[RADIOLAB INTRO]

JAD ABUMRAD: Three, two, one. Hey, I'm Jad Abumrad.

ROBERT KRULWICH: I'm Robert Krulwich.

JAD: This is Radiolab.

ROBERT: And for today ...

JAD: We're gonna talk about drugs, I guess. Or really sort of the promise that you sometimes hear, that maybe these diseases that define our lives, like alcoholism or Alzheimer's, maybe those have very simple fixes like a drug or even a beam of light.

AMY O'LEARY: Yeah.

ROBERT: We're gonna begin with a conversation that we had actually quite a while ago.

JAD: It's a conversation that we had with a reporter, actually, someone we used to work with.

ROBERT: Yeah.

JAD: An ex-intern.

ROBERT: Yeah.

JAD: One of our great interns has gone off in the world.

ROBERT: Amy O'Leary is her name.

JAD: Amy O'Leary is her name. She at the time was a New York Times reporter, but is now the editorial director of Upworthy.

AMY O'LEARY: So this started actually through a personal interest. So I was in a relationship with an alcoholic, and was very open about that. Talked about it with all my friends and ...

JAD: Were you open with him about it too?

AMY O'LEARY: Yeah. I mean I would—he was in some denial, and—but yeah, I was—I mean, I regularly would tell him, "Hey, like, you have a problem with this." And, you know, he would be clear back and say, "You know, if you're gonna make me choose between me and vodka I'm gonna choose vodka." So ...

JAD: He would say that really?

AMY O'LEARY: He did say that once, yeah.

JAD: Wow!

AMY O'LEARY: And I was, you know, young, but every night after 11:00 my life became [bleep].

JAD: There were fights, arguments, a lot of rage.

AMY O'LEARY: And I didn't know what to do, and—and felt really out of control. And, you know, I'd been to Al-Anon meetings. And it just seemed like this, like, terrible, tragic problem that, like, a really smart, cool person would turn really awful on you.

ROBERT: But then one day Amy found herself in Barnes & Noble on Union Square.

AMY O'LEARY: Union Square. I think I'm on the third floor, and there was a table of mostly self-help books, and there was this one called The End of My Addiction.

JAD: She picked it up.

AMY O'LEARY: This book was super fascinating. It was the memoir of a French cardiologist, this French doctor who had had his life completely ruined by alcoholism. And I looked at it, and I probably stood there, like, feet glued to the floor, and just, like, read 70 percent of the book.

JAD: The book described in very vivid detail this successful doctor just sliding off the rails.

AMY O'LEARY: He'd been in detoxes and medical treatment facilities, you know, upwards of a half dozen times. His practice had fallen off. He was losing everything in his life.

JAD: At one point he describes this terrifying moment of waking up in the back of a taxi, blood all over himself. Doesn't know whose blood it is, doesn't know where he's going.

AMY O'LEARY: He was totally desperate. Killing himself was the next option. And then at one point he says that he had read this tiny nugget.

JAD: In the New York Times. Apparently he'd stumbled across this short piece about a guy who'd been addicted to cocaine, taken some muscle relaxants ...

AMY O'LEARY: And his cravings for cocaine completely ceased.

JAD: It was just one guy. One guy's experience.

AMY O'LEARY: But he saw that and he basically just felt like, "I'm just gonna experiment on myself."

JAD: So he gets the drug, starts taking it.

AMY O'LEARY: And he slowly, like, doses up more and more amounts of the drug.

JAD: Nothing happens, nothing happens.

AMY O'LEARY: And then at one point, he says, the switch flipped. And once the switch hit, he just became absolutely indifferent to alcohol.

JAD: Like, boom?

AMY O'LEARY: Yep.

ROBERT: Apparently this obsessive need for alcohol that had burdened him his entire life just went away.

AMY O'LEARY: Total indifference.

JAD: What is the drug called, by the way?

AMY O'LEARY: Baclofen. B-A-C-L-O-F-E-N.

JAD: Baclofen.

AMY O'LEARY: Mm-hmm.

JAD: Amy says at this point, standing there in the Barnes & Noble, she was skeptical but interested.

AMY O'LEARY: Yeah. So I found an email address. Like you do as a reporter, I Googled every combination of his name until I found some little dot Fr email address, and emailed him. And he wrote back right away.

JAD: And they set up a time to talk.

AMY O'LEARY: You know, I'm all ready. We have it planned in advance. I confirm it with him. I'm all set up at my desk in New York, and he picked up and I was like, "Dr. Ameisen, how are you? It's so good to speak with you." And he immediately was like, "Amy, Amy, I am so sorry. I am rescuing my girlfriend. We are in the Alps. I'm carrying her down a mountainside. Can I call you back?"

JAD: [laughs]

ROBERT: [laughs] Did you hear wind in the background? And the sound of the birds above him?

AMY O'LEARY: I heard no sound effects, no.

ROBERT: No.

AMY O'LEARY: But he did seem like he was exerting himself to some extent. So, you know, we schedule a second appointment and, you know, I recorded the phone call.

[ARCHIVE CLIP, Olivier Ameisen: Hello?]

[ARCHIVE CLIP, Amy O'Leary: Hello is this Dr. Ameisen?]

[ARCHIVE CLIP, Olivier Ameisen: Yes. It's Amy?]

[ARCHIVE CLIP, Amy O'Leary: Yes.]

[ARCHIVE CLIP, Olivier Ameisen: Amy, finally!]

AMY O'LEARY: I'm like, "Hi, it's nice to talk to you." And then, like ...

[ARCHIVE CLIP, Olivier Ameisen: It's like miracles happen, you know? The last time we spoke, I was rescuing my girlfriend. My God, it was like a nightmare. We were in Switzerland in the—at 10,000 feet.]

JAD: So he launches into the mountain story, and then ...

[ARCHIVE CLIP, Olivier Ameisen: Strong, and the ...]

JAD: ... just kind of goes off.

[ARCHIVE CLIP, Olivier Ameisen: When Moses opened the Red Sea, people say it was a miracle, although there is some science. Like Nietzsche said, "Become who you are." And I am who I wanted to be. Einstein might have been wrong, and they were wrong, but Einstein was right. And I mean, Rubinstein told me he's never heard a pianist like me. He's heard Rachmaninoff or Horowitz too. If comes the Nobel, you never know. People tell me I may have made the discovery of the century. I mean, there's no ...]

AMY O'LEARY: He, like, literally went on for 20 minutes before I got in ...

[ARCHIVE CLIP, Amy O'Leary: Well, I wanted to ask you ...]

AMY O'LEARY: ... with a little question.

[ARCHIVE CLIP, Amy O'Leary: You know, I read your book, I think, close to when it first came out in the United States.]

[ARCHIVE CLIP, Olivier Ameisen: Oh, really? Yeah, it's really like a thriller. I mean, it's humorous and it's fun. I mean ...]

JAD: And then he was off again.

[ARCHIVE CLIP, Olivier Ameisen: Sometimes I read it and I can't believe I—sometimes I want to say—you know, I say that, and that personally a lot has happened, but I mean if you look at just the back ...]

AMY O'LEARY: And then, like, literally it was 20 minutes of how important our shared mission was to, like, save the world.

[ARCHIVE CLIP, Olivier Ameisen: What I want to break is the shame.]

AMY O'LEARY: Red flags going off left and right, and I sort of started to downshift my thought of doing a story. And right about this time my reporting group got disbanded due to an internal reorganization, and so I moved to a different desk, and it was just like pshh okay. Maybe someday Radiolab will be interested in this story. [laughs]

JAD: [laughs]

JAD: Because we'll eat anything! No, in all fairness, Dr. Ameisen, who unfortunately passed away a few years ago, may have been in the middle of a manic episode, which doesn't necessarily negate the story he was telling.

ROBERT: No, not at all.

JAD: And even after dropping the story, Amy ...

AMY O'LEARY: As a journalist, and as someone who'd been personally affected by alcoholism I was incredibly torn. As a journalist, you have to be skeptical of everything, but at the same time, like, wouldn't it be great if we lived in a world where you could deal with this problem which, you know, tears apart so many lives, kills so many people, creates all kinds of pain and agony with, like, a medication. That just seems great.

JAD: Yeah.

AMY O'LEARY: You know?

JAD: And, like, the question for me is, like, we often see addiction as, like, this thing that you've got to morally conquer, like a spiritual calamity that you've got to somehow reorganize your entire being in order to get through. But what if it's not that way? What if it's—what if it's simply a switch in your brain that got stuck in the "On" position, and you can use a pill to just switch it right off?

ROBERT: Oh, that would be nice.

JAD: Now we were super skeptical of this idea, but we also couldn't stop thinking about it.

ROBERT: Yeah.

JAD: We started making some calls.

ANNA ROSE CHILDRESS: Hi, it's Anna Rose Childress. I'm all here.

JAD: Dr. Anna Rose Childress is an addiction researcher at the University of Pennsylvania, and Amy pointed us to her because it was her work that actually inspired Dr. Ameisen.

ANNA ROSE CHILDRESS: I don't know if you mentioned throbbing, pulsing desire states, but somehow that comes to mind.

JAD: That's her specialty.

ANDY MILLS: Throbbing, pulsing desire states.

ANNA ROSE CHILDRESS: [laughs]

ANDY: Yeah, that sounds great.

JAD: She spoke with producer Andy Mills and I in the studio. And for decades, she's been studying that craving state in addiction. She's interviewed people about it.

ANNA ROSE CHILDRESS: So what patients described to me is that they would sometimes describe a sort of a wave of sensation.

[ARCHIVE CLIP, patient: Some enormous wave just pulsates throughout your whole body.]

ANNA ROSE CHILDRESS: Would go from their toes up to their head, and back down again.

[ARCHIVE CLIP, patient: From my toes to my head, to my toes to my head.]

ANNA ROSE CHILDRESS: Sort of a zoom, a zoom, a zoom.

[ARCHIVE CLIP, patient: Vroom, vroom, rushing, pulsing.]

JAD: Okay. One day in 1995 she's at a conference. She bumps into a guy who tells her he has managed to get some rats addicted to cocaine, give them Baclofen, and they totally lost interest in the coke.

ANNA ROSE CHILDRESS: They were disinterested for several hours. So I saw this and I thought, "Wow!"

JAD: So she began to give Baclofen to people who were addicted to crack—small doses. And initially ...

ANNA ROSE CHILDRESS: There was a lot of disappointment.

JAD: Results weren't great. Then, she says, one day she was sitting in the staff lounge, just chilling, and a colleague ran in.

ANNA ROSE CHILDRESS: And said, "You know, there's this—this guy over at the hospital next door and, you know, Anna you've got to talk to him!"

[ARCHIVE CLIP, Anna Rose Childress: Acute episode when the desire was strong.]

JAD: His name was Ed Coleman. He was a paraplegic.

ANNA ROSE CHILDRESS: He had had a drug deal gone wrong, been shot in the neck.

JAD: Paralyzed from the waist down. So he was in a wheelchair, taking Baclofen.

[ARCHIVE CLIP, Ed Coleman: I was having bad spasms.]

JAD: Because he was having these spasms in his legs.

ANNA ROSE CHILDRESS: He recounted this to me, and I actually have the tape of it.

[ARCHIVE CLIP, Anna Rose Childress: So you were doing the low dose at first, and that was 10 milligrams four times a day?]

[ARCHIVE CLIP, Ed Coleman: Yeah, and ...]

[ARCHIVE CLIP, Anna Rose Childress: And then you upped the dose. Tell me why you upped the dose.]

[ARCHIVE CLIP, Ed Coleman: I upped the dose because I found that the 10 dose wasn't taking care of the muscle spasms.]

[ARCHIVE CLIP, Anna Rose Childress: Right.]

[ARCHIVE CLIP, Ed Coleman: But I still lit up, and my legs were still just tightening up and shaking. So I said, "Well maybe if I take two of these it will calm them down."]

[ARCHIVE CLIP, Anna Rose Childress: And what did you notice?]

[ARCHIVE CLIP, Ed Coleman: Well ...]

ANNA ROSE CHILDRESS: What Edward found was that when he doubled his Baclofen dose ...

[ARCHIVE CLIP, Ed Coleman: I would try to use cocaine. I couldn't feel the effects of it.]

ANNA ROSE CHILDRESS: ... the cocaine no longer had the high.

[ARCHIVE CLIP, Ed Coleman: And when I was taking it, I didn't have any cravings, you know?]

JAD: He then went on to tell her that when he stopped taking Baclofen, because he did stop for two days ...

[ARCHIVE CLIP, Ed Coleman: I was having bad spasms.]

JAD: ... the leg spasms came back.

[ARCHIVE CLIP, Ed Coleman: But I was getting the full effect of the coke.]

ANNA ROSE CHILDRESS: He could get the high again, and the craving went through the ceiling. So Edward had been doing his own experiments. He had doubled the dose, he had halved the dose to see what was the dose where he could still feel the cocaine high but his spasms wouldn't be driving him crazy.

JAD: Wow! So he was like a one-man study.

ANNA ROSE CHILDRESS: Yeah.

JAD: Now this was actually the specific story that inspired Dr. Ameisen to do his one-man study, and to write that book which held Amy glued to the floor in Barnes & Noble. Now even though none of this was rock-solid science by any means, Amy says that since then people have begun to quietly take this drug, and some doctors have even begun to prescribe it.

AMY O'LEARY: You know, I talked to a guy who runs a halfway house in Youngstown, Ohio, who was using Baclofen with people that were under his care. There was a doctor in Chicago who was prescribing it to a lot of people that ...

JAD: This is all off label use?

AMY O'LEARY: Yeah. Yeah, absolutely.

JAD: She told us that after Ameisen's book, message boards popped up.

AMY O'LEARY: Hundreds of people on these boards swapping stories about how much they took, when they took it. They were crowdsourcing their own cure, in effect.

JAD: But the really surprising thing is that, as we kept calling around, we realized that Baclofen was just the tip of the iceberg.

MARK WILLENBRING: Yes. Yes. Well, there's another drug Acamprosate or Campral, and this other drug Gabapentin. There's Topiramate or Topamax. A Disulfiram, Chantix, Suboxone, Naltrexone, Epinephrine.

JAD: This is Dr. Mark Willenbring.

MARK WILLENBRING: I'm an addiction psychiatrist here in Saint Paul, Minnesota.

JAD: Mark says that some of these drugs try to target the craving. They try to block the craving. Others try to target the high that you get.

MARK WILLENBRING: The simple way to put it is this: it's a buzz kill.

JAD: It's a buzz kill. Interesting.

MARK WILLENBRING: Yeah.

JAD: So you drink, but you don't get the ...

MARK WILLENBRING: You don't get the happy warm feeling.

JAD: Apparently, it takes all the fun out of it. According to one journalist that we talked to, Gabrielle Glaser, who does a ton of reporting about mental health and addiction ...

GABRIELLE GLASER: Took my 6:30 pill.

JAD: ... she tried one of these drugs during the course of reporting.

GABRIELLE GLASER: And it honestly, it made a second glass of wine seem about as enjoyable as a big glass of Dimetapp. I mean, really. It was just—it was like drinking water.

JAD: Why? What is the drug supposedly doing?

MARK WILLENBRING: Well, it blocks opioid receptors in the brain which is our pleasure system.

JAD: According to Dr. Willenbring, basically if you think of, like—if you think of a good buzz as like a chemical handshake.

ROBERT: Mm-hmm.

JAD: Like, you've got the alcohol molecules, and they need to click in with the receptors in your brain. And that's what creates ultimately the good feeling.

ROBERT: Right.

JAD: What this category of drugs do is they get in the middle of the handshake. They—sort of like a blanket, prevent the hands from shaking.

ROBERT: Or muffle them, sort of.

JAD: Right. And if you're not getting as much enjoyment out of the drinks, then the idea is you're not gonna drink as much.

MARK WILLENBRING: And these are home run drugs. These are drugs that you just don't see these kinds of effects in medicine, in hardly anything.

JAD: Mark pointed us to some studies that had been done in Finland, the Netherlands, the UK, Iran, a bunch that have been done in the US, that look at this one particular drug called Naltrexone and show that it has a very high success rate. Like, one particular study in Finland with about 150 people showed that this drug had a 78 percent success rate in helping very heavy drinkers reduce their drinking to normal levels.

MARK WILLENBRING: Right, right.

JAD: So are these drugs being used?

MARK WILLENBRING: No. Oh, no. Basically, the pick up has been near zero.

JAD: This is something that we heard over and over again, these drugs are out there, that there is some evidence that they work, but they're kind of invisible.

GABRIELLE GLASER: Yes. Exactly.

JAD: That's Gabrielle Glaser again.

GABRIELLE GLASER: Here, about one percent of people who suffer from alcohol use disorder are ever given the choice or an option to take any sort of medication.

JAD: She says maybe one, two percent at best.

GABRIELLE GLASER: Yes.

JAD: Which is particularly weird, she says, because that drug Naltrexone that was used in the Finnish study that did well, it's been out for a while.

GABRIELLE GLASER: This drug was approved by the FDA in 1994.

JAD: That's so weird!

ROBERT: Why wouldn't we have heard of it?

GABRIELLE GLASER: Well, that's a very complicated question.

JAD: It's just that addiction treatment has never really been part of the rest of medicine.

GABRIELLE GLASER: It has been completely segregated.

JAD: It's been its own self-contained world. And this actually goes back to how it was set up at the very beginning. And this I found fascinating. If you go back about 80 years ...

GABRIELLE GLASER: We had in hospitals at the time, in the late 1930s and early 1940s, we had ...

[ARCHIVE CLIP: The white plague, tuberculosis.]

GABRIELLE GLASER: ... TB wards. But then suddenly ...

JAD: After World War II ...

GABRIELLE GLASER: ... TB had a cure. You got better. You didn't have to stay in the hospital in the sanitarium just to recover. And suddenly these TB units were empty.

JAD: And she says it was just a few years earlier that a group of mostly men had got together to form Alcoholics Anonymous. Now at the time, doctors had no idea what to do with alcohol-addicted people. They were called drunkards.

GABRIELLE GLASER: Inebriate was another word that was commonly used.

JAD: They were basically seen as hopeless cases. Of course, the founders of AA knew this, so when they saw all those empty TB wards, they went to the hospitals ...

GABRIELLE GLASER: And said, "Let's make those alcoholism units in your hospital."

ROBERT: Really?

GABRIELLE GLASER: Yes. Doctors thought, "Okay, we don't have an answer for these guys, so we'll just let them do it." And thus began 80 years ...*

JAD: Of separation.

GABRIELLE GLASER: And that's where we are now.

JAD: Out of this physical separation, according to Gabrielle Glaser, you got a cultural separation—two very different ways of seeing addiction.

ROBERT: Cultural—all right. What does that mean?

JAD: Just to state it in the extremes. On one hand you've got, like, someone in the medical sciences who might be inclined to see addiction as a purely biological phenomenon. You know, that's all this is.

ROBERT: And we'll just fix it.

JAD: We'll just fix it.

ROBERT: Yeah.

JAD: On the other hand, you have the idea that no, that you can't just fix this biologically. There is something deeply wrong here. There's something in the person, in the spirit, in the soul.

ROBERT: This is a reflection of your inner broken self.

JAD: Yeah, which just has to be addressed at a higher level.

GABRIELLE GLASER: In the AA curriculum—I may have my facts wrong—I believe five out of the 12 steps mention God.

JAD: Actually, when we checked it's six out of the 12. Half.

GABRIELLE GLASER: And the big book, which is the bible of Alcoholics Anonymous, there is a mention of God, or him, or your higher power on almost every page.

ROBERT: What is the recovery rate from the AA crowd?

GABRIELLE GLASER: Well, what many researchers say is that the success rate of AA is in the single digits. One study showed that, for every 100 people who show up in an AA meeting on January 1, only five of those people will be sitting there on December 31.

ROBERT: Of the same year?

GABRIELLE GLASER: In that same year.

JAD: Really, so the ...

GABRIELLE GLASER: Yeah.

JAD: ... so the—what do you call that? The drop out rate is—is 95 percent?

GABRIELLE GLASER: Yeah. I was really surprised to find that out.

JAD: Now to be fair ...

ROBERT: Hmm. I think we should be fair.

JAD: ... we have to say that—a couple things. Like, first of all, AA is a volunteer organization, it's a support group. It doesn't claim to be a treatment.

ROBERT: Mm-hmm.

JAD: And also, when you start talking about success rates, that gets really squishy. I mean, if a person doesn't show up to an AA meeting, it doesn't necessarily mean that they're drinking again. They may be doing just fine.

ROBERT: Or perhaps they've switched groups.

JAD: Exactly.

ROBERT: They've moved—moved on to another ...

JAD: So it's really, really hard to sort of define your terms here. Clearly, AA is important to a lot of people. And that's something that actually Gabrielle Glaser found out last spring when she published an article in The Atlantic where she basically laid all this out.

GABRIELLE GLASER: When that article came out, I received thousands of emails. "You are a horrible person. You deserve to die. AA saved my life. I hope your kids get killed by drunk drivers."

JAD: But ...

MARK WILLENBRING: So there was this article in The Atlantic in April.

JAD: ... when we talked to Dr. Willenbring, who Glaser mentioned in the Article as somebody who believes more in medication than 12 step. He said that when that article came out ...

MARK WILLENBRING: Since then our phone has rung off the hook. We get about half of our calls from out of state. Is there anybody in North Carolina or in New York or in Texas or in California or wherever it is? And they're desperate, and the families are desperate for an alternative, and they can't find one.

JAD: He says all of this makes him think back about 30 years.

MARK WILLENBRING: When I was a resident, there was this debate raging. There was this big debate about depression, whether people should be treated with antidepressants.

JAD: But he said the debate completely shifted ...

[ARCHIVE CLIP: Here we go. Here comes the Prozac.]

JAD: ... when we got Prozac.

[ARCHIVE CLIP: Doctors have prescribed Prozac to two million Americans.]

JAD: Suddenly you had this drug that was a massive success, spawned other drugs, and in the process changed how people fundamentally see depression.

MARK WILLENBRING: And now most people, you know, get treatment for anxiety or depression with antidepressants, compared to psychotherapy.

JAD: Do you think we're heading in the same place with addiction?

MARK WILLENBRING: Oh, we are. Oh, we are. We are, there's no question. I do predict in 10 or 15 years we'll have a Prozac moment.

JAD: Radiolab will return in a moment.

[LISTENER: This is Jean Pelletier in Boston, Massachusetts. Radiolab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world. More information about Sloan at www.sloan.org.]

JAD: All right, welcome back. I'm Jad.

ROBERT: Robert.

JAD: And if you know this music you already know ...

[ARCHIVE CLIP, Brian Lehrer: It's The Brian Lehrer Show on WNYC. Good morning everyone.]

ROBERT: This is The Brian Lehrer Show at our own home station WNYC in New York. Very, very popular show.

JAD: Yes. And to explain, we wanted a gut check, because we had been hearing all of these things from experts saying that we're undergoing a sea change, and we wanted to know is that actually happening out there in the world?

ROBERT: And the world, at least our local world, is full of Brian Lehrer listeners.

[ARCHIVE CLIP, Brian Lehrer: It's your stories of what kinds of treatment you were offered and actually used for alcohol and substance abuse.]

JAD: So we asked the Brian Lehrer team if they would help us out.

[ARCHIVE CLIP, Brian Lehrer: Call us at 212-433-WNYC.]

JAD: And they helped us out.

ROBERT: Big time.

[ARCHIVE CLIP, Brian Lehrer: And we'll explain more now with Radiolab host, Jad Abumrad. Hi Jad.]

[ARCHIVE CLIP, JAD: Hey, Brian. Thank you for having me on.]

[ARCHIVE CLIP, Brian Lehrer: And you believe we're in the midst of a cultural and medicinal shift for the way we both view and treat people with addictions, right?]

[ARCHIVE CLIP, JAD: Yeah. So I mean, we—we're not sure, to be totally honest. You know, we—we bumped into a reporter a couple years ago who told us this story of a guy ...]

JAD: So I sort of summarized Amy O'Leary's story about Dr. Ameisen.

[ARCHIVE CLIP, JAD: He described a moment where the addiction just switched off.]

JAD: Then I sort of summarized what the experts had told us, that maybe something is happening, but we weren't sure.

[ARCHIVE CLIP, JAD: And we're just not sure. And so we're curious to hear from people who've struggled with substance abuse. I'm wondering what sorts of treatments they've been offered. Have they seen pills like Naltrexone or Baclofen? Have they used them? Have they worked? What's been the experience?]

[ARCHIVE CLIP, Brian Lehrer: So listeners ...]

JAD: And just like that ...

[ARCHIVE CLIP, Brian Lehrer: ... help Jad report this story.]

[ARCHIVE CLIP, listener: Hi.]

[ARCHIVE CLIP, listener: Hi.]

[ARCHIVE CLIP, listener: Hi.]

[ARCHIVE CLIP, listener: My name is Paul.]

[ARCHIVE CLIP, listener: My name is Nicole.]

[ARCHIVE CLIP, listener: I'm calling from New Hampshire.]

[ARCHIVE CLIP, listener: I'm actually in Afghanistan.]

[ARCHIVE CLIP, listener: I've overdosed many times on heroin, cocaine.]

[ARCHIVE CLIP, listener: Celebrating a year of sobriety next month.]

JAD: ... there was an explosion of calls.

[ARCHIVE CLIP, Brian Lehrer: Ginger in Mahopac, you're on WNYC.]

[ARCHIVE CLIP, listener: Hi, how are you? I'm an alcoholic and an addict, and I've been in recovery for 18 years.]

[ARCHIVE CLIP, listener: I was setting up at an AA meeting listening to this.]

JAD: We heard from a lot of people who felt like this idea of a pill that can treat addiction was idiotic.

[ARCHIVE CLIP, listener: I just don't see psychotropics as really a solution.]

[ARCHIVE CLIP, listener: There is no quick fix. There is no magical medication. If it was just a physical disease, they would all be cured.]

JAD: But we also heard from a lot of people who had just been offered these drugs.

[ARCHIVE CLIP, listener: I was prescribed Campral.]

[ARCHIVE CLIP, listener: I had been offered Naltrexone, and ...]

[ARCHIVE CLIP, listener: Naltrexone ...]

[ARCHIVE CLIP, listener: And it's very effective. It does help cut the cravings.]

JAD: One guy who called ...

[ARCHIVE CLIP, listener: This is so incredibly crazy that I heard this show today as I'm about to embark upon this thing.]

JAD: ... he'd just got prescribed addiction medicine that morning.

[ARCHIVE CLIP, listener: One way or another, I'm gonna fix this.]

JAD: He was excited, as were a lot of the callers in this category, because ...

[ARCHIVE CLIP, listener: It's a huge social stigma.]

JAD: ... if these pills work for them, it kind of means that they're just sick, they're not bad people.]

[ARCHIVE CLIP, listener: It's not something that people choose, even though it seems that way.]

[ARCHIVE CLIP, Andy Mills: Well, let me ask you this because I ...]

JAD: That's producer Andy Mills again. After the Brian Lehrer show, we had so many calls that he set up a Google voicemail and he talked with an additional 40 or so people. And he asked everyone ...

[ARCHIVE CLIP, Andy Mills: Do you feel that we're headed toward a sea change where we're gonna start treating addictions in a new way?]

[ARCHIVE CLIP, caller: No.]

[ARCHIVE CLIP, caller: I completely do. You know, you got a drug problem, find a drug that fixes the drug problem.]

[ARCHIVE CLIP, caller: There's no pill that will make you want to put down the drink and the drugs.]

ANDY: Hello, Billy?

BILLY WEBB: Hey.

ANDY: Will you just introduce yourself, tell me who you are?

BILLY WEBB: My name's Billy Webb. I am from Shaker Heights Ohio, and I currently live in Saint Paul, Minnesota.

ANDY: Hey, this is Andy. So in talking to all those people on the phone, Billy's—it was a story that I just kept thinking about over and over again. And so eventually, we ended up getting him into the studio.

ANDY: Do you remember what it was like the first time that you had alcohol?

BILLY WEBB: Yeah. It was the summer that I turned 16. And I was a quieter kid, and I was kind of a nerd. The tide sort of swung and I got into music, and most specifically punk rock and ska.

ANDY: He says it was this time that he was coming out of his shell. He learned how to play the bass, started practicing all the time. He made these new friends, and they started a band.

BILLY WEBB: I had gotten my first girlfriend at that time, and I was very excited and nervous to see her, so I figured why not—why not loosen myself up a little bit?

ANDY: So one day he breaks into his fathers liquor cabinet, takes a couple shots of Mount Gay Rum.

BILLY WEBB: It was euphoric, to be honest with you, and I finally felt like I was myself. That's sort of when things started to take off.

ANDY: By the time Billy was 24 ...

BILLY WEBB: I was becoming an entrepreneur.

ANDY: He was running his own business. It was a storage facility that he planned to convert into art spaces.

BILLY WEBB: Where we would have shows, and maybe even a little small record shop. I was in a relationship. We had a dog.

ANDY: He was in a new band that toured.

BILLY WEBB: It was fun. I can say that for sure. I could even conduct business out of the bar down the street if I wanted to, because the business line forwarded to my cell.

ANDY: But he said that it was also around this time that he started to wake up in morning with the shakes.

BILLY WEBB: And I remember drinking beer in the morning in the bathroom.

ANDY: How much do you think you were drinking at this point?

BILLY WEBB: 20 drinks a day, 25 sometimes.

ANDY: Wow!

BILLY WEBB: And usually the night before, before I passed out or went to sleep, I would say, "You know, I'm gonna turn it around in the morning. I'm gonna—I'm gonna get out of bed and work out, eat a full meal." And that never ended up happening.

ANDY: What eventually did end up happening is that Billy asked for help. Both his mom and his sister, they flew Billy up to Minnesota where he checked into one of the best rehab centers in the Midwest.

BILLY WEBB: And when I got there, it looks like a small college campus. I mean, it was very serene, sort of peaceful setting. Very welcoming.

ANDY: He started going to group meetings, started working out, and was like, "All right."

BILLY WEBB: I was actually excited. I thought that things would turn around when I got back, but ...

ANDY: Within just a day of being back in Cleveland ...

BILLY WEBB: ... it was right back to where I was: 20 drinks a day, 25 sometimes. So I ended up back in treatment. We figured, you know, I just didn't do it right the first time, so if we go back we'll get it right this time. And once again, you know, I crashed and burned.

ANDY: This time not even in Cleveland.

BILLY WEBB: I had relapsed at the airport. I didn't even make it to Cleveland.

ANDY: And he said this is just how things went for years.

BILLY WEBB: It was just this same old story of in and out, in and out.

ANDY: In the span of about four years' time, Billy tried seven different treatment centers and detox centers. Lots of AA meetings.

BILLY WEBB: I went to 110 meetings in 70 days. I went to 28 in one week one time.

ANDY: Nothing worked. He says that his AA sponsors would tell him ...

BILLY WEBB: You know, you can do this. You'll get it right.

ANDY: So he'd leave those meetings ...

BILLY WEBB: Feeling positive.

ANDY: ... end up at a liquor store.

BILLY WEBB: I just considered myself a failure at this point in time, that I was never gonna get better. And that led to more and more drinking.

ANDY: He said that he lost his girlfriend, pretty much all his friends, got fired from his job.

BILLY WEBB: Due to drinking. And my days just consisted of walking to the liquor store, buying two fifths and walking home. And then I woke up one day with severe, severe pain in my abdomen, and I couldn't move or walk or keep water down. And it was really scary, and it was pancreatitis. So I ended up checking myself into a hospital in Grand Rapids, and I saw these people and they said, "Wow we don't even—we don't see this condition until people are usually in their mid 40s."

ANDY: Billy was only 29 years old.

BILLY WEBB: When I got out, I moved into a sober house in Saint Paul, and that's when I got hooked up with the Alltyr Clinic.

ANDY: Now at the Alltyr Clinic, which I should say really quick, is run by Dr. Mark Willenbring who we talked to earlier, there they do something that they call evidence-based treatment. So if a patient shows up looking for help, they are given a therapist to treat any underlying mental health conditions that they may have, and for everything connected to their addiction, they're given medications. In Billy's case, they gave him Naltrexone.

BILLY WEBB: When I took the Naltrexone, I actually was able to limit my drinking to two to six drinks a night, which was, quite frankly, felt like a normal amount to me.

JAD: He was able to drink moderately?

ANDY: Yeah, almost overnight.

BILLY WEBB: I was blown away. That's all I wanted was to be like everyone else who can ...

ANDY: Right.

BILLY WEBB: ... have a couple drinks and set it down.

ROBERT: Well, what does that tell you? That tells you that you are cured? Or ...

BILLY WEBB: I just felt like there was—there was no compulsion to keep going and going.

ANDY: And being able to drink without that rush, for a while that made all the difference.

BILLY WEBB: For a couple months, I was okay. You know, now I can just have a couple. But what happened was I was taking it, and then on one weekend I just decided, you know what? I don't need it.

ANDY: Billy says that even though the urge to drink, which was something that had been nagging at him for years, even though that was now gone, he told me that there was just some part of him that missed being drunk.

BILLY WEBB: I wanted to be intoxicated.

ANDY: Even with this medication that was helping you, you missed it?

BILLY WEBB: Yeah.

ANDY: Knowing all that it cost you, what about it did you miss?

BILLY WEBB: I missed feeling like myself. I didn't picture life being possible without alcohol. That's the only person that I knew.

ANDY: And basically what he told me is that if you think back to the beginning of his story, he came out of his shell alongside alcohol. Being creative, writing music, performing music, alcohol's there. His first girlfriend? Alcohol was there. He's had drinking associated since puberty with the best parts of himself. And so, like, you know how we all have this sense of, like, who we are inside of us? Like, you have your inner Jad where, like, people can think what they want about you, and you've got your reputation, but you—you know who you are down deep. Well, his? It was all wrapped up in alcohol. So you take that alcohol away ...

BILLY WEBB: What was left was an empty guy that I didn't know.

ANDY: Just this void. And filling up that void, he says, was this onslaught of these terrible memories.

BILLY WEBB: Sequestered detox wards, and punitive treatment, and all the people I've alienated over the years, all the lost opportunities, and all the failed attempts.

ANDY: He says that's what he would think about when he was sober, and he just wanted not to. Last time we talked to Billy, he was doing really well.

BILLY WEBB: I had the job. I had the girl. I had the band back.

ANDY: But he says that in the course of just this month and a half, since the last time that we talked ...

BILLY WEBB: Lost the girl, isolated a bunch of friends, and lost a good job that I wanted to keep for a while until I could get into grad school, so kind of having to start over now.

ANDY: Even just listening to your voice right now, you sound so different.

BILLY WEBB: I know that I sound different, because I was coming in here with more of a positive spirit last time. I really was flying high last time. People were excited for me to come in, and now they said, "Are you sure you want to come in today and talk to them?" I mean, the people who would even talk to me right now. So it's hard to do a triple back flip. You know, I tried to—didn't want to come in here crying or anything but, you know, it's pretty sad. It's pretty sad, but at the same time, you know, I feel hopeful that I can beat this.

ANDY: Now Billy's still seeing a therapist. He's still going to Alltyr. He's actually on this new medication now called Gabapentin, which he says has been helpful.

BILLY WEBB: And I know I was pretty staunchly against the 12 steps last time, but I am actually going back to meetings these days.

ANDY: Just to be with people who are in the same boat.

JAD: So he's doing both?

ANDY: Yeah.

JAD: Huh. I hear a story like that and I think—yeah, I think we're ready to see addiction in a new way. And we're definitely—I think, pills will be a big part of that.

ANDY: Mm-hmm.

JAD: Seems to me. But the pills can't get all the way down, you know?

ANDY: Right.

JAD: The thing that makes the addiction go is really deep.

ANDY: Right. And this reminds me of when we were talking to Nora Volkow.

NORA VOLKOW: I'm director of the National Institute of Drug Abuse at the NIH.

ANDY: She sort of pointed at the same idea in a really interesting way.

NORA VOLKOW: One of the questions that I've always had in my brain is: why do we become addicted? I mean, why is it that we can fall into a state where we actually become obsessed about something, and compulsive, despite the fact that it can have negative consequences? And romantic love is exactly that situation.

ANDY: Nora says that one thing that biologists know, and actually have known for a while, is that ...

NORA VOLKOW: Drugs hijack systems in our brain that are there for other purposes.

ANDY: She says literally drugs will light up the same circuits in your brain that are usually engaged when you're in love, when you're hanging out with your friends, when you're being hugged by your kid.

NORA VOLKOW: It's almost like randomness of chemistry that you have these chemical compounds that can go directly and activate these centers.

JAD: So it hijacks the very things that make us, you know, good friends and good parents.

NORA VOLKOW: Correct.

JAD: It's like a weakness born of a strength in a way.

ANDY: Yeah. And actually, according to Anna Rose Childress, who we had talked to earlier, people with addictions ...

ANNA ROSE CHILDRESS: Ironically, they're the fittest of the fit in evolutionary terms, right? They're the people who would have been earliest for the food, earliest for the sexual partner.

ANDY: The idea here is that deep down inside of them, like, we're talking at a genetic level ...

ANNA ROSE CHILDRESS: They have the greatest sensitivity. They would be exquisitely attuned to the promise of rewards. And most of the time, and for most of the millennia, all the priorities were on being good reward appreciators. That—that was our only job.

ANDY: That's interesting.

ANNA ROSE CHILDRESS: But now we're in a different environment where we've got huge opportunities for many sexual encounters that carry ...

ANDY: Yeah.

ANNA ROSE CHILDRESS: ... lethal viruses, rather than just the possibility of survival of the fittest. And we've got, you know, calorie-dense meals that we can acquire without expending a calorie.

ANDY: Mm-hmm.

ANNA ROSE CHILDRESS: And see, in almost every circumstance that you can think of, except for the last, you know, 50 years, being on the side of being overly responsive to reward was probably mostly an advantage, you know?

JAD: That's so interesting. I've never heard it said that way.

ANNA ROSE CHILDRESS: And for our patients, in some sense, they're the fittest of the fit and being punished for it.

JAD: Yeah, it's like a terrible joke.

ANDY: And the terrible reality of that joke is something that just kept showing up on our voicemail over and over again.

[ARCHIVE CLIP, caller: Hello. Yes, this is Pat Rousse. I was listening to The Brian Lehrer Show on the way home from work today, and I had a son who died of heroin addiction and alcohol abuse last May. And since then, I've been trying to come to terms with it. This is my son. He was a great person. I think he just couldn't see how to be sober in this world that he knew. That was really hard for him. How do you live your life when you have to be sober?]

JAD: After the break, we visit another type of drug, although this one doesn't come in a pill. It's, well, light. That's coming up.

[LISTENER: This is Bree calling from Austin, Texas. Radiolab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world. More information about Sloan at www.sloan.org.]

JAD: Hey, I'm Jad.

ROBERT: I'm Robert.

JAD: This is Radiolab. In this section, we're gonna revisit a conversation we had with Radiolab producer Molly Webster about what was then breaking news about a truly enlightening discovery.

MOLLY WEBSTER: This is a discovery about Alzheimer's disease.

ROBERT: Uh-huh.

MOLLY: Which I think at this point is something that affects basically every family.

ROBERT: Affected my family, yeah.

MOLLY: Yeah. And this is a discovery that is not a cure, but it's basically about looking at the brain, which is one of the most complicated things in the universe, I think, and poking at it in this super simple way, and getting this bizarre result.

ROBERT: How bizarre?

MOLLY: Pretty bizarre.

ROBERT: [laughs]

LI-HUEI TSAI: Hello.

MOLLY: Hello, hello?

LI-HUEI TSAI: Hi, Molly.

MOLLY: Hi.

LI-HUEI TSAI: Hi, how are you?

MOLLY: All right, I was talking to some folks over at the Brain Institute at MIT, and while I was on the phone with them, they started telling me about some research that hadn't been published yet, so it was all very hush hush. It was pretty cool, though. We ended up deciding to sign a non-disclosure agreement, and it was based on the work of this woman Li-Huei Tsai.

LI-HUEI TSAI: Li-Huei Tsai. I'm a professor and a director of the Picower Institute for Learning and Memory at MIT.

MOLLY: So her work all centers around something called ...

LI-HUEI TSAI: The gamma frequency.

ROBERT: The gamma frequency?

MOLLY: Mm-hmm.

LI-HUEI TSAI: Gamma.

MOLLY: And what is—I'm like, it feels like something from Battlestar Galactica.

LI-HUEI TSAI: [laughs]

MOLLY: So I don't think it's that.

LI-HUEI TSAI: So, this gamma ...

MOLLY: You could think of it as a particular beat in your brain.

ROBERT: A beat in the brain.

MOLLY: Yeah.

LI-HUEI TSAI: Yeah.

ROBERT: Which means what, exactly?

MOLLY: Well, just to oversimplify one of the most complicated things in the known universe ...

ROBERT: [laughs] Okay, please do.

MOLLY: You've got your brain. It's full of neurons, which are a certain type of brain cell.

LI-HUEI TSAI: We have billions of neurons in the brain.

MOLLY: They have these long tentacles that are reaching out towards other neurons.

LI-HUEI TSAI: And for the brain to function, neurons have to communicate with each other to process information.

MOLLY: And the way they do that is they fire.

LI-HUEI TSAI: Yes.

MOLLY: An electrical signal will go through them and it'll, like, zap another neuron, and it'll turn it on. And then an electrical signal will go through it and it'll zap another neuron, and it'll turn it on. But the cool thing is is that when your brain is doing things like making you move, or write a poem, or think great thoughts, groups of neurons ...

LI-HUEI TSAI: Fire in sync.

MOLLY: All together on the same beat. And there's a bunch of different beats that happen in the brain. Some of them are slow, like one beat per second, and that's when you're sleeping. If you're beating around 10 beats per second, like, maybe you're sitting next to a campfire in an Adirondack chair. Or on, like, the totally other end of the spectrum, like, some neurons fire at 600 beats per second.

ROBERT: What are they doing?

MOLLY: That I have no idea.

ROBERT: And all this is going on in your head simultaneously?

MOLLY: Yeah, yeah, yeah. No, that's the cool thing is that when all of these beats in your brain come together, that's when you're able to process the world and understand it as it exists as human beings.

ROBERT: Huh.

MOLLY: But when your brain is doing something really tricky that requires super focused ...

LI-HUEI TSAI: Attention, working memory, and so on.

MOLLY: You're, like, trying to find your way home from the subway station, or if you're in a new city, navigate around it, there's a certain beat that sort of rises above them all, and that is ...

LI-HUEI TSAI: The so-called gamma frequency.

MOLLY: This range between 30 beats per second all the way up to 100 beats per second.

LI-HUEI TSAI: And this gamma frequency has been considered to be very important for the higher order cognitive function.

MOLLY: The interesting thing is that when you look at an Alzheimer's brain, what you see is there's actually less gamma happening, or people say the power of gamma is reduced.

LI-HUEI TSAI: Not all the neurons can be recruited to oscillate at the gamma frequency.

MOLLY: It's still there, it's just quieter.

MOLLY: It's like you turn the volume down.

LI-HUEI TSAI: Right.

ROBERT: All right, so just to briefly sum up here, what we've got is a rhythm, which we call gamma, which is used when we have complicated or higher thoughts in the brain, which when you've got Alzheimer's, kind of gets saggy, or tired. It vanishes.

MOLLY: Yeah. Yeah, totally, and of course, obviously in an Alzheimer's brain, there's a lot going on, and this is just one of the things, right? You've got the plaques that build up around the neurons, and then the connections between neurons gets all muddied, and immune cells get messed up. But Li-Huei Tsai was like, "Forget all that. What would happen if I just bring the gamma back?"

LI-HUEI TSAI: Yeah. We decided to just manipulate gamma oscillations.

ROBERT: And how do you—how do you do that?

MOLLY: Well ...

MOLLY: [blows into mic] Hello, hello, hello, hello, hello, hello, hello, hello?

MOLLY: ... technology ...

MOLLY: Hi, this is Molly. Hi, hi, hi.

MOLLY: ... technology you can find at the Massachusetts Institute of Technology. And actually, I went and took a train up to Boston to MIT not too long ago.

MOLLY: We're walking into the Picower Institute.

MOLLY: It's a ...

MOLLY: Wow!

MOLLY: ... big shiny glass building.

LI-HUEI TSAI: Molly, hi! Nice to meet you.

MOLLY: Eventually, Li-Huei Tsai came striding into her office to meet me.

LI-HUEI TSAI: My understanding is that you want to see some of the experimental setup.

MOLLY: And so Li-Huei led me down the hall to this tiny room.

MOLLY: Ooh, the mice just entered the room!

MOLLY: Brought in these adorable little mice.

LI-HUEI TSAI: So ...

MOLLY: So here's what they did: they get some mice.

LI-HUEI TSAI: We started off with a mouse model.

MOLLY: Not the mice I actually got all excited over, but mice that have an early stage of Alzheimer's disease.

LI-HUEI TSAI: With multiple notable defects.

ROBERT: Do they have the gunky plaque stuff in them yet, or is that later?

MOLLY: No, but they do have ...

LI-HUEI TSAI: Elevated levels of beta-amyloid peptides.

MOLLY: Which is this protein that forms the plaques, so it's like basically pre-plaque gunk. But the important thing to Li-Huei Tsai and her team is that they have less gamma going on in their brains. If you remember, the whole plan here is to bring the gamma back.

LI-HUEI TSAI: Yes.

MOLLY: So to do that, they get what might be the world's tiniest drill, and they drill a small hole into the skull of the mouse, and then they take a really thin fiber-optic cable, they slide it through the hole into the brain. And then they get this laser of blue light ...

LI-HUEI TSAI: To flicker.

MOLLY: At 40 beats per second.

LI-HUEI TSAI: Gamma frequency.

MOLLY: And they turn that on, and the light travels down the fiber-optic cable, deep down into the brain, to this group of cells that they've modified ...

LI-HUEI TSAI: In the hippocampus.

MOLLY: ... to be sensitive to light. So when this pulsing light hit these cells, they actually began to fire at 40 beats per second.

LI-HUEI TSAI: At gamma frequency.

MOLLY: And they would keep these cells firing at gamma ...

LI-HUEI TSAI: For one hour.

MOLLY: Firing and firing and firing and firing and firing.

LI-HUEI TSAI: And then after one hour ...

MOLLY: They turn off the light, and then eventually they started looking at the brains of these mice, trying to figure out if anything was different after the light flashed. And they see ...

LI-HUEI TSAI: To our much surprise ...

MOLLY: They were not expecting this at all.

LI-HUEI TSAI: We found ...

MOLLY: After they shot this pulsing light into the brain, there was suddenly nearly half as much of that soon-to-be nasty plaque gunk stuff that was filling up their hippocampus.

ROBERT: A half of the ...

MOLLY: Yeah.

ROBERT: Half?

MOLLY: Half of the stuff was just swept away.

LI-HUEI TSAI: Yes. 40 to 50 percent reduction of beta amyloid.

MOLLY: That just seems crazy! [laughs]

LI-HUEI TSAI: This is crazy! I mean, we were just so surprised.

ROBERT: Do they know why the flood of light would ...

MOLLY: Yeah, yeah. So ...

LI-HUEI TSAI: Turn out ...

MOLLY: ... the pulsing light somehow triggered the brain's cleanup crew.

LI-HUEI TSAI: Microglia.

MOLLY: These cells in the brain that are called microglia.

LI-HUEI TSAI: You can say they're the janitors of the brain.

MOLLY: And in a normal brain, these janitor cells usually gobble up the gunk.

LI-HUEI TSAI: But in Alzheimer disease, it's known that microglia, they don't sort of function normally anymore.

ANTHONY MARTORELL: There we go. Okay. Cool.

MOLLY: Okay, so we're looking at a screen that's now flat. It's not ...

MOLLY: When I was at MIT, one of Li-Huei's graduate students ...

ANTHONY MARTORELL: My name is Anthony Martorell. Second year.

MOLLY: ... was showing me side-by-side comparisons of these mice brains on a screen.

LI-HUEI TSAI: After one hour of gamma ...

MOLLY: Wow! So yeah, that part ...

LI-HUEI TSAI: ... the microglia, the cell, seems a lot bigger.

MOLLY: Can clearly see these round bodies.

LI-HUEI TSAI: Yeah.

MOLLY: Yep.

LI-HUEI TSAI: Yeah, and also, the belly seems to have more amyloid.

MOLLY: Oh, like they're doing more eating.

LI-HUEI TSAI: Yes, they go back to eat more amyloid again.

MOLLY: It's like somehow making the neurons fire turned on the sanitation system in the brain. So one of the things Li-Huei and her team were starting to think was that drilling and fiber-optic cable ...

LI-HUEI TSAI: Is very invasive, right?

MOLLY: You'd never be able to do that on a human.

LI-HUEI TSAI: Exactly. So we started to say ...

MOLLY: "Well, what if we can get the light into the brain in a different way. Like, maybe we could go through the eyes."

ROBERT: So the hole in your head would be your eyes instead of a hole in your head?

MOLLY: Yeah. Yes.

ROBERT: Hmm.

MOLLY: So Li-Huei and her team created what I like to think of as the flicker room.

MOLLY: Wait, is this the room?

LI-HUEI TSAI: This is the room, and ...

MOLLY: Okay.

MOLLY: It turns out, I learned upon my visit, that it is just a storage closet.

MOLLY: You know, you have a—what is this, just a plastic table?

MOLLY: Very DIY.

ANTHONY MARTORELL: Yeah, it's a plastic table you can buy at Target.

MOLLY: There were some plastic shoebox-sized containers lined up on the table for the mice, and then ...

LI-HUEI TSAI: You see the strip?

MOLLY: ... around the edge of the table ...

LI-HUEI TSAI: Basically, surrounding all the cages.

MOLLY: ... are duct-taped strips of LED lights.

ANTHONY MARTORELL: And the reason why we use LEDs is because a regular light bulb, it can't flash fast enough.

MOLLY: And so the idea is: what if we just put the mice in this room, and just let the light flicker at 40 beats per second?

LI-HUEI TSAI: So you want to show Molly? Like, turn this on?

MOLLY: Yeah!

MOLLY: And so we turn off the overhead light in the room so it's very black, and then ...

MOLLY: Oh, wow!

MOLLY: ... the room was now glowing with this white LED light.

ANTHONY MARTORELL: Okay, so the light is turning on and off 40 times a second.

MOLLY: So you don't see anything going, like, on or off. It just looks like something's on, but it kind of feels like my eye is twitching.

LI-HUEI TSAI: Exactly.

MOLLY: And so it's blurring the light a little.

LI-HUEI TSAI: Correct.

MOLLY: Just on the edges, though.

LI-HUEI TSAI: Yeah, just on the edges.

MOLLY: And so they put mice in this room for an hour, and just let them kind of bathe—bathe in this glow.

LI-HUEI TSAI: And guess what?

MOLLY: What?

LI-HUEI TSAI: We look at the amyloid beta levels in the visual cortex, and we found there is a 50 percent reduction.

MOLLY: [gasps] 50 percent?

LI-HUEI TSAI: 50 percent reduction.

MOLLY: Just from shining light in their eyeballs?

LI-HUEI TSAI: Yes!

ROBERT: Wait a second, they didn't do any drilling in their skulls or anything?

MOLLY: No! No, they didn't drill. They didn't tweak the mouses' brain cells to be sensitive to light. This is just ...

ROBERT: They just filled the room with occasional LEDs flashing at a particular frequency?

MOLLY: For an hour.

LI-HUEI TSAI: Now do you see? [laughs] Are you going to tell me, "I don't believe it. It's science fiction"?

MOLLY: And they followed this study up with another study which was done in the same way, so the same flicker room, light through the eyeballs. Only this time, they put the mice in there for one hour a day for seven days, and they took mice that had full-blown Alzheimer's. So this is cognitive decline, they're forgetting things, and they've got hardened plaques in their brain. And they see the same thing: Nearly half of the stuff was cleared away.

ROBERT: Wow!

MOLLY: Half!

ROBERT: Wow!

LI-HUEI TSAI: It's just flickering light in front of the mice.

MOLLY: I mean, that's the shocking thing. The thing I didn't understand after talking to you about your study was, I was like, "Why hasn't everyone done this before? Like, why didn't everyone go, "We should just shine light through eyes?"

LI-HUEI TSAI: Well, you know, that's really the most unexpected and exciting aspect of our study, which is something this simple, yet it has never been done before.

ROBERT: If the mouse no longer has quite as much junk in its head, does that mean that it can remember things that had happened to it? It gets mentally more acute?

MOLLY: Yeah. Yeah, that is their big next research. That's what they're ...

ROBERT: So they don't know.

MOLLY: They don't know. That's what they're—that is now the next step. But nobody really understands how plaques and the gunk buildup in the brain relates to memory and cognition, and the dogma in the field is that when you have Alzheimer's, you can't form new memories, and once you lose a memory, it's gone for good.

ROBERT: Huh. Okay.

MOLLY: But there is another group at MIT that is actually sort of challenging that assumption that you can never get a memory back.

DHEERAJ ROY: Because the patient could never tell us, we all assumed the information had to be gone.

ROBERT: Oh, really?

MOLLY: Yeah.

DHEERAJ ROY: Why are we so quick to jump to the conclusion that the information was somehow completely gone? I'm Dheeraj Roy. I'm a fourth-year graduate student in the Susumu Tonegawa lab.

MOLLY: Over at the Tonegawa lab, they were thinking, "What if we could figure out exactly where the memory should be in the brain, and just give that spot a little bit of juice?"

DHEERAJ ROY: Right.

MOLLY: So they took some mice that were just starting to lose their ability to remember things, and they thought, "Okay, let's try to give them a memory."

DHEERAJ ROY: We put them in a box that has a particular smell, some sort of lighting, and some texture on their feet.

MOLLY: A little mouse carpet, or ... [laughs]

DHEERAJ ROY: That's exactly what it is.

MOLLY: Wait, really?

DHEERAJ ROY: Yeah. [laughs]

MOLLY: Okay, mice on carpets. Got it.

MOLLY: The point is the box looks and feels and smells different than any other box they would hang out in.

DHEERAJ ROY: And then we give them a light electrical shock.

MOLLY: And the mice, they just freeze.

DHEERAJ ROY: They don't move at all.

MOLLY: Which is a sign that they're afraid.

DHEERAJ ROY: They hate the box.

MOLLY: And for the rest of the afternoon—which is a very long time in mouse time—they go on hating the box, which means with the carpet and the light and the smell, if you put it back in there, it'll freeze because it remembers the shock.

DHEERAJ ROY: Yes.

MOLLY: But ...

DHEERAJ ROY: A day or a week later ...

MOLLY: When these same mice were put back into the same box ...

DHEERAJ ROY: Instead of being scared of the box, they would just continue investigating as if nothing happened. They could not remember.

MOLLY: So Dheeraj and his team did what Li-Huei did: they got some modified mice, and then they put a little hole in their head. They slid in a fiber-optic cable. They shined some light to trigger the neurons that they think hold this memory. And they were ...

ROBERT: In the fear section.

MOLLY: Near the fear section. So leading on the path to the fear section.

DHEERAJ ROY: So we do this ...

MOLLY: And then ...

DHEERAJ ROY: Put them back into the box.

MOLLY: The box with the particular lighting and smell and carpet.

DHEERAJ ROY: And ask is there any change in their behavior?

MOLLY: Will they act afraid again?

DHEERAJ ROY: Do they show any more memory? And they did.

MOLLY: Wait, shut up. They actually were scared of the box again?

DHEERAJ ROY: Exactly. They showed recovered memory.

MOLLY: Wow!

ROBERT: Whoa.

MOLLY: So that's like bam, that memory's in there.

DHEERAJ ROY: Exactly. Voila, the behavior was back.

ROBERT: You can dig up the memory by shining light in the right place?

MOLLY: Yeah.

DHEERAJ ROY: Mm-hmm.

MOLLY: I was always under the impression that the memories were totally lost.

DHEERAJ ROY: Right. So I think that's not just you. I think that's essentially the entire field, what you described.

MOLLY: Oh, okay. Well, that's good.

DHEERAJ ROY: Just because the patient could never tell us, we all assumed the information had to be gone.

ROBERT: You know, when you—when you have someone in your house, and you live with this disease day in and day out, the disease just goes its own way.

MOLLY: Mm-hmm.

ROBERT: And it can puzzle you or frighten you or suddenly declare something new that you didn't expect. So for example, my dad had it for about nine, ten years. It was a slow act of disappearing that he did. I mean, the last time my father came to was so far into the disease, he hadn't spoken for a year and a half. He was sitting at the table for the Passover Seder, and there's a song that you sing, and it goes [singing]. So it's just a chorus, and from out of nowhere, this being at the end of the table who I knew was my father, who hadn't spoken in a year and a half or two, and had not spoken coherently for three, suddenly flew into the song, and sang the song full-throatedly at the table, like the reappearance of some last figment of himself. And it was—it was both horrifying and extraordinary. Both.

DHEERAJ ROY: I mean, I think that's—the fact that maybe some information still persists, hopefully someday we could kind of—maybe there's something we could do. But yeah, this is all in my mind at the moment.

LI-HUEI TSAI: As long as we can figure out how to rebuild the pathway to retrieve the memory, then I think there is hope.

MOLLY: This is Li-Huei Tsai again.

LI-HUEI TSAI: But, you know, I personally think the most important question is whether humans respond similarly.

MOLLY: I mean, keep in mind that both Dheeraj's study and Li-Huei Tsai's are in mice, not humans.

LI-HUEI TSAI: Right, so I ...

MOLLY: And do you have a thought that why—like, is there a reason that a human neuron might react differently than a mouse?

LI-HUEI TSAI: The thing is, I think, you know, especially in Alzheimer's field, I mean, people got burned a lot.

MOLLY: You know, there's like a 99.6 percent failure rate in moving something that seemed to work in mice to humans in Alzheimer's.

ROBERT: 99.6?

MOLLY: Yeah. Yeah, that was a study that came out in 2012.

ROBERT: That's a horrible number.

LI-HUEI TSAI: You know, I'm gonna keep my mind open when it comes to humans.

MOLLY: The plan is they're going straight to humans.

ROBERT: Oh, so they're gonna do human trials.

MOLLY: Well, they want to, so yeah, I guess we'll see. It's like almost even if it doesn't lead to any treatment in humans or something super concrete, it's like we know this little secret about the brain now, and there's something that feels, like, beautiful in that.

LI-HUEI TSAI: Yeah, I'm actually setting this up for my Christmas tree.

MOLLY: Are you really?

LI-HUEI TSAI: Yes. Yeah, we—I just bought the new LED lights, and they can flicker a different color, with different colors.

MOLLY: Oh, so each individual bulb can travel through colors, but while they're doing that ...

LI-HUEI TSAI: We're gonna have a very therapeutic Christmas.

MOLLY: In the Li-Huei Tsai household? This is the tree in your home?

LI-HUEI TSAI: Yes. Yes.

MOLLY: Are you using ...

MOLLY: I want to have an eggnog next to that tree.

ROBERT: Yeah.

MOLLY: [laughs]

ROBERT: Okay, thank you Molly for—what a remarkable story that was.

MOLLY: You're welcome.

ROBERT: It was also produced by Annie McEwen, Matt Kielty, Molly Webster again, with help from Simon Adler, and special thanks to Susumu Tonegawa at MIT.

JAD: I'm Jad.

ROBERT: I'm Robert.

JAD: That was Molly Webster. Thanks for listening.

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