chronic opioids.

(25:12):

And in the secondary analysis, I basically re-ran the results. Instead of looking at groups based on what they received, I looked at whether or not they were taking opioids before their surgery. And when you look at participants who got placebo, what came out that was very interesting is that participants who were taking chronic opioids before actually had a smaller placebo antidepressant response. This was surprising.

(25:44):

The other surprising finding is that when you turned your eyes towards the ketamine group, participants who had been taking opioids did just as well as participants who were not taking opioids. So it turns out that ketamine's antidepressant effect doesn't seem to be affected by the chronic opioid exposure before the trial. Whereas the placebo group, the placebo response was.

Nicholas Weiler (26:09):

That's really interesting. And so, in the original study, you see that the placebo effect is pretty similar to the ketamine effect. Both of them help people with their depression, but if you just look at the people within that study who had been using chronic opioids, their opioid system was desensitized, they lose some of that placebo effect if they didn't get ketamine. But if they did get ketamine, they still get the antidepressant effect.

Theresa Lii (26:37):

Yeah. They get the ketamine effect. We still don't know whether or not the ketamine effect is purely placebo or if there's actually a intrinsic ketamine drug effect. But we know that in the ketamine group, the antidepressant response didn't seem to be affected by chronic opioid use.

Nicholas Weiler (26:54):

Those people, the placebo is turned down, and it sort of unmasks some ketamine-specific effect. That's not the same as what was going on in the placebo group.

Theresa Lii (27:05):

Right.

Boris Heifets (27:05):

I'm going to put it... Theresa is being appropriately conservative here.

Nicholas Weiler (27:09):

Right. I was just about to get to that. So please tell me.

Boris Heifets (27:11):

So I'm going to put it a little bit differently is that my read... This is preliminary. Requires further study, but it looks like ketamine may reset placebo sensitivity.

Nicholas Weiler (27:24):

Interesting. Okay. Tell me more about that.

Boris Heifets (27:26):

That's my takeaway from this. This is the question that we are now asking based on this preliminary analysis is that some people just aren't sensitive to placebo. We know that they're responders. They're not responders to placebo interventions, and there are a lot of things that can modulate the same thing.

(27:44):

Some people are hopeless, some people are hopeful, some people are hypnotizable, right. All of these things are just the normal range of human capability, and some of them are influenced by our diet or psychological makeup and the drugs we take, right. So opioids could be a potentially powerful influence on that.

(28:03):

And if you have reduced your placebo sensitivity through chronic opioid use, that then maybe there's a way that you can grow it back, at least for a little while, with a single infusion of ketamine that would tie together a lot of these kind of oddball findings in the field and trying to understand how exactly ketamine interacts with the opioid system, and also explaining why placebo seems to be so important for ketamine and maybe psychedelic effects.

Theresa Lii (28:37):

I'll add that anesthesiologists probably won't find this finding terribly surprising. We've observed for a long time that ketamine is fantastic for treating pain in patients who are opioid-tolerant. Patients who have opioid tolerance, and if they're having pain, it's very easy to just ratchet up higher and higher doses of opioids to try to treat their pain. But because they're tolerant, it ends up being rather ineffective.

Nicholas Weiler (29:04):

Right. And it just continues to desensitize their opioid system.

Theresa Lii (29:07):

Exactly. Exactly. And so anesthesiologists have long observed that ketamine is actually really good at treating pain in these kinds of patients, and potentially the mechanism under this is just as Boris said, resensitizing the endogenous opioid system so that it's ready to respond to your own opioids or other exogenous opioids.

Nicholas Weiler (29:31):

So with the proviso, as you brought up, Boris, I mean, this is quite a small study. It's a subset of your original study who happened to be using chronic opioid drugs. It hasn't gone through peer review yet. This is not yet published. This is sort of early results that we're still processing. I want to sort of take us out by thinking about where does this leave us.

(29:51):

What are the big questions now with these findings? So you've talked about ketamine potentially resetting the placebo effect even for people for whom it's not effective or it's been desensitized. Coming back to what we were talking about at the top of the conversation, where does this leave us on the potential effectiveness of ketamine for depression?

Boris Heifets (30:14):

I want to take a stab at this and actually even go more broadly about psychedelics in general and how we think about these studies. So I think your audience is a little savvier than most in terms of people tend to know what a randomized controlled trial is, and you want to look at those studies, and you want to see a difference between your active group and your placebo group, and you interpret the true drug effect as the difference between those.

(30:42):

And that might be really small. For example, for an SSRI, I want to suggest a different interpretation to these types of studies, and I'll start with a quote that I heard from an actual psychiatrist is, "Sometimes you need a little placebo to really make the drug work." And it's this idea that placebo is a real and obligate mechanism that is required, it's permissive, and it's part of the therapeutic mechanism. It does not make sense to interpret effect sizes in these trials as just the difference between these two groups.

(31:18):

That's not actually what is being applied clinically. When you see these in practice, there's plenty of placebo that's going into these treatments. A lot of hope. A lot of, "This is what you should expect, this is what you're going to get, this is how it's going to work." All of those things are placebo mechanisms. And when we think about the effect size of these things, really I think that it makes more sense to think about them as the so-called common factor, the placebo element, and the drug effect. It's a joint and intermixed complex therapeutic process that's going on.

(31:55):

It doesn't make sense to separate the way we're separating them. Now, how do you study that? That's a little more challenging, and I'll just say, at least in terms of trial design, it requires that we start thinking about what is the no-treatment effect. That's the real baseline we should be comparing to where we didn't even give a placebo. That comparison makes sense now, right. It's a different sort of way of setting up studies and analyzing them. But we really, I think, should start thinking about placebo mechanisms as intrinsic to how some of these drugs, particularly psychedelics, especially ketamine, might be working.

Nicholas Weiler (32:36):

So what this is saying to me is that the placebo, which we're now discovering is tightly intertwined with our brain's internal opioid system, probably should be considered a feature and not a bug.

(32:49):

And that not only does that affect our, as you're saying, ability to do clinical trials, that maybe the placebo effect is actually necessary for the effect of whatever treatment. But also, maybe we need to be thinking about what are the best ways of engaging this powerful effect that is really good at treating conditions from chronic pain, depression, and so on.

Boris Heifets (33:14):

You hit the nail on the head. I think that even how do you prioritize that and reward good placebo, good medicine, that intangible thing that people call the art of medicine that you can't really bill for directly, it doesn't have a procedure code, that's clearly the stuff that recovery is made of.

Nicholas Weiler (33:35):

Right. It's a doctor making you feel hopeful.

Boris Heifets (33:37):

Yeah. How do you get more of that? How do you... Can you train people to do that? I mean, we're not the first people to suggest that, yes, you can. But the question is, how do you really put that front and center in these new paradigms for mental health recovery and stop what I think is really a distracted focus on the pill at the center of all this? That is a part of it, but that's not... I would say maybe that's actually dispensable elements of all this.

Nicholas Weiler (34:02):

All right. Well, I love the idea of de-centering the pill and re-centering the experience and just how much we can learn about how our experience of treatment is going to affect our outcomes. So thank you both so much for joining us on the show.

Boris Heifets (34:20):

Thanks, Nick. Thanks for having us on.

Theresa Lii (34:22):

Yeah, thank you.

Nicholas Weiler (34:26):

Thanks again so much to our guests, Boris Heifets and Theresa Lii. To read more about their work, check out the links in the show notes. 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.

(34:42):

We'd also love to hear from you. Tell us what you love or what you hate in a comment on your favorite podcast platform or by email at neuronspodcast@stanford.edu. From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios, with production assistance from Morgan Honaker. I'm Nicholas Weiler at the Wu Tsai Neurosciences Institute at Stanford University. Until next time.