Science Vs - Ketamine: How Special is Special K?

Episode Date: April 27, 2023

For years, ketamine has been thought of mostly as a horse tranquilizer — or a street drug that puts you in a scary-sounding K-hole. But now, we’re hearing reports that it could be almost a miracle medicine, treating stubborn depression and other mental illnesses. So how good is it, really? And could using a drug like this for depression actually be dangerous? We talk to researchers Dr. Rebecca Price, Prof. Colleen Loo, and Prof. Gerard Sanacora – and Fernanda Graciolli.  UPDATE 4/28/23: A previous version of this episode incorrectly described Dr. Rebecca Price’s role in a 2009 study of ketamine’s effect on depression and suicidal thoughts, back when she was a graduate student. The episode has been updated accordingly. This episode does deal with depression and suicidal thoughts. Here are some crisis hotlines:  United States: US National Suicide Prevention Lifeline 1-800-273-TALK (2755) (Online chat available); US Crisis Text Line Text “GO” to 741741 Australia: Lifeline 13 11 14 (Online chat available) Canada: Canadian Association for Suicide Prevention (See link for phone numbers listed by province) United Kingdom: Samaritans 116 123 (UK and ROI) Full list of international hotlines here  Find our transcript here: https://bit.ly/ScienceVsKetamine In this episode, we cover: (00:00) Intro: Ketamine - a new wonder drug?  (05:47) Chapter One: Ketamine and depression (10:37) Chapter Two: What does ketamine do in the brain? (15:04) Chapter Three: But ketamine doesn’t help everyone … (20:17) Chapter Four: The risks of using ketamine (24:30) Chapter Five: Ketamine and addiction (25:54) Chapter Six: Overall — what should we make of ketamine? This episode was produced by Michelle Dang,Wendy Zukerman, R.E. Natowicz, Joel Werner, Rose Rimler, and Meryl Horn. We’re edited by Blythe Terrell. Gimlet’s managing director is Nicole Beemsterboer. Fact checking by Erica Akiko Howard. Mix and sound design by Catherine Anderson. Music written by Bobby Lord, Peter Leonard, Bumi Hidaka, So Wiley, and Emma Munger. Thank you to researchers Prof. Bita Moghaddam and Grace Forsyth. Special thanks to Flora Lichtman, Jorge Just, the Zukerman Family and Joseph Lavelle Wilson.  Science Vs is a Spotify Original Podcast and a Gimlet production. Follow Science Vs on Spotify, and if you want to get notifications every time we put out a new episode, tap the bell icon in your app. Learn more about your ad choices. Visit podcastchoices.com/adchoices

Hi, I'm Wendy Zuckerman and you're listening to Science Versus from Gimlet. And we are pitting facts against falling into a K-hole. Today on the show, ketamine. You might know it as a horse tranquilizer or even a party drug. But these days, there's all this talk that it can treat depression and a whole bunch of other mental health conditions. So we want to know, is this for real? And in today's episode, we are talking about suicidal thoughts and depression.

So please take care when you're listening to the show. And if you are feeling depressed or you just want to talk to someone, we'll put some numbers that you can call in our show notes. Okay, let's get started. Fernanda Gracioli is a web developer from Massachusetts. And ever since she was a little kid, she struggled with depression. I would have these periods of time where I would come home from school, for example, and I would just cry for an hour or two hours, you know,

and I wouldn't want to do anything. I didn't want to play. I just wanted to be in my room by myself. And that was when I was a really little kid. But by the time I was 10, I was truly depressed, like grown-up depressed. In her teens, she was diagnosed with bipolar disorder, and she'd have these terrible bouts of depression. Doctors prescribed her all sorts of meds, but nothing really worked,

which is true for maybe a third of people with depression and bipolar. Several years ago, things got really bad. Fernanda was having suicidal thoughts. I was catatonic. I couldn't speak very much. You know, like I couldn't feed myself. My partner was feeding me at the time because I couldn't care for myself. Like, I don't think I would have lasted much longer.

And, you know, I talked to my partner about this beforehand, and she completely agrees that I was very close to the end. But meanwhile, a surprising new treatment was right in front of her. I was just sitting on the couch, and I picked up a magazine, and I was flipping through it, and I saw an article in it about a guy who sounded just like me. He'd also had really bad depression. And what helped him was ketamine.

Fernanda decided to give it a shot. She found a ketamine clinic, went to see a doctor there. And a few days later, she was in a comfy recliner chair, IV drip connected to her arm, and ketamine started flowing into her blood. It feels like I'm like, let me try to put this into words. Sorry, I want to pause for a second. When it first hits you and you start feeling it your body starts to feel a little funny something's happening to your body but you're not 100% sure what yet and then it feels like I have no control over my body I have no control over where my thoughts go

a few minutes in my body gets really heavy. Like I really truly become almost paralyzed. And it feels like my body is gigantic. I'm the size of the building. And then it was almost like her mind was moving out of her body. I was completely gone from the room. To me, it looks very dark, but it feels very calm. The feeling faded after about an hour. And at first, Fernanda didn't see any changes with her depression. She kept going back though. And it was after her fourth session that something really switched.

I was ecstatic. I was so happy. I had hope for the first time in so long. That promise of bringing me back to life, the possibility that I would go from being so close to wanting to end everything to being able to not feel the constant pain. Like that, it just, there's no better feeling in the world than feeling like you were in pain for your entire life and now you're not anymore. It's, it's, I was telling everybody about it. And there are tons of stories like Fernanda's out there. So today we're asking, what is the science on ketamine? Like, can it really turn things around for loads of people who are struggling with their mental health? And what are the risks here? Because some people say that ketamine can be a dangerous drug that can mess you up from your bladder to your brain. So we are going to get to

the bottom of all of this by diving into a K-hole of our own a k-hole of science the best kind of k-hole science versus ketamine is coming up just after the break it's season three of the joy of why and i still have a lot of questions. Like, what is this thing we call time? Why does altruism exist? And where is Jan 11? I'm here, astrophysicist and co-host, ready for anything. That's right. I'm bringing in the A-team.

So brace yourselves. Get ready to learn. I'm Jan 11. I'm Steve Strogatz. And this is... Quantum Magazine's podcast, The Joy of Why. New episodes drop every other Thursday, starting February 1st. What does the AI revolution mean for jobs, for getting things done?

Who are the people creating this technology, and what do they think? I'm Rana El-Khelyoubi, an AI scientist, entrepreneur, investor, and now host of the new podcast, Pioneers of AI. Think of it as your guide for all things AI, with the most human issues at the center. Join me every Wednesday for Pioneers of AI. And don't forget to subscribe wherever you tune in. Welcome back. Today on the show, we are snorting up the science on ketamine. And even though these days people are saying that this drug can help with loads of different things,

its potential as a treatment for depression is what really started this ketamine craze. So for decades, ketamine has been used as an anaesthetic to put people under, even to put horses under, hence the horse tranquiliser. But to start our story, we're going back to the 2000s. Picture it. People are still obsessed with Gilmore Girls, which I don't get. Snoop Dogg was dropping it like it's hot, which I do get. And in the lab, scientists were seeing that sometimes when they gave people ketamine,

their mood seemed to lift. And so some started thinking, could we try this as a medicine for depression? I thought it was an interesting idea. I didn't, you know, at that time, there was so little that had been done. Rebecca Price, who's now an associate professor of psychiatry at the University of Pittsburgh,

helped with one of the first clinical trials looking into this. She was a grad student at the time working with researchers who wanted to see whether ketamine could actually help people with depression and suicidal thoughts. Her team got around two dozen patients who were dealing with this, where other medication hadn't worked. They had them come into the hospital. And for this kind of thing, patients would get hooked up to an IV. And then you're going to slowly be administered the medication over about 40 minutes. And the researchers wanted to know, after the effects

of the drug wore off, did they feel any better? So she had them stay overnight in the lab and her team checked them again 24 hours later after the ketamine. And she told us that she wasn't expecting much. You know, all the thinking at the time was that depression can be stubborn, very hard to treat. Classic antidepressants and even therapy can take weeks or months to kick in. But what she saw blew her mind. These patients had tried everything, nothing had helped, and then I would come back literally the next day and it was almost like talking to a different human being with this whole different mindset and outlook. They were just well. Before the infusion, about half of the patients had actually been borderline suicidal.

The next day, most of them were having no suicidal thoughts. None. Suddenly we had almost like a depression switch that could be flipped, and that was something really new. So that was very hard to ignore. It was hard for lots of academics to ignore, that a drug could have this kind of antidepressant effect just 24 hours later.

In fact, researchers all over the world were jumping on this, like Professor Colleen Liu with the Black Dog Institute at the University of New South Wales in Sydney over in Australia. Colleen had started testing ketamine in her severely depressed patients. And I must say, I was astounded. And Colleen wanted to know, could this be due to the good old placebo effect? So she set up a small trial to find out, when neither she nor her patients knew whether they were getting ketamine or a placebo.

And she found it still worked. Yeah, this will be a familiar story by now, but Colleen told us about one of her patients. He'd been depressed for ages, nothing helped, he got ketamine. And the very next day... He looked like a completely different person. And he was astounded. We were both sitting there. It's very funny because, you know, colleagues of mine who were skeptical say it's all because of the placebo effects, because of the expectations. But in fact, it was exactly the opposite. You know, he was saying to me, I don't actually, I'm having trouble believing I could feel so well one day later.

And I said to him, I'm having trouble believing it as well, that you look so well compared to the person I saw yesterday. We both actually had trouble believing, you know, what we were seeing with our own eyes. It's truly remarkable when you see it, because I don't know of any other treatments in psychiatry where you can get someone from being seriously depressed to being well in one day. These days, there are dozens of studies which find that as soon as people with really bad depression get ketamine, it can help. And based on some of that data, in 2019, the FDA approved a version of ketamine treatment for people who have depression where other meds haven't worked. It was even fast-tracked as a breakthrough therapy.

And so our next question is, how is this happening? Like what is going on in the brain of someone who's depressed after they have ketamine? And Colleen told us that to get to the bottom of that, you first have to know what's happening in the brain of someone who's been depressed for a long time. In some parts of your brain, your brain cells can actually shrink and they become a bit sick. So for decades, in fact, people have said, you know, when they're quite depressed, my brain doesn't work. Like I can't think, I can't remember things. There's also evidence that the connections between neurons change in people who have depression.

It's almost like if you imagine your brain as a whole bunch of roads that allow you to drive to different places and think different thoughts, when you've had depression for a long time, it can be harder to make new roads in some parts of your brain. But some research is showing that ketamine might be changing that. So, for example, we know that when you take ketamine, it gets up into your brain and can latch onto a receptor that lives on our brain cells. And this triggers a domino effect, which can do a bunch of stuff, like change how an important neurotransmitter called glutamate works in our brain. And all this could just really shake things up in there.

Yes, it kind of loosens up your brain circuits, which we think actually allows people to escape from the circuits where they're stuck. You know how often people ruminate or they're stuck in a negative pattern of thinking they can't get out of it? And what ketamine does, and that's why some people feel a bit weird for half an hour or so when they're under the influence, it kind of almost like liberates your brain to allow it to think in different ways. And even after ketamine is gone and out of your system, some of those circuitry changes seem to stick around. So from studies in rodents, you can see that after these little tackers get ketamine, this kind of amazing thing happens. Their brain cells and the branches that they use to talk to each other...

Plump up and regrow. That's such a lovely image, isn't it? Yeah, I mean, they've actually shown this. Oh, really? Yes, yes. Mainly done in animal studies where they give the animals ketamine and look at it under a microscope. So when I say that their brain cells are growing new connections,

literally that's what they're seeing in these microscope slices. Wow. Yeah. Studies are finding that after rodents get ketamine, some neurons are chatting and connecting that weren't before. Now, obviously, the brain and depression is super complicated and scientists are still muddling through all this. But what we're finding is that ketamine is a very interesting drug.

Have you ever tried ketamine? No, actually, I haven't. Really? Are you not curious? Oh, look, I'm very curious. The issue would be, Wendy, how one would, you know, legally and properly try ketamine. So because the prescription is so strict. Yes, you'd have to get it off the street, Chloe.

Well, exactly. But what makes you curious? I think just in seeing, because I've heard from so many patients what it's like, it would just be really curious to experience it yourself, to have a firsthand knowledge of that. You know, what is actually happening subjectively at the brain level. Yeah. Yeah. That's such a wonderfully nerdy way to probably explain why a lot of people take it, isn't it? So this is all sounding pretty great for ketamine, but we got to hold our horses here, which some tranquilizer might help with.

Because there are claims that ketamine can mess up your bladder and your brain. And that is coming up after the break. Welcome back. So far, ketamine is looking pretty darn fabulous. But now, it's time to crash the party. Because while those early studies got scientists saying, giddy up, Dr. Rebecca Price told us that as researchers have kept looking into this, some of the newer studies are a little more meh. As is often the case in science, the initial findings were a little too good to be true. So a big thing is

that ketamine doesn't help everyone who's getting it. Far from it. Rebecca just brought together data from more than 350 patients who had used ketamine and found that 24 hours later, it only helped around half of them. Another study found that for about 8% of people, their depression actually got worse after taking ketamine. And the thing is, even when it does work, perhaps a bigger bummer here is that on average, the benefits don't stick around for long. A typical patient who gets a good response to a single infusion of ketamine will get about a week to two weeks of relief and then be back sort of where they started. But that's not particularly helpful. Maybe in certain

circumstances, like a crisis, a situation, but patients want to feel better a lot longer than one or two weeks. While some people can have these amazing responses to ketamine and feel better for months after, for most people, it's not like that. Which is all a bit befuddling for scientists working in this space, given all of those things that they're seeing in the brain. But for now, the next big push is to figure out a way to make the benefits of ketamine last longer. They're trying all kinds of things, like combining ketamine with therapy, upping people's doses, or just giving people ketamine week after week after week. Which might help a little, but according to the studies, a lot of people are still relapsing. We talked about this with Gerard Sanicora

a professor of neuroscience at Yale University. What's the end game? So great, we're going to treat you and we have a good chance of getting you feeling significantly better. Then what? Then what are you going to do? You're going to need to take this treatment for the rest of your life.

And here is where the science on ketamine falls into a keyhole of its own. A few years ago, Gerard was asked to write a report for the American Psychiatric Association. And his task was to write guidelines for how doctors should use ketamine. You know, basic things like how much should you use? How often? The best way to give it. The reality that we came to very quickly is, well, we really can't write guidelines

because there just isn't enough information. You need information to write guidelines and we don't have enough information. And we know at this point there are tens of thousands of people around the country being treated. But what is the right dose? What is the frequency that should be used? We don't know this. So that's where the research is at with ketamine and depression. But now there's all this excitement that ketamine can help with a whole bunch of other stuff.

Our producer, Michelle Dang, talked to Gerard about it. Some of these sites I've read, like, they list treating autism or work stress or insomnia. Boredom. Have you seen it advertised for boredom? No, no, I haven't necessarily, but I'm joking there. Gerard, please, leave the jokes to the professionals. I mean, people are listing, you know, so many different things. And other than depression, where we have the next best data is in PTSD and OCD. And even for those conditions, some studies suggest that ketamine can help and others don't. A big review on bipolar disorder found that there's some evidence

it can help 24 hours later, but on average, again, the benefits don't last long. Generally speaking, Gerard says it makes sense to try other stuff first. So I'm not saying that you shouldn't use it. I want to be careful because we wouldn't do anything in medicine if we needed to be 100% sure of what everything was. It's just to jump to something like ketamine before you try something like cognitive behavioral therapy to me seems a really poor decision. People are desperate for treatments. Clinicians really are trying to help people for the most part.

It's just you can't let the cart get ahead of the horse. Which is easy to do because the horse has been tranquilized. Can we make this joke too many times? Nay. Okay, so our final question for today is this. what are the downsides of taking ketamine like why wouldn't you just give it a go anyway well for one there are some side effects soon after you start an infusion your heart rate can go up and you can feel nauseated. Fernanda told us that an infusion of ketamine made her feel nauseous, extremely nauseous, disoriented. Walking was really difficult because I felt like

the ground was moving underneath me. It was really physically taxing. So that's soon after you get ketamine. But what about in the longer term? Like if people are going to be taking this for the rest of their lives? Well, Colleen over in Australia wrote a big paper on this. And she said that because a lot of this depression research is pretty new, where we have the most long-term data is in people who took ketamine for funsies. Which is a very messy literature because basically we don't know what dose people are using, how often they're using it and what else they're using it with.

Still though, she scoured through that messy literature to see was anything bad happening in these people. And there were some quite worrying reports. And one of the weirdest things has to do with our pee plumbing, the bladder and urinary tract, because for some recreational users... You feel you need to go to the toilet often. It feels a bit of burning and stinging when you pass urine, you know, that kind of thing.

Yeah, like that barbed wire feeling. Yeah. If you've ever had a UTI, kind of thing. Yeah, like that barbed wire feeling. Yeah. If you've ever had a UTI, she says it's a bit like that. And here's why ketamine might mess up your bladder. So when ketamine gets broken down in your liver, the little breakdown products move into your bladder and there they can irritate the lining of your pee balloon.

Colleen says that in really rare cases where people are using a ton of ketamine to party, it can get so bad that the bladder has to be removed. A paper from about 10 years ago called ketamine, quote, a murderer of young bladders, which is a Knives Out sequel that I am not ready for. Anyway, this is not common. But Colleen says she has seen the odd irritated bladder in her clinics too. And she says it's only a real problem if you keep taking ketamine after you feel those symptoms. Right.

So if it's caused by a reaction to ketamine and its breakdown products, then once you flush out ketamine, as painful as that might be, then does your bladder go back to normal? Exactly, exactly. So it's not as if it happens then, oh no, this is terrible and we're having a serious problem. It means that it's starting to irritate the bladder. And what we do is we then say, okay, we need to give the bladder a rest and it recovers. So that is the whiz machine.

But Colleen also found that for people taking ketamine recreationally, some of them had problems with their thinking and memory. So, for example, there was this one study that got a bunch of people, some who used ketamine a lot, we're talking at least four times a week, and then others who just dabbled with it, say once a month, and others who didn't use ketamine at all. They followed them for a year and found that the ones who used ketamine a lot, they did worse on memory tests. But the thing is, while we don't have much long-term data here, studies into people using ketamine for depression, who are probably taking less of the drug, they're not seeing problems here. In fact, all the research studies and also the clinics are not finding any cognitive issues as a result of ketamine. For Fernanda, who has been taking ketamine fairly regularly, she said about six

months in, she actually did develop some problems with her memory. Overall, we just really need more data on this. And then finally, if we're talking about drugs, we better talk about addiction. It is possible to get addicted to ketamine. We found a case report of a nurse who they rather conveniently called Mrs K. She was using ketamine to help with her depression. And at first it was very helpful. But after a while, you know, the same dose wasn't as helpful. So she was taking a higher and higher dose and just kept going up and up and up. She started stealing it from the hospital she worked at until one day she was found confused and euphoric

with 14 ketamine vials and matching syringes stuffed into her pockets and purse. Other researchers wrote that ketamine has, quote, the potential for misuse and addiction. Now, the frustrating thing is that we don't know how many Mrs. K's there are out there. We do have one small study from last year that asked people who took ketamine for depression if they had any cravings for it afterwards, and most people didn't. Yeah, I don't think from everything I've seen that ketamine is highly addictive. And in fact,

you know, patients coming through our clinic often say, I don't know how everything I've seen that ketamine is highly addictive. And in fact, you know, patients coming through our clinic often say, I don't know how this is a drug of addiction. They're not having that much fun at your clinic. Is that what you're saying? Well, exactly. It's not like they're getting a euphoric high. What they're coming for is the lifting in mood. So when it comes to ketamine, how does it stack up? Miracle cure or just another fad?

Well, ketamine doesn't help everyone. A lot of people with depression don't get better after they take it. And even for those it does help, on average, the benefits aren't sticking around for long. Plus, there are side effects. Still, though, this doesn't mean that ketamine is useless. Like for Fernanda, she goes back for infusions every few months and she says

that while this isn't some miracle drug that completely took away her mental health problems, in fact she still takes other, more traditional medication. For her, this has still been huge. It is ketamine and it was ketamine that keeps me not only functional but actually feeling well. I don't want to sound like super dramatic when I say this but I really was very close to the end you know I was I was very close to making the choice to just just that it wasn't worth it anymore and ketamine took away all the reasons why I thought it wasn't worth it anymore

and gave me many, many reasons to feel like this is all very much worth it. Ketamine has given me my life back. That's Science Versus. Hello. Hey, Michelle. How's America? Oh, it's dark. How are you?

All right. Well, I shall let you sleep soon then. Producer Michelle Dagg, how many citations are in this week's episode? There are 101 citations this week. 101? Yes. Not Dalmatians. Citations.

Not Dalmatians. Citations. If people want to see these citations, where should they go? Head over to our show notes and there's a link to our transcript with all the citations. And next week, Michelle, what is next week's episode? Oh, there's a mini episode on beavers. It involves some very sexy, sexy beaver talk?

Did you just say sexy beaver talk? Yes. That's true. I think that's fair. It's like, you know, beaver sexy time, but also the sexy things they're doing for the environment. Very nicely done. Thanks, Michelle.

All right. Thanks, Wendy. See you. Bye. This episode was produced by Michelle Dang, me, Wendy Zuckerman, Irene Natavich, Joel Werner, Rose Rimler and Meryl Horn. We're edited by Blythe Terrell. Gimlet's managing director is Nicole Beamster-Bohr.

Fact-checking by Erica Akiko Howard. Mix and sound design by Catherine Anderson. Music written by Bobby Lord, Peter Leonard, Bumi Hidaka, So Wiley and Emma Munger. Thank you to the researchers we spoke to for this episode, including Professor Bita Mohagdam and Grace Forsyth. A special thanks to Flora Lichtman, Jorge Just, the Zuckerman family and Joseph Lavelle-Wilson.

I'm Wendy Zuckerman. Back to you next time. Thank you.