How Ketamine, Psilocybin And Other Psychedelics Are Changing Psychiatric Care : Short Wave Psychedelics like ketamine and psilocybin are getting a second look as a way to treat psychiatric problems like depression, anxiety, substance use disorders, even PTSD. NPR neuroscience correspondent Jon Hamilton explains how these drugs are helping brain scientists understand what causes mental illness and find new ways to treat it.

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The Resurgence Of Psychedelic Psychiatry

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MADDIE SOFIA, BYLINE: You're listening to SHORT WAVE from NPR.

EMILY KWONG, HOST:

Hi, everybody. Emily Kwong here with NPR science correspondent Jon Hamilton. Hi, Jon.

JON HAMILTON, BYLINE: Hi, Emily.

KWONG: So as NPR's neuroscience reporter, you're always reporting on the most interesting things. So what do you got for us today?

HAMILTON: What I've got for you today is psychedelic drugs - not literally, of course.

KWONG: (Laughter) OK.

HAMILTON: But I want to talk about how these drugs are getting a second look, you know, as a way...

KWONG: Ah.

HAMILTON: ...To treat psychiatric problems like depression, anxiety, substance use disorders, even PTSD. In the past decade, it has become a very hot topic in brain science.

KWONG: Yes. It is a very hot topic. In fact, Jon, our first SHORT WAVE episode was about using psilocybin as a treatment for smoking cessation. So I'm glad you're bringing this topic back to the podcast. What are some of the drugs we'll be talking about today?

HAMILTON: A lot of familiar names. You mentioned psilocybin. There's also ketamine, mescaline, ibogaine, ecstasy, even LSD in some cases.

KWONG: And those are all drugs that can cause hallucinations or out-of-body experiences, right?

HAMILTON: Right. And most of them are not legal.

KWONG: Right. But how do they work for depression and all those other psychiatric conditions?

HAMILTON: So ketamine, for example, is able to help a lot of people with major depression even when nothing else works. About 10 years ago, I was able to talk to one of the first people to take part in a clinical trial of ketamine. His first name is Christopher (ph). He asked me not to use his last name. Christopher had depression that made him suicidal. And before he got ketamine, he had been prescribed just about every drug out there to treat his depression. He told me it started with Prozac and Paxil and went on to...

CHRISTOPHER: Klonopin, Ativan, Valium, Xanax, Remeron, Gabapentin, Buspar. Depakote they had me on for a while.

KWONG: That is a long list. And none of those helped him?

HAMILTON: Either they didn't work or the side effects were so bad, he had to quit taking them. But Christopher was lucky. He managed to get into one of the first studies of ketamine. And now, 15 years later, the FDA has actually approved a version of ketamine for use in people like Christopher.

KWONG: Well, today on the show, we're going to talk about that - the resurgence of psychedelic psychiatry.

HAMILTON: And how these drugs are helping brain scientists understand what causes mental illness and find new ways to treat it.

KWONG: You're listening to SHORT WAVE, the daily science podcast from NPR.

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KWONG: OK, Jon Hamilton, neuroscience correspondent, why are psychedelic drugs getting so much attention now? I mean, they've been around for a long time.

HAMILTON: Yeah, a really long time. I mean, people have been taking plant-based psychedelics like mescaline and psilocybin for thousands of years. And back in the 1950s and early '60s, scientists were actually looking at whether some of these drugs might be useful in psychotherapy or to treat alcoholism or mood disorders like depression. But then there was the Summer of Love - a lot of drug experimentation, a lot of social upheaval. The upshot was that drugs like LSD were labeled a menace to society. And by 1970, they were pretty much outlawed.

KWONG: And did that end all of the research?

HAMILTON: For the most part, yeah, at least until the 1990s. I think the real change, though, came from the ketamine study I mentioned.

KWONG: OK.

HAMILTON: It was published in 2006. And it got people's attention because it was done by a very prominent psychiatrist at the National Institute of Mental Health, Dr. Carlos Zarate. Also, the results were spectacular. The study was of people who all had major depression that had not responded to other treatments. And they got a very low dose of ketamine that wore off in an hour or so. But more than 70% of them got better, and they got better within a few hours of being treated.

KWONG: Wow.

HAMILTON: You remember Christopher from earlier? He told me about getting his first dose at the National Institutes of Health as part of Dr. Zarate's study. It was on a Monday morning, he said. And his mood was really, really dark.

CHRISTOPHER: Monday afternoon, I felt like a completely different person. It was, you know, same-day effects. And, you know, I woke up Tuesday morning, and I said, wow, there's stuff I want to do today. And I woke up Wednesday morning and Thursday morning. And for the first time in I don't even remember, I actually wanted to do things. I wanted to live life.

KWONG: Oh, I'm so glad to hear that. And the effects for Christopher sounded almost immediate. Did those early results hold up for him?

HAMILTON: Well, I checked in with Christopher just a couple of days ago, and now 15 years later, he is still...

KWONG: Still?

HAMILTON: ...Taking ketamine and still doing well.

KWONG: Wow.

HAMILTON: And after the NIH study, lots of scientists began studying ketamine for depression. And they confirmed that it worked for most patients. So pretty soon you had doctors that were opening up these ketamine clinics all around the country where people could go to get infusions of the drug. And these clinics are still giving ketamine to thousands of people with problems like depression, anxiety, PTSD and chronic pain.

KWONG: But ketamine, at least in popular culture, is still kind of known as a party drug, right? It's technically not legal when used that way.

HAMILTON: No, it's not. But it's been approved for use as an anesthetic since 1970. My son actually got it in the emergency room a few years ago. He was 9. He'd broken his arm.

KWONG: Oh.

HAMILTON: And it was the safest way to anesthetize him while they set the bone.

KWONG: OK.

HAMILTON: So ketamine is out there, and doctors can legally prescribe it for purposes other than anesthesia if they think it's in the patient's best interest. And just to finish the story about ketamine for depression, in 2019, the FDA approved a drug called Spravato. It's a nasal spray that contains a version of ketamine, and it's specifically for patients with major depression who haven't been helped by other drugs.

KWONG: OK. So a lot has changed in the world of ketamine, and this sounds like possibly lifesaving treatment. And that must mean researchers are hopeful about what other psychedelic drugs could do. So what else are researchers looking at?

HAMILTON: Well, one thing they're looking at is psilocybin. It's the substance that makes, you know, some mushrooms magic or, if you want to sound like a scientist, psychoactive.

KWONG: Right. And with a psilocybin trip, there's a sense of, like, peacefulness and happiness and of being somehow disengaged from your surroundings.

HAMILTON: Yeah. It can also, though, sometimes cause nausea and really frightening hallucinations. Anyway, researchers did a lot of experiments with psilocybin back in the '60s. That was when a pharmaceutical company, Sandoz, was making a synthetic version of the drug for research purposes. So scientists could get these little pink pills to give to people in their studies. That pretty much ended in the U.S. when the Controlled Substances Act was passed in 1970. At that point, psilocybin became what's known as a Schedule 1 drug - so in the same legal category as heroin. But now there's a lot of interest in treating anxiety, depression and addiction with something called psilocybin-assisted therapy.

KWONG: Yeah. How does that therapy work?

HAMILTON: I will let Alan Davis explain it. He's on the faculty of the Ohio State University and also works at Johns Hopkins University. Here's how he described a therapy session using psilocybin.

ALAN DAVIS: They have a blindfold on. They have headphones on, listening to music. And we really encourage them to go inward and to experience whatever is going to come up with the psilocybin. And then at the end of the day, we have time for reflection and to talk about what their experiences were before sending them home with a support person.

KWONG: Wow. Yeah. Psilocybin-assisted therapy just sounds extremely different from the usual talk therapy.

HAMILTON: Oh, yeah. Yeah. And at least two scientific studies have found that it actually works. What Alan Davis was describing there was part of a randomized clinical trial of 24 people with major depressive disorder, and he told me the results with psilocybin were a lot like the early results with ketamine. So I should add that drug companies in both the U.S. and Europe are now doing larger studies of psilocybin with the goal of eventually bringing a prescription version to market.

KWONG: OK. So, Jon, we've talked about the promise of these drugs, of ketamine and psilocybin specifically. But I'm curious how exactly they work on a neurochemical level because they sound just very different from drugs like Prozac or Zoloft that we're so familiar with for treating depression.

HAMILTON: Yeah, they're definitely different. They target different systems in the brain. And scientists say they seem to help rewire our brain circuits. So, for example, there's evidence that all of these drugs cause the brain to somehow make lots of new connections between brain cells. The drugs also seem to cause some existing connections to weaken or fade away. And there may be something else going on, something that's related to this out-of-body experience these drugs can produce. It's called dissociation - right? - a state where you no longer feel connected to your own body or even your own thoughts and feelings. And that state may actually make it easier for people to evaluate what's going on in their own head.

KWONG: Yeah. I just find that really incredible. So clearly, these drugs work in a very different way. And I'm wondering, which is more therapeutic in the long run - the brain rewiring part or the dissociation part? Do we even know?

HAMILTON: No. And there's a lot of debate about whether dissociation is necessary if you want to use psychedelic drugs to treat psychiatric disorders. I talked to Dr. Ken Solt. He's an anesthesiologist at Harvard Medical School, and he thinks that dissociation is important, at least with ketamine.

KEN SOLT: There seems to be this link between dissociation and the anti-depressive effect of ketamine because if you don't give enough to at least induce dissociation, it seems like you won't get this anti-depressive effect.

HAMILTON: But that may not be true with other psychedelic drugs. So late last year, scientists published a paper about this tweaked version of the drug ibogaine. The version you get from plants will cause hallucinations and dissociation. But this synthetic version, called TBG, has been altered to eliminate those effects. Even so, when scientists gave TBG to mice who'd been bingeing on alcohol, the mice cut way back. And when they gave it to mice with behaviors associated with depression, the mice got better.

I talked about the ibogaine study with Gabriela Manzano. She's a post-doctoral researcher at Weill Cornell Medicine in New York. Manzano told me that if scientists could make safer versions of other psychedelic drugs, it might allow doctors to prescribe these drugs to lots of people instead of just those with no other options.

GABRIELA MANZANO: Ketamine, for example, has huge effects on depression. But it has some really - some side effects that we would like to get rid of. So this provides a roadmap on how we could start tweaking these chemical compounds to make them very useful in the clinic - keep the good parts, get rid of the bad parts.

KWONG: Got you. All right. Well, Jon, you have been reporting on brain science and depression for a long time. What is your take on these drugs?

HAMILTON: I think they are a sign that we're probably at the beginning of a new era in drug treatment for depression and anxiety and maybe for addiction and PTSD as well. I mean, the FDA approved Prozac for depression way back in 1987. And for, like, the next 30 years, there was really nothing new. You had drugs like Paxil and Zoloft come along, but they worked pretty much the same way as Prozac. But when ketamine got approved in 2019, suddenly there was a depression drug on the market that did something totally different in the brain. And now it looks like there will be other drugs based on psychedelics that will be able to help a lot of people who haven't really been helped by anything else before.

KWONG: Well, Jon, thank you for bringing this reporting on a kind of watershed moment for psychedelic drugs. And we look forward to having you on the show to talk more about them.

HAMILTON: Always a pleasure, Emily.

KWONG: This episode was produced by Brit Hanson, fact-checked by Rasha Aridi and edited by Gisele Grayson. The audio engineer for this episode was Jay Ciz (ph). I'm Emily Kwong. Thanks for listening to SHORT WAVE, the daily science podcast from NPR.

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