The accidental rise of Botox

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17:00Oh, it tastes sweet.

17:02Jean Carruthers:Her boy's in you. It's not as if you ingested a lethal amount.

17:08David Simpson: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 years and come back? 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?

17:27Jean Carruthers:That would take probably much longer than we have time to do.

17:32David Simpson: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.

17:42Jean Carruthers: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.

17:57David Simpson: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.

18:12Jean Carruthers:The elbow was flexed. It was crunched up like a pretzel. And he developed a large calcium deposit in the inner elbow.

18:21David Simpson:He needed surgery to fix this, but his surgeon couldn't get the arm to relax. So he goes to David.

18:28Jean Carruthers: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 into this patient and he responded nicely and the arm opened up.

18:51David Simpson: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.

19:30David Simpson:And there's a plastic surgeon out in Beverly Hills.

19:33Jean Carruthers: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.

19:52David Simpson: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.

20:14Jean Carruthers: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.

20:35David Simpson: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.

21:19David Simpson: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.

21:43Jean Carruthers: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 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.

22:30Jean Carruthers: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.

22:39David Simpson:It's interesting to me how it kind of travels through medicine. 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.

22:54Jean Carruthers: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. For me, it was really striking how immediately the psychotropic effect occurred.

23:30David Simpson:Axel Vollmer 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.

23:47Jean Carruthers:It was a little bit painful. The pressure of the fluid in the tissue, it's not 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.

24:27David Simpson: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. 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.

25:11Jean Carruthers:If you're angry, you frown. And this frowning communicates your anger to others. But it also communicates this anger to yourself.

25:23David Simpson:And is this a proven idea or it's just something?

25:26Jean Carruthers:No, it's a very old hypothesis, and it has been proven experimentally. Time and again.

25:34David Simpson: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.

25:40Jean Carruthers:Take it till you make it.

25:42David Simpson: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 Browning 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.

26:19Jean Carruthers:There were several independent replications of our findings that uniformly confirmed this effect.

26:27David Simpson: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. 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.

27:06David Simpson: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.

27:26Jean Carruthers:So maybe you can inject it into your butt or into your thigh or whatever. You'll be so happy. Yeah, and 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.

27:47David Simpson: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.

28:27David Simpson:Botulinum toxin and pain.

28:29Jean Carruthers:For me, cancer was the most fascinating new indication. I wasn't aware of that.

28:34David Simpson: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.

29:00David Simpson:This episode was produced by me, Sally Helm. It was edited by Joanna Solitaroff 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 Finzi, and Peter McAllister. Meredith Hodnott 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 Bird Pinkerton kept thinking about what the doctopus had told her. At the station, where the sun never shines. Where the sun never shines. And then it hit her.

29:37David Simpson:the deepest station in New York 190th Street she needed to get to Washington Heights thanks as always to Brian Resnick for co-creating the show along with Bird 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 unexplainable at vox.com you can also leave us a nice rating or 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 slash members to sign up. Unexplainable is part of the Vox Media Podcast Network, and we will see you next time.

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