The accidental rise of Botox

One of the deadliest poisons known to man is now used to treat wrinkles, migraines, and even, maybe, depression. How did that happen? Guests: Jean Carruthers, ophthalmologist and “godmother” of cosmetic Botox. David Simpson, neurologist at Mount Sinai hospital in New York. Axel Wollmer, psychiatrist at the Asklepios clinic in Hamburg, Germany. For more, go to http://vox.com/unexplainable It’s a great place to sign up for our newsletter, view show transcripts, and read more about the topics on our show. Also, email us! [email protected] We read every email. Support Unexplainable by making a financial contribution to Vox! bit.ly/givepodcasts Learn more about your ad choices. Visit podcastchoices.com/adchoices Learn more about your ad choices. Visit podcastchoices.com/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:01Noam Hassenfeld?

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• 0:37Speaker 01

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• 1:06Speaker 02

  It's Unexplainable. I'm Sally Helm. And a couple of months ago, I was up very early, walking down the street in Manhattan. Oh my lord, there's someone on a 5 a.m. run. Wow. I was heading to the hospital to get this procedure that would help me learn to burp. Before that, I had been a lifelong no burper. You can go back and listen to the whole episode about this if you want. But all you need to know today is that the treatment for this condition involves a drug, a very famous one. I'm getting Botox in my throat. And not in like a make my throat look younger kind of way, but like inside my throat. I guess inside it will look very young.

• 1:50Speaker 02

  Botox has this amazing, unusual ability to paralyze a muscle locally, like just the muscle that you injected into. So in my case, a muscle in my throat was clamping up so that I couldn't burp. But if you relax that muscle with Botox, you can burp. I got the procedure that morning and it worked. Now, before this, I had obviously heard of Botox mostly in a cosmetic context. I am from Los Angeles, definitely a city that believes wrinkles are optional. I also knew that it is derived from a poison. And I found myself wondering just more and more about the bizarre journey that this toxin

• 2:34Speaker 02

  has taken in the world. Because as I started telling people that I had gotten Botox, they started telling me that they had gotten Botox, for wrinkles, some of them, yes, but also for migraines, for excessive sweating. It's even being studied as a treatment for depression. And I wanted to know, how did we figure out that it can do all that? Like, who looks at a toxic, toxic poison and sees a medicine? And what else might this weird little wrinkle cure someday be able to do?

• 3:30Speaker 02

  The story begins in the early 1800s in the German countryside. People are coming down with a mysterious illness. I heard about it from Dr. Jean Carruthers. She knows this story because Botox will become very important in her career. And when these Germans got sick, their eyelids would droop, their speech would slur.

• 3:51Speaker 03

  They have a descending paralysis of their face and then of their diaphragm. Essentially, their diaphragm stops working, and so they no longer can live.

• 4:03Speaker 02

  There's a young, newly minted doctor living nearby, Justinus Kerner, and he is called in to investigate.

• 4:12Speaker 02

  Justinus Kerner had decided to become a doctor after he awoke from a prophetic feeling dream to find that a paper prescription from a nearby hospital had wafted in through the window while he was sleeping. And he was like, it's a sign. He became a doctor. He also later became famous as a romantic poet, and he has a wine named after him.

• 4:30Speaker 03

  I've tasted it. It's very delicious. He was a true polymath. He had in his house all kinds of contraptions that were sort of magical. But anyway, going back to the 1820s, Justinus Kerner did his medical thesis on these poor people.

• 4:51Speaker 02

  These people in the German countryside who were struck by this mysterious paralysis. He documents a pattern. All the patients seemed to have eaten the same food.

• 5:04Speaker 03

  They made sausages. And these sausages maybe weren't totally clean. You know, maybe there was dirt in the sausages.

• 5:15Speaker 02

  Food safety standards in this region at this time have kind of gone down. It's the aftermath of the Napoleonic Wars. Things are rough. And one result is these unhygienic sausages.

• 5:26Speaker 03

  And so the disease itself, this mysterious paralytic disease, became known as botulism, because botulus is Latin for sausage.

• 5:40Speaker 02

  Okay, so Justinus Kerner, this polymath winemaker, poet, physician. He describes these symptoms in detail. And he does one other surprising thing.

• 5:50Speaker 03

  He tried it himself. He put some of the fatty substance that they had ingested into his own mouth, against the advice of his friends.

• 6:00Speaker 02

  Why did he do that?

• 6:01Speaker 03

  Oh, because he wanted to know. So his mouth became dry. This was the first instance that anyone had shown that a toxin could stop the activity of your salivary glands.

• 6:15Speaker 02

  Wow. I mean, it just seems so reckless to do when he knew that it had killed people. What do you make of it?

• 6:24Speaker 03

  I think that he just had a little taste. I think he was a very smart man. Didn't eat the whole sausage because he had this idea. All these people are paralyzed. Maybe there's something in this where we could use whatever it is to treat people who have overactive muscle conditions. He saw the other side of the poisoning as a potential treatment. It was brilliant.

• 6:49Speaker 02

  I have an instinct here to be like, that is poison just in us. Do not put that in your mouth. But he did have some reason to think that this could be okay. Another doctor had actually written this idea down a couple hundred years earlier. Paracelsus, the father of toxicology. He wrote this famous line that kind of sounds like a riddle. What is there that is not poison? All things are poisonous and nothing is without poison. Only the dose permits something not to be poisonous. Körner sees early that botulinum toxin could be the poster child for this idea. That in small doses, it could be useful to medicine. But no one really picks up on that thought for another 100 plus years.

• 7:34Speaker 02

  We did figure out some stuff about how to prevent botulism. And then during World War II, the US is worried that Germany and Japan are going to develop botulinum toxin as a biological weapon. So they got a whole bunch of researchers together to study it and look at anecdotes. One of them, a guy named Ed Shantz, is able to isolate the toxin from the bacterial sludge that it grows in. After the war, he makes a whole batch of it in his lab in Wisconsin.

• 8:03Speaker 03

  And he was actually quite noble and supplied it to people who were wanting to do research on botulinum toxin. And he sent, I think, 100 milligrams to Alan Scott.

• 8:18Speaker 02

  Alan Scott is an ophthalmologist. And he has this idea that botulinum toxin could help cure strabismus, that condition where one eye turns in. He thinks if you weaken the muscle that's pulling on that eye, you could cure this condition without surgery. He does some experiments and it works. And this is where Jean Carruthers enters the story.

• 8:42Speaker 03

  I was a paediatric ophthalmologist at the University of British Columbia in Vancouver. And I started reading about it and it got really fascinating.

• 8:52Speaker 02

  So she gets herself a fellowship with Alan Scott. He's now investigating another use. Maybe botulinum toxin can treat a condition called blepharospasm.

• 9:03Speaker 03

  These poor people, they can't count on their eyes opening. Their eyes spasm shut, so they can't drive a car. They can't cross the street on their own. They can't hold down a job. And after they've been treated with botulinum toxin, they can drive a bus with hundreds of other people in it. I mean, it's a total game changer.

• 9:27Speaker 02

  Alan teaches Jean how to inject this toxin. She starts treating blepharospasm patients at her clinic in Canada. And one day during treatment, one of those patients gets mad.

• 9:41Speaker 03

  She said, "You didn't treat me here." Between her eyebrows. And I apologized to her and I said, "I'm sorry. I hadn't thought you were spasming there." And she said, "Oh, I'm not spasming there. But every time you treat me there, I get this beautiful, untroubled expression." And this is when the penny dropped. Because I happened to have the perfect husband.

• 10:06Speaker 02

  Jean's perfect husband, Alastair, is a dermatologist. And Jean's heard him complain about how difficult it is to treat those round lines between the eyebrows, the elevens. A lot of people want them gone. But the best treatment at the time doesn't really work. It can even be dangerous. So Jean goes home and, over dinner, she tells Alastair that she has this idea. Botulinum toxin could solve that problem. You freeze the underlying muscle, you get rid of the wrinkles. He is interested and they put together a study to test it. They need 18 patients to sign up. And that is not happening.

• 10:45Speaker 03

  Most people in the world were running a mile from it. They would, no, that's a terrible poison. I don't want to have that injected. And it's a cosmetic treatment. Everyone thought we were over the edge, crazy.

• 10:58Speaker 02

  They finally find one person who has had enough up-close experience to know that this drug is not going to kill you. And that is Jean's receptionist, Kathy Bickerton-Swan.

• 11:08Speaker 03

  She had sat there for four years, watching all my research patients coming in, out, always happy, always polite, always grateful. And so when we said, Kathy, how would you like to be part of the study? She said, yeah, whatever. You know, it was no big deal to her.

• 11:26Speaker 02

  And then Jean pulls a Justinus Kerner. The second cosmetic patient that she treats is herself. Her husband gives her the injection. It's the first cosmetic treatment she has ever gotten, but she's sold.

• 11:42Speaker 03

  And I make a joke of it now. I haven't frowned since 1987. But that's how I got 18 patients into our study. They would say, no, it's a poison. And I would say, well, what do you think? And I'd show them my frown line picture from before and my brow now.

• 12:01Speaker 02

  Eventually, as we all know, way more than 18 people try cosmetic Botox.

• 12:07Speaker 04

  Well, girls, we've done it. We're now international champs when it comes to Botox.

• 12:12Speaker 05

  People are paying good money these days to be injected with food poisoning or at least a form of it.

• 12:18Speaker 06

  Mark Twain said wrinkles should merely indicate where smiles have been. He didn't know about Botox.

• 12:25Speaker 02

  Alan Scott had sold his initial patent to a pharma company called Allergan that mostly did eye care. The Carruthers sold them a patent too. Botox, by the way, is actually just one of the brand names for botulinum toxin. It's like how we call all tissues Kleenex. Now, Jean also makes money on this, including by doing research and consulting for the pharma company. And the old sausage poison goes totally mainstream. It has a whole life that Justinus Kerner could never have foreseen.

• 12:55Speaker 03

  Botox is now made in California at an undisclosed location and flown in a private jet with guards to the bottling plant, where it is made into the Botox vials that are shipped around the world.

• 13:09Speaker 07

  This stuff is still poisonous at large doses. Don't want that plane getting hijacked. And things can very occasionally go wrong with cosmetic Botox, especially if you get it from a bad injector. But for Jean, obviously, it's been a good thing. I mean, she hasn't frowned since 1987. I've seen you called the godmother of Botox. Why godmother?

• 13:31Speaker 03

  Well, I guess, I don't know. Maybe it's sort of like fairy godmother discovering that that you can do something magical with it. It's now such a magical new drug with so many uses.

• 13:47Speaker 07

  Botox made this jump from ophthalmology to dermatology. But soon enough, it jumps again. When dermatologists and other doctors begin to notice that it might be able to treat all kinds of conditions that we previously had no way to cure.

• 14:07Speaker 07

  That's after the break.

• 14:12Speaker 07

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• 17:25Speaker 08

  Oh, it tastes sweet.

• 17:26Speaker 09

  Her boy's in ya.

• 17:29Speaker 09

  It's not as if you ingested a lethal amount.

• 17:32Speaker 10

  If I have a patient that comes in, they're 18 years old, they don't have any lines. I might say, you know what? Why don't you wait a couple of years and come back?

• 17:41Speaker 07

  Let's start here. Maybe this is a really hard one, but can you do your best to give me a list of all of the conditions that botulinum toxin is used to treat?

• 17:51Speaker 11

  That would take probably much longer than we have time to do.

• 17:57Speaker 02

  David Simpson, neurologist. And to be fair, I had a hard time even finding a list of all of the uses that this toxin now has in medicine.

• 18:06Speaker 11

  It's really used by almost every field in medicine, from neurologists like me to dermatologists, plastic surgeons, ophthalmologists, gastroenterologists, urologists, and on and on.

• 18:21Speaker 02

  David himself first uses this toxin back in the early 90s, so just a little while after Jean makes her wrinkle discovery. He is treating a patient with a traumatic brain injury who has what is called spasticity in one of his arms. The muscles tense up.

• 18:36Speaker 11

  The elbow was flexed. It was crunched up like a pretzel, and he developed a large calcium deposit in the inner elbow.

• 18:45Speaker 02

  Ooh. He needed surgery to fix this, but his surgeon couldn't get the arm to relax. So he goes to David.

• 18:53Speaker 11

  And he and I discussed this very new medicine. And he said, what if we inject it into the muscles of the upper arm so we could relax the elbow? There was no reports of it done at that time. And so we got approval from the medical board for use. We injected it into this patient, and he responded nicely, and the arm opened up.

• 19:16Speaker 02

  Over time, as doctors get more and more confident with this drug, they also get more and more ideas for what it could do. The company that makes Botox obviously wants it to be used for more conditions. David, by the way, has done consulting for that company and gotten research grants from them. And as time goes on, that company starts testing, doing trials. The drug works for various movement disorders. It also works on hyperhidrosis, or excessive sweating. They try it on overactive bladder, where you have to pee like 50 times a day. It helps those patients, too. And meanwhile, the cosmetic use is picking up steam. And there's a plastic surgeon out in Beverly Hills.

• 19:57Speaker 11

  Who was injecting individuals for their wrinkles cosmetically. And the individuals he was treating for wrinkles came back and said, you know, my migraines are less. And that led to studies in migraine that ultimately received an FDA approval and widely used today.

• 20:16Speaker 02

  We don't totally know what causes migraines. Especially back then, we didn't have a lot of good treatments. And it wasn't clear exactly why this toxin could help, but it did. An early idea was, maybe it's relaxing the muscles in your head? Because that's generally what this drug does. It stops muscles from moving.

• 20:38Speaker 11

  One of the adages I often use to describe the indications is, if it moves, botulinum toxin can stop it. And actually, we now extend that to if it hurts, then botulinum toxin may help relieve the pain as well, because that's an emerging area of use.

• 20:59Speaker 02

  This toxin basically stops nerves from secreting chemicals, neurotransmitters, especially one major neurotransmitter that's key for telling muscles to move. But also, it turns out, other neurotransmitters that can make us feel pain. That's probably roughly how it works for migraine. This toxin affects just a really fundamental process in our body. That, plus the fact that you can use it so locally, like just inject it into the one muscle that you want to treat, that makes it into this little medical Swiss Army knife. Today, it is officially approved for nine different medical problems, and it is used off-label for many, many more. Like my burping.

• 21:43Speaker 02

  Off-label means it's for a use that the FDA hasn't officially approved. Now, obviously, no drug is perfectly safe, and this one comes from an extremely poisonous poison. There are some dangers here. In fact, in 2009, the FDA put a black box warning on this drug and others like it, a reminder that they can cause serious complications, including difficulty breathing.

• 22:07Speaker 11

  Now, that's extremely rare in the doses we use, but the more common concern is that in the process of causing localized muscle weakness, which is what we're trying to do, it can cause excess weakness of the muscle you're injecting, or it can spread to other muscles. For example, if you're injecting a patient with facial spasm around the eye...

• 22:33Speaker 11

  And the botulinum toxin spreads to the muscle that keeps the eyelid open, you can get a droopy lid. And so there's really a skill set that needs to be learned. In fact, I usually encourage doctors to find a mentor to train them properly, almost like surgery. I often say there's a lot of science in the field, but there's also a lot of art that needs to be passed through the generations.

• 23:03Speaker 02

  It's interesting to me how it kind of travels through medicine. It's like a doctor notices something, a patient notices something, people experiment. It all feels sort of much more, I don't know, kind of ad hoc and creative than I think we're used to thinking of it.

• 23:18Speaker 11

  Well, I think one of the lessons we learn is to be open to serendipity and to be creative in pursuing new indications that others may not have thought about or pursued. There's an interesting emerging literature on depression. Certainly, I would put that into one of the categories of one of the mystery uses that we don't quite understand.

• 23:48Speaker 08

  For me, it was really striking how immediately the psychotropic effect occurred.

• 23:54Speaker 02

  Axel Volmer is a psychiatrist, and he has studied the question of whether botulinum toxin can help with depression. We'll get into that. But at a certain point in his research, he got curious enough to try it himself. So he had a colleague inject him right between the eyebrows on those frown lines.

• 24:11Speaker 08

  It was a little bit painful. It's the pressure of the fluid in the tissues. It's not a very pleasant feeling. But then it took a couple of days until the muscle relaxing effect set in. And I have four children and it's very crowded and noisy and busy at home. And it was just like a layer of Teflon covering. It just didn't bother me the way it sometimes does. An injection of resilience, so to speak.

• 24:52Speaker 02

  Axel would be the first to say that he is not actually a good test subject for himself because he went into this with a theory. It goes back actually to a very old idea.

• 25:03Speaker 02

  Charles Darwin wrote about it in one of his lesser-known works called "The Expression of Emotions in Man and Animals." That came out a little over a decade after his real banger on the origin of species. In this other book about emotions, he talks about how our facial expressions are tied to what we feel. Those muscles that make your eyebrows contract and cause those frown lines, he calls them the grief muscles. People build on this idea and come up with something called the facial feedback hypothesis.

• 25:35Speaker 08

  If you're angry, you frown. And this frowning communicates your anger to others. But it also communicates this anger to yourself.

• 25:46Speaker 02

  Hmm. And is this a proven idea? Or it's just-

• 25:49Speaker 08

  Yeah, no, it's a very old hypothesis. And it has been proven experimentally, time and again.

• 25:57Speaker 02

  That it's not just that I'm happy, I smile. Also, if I smile when I'm not feeling happy, I start feeling happy.

• 26:04Speaker 08

  Make it till you make it.

• 26:07Speaker 02

  So a while back, Axel and one of his colleagues got curious about botulinum toxin as a treatment for depression. Because it freezes your frown lines. And that's where you express all this negative emotion. So per the facial feedback hypothesis, if you make frowning impossible, you should feel better. They looked into it and found that a dermatologist in the United States had actually already done a study on this with promising results. Axel did his own small study, a randomized controlled trial. It also suggested that Botox could work as an antidepressant. Then other researchers got in on this.

• 26:43Speaker 08

  There were several independent replications of alphas that uniformly confirmed this effect.

• 26:51Speaker 02

  Axel, by the way, also did some consulting for the company that makes Botox along the way here. And he told me there still needs to be a large randomized controlled trial to really be sure that this effect is a thing.

• 27:05Speaker 02

  But even if it is true that botulinum toxin can work as an antidepressant, we still don't know why. We don't know if it is because of the facial feedback hypothesis. There is some evidence that small amounts of Botox could travel into the central nervous system. Axel thinks it would be too small to really do anything, but it's possible that it has some antidepressant effect that we don't understand. There's also an interesting study Axel was involved in that looks at people who had gotten either Botox or other treatments for conditions like migraine, excessive sweating, and spasms. And it found that overall, people who were treated with Botox for any of the conditions they looked at were less likely to report depression.

• 27:50Speaker 08

  So maybe you can inject it into your butt or into your thigh or whatever.

• 27:55Speaker 02

  You'll be so happy.

• 27:56Speaker 08

  Yeah. And this is, of course, this is really intriguing. But on the other hand, we don't want to do this study because it leads us too far away from what we know is working.

• 28:11Speaker 02

  He said first, they want to do the big trial to confirm that these frown line injections really, really work. And his money is still on the facial feedback hypothesis. He said the most likely explanation for that other finding is just that Botox works really well as a treatment in general. So maybe that is why patients report less depression when they get it, because their excessive sweating or their migraines really improved. This toxin has a lot of uses, and we are still finding more. Axel told me he went to a conference recently. It was called Toxins 2026. And there were presentations on botulinum toxin and wound healing, botulinum toxin and pain.

• 28:53Speaker 08

  For me, cancer was the most fascinating new indication. I wasn't aware of that.

• 28:58Speaker 02

  Yeah, some new work suggests that nerves might help tumors grow. So using Botox to block those signals might help tumors shrink. Botox to treat cancer. Not a bad journey for one of the deadliest poisons known to man.

• 29:24Speaker 02

  This episode was produced by me, Sally Helm. It was edited by Joanna Solotaroff with help from Julia Longoria. Mixing and sound design from Christian Ayala. Fact checking from Melissa Hirsch and Sarah Schweppe. Special thanks today to Ed Chapman, Eric Finsey, and Peter McAllister. Meredith Hodnot runs the show. Jorge Just is our editorial director. Amy Padula and Noam Hassenfeld are not experimenting on themselves, unlike many people in this story. And Burt Pinkerton kept thinking about what the octopus had told her. At the station where the sun never shines. Where the sun never shines. And then it hit her. The deepest station in New York. 190th Street. She needed to get to Washington Heights.

• 30:12Speaker 02

  Thanks as always to Brian Resnick for co-creating the show along with Burt and Noam. And if you out there have any thoughts about the show, please send us an email. We love getting your emails. We are [email protected]. You can also leave us a nice rating or a review wherever you are listening right now. That really, really helps. And if you are into supporting the show and all of Vox in general, join our membership program. You can go to vox.com/members to sign up. Unexplainable is part of the Vox Media Podcast Network, and we will see you next time.

• 30:49Speaker 12

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