Pod Insights Short Wave What If You Took The "Trip" Out Of Ketamine? About this episode What if you could get all the potential benefits of ketamine without the "trip"? For part two of our series on psychedelics, we look at how some researchers are trying to disentangle the "trip" from the drugs' effects on the brain — and why the answer could help direct the future of psychedelic research. (Spoiler alert: People generally know if they're tripping or not.) This episode: a researcher navigating this challenge by putting his patients to sleep.
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0:22 Regina Barber? Hey, Short Wavers. Regina Barber here. I'm talking with one of our producers, Rachel Carlson, who's been reporting a series on psychedelics and related drugs. Hey, Rachel.
0:30 Speaker 02 Hi, Gina. So in our last episode, we talked about how drugs like psilocybin and ketamine are raising all these questions about the limits of what we know about our brains and how we experience reality.
0:42 Regina Barber? Definitely check out that episode if you missed it. But also, this one will make sense without it. Rachel, you touched on one thing in that episode that we're going to go a little deeper on today, and that's the challenge of studying these drugs.
0:54 Speaker 02 Exactly. So when we're talking about how drugs like psychedelics and ketamine work, or if they work at all, what the heck are we actually talking about?
1:02 Speaker 03 There's the drug, there's the trip, and then there's all these non-drug factors, meaning the stuff at the beginning, like the expectations you set, the hope you have, the lessons you learn.
1:16 Speaker 02 This is Dr. Boris Heifetz. He's an anesthesiologist and neuroscientist at Stanford University. And he told me that researchers have been wondering for a while if the trip that comes with a lot of psychedelics, this journey or experience, is really important, or if it's just this unnecessary byproduct when it comes to making people feel better.
1:36 Speaker 03 So a lot of people, actually, have been talking about this for years, like, well, what if you just knock someone out?
1:44 Speaker 03 What if you eliminated experience during a psilocybin trip or during one of these drugs in this broad class, in which I'll include ketamine for a variety of reasons?
1:55 Speaker 02 So that's exactly what Boris did.
1:58 Regina Barber? So today on the show, the creative ways some researchers are trying to navigate research on drugs like psychedelics and ketamine.
2:04 Speaker 02 They're asking, is it the drugs themselves making people feel better, or everything else that comes with them? We'll even hear from a patient about her experience. I'm Rachel Carlson.
2:14 Regina Barber? And I'm Regina Barber. You're listening to Short Wave, the science podcast from NPR.
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3:46 Regina Barber? OK, Rachel, so when people say drugs like psychedelics and ketamine can help treat different conditions, there could be a few things happening. Any beneficial effects of the drug could be related to: one, simply mentally and therapeutically preparing to take a drug like a psychedelic; two, the experience of actually taking it, like the trip; or, three, the effect of the drug itself on a person's brain, right?
4:10 Speaker 02 Right, or Gina, it could be a combination of all of these things or others, and it's pretty hard to parse out. But Boris tried to disentangle all of these factors in a 2023 study he did on ketamine and depression. That was out in the journal Nature. So to do this, they used anesthesia. And in Boris's trial, they looked at 40 patients who were already scheduled to have some kind of basic surgery and go under anesthesia. All of the patients also had a history with major depression.
4:40 Regina Barber? OK.
4:42 Speaker 02 And Boris told them that while they were under anesthesia, they would either be getting an infusion of ketamine or saline. Based on research in animal models, scientists think that ketamine works by binding to this specific receptor in the brain. It's called the NMDA receptor. But what also happens there is that it can give people this kind of dissociative feeling, like they're separated from their own bodies.
5:04 Regina Barber? And for anyone listening who also doesn't know what it is, ketamine isn't a psychedelic like LSD or psilocybin, mushrooms. Those seem to work on different receptors in the brain. But like you said, Rachel, ketamine can kind of have like similar effects to psychedelics, depending on like the dose a person takes.
5:21 Speaker 02 Yeah, it is not a psychedelic, but it does kind of get thrown into this psychedelic related bucket because it can have sort of similar-ish effects, depending on how much a person takes. And so the idea with Boris's study was that by putting patients under anesthesia, it might help solve this big problem that most studies of psychedelics and ketamine have.
5:42 Regina Barber? Right, because patients usually like know if they've gotten the drug or the placebo.
5:46 Speaker 02 Yeah, if someone gives you LSD, you are probably going to know. So I spoke to one of the participants in this study.
5:54 Speaker 05 Hi, my name is Cindy Dolman.
5:56 Speaker 02 Cindy had an ongoing relationship with depression.
5:59 Speaker 05 Off and on, probably since I was a teenager. Yeah, I think the awareness of it didn't come to me until I was probably my 30s. I'm 61 now.
6:10 Speaker 02 She's from Santa Cruz in California. She told me she felt like she should be enjoying her life in the sun, outside, by the beach.
6:17 Speaker 05 But it wasn't in my head. And I was spending more time indoors, sleeping. Felt like a truck stuck in the mud. And like I'd ran out of gas, too.
6:29 Speaker 02 Before the trial, Cindy told me she didn't know anything about ketamine.
6:32 Speaker 05 Ketamine, I knew absolutely nothing about. In fact, I don't even know that I'd even heard of it.
6:37 Regina Barber? Okay, so these patients like Cindy are going like under anesthesia for their surgeries. And then they either get ketamine or they don't.
6:44 Speaker 02 Exactly. And Gina, another thing Boris told me is really important here is that we've known for a long time that after people go under anesthesia, their mood often gets a bit low. So things like depression can get worse.
6:56 Regina Barber? Wow.
6:56 Speaker 02 And in a group of patients who were already suffering from depression, that's what Boris says they expected to see. At least in the group that didn't get ketamine.
7:05 Regina Barber? And what about Cindy?
7:07 Speaker 02 So Cindy got the drug. She got ketamine. But remember, she didn't know that. And neither did Boris or the other researchers.
7:13 Regina Barber? Okay, okay. So what happened when she woke up?
7:16 Speaker 02 Here she is.
7:16 Speaker 05 Not like Snow White and the little birds, you know, happy as the day. But I did have a little bit of a bluebird on the windowsill kind of feeling. The joyfulness of more awareness of the presence of the day around me. And not just the funk in my head.
7:36 Speaker 05 I was still a bit groggy. It was like the next day that I really felt the overall, oh, this is, something's different, you know?
7:45 Regina Barber? What about the other patients?
7:47 Speaker 02 So in the group that did get ketamine, 60% of those patients felt better the day after surgery. And most of those people had stayed better when the researchers checked on them two weeks later.
7:56 Regina Barber? Wow.
7:59 Speaker 02 So for context, Gina, this is much faster than something like Prozac or Zoloft, which could take at least a month to see results and has to be taken every single day.
8:07 Regina Barber? Mm hmm, right.
8:07 Speaker 02 So Boris says they figured, okay, ketamine works even under anesthesia. So even if the patient doesn't know that they actually got it.
8:14 Regina Barber? So it wasn't just Cindy who felt better?
8:17 Speaker 02 Boris told me about a different patient, not Cindy. He also talked to.
8:21 Speaker 03 This was like her, you know, and like fifth like cancer surgery. Like this has been recurrent cancer.
8:27 Speaker 02 He saw this patient a couple of days after her surgery.
8:29 Speaker 03 She was almost like dancing. This is, you know, someone who had like a lot of stuff in their belly, like still had drains, bandages. She was like, you know, it was infectious. And I thought to myself at the time, like, if she didn't get ketamine, like, I'm quitting. Like, I don't know, like, or even, I mean, in retrospect, it was more like, I want to know what's, like, what we did so we could do it again.
8:50 Regina Barber? And?
8:51 Speaker 03 She was in the placebo group.
8:56 Speaker 02 So statistically, there was no difference between people who got ketamine and people who got placebo. Boris told me the people who got placebo...
9:05 Speaker 03 They got so much better, they were indistinguishable from the patients who got ketamine.
9:14 Speaker 02 And even Cindy, who did get ketamine and did feel like it helped her depression symptoms, told me she thought about whether it was really the drug that helped her or other parts of the study. Like, what was it that really made her feel better?
9:29 Speaker 05 I was so stripped raw emotionally that I was so grateful for everybody's participation in my wellness journey. You know, even now, a little bit of love leaks out of my eyes, but it's because of gratitude.
9:45 Regina Barber? So you're saying that even though she got ketamine, her feeling better could also have been like related to these other parts of the experience, like working closely with Boris and like feeling like people are actually like listening to her?
9:55 Speaker 02 Exactly. And she told me that she wondered like, how far would it take other people who were struggling with something like depression if they just had the same kind of support that she got from Boris and her surgery team?
10:06 Regina Barber? Yeah.
10:07 Speaker 05 But who doesn't respond to love and kindness, right?
10:10 Speaker 02 Boris told me that a lot of patients seemed to think that if they felt better, they probably got ketamine, even if they didn't, which to him points to this expectation or hope that patients might have about being in a study where they might get some kind of drug at all.
10:26 Speaker 03 You know, there's a lot of the same reactions, like, well, I, you know, I can't explain it either. But this, it's important. It's, you know, I got, I got better. In some cases, they stayed better.
10:36 Regina Barber? But that could have just been the placebo effect.
10:38 Speaker 02 Yeah, I mean, that's what Boris is saying. And what he really emphasized to me is that placebo can sort of be seen as this fake thing or a sign of failure in a study, but there's science supporting its effectiveness. It can actually change our brain chemistry, but people often see it as this imaginary treatment.
10:55 Speaker 03 Imaginary is like something that doesn't exist. This is a real thing, and placebo has real biology behind it. And it is one of the most valuable treatments we have in medicine, full stop.
11:07 Regina Barber? Wow, it's like that expectation. And this brings us back to the question you asked earlier, like, do we even need a trip at all? It's kind of related to all this.
11:16 Speaker 02 Right. So Boris tackled this question with anesthesia. He came away feeling like maybe these other factors are really important. And a lot of people in the field argue this. Other researchers are focusing on creating new drugs altogether, ones that work like psychedelics but don't have a trip at all.
11:33 Regina Barber? Wow.
11:34 Speaker 02 David Olson is one of these researchers. He's a chemical neuroscientist at UC Davis. And he says neuropsychiatric disease is a huge problem globally. We're talking in the neighborhood of a billion people.
11:45 Speaker 06 And if the drug needs to be administered in the clinic under the supervision of multiple healthcare professionals, we're just never going to be able to reach all those patients.
11:56 Speaker 02 Hmm. So Gina, let's go back to our big question here. Why might drugs like psychedelics or ketamine help people? Is it because of the way they could alter the brain? Or the trip or experience that comes with them?
12:08 Regina Barber? Yeah.
12:09 Speaker 02 David's saying, forget the trip. He's betting on their chemical and biological effect. A lot of his research is focused on creating new psychedelics and even drugs that are inspired by psychedelics that he says could be more accessible and safer since lots of people can't take psychedelics.
12:24 Regina Barber? Right.
12:25 Speaker 02 And researchers still don't really know the long-term effects of taking these drugs.
12:29 Speaker 06 Fortunately, that's what medicinal chemists are very good at. They can take a chemical structure and tweak it just a little bit to improve its properties.
12:40 Regina Barber? OK, wait, wait. So he's like re-engineering these drugs and taking out the trip?
12:45 Speaker 02 That's one aspect of his work. So we'll get into this process tomorrow on Short Wave.
12:50 Regina Barber? I can't wait. Thank you so much, Rachel, for bringing us this reporting.
12:53 Speaker 02 Thanks, Gina.
12:59 Speaker 02 I produced this episode with Burley McCoy. It was edited by our showrunner Rebecca Ramirez and Jeff Brumfield. Tyler Jones checked the facts. Kwasi Lee was the audio engineer. Special thanks to John Hamilton, Brent Bachman, Johannes Jergi, and our incredible standards team.
13:15 Regina Barber? Beth Donovan is our senior director and Colin Campbell is our senior vice president of podcasting strategy.
13:20 Speaker 02 I'm Rachel Carlson.
13:21 Regina Barber? I'm Regina Barber. Thank you for listening to Short Wave, the science podcast from NPR.
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