This is a transcript of the Gastropod episode Sweet and Low (Calorie): The Story of Artificial Sweeteners, first released on January 15, 2019. It is provided as a courtesy and may contain errors.

MATT LAUER: A lot of people opt for diet drinks thinking they’re doing something better for them, it’s a better option—well a new study is now calling into question.

DR. OZ: Very provocative. Big study, thousands of people followed over years. Let me break it down for you. Specifically, what they looked at was often they had strokes: 3 times more likely than normal.

DR. MARK HYMAN: There’s been mounds of research that artificial sweeteners—both in human studies, animal studies, experimental studies, population studies—is bad news. So let me share with you what’s going on. First, they are linked to obesity. So, number one, it makes you fat. Number two, it does it by rewiring and screwing up your brain chemistry and your metabolism.

CYNTHIA GRABER: Wow, this sounds pretty bad—they’re making it seem like artificial sweeteners are just the worst thing ever.

NICOLA TWILLEY: Well, Cynthia, that is the question. First of all, I take everything that comes out of Dr. Oz’s mouth with a wheelbarrow full of salt. But there are a lot of headlines out there saying that artificial sweeteners will give us everything from cancer to heart disease.

GRABER: But for decades, we’ve also been hearing that Sweet’N Low, Splenda, NutraSweet, they all promise guilt-free pleasure. Is that true?

TWILLEY: And on top of all the health scares—where do these curious substances that taste like sugar but have no calories actually come from anyway?

GRABER: And do they deliver on their promise—can they actually help us lose weight? You’re listening to Gastropod, the podcast that looks at food through the lens of science and history, I’m Cynthia Graber.

TWILLEY: And I’m Nicola Twilley. And this episode is the first episode of our new season. And it’s all about artificial sweeteners—the science, the history, and Donald Rumsfeld. Yes, that Donald Rumsfeld.

PRE-ROLL

GRABER: So the earliest artificial sweetener we know about was discovered in ancient Rome.

RICHARD MATTES: So what they discovered was that if you boiled grape juice in leaded pots it would produce a sweet substance.

GRABER: Richard Mattes studies artificial sweeteners at Purdue University.

TWILLEY: Boiled grape juice is sweet already. You knew that. But this substance was even sweeter.

GRABER: Basically the lead ended up concentrated in the grape juice and made it extra sweet—without adding any more calories. You might have heard that lead is sweet—it’s one of the reasons children are particularly at risk in areas that have lead paint. They want to put paint chips in their mouth, because the lead paint is actually sweet. And super dangerous. But the Romans didn’t know that.

MATTES: So once they got it boiled down they would add it to foods and beverages and so on as a sweetener. Of course there are theories about lead toxicity, lead poisoning having some role in the decline of the Roman Empire. Whether it had really anything to do with the use of these concoctions, I don’t know. But it was arguably the first low calorie sweetener.

TWILLEY: Not necessarily a good start for artificial sweeteners. But that was pretty much that … until a chemist licked his finger.

CAROLYN THOMAS: In the 1870s, there was chemist Constantin Fahlberg who was working at Johns Hopkins University. They were trying to find new food preservatives.

GRABER: Carolyn Thomas is a professor of American studies at UC Davis and she’s the author of the book, Empty Pleasures: The Story of Artificial Sweeteners from Saccharin to Splenda.

THOMAS: And is this kind of this odd little story that repeats in the history of artificial sweetener—he apparently licked his finger by accident after a day of working in the lab, noticed that it was sweet, and instead of working on a food preservative he decided to work on a substitute for sugar.

GRABER: Constantin was doing this food preservative-slash-sweetener research on coal tar. Because that’s what people were really into at the time.

TWILLEY: It was the late 1800s, and petrochemicals were the shiny new kids on the science block. People were figuring out you could use these ancient dead plants to make plastics and rubber and synthetic dyes. So why not a synthetic spice, sweeter than the sweetest sugar?

GRABER: That’s actually what Constantin called it, he called his discovery a perfectly harmless spice. Made from coal tar.

TWILLEY: And he took it to market under the brand name saccharin, because it was so, so, so sweet. One gram of saccharin was five hundred times sweeter than a gram of sugar.

GRABER: At the time, when you invented or discovered a new food, you introduced it at the World’s Fair to convince people to eat it. That was the palace of all things new and fabulous in America.

THOMAS: But saccharin is one of these things that even when it first started showing up at say the World’s Fair in 1893, or other food expos, it was likely already something that people were tasting in their carbonated beverages.

TWILLEY: At the time, when you wanted a soda you would go down to the local soda fountain and get the soda jerk to pour you one. And many of those soda jerks had already started using saccharin instead of sugar

THOMAS: Because it was cheaper and it was easy to work with. So consumers were actually tasting it before they even knew what it was.

GRABER: The folks who were adding saccharin so gleefully into soda, they were doing it because it made good business sense.

TWILLEY: A lot of the countries that produced sugar were, let’s say, volatile. Cuba was a big source, and they were fighting a war of independence in the 1870s.

THOMAS: And then there were also efforts in the US to create a sugar industry here at home. And that meant tariffs.

GRABER: So the price of sugar was all over the place. And then on top of that, saccharin was, as you’ve heard, a lot sweeter than sugar, gram for gram. So you didn’t have to use very much of it. Saccharin just made good business sense.

TWILLEY: So a little company you might have heard of called Monsanto, they were the ones making all this saccharin, the soda fountain companies were using lots of saccharin, and people were drinking lots of saccharin, in blissful ignorance. Until.

GRABER: Until our old friend Harvey Washington Wiley came into the picture. As you might remember from our episode Keeping it Fresh, he was a crusader for what he called pure food, and he was the force behind the Pure Food and Drug act of the early 1900s.

TWILLEY: Harvey published lists of adulterants that were in your food—chemicals that the average American consumer had no idea were there. And saccharin was one of those adulterants—this fake substance posing as sugar.

THOMAS: So the soda companies that had never switched to saccharin saw an opportunity to grab some market share. And they didn’t waste any time in putting out like full page ads, even in The New York Times, telling consumers you’ve been feeding these impurities to your children, including saccharin! It’s terrible! You know, make sure that your soda just has sugar!

GRABER: This might sound kind of funny to you all today but weirdly, at the time, sugar was considered a health food, because it had a lot of calories.

TWILLEY: Back then a lot of people were doing more physical labor.

THOMAS: So for a lot of Americans, the thought was that sugar was a really important part of the diet. So to find out that it had been taken out of your food and replaced with some chemical adulterants was really disturbing to a lot of consumers.

TWILLEY: Harvey came this close to getting saccharin banned. It took a Presidential pardon to save it. Teddy Roosevelt was President at the time, and he was a diabetic, and he loved saccharin.

THOMAS: Roosevelt was like, you know, anybody who would ban saccharin is an idiot.

GRABER: Roosevelt basically single-handedly kept saccharin from being banned.

TWILLEY: Saccharin was still on the shelves, yes, but it wasn’t in with foods. It was in with medicines. You bought it as a pill, to dissolve in drinks instead of sugar, if you were diabetic.

GRABER: This sets the scene. Sugar was a health food, and saccharin was a medicine. And then there were two world wars, and sugar was rationed.

TWILLEY: So this was obviously a challenge. You want to be a good mother and feed your ruddy-cheeked children all the healthy sugar they supposedly need to grow big and strong, but there’s not enough to go around.

THOMAS: And that was actually what I think the first real opening for saccharin was.

GRABER: What happened was: Women ended up sacrificing their own sugar for their families. They saved the good stuff, the sugar, for the desserts for their kids. But instead of depriving themselves of sweetness, they turned to saccharin.

TWILLEY: This was how saccharin broke back out of the medical world, and got into regular food again—with these housewives who were saving sugar but not giving up sweetness. And what that meant is that saccharin became feminized—it was a treat just for women. Women bought these pills, women put them in their coffee and tea.

GRABER: And there’s a cool story here that we saved for our special supporters newsletter—that’s for those of you who give $5 an episode on Patreon or $9 a month at gastropod.com—women had special saccharin jewelry!

TWILLEY: So saccharin has gone from a cheap, almost fraudulent ingredient in soda fountain drinks, to a diabetic medication, to a light and dainty special treat for women. And then the Second World War ends, rationing eventually ends, and the opposite of rationing begins.

GRABER: You’ve heard this same basic story before on Gastropod. After World War 2, there was all this machinery and workers and production capacity and nitrogen for bombs. And instead of the war effort, that nitrogen became fertilizer and the machines became tractors and food processors. Big processed food was born.

TWILLEY: And in order for the economy to keep growing so that everyone could have some of that lovely American abundance they’d been fighting for—well, people had to consume all that processed food. All the food they could fit in their growing bodies—and some.

GRABER: Really, Americans were kind of essential receptacles for all this new processed food. To keep the booming food market growing, we literally had to eat more than we needed, more than we even could. And we needed artificial sweeteners to give us a good excuse to do just that.

THOMAS: So suddenly artificial sweetener, instead of being the thing you’re finding in the medicinal aisle, now it’s being promoted as a way that you can basically have your cake and eat it too. We’ll make food with artificial sweetener in it, and then there won’t be very many calories in it, and that way you can continue to eat all this great food around you without actually, you know, gaining weight or having to decide to have less.

TWILLEY: This is the part that kind of blew my mind. What Carolyn is saying is that artificial sweeteners—they are like a trick, a magic wand the food industry waved to convince us that we can consume even more. More than we did, more than we should. More and more, so that the industry could continue to grow.

GRABER: This trick, these artificial sweeteners, they led us to think we were making good choices. But instead we just ate more of everything, more of the fake sweeteners, and more calories, too.

TWILLEY: And the result was, the food industry grew, and American bodies grew too.

GRABER: But there was one stumbling block for the food industry and for home cooks. Saccharin tastes like crap if you cook with it. That’s why people used it to sweeten drinks. But they couldn’t make cookies with it.

TWILLEY: It took another chemist basically licking his finger to make artificial sweeteners into the food industry saviors they were to become.

THOMAS: In the 1930s, another artificial sweetener is developed and ultimately Abbott Pharmaceuticals markets it as something called cyclamate, or what they call Sucaryl—it’s kind of their brand name .

GRABER: Sucaryl was discovered by accident in 1939, by a chemistry graduate student at the University of Illinois. He was looking for a way to mask the bitter tastes of medicines. Apparently he rested his cigarette on the table and then put it back in his mouth and noticed that the chemical was sweet. Sounds like great lab protocol.

TWILLEY: Again with the sloppy science. But the point is, Sucaryl—this new chemical—had something very important going for it. It still tasted great when you heated it.

THOMAS: So, okay—now an artificial sweetener is on the market that can be heated. You can bake with it. You can cook with it. You can put it in sauces.

GRABER: So artificial sweeteners were helping Americans be the super consumers the food industry wanted us to be. And cyclamates meant that these sweeteners could be used in nearly all foods. But there’s one missing piece, one more thing going on in the second half of the twentieth century that really set the stage for their takeover.

THOMAS: Tillie Lewis is amazing. And I’m waiting for the movie called “Tillie.”

TWILLEY: Tillie Lewis is that missing piece—she is the final part of the story of how artificial sweeteners went mainstream.

GRABER: Tillie grew up in Brooklyn. Her parents were Jewish immigrants, they were grocers.

THOMAS: Her story is that she was sitting and putting canned goods on the shelf at the grocery store and she saw a can of pomodoro tomatoes. And she just thought to herself, I’m going to bring this pomodoro tomato to America. Because they were imported from from Italy.

GRABER: And she did—Tillie went to Italy to learn both tomato growing and canning, and she moved to California and she became really successful. Tillie wasn’t just canning tomatoes, but fruit, too. And then she saw another market opportunity: diet canned foods.

THOMAS: Tillie was really the first to create a line of diet foods, right? She was a tomato grower and canner, but she branched out into canning fruit and canning syrup and canning different kinds of desserts—all with the artificial sweetener.

TWILLEY: These cans of Diet Delite sold like hot cakes—artificially sweetened hot cakes.

GRABER: Tillie wasn’t the only person in America to spot this opportunity of course.

THOMAS: But what she was really good at doing was self promoting. And so Tillie went from newspaper to newspaper, kind of starting around her in California and then branching out across the country. And she paired her line of diet foods with these 21-day Tillie diet plans.

GRABER: And these diet plans, this is where Tillie was really successful. And where she helped change American diet culture.

THOMAS: She said, I personally was told by my doctor that I needed to lose weight. And I said no way, I’m not going to do without the sweet foods that I love. So I went back and I created a whole line of foods that mean you don’t have to do without sweets. We will make your sweets skinny, and you can have them.

TWILLEY: Before Tillie and her artificially sweetened diet plans, losing weight pretty much meant cutting back. It meant you had to skip dessert. Post Tillie, that sort of self control was no longer necessary.

GRABER: Weight Watchers took this philosophy to the ultimate extreme. They had all sorts of ads showing women who couldn’t control their cravings, but with artificially-sweetened Weight Watchers desserts, they didn’t have to. Dessert became legal, to use one of Weight Watchers’ favorite words.

TWILLEY: And so you have this new diet culture and you have the spread of cyclamates into all kinds of desserts and baked goods, and you have regular Americans doing their best to step up to the plate and consume more. And the whole thing adds up to artificial sweeteners becoming totally integrated into our every-day consumption.

THOMAS: By 1970, 75% of the U.S. population was using artificial sweetener in one way or another on a regular basis.

GRABER: But there had been a slight hiccup. Cyclamates were banned in the U.S. in 1969, because huge doses caused increased levels of bladder cancer in rats. The animals were ingesting the equivalent of 550 cans of diet soda a day. Again, a huge—and unrealistic—amount. But the word cancer scared consumers and the federal agencies.

TWILLEY: Cyclamates are actually still allowed in a lot of other places, including the European Union, and they’re currently being re-evaluated in the US. But at the time, this was a problem. Cyclamates are off the market, and then, horror, scientists discover that giving rats a bathtub full of saccharin turns out to also maybe give them cancer.

GRABER: So is saccharin bad for us? What about all these other new sweeteners that are on the table today—Equal and Splenda and Stevia? Are those okay for us? Where do they come from?

MID-ROLL

GRABER: As we said, cyclamates were banned because of cancer. And saccharin looked like it caused cancer in megadoses in rats, too. So saccharin was threatened with the exact same thing. A ban.

THOMAS: And what happened, in 1977, was a massive public revolt. And it’s interesting, if you look, you can see these folks in Congress making comments like, they had never seen such an outcry from the public over any issue in office. And keep in mind it’s 1977, and these are people who’ve been in office for decades. So we’ve been through quite a few political upheavals that didn’t generate the same number of letters.

TWILLEY: Carolyn was intrigued. There was so much to protest in the 70s. You could have written to your Congressperson about civil rights. Or about the Vietnam War. But, no. The thing that persuaded more Americans to pick up their pens was the idea that big government was going to take their beloved saccharin away.

GRABER: These protests worked. The letter writers convinced the government not to take away their saccharin. Basically, Congress kept pushing off a decision about banning it until the issue just kind of went away.

TWILLEY: We are going to come back to this question of whether saccharin and even cyclamates are actually bad for your health. But in fact, it turns out that even though in the late 1970s, Americans were so committed to saccharin that Congress would have had to pry it out of their cold dead hands, a few years later, saccharin was old news.

NUTRASWEET JINGLE: Would you like to have something sweet?

THOMAS: NutraSweet!

NUTRASWEET JINGLE: It’ll be my treat!

THOMAS: Aspartame took its place. and for our listeners that would be the blue packet on the table. So, Equal.

NUTRASWEET JINGLE: Would you like to have something sweet?

TWILLEY: By this point, the artificial sweetener market was huge, and so a lot of pharmaceutical companies were looking for the next big sugar alternative. And the winner was a company called G. D. Searle—it’s now owned by Pfizer.

GRABER: James Schlatter was working at Searle. And apparently he also licked his finger.

TWILLEY: What is with these chemists and their poor lab hygiene?

GRABER: I know. James was trying to develop a chemical that would help test an anti-ulcer drug candidate. And it turned out to be incredibly sweet.

TWILLEY: This was artificial sweetener number three. And you are not going to believe who was in charge of launching it.

THOMAS: In fact, they brought Donald Rumsfeld in to lead the effort.

GRABER: Yes, that Donald Rumsfeld. So Carolyn was a kid at the time.

THOMAS: It was so exciting. I have this very strong memory of coming home and—I guess it was 1984—and opening up the mailbox and finding a little clear packet of gumballs attached to, I don’t know, it must have been an advertisement. But all I paid attention to were the gumballs. And, you know, I opened them up and I was probably 12 or 13 years old. I opened up the gumballs and I ate them.

TWILLEY: This gumball launch—this was some of that Rumsfeldian manipulation at its finest.

THOMAS: You know, it was no accident that the gum ball came in the mail and that the child ate the gumballs, right? Because that’s what kids do. it looked playful. It looked like something brand new.

GRABER: This was important. Because after World War II, artificial sweeteners had been seen as awesome because they had science behind them. But the marketing for NutraSweet took an entirely different approach. Because artificial had turned into a dirty word.

THOMAS: And trying to create the first artificial sweetener that wouldn’t be artificial—that we would kind of get rid of that word all together, and then we would just call it something new. we would call it just NutraSweet—sort of nutritious or maybe natural. And they combined these gumballs with a fairly simple message that basically said NutraSweet isn’t like any other sweetener that’s existed.

TWILLEY: NutraSweet was amazing. It had no calories, no bitter aftertaste like saccharin. And it was made from two amino acids, simply joined together.

GRABER: And amino acids are the building blocks of protein. But of course you can’t find NutraSweet in nature. Those two amino acids could only be combined together in a lab. But that was just a matter of semantics to the NutraSweet marketing folks.

THOMAS: Now that there finally was a sweetener—you could heat it, you could eat it. It was like what sugar always wanted to be and it was just as natural as a banana.

NUTRASWEET AD: Banana plants don’t make NutraSweet. Neither do cows. But they might as well—if you’ve had bananas and milk, you’ve eaten what’s in NutraSweet.

THOMAS: Which is really not true. It’s phenylalanine and it’s different in how your body interacts with it.

TWILLEY: No matter—with Rumsfeld at the helm and gumballs in American mailboxes, NutraSweet stormed the shelves. It’s still one of the most popular artificial sweeteners on the market—it’s the sweetness in your Diet Coke. But in the past couple of decades, it’s been joined by some competitors. There’s Splenda—that’s a chemical called sucralose that came out in the 90s.

GRABER: And today, Sweet”N Low and Equal and Splenda have all been joined by the latest new trendy low-cal sweetener. This one is marketed as truly natural. It’s called Stevia, it’s a super sweet extract from a plant native to South America.

TWILLEY: So for a while back there, in the late 1970s, it looked as though we would have no artificial sweeteners. And now we have a whole bunch to choose from. But still, there’s this aura of doubt that surrounds them.

THOMAS: When I give talks on this research, even though for me the thing that I’m so interested in is just, you know, how we develop and manufacture foods and find new meanings for them—I’m not an expert in health—I am always asked the question by people: is that bad for me? Should I—should I not have that? Does that cause cancer?

GRABER: These are questions nearly everyone has because, frankly, the news has been filled with stories about rats getting sick when they OD on sweeteners. So, what does the science say? We asked Rick Mattes, he studies artificial sweeteners at Purdue University.

MATTES: Every governmental body from the U.S. to the European Union to Australia to Japan to Canada—they have all scrutinized each of the sweeteners that are commercially available and they have unanimously agreed that when consumed within reasonable boundaries they are safe. So I take that literature on face value myself.

TWILLEY: Sorry Internet conspiracy theorists, but the scientific evidence is pretty clear and conclusive on this. The Roman lead grape syrup—that was toxic. But today’s artificial sweeteners are not carcinogenic at the doses that we consume them. They’re just not. But that’s not the only question people have.

GRABER: Right, the fact that they won’t cause cancer, that’s not the only question about artificial sweeteners. There are two other big ones: one, there’s some research linking them to heart attacks and strokes. What’s the deal with that? And two: Do they actually help people lose weight? That’s the big one, because, after all, that’s people are using them for.

VASANTI MALIK: And that’s the issue because there’s not consensus in the literature yet. And so this is a really hot area for research. There’s a lot of researchers trying to get at that question. And part of the confusion is coming from the research.

TWILLEY: This is Vasanti Malik, you heard her in our recent soda wars episodes. She’s a research scientist in the Department of Nutrition at Harvard’s School of Public Health.

GRABER: Vasanti told us that previous studies showed that using artificial sweeteners might strangely actually make you gain weight. But other studies showed that they could help you lose weight.

TWILLEY: Similarly, there are studies that seem to show that artificial sweeteners can lead to more heart attacks and strokes. And other studies that say they have no effect or even reduce your risk of heart disease.

GRABER: So why is this so confusing? Why don’t these studies all come to the same conclusion?

TWILLEY: So we need to unpack this. Vasanti told us there are a couple of major problems. The first one is called a confounding effect. And it is less confusing than it sounds. It’s basically everything else you eat alongside those diet sodas.

MALIK: You know, maybe some people always you know go out for fast food and have a diet soda with it. And then it’s the French fries that also have a relationship with increased risk of the cardiometabolic diseases.

GRABER: In this example, all those French fries are leading to a higher risk of heart attacks and strokes. They’re the confounding factor, if people always have French fries with their diet soda. Also, if people always eat French fries with their diet soda, maybe this is why they’re gaining weight.

TWILLEY: This was me: Diet Coke and a slice of cake. The afternoon pick-me-up of champions. At least in my teens and twenties.

GRABER: I’m sure that Diet Coke totally canceled out the calories from the cake.

TWILLEY: You know I can’t add up, Cynthia. You do our accounting.

GRABER: True. But so scientists have statistical tools and other methods to try to take into account these confounding factors like French fries and chocolate cake, so that they don’t confound the result.

TWILLEY: There’s another issue—this one is called reverse causation by the scientists, and it has to do with what risk factors you have before you start drinking diet soda.

GRABER: So in this example, maybe a group of people is already at a high risk for heart attack and strokes, and so they drink diet soda to try to manage their weight. And then they still end up with more heart attacks and strokes than everyone else, but it has nothing to do with the soda.

TWILLEY: So Vasanti did a study to try to tease this out. She used statistics to account for reverse causation and for confounding factors, and she found there was no connection between diet sodas and heart disease

GRABER: But what about weight gain? When she and her colleagues actually took out any confounding factors, well, it looked like diet sodas helped.

MALIK: And so yeah, so non-nutritive sweetened beverages were associated with less weight gain.

TWILLEY: This was not a dramatic difference we’re talking about.

MALIK: We’re talking small numbers. We’re talking about like a quarter of a pound over four years.

TWILLEY: Barry Popkin—you might remember him as the star of our soda wars episodes—he’s the guy that the governments of Mexico and Chile call when they want to have a soda tax or a new label scheme. So he has also studied the impact of replacing sugary sodas with diet sodas, and, like Vasanti, he made sure to take into account what else his study participants were eating.

GRABER: And he found the same thing—that the best studies we have show that artificial sweeteners can potentially help—a little—with weight loss, if you’re generally eating a healthy diet, and if you replace a daily sweetened soda with a diet one. So maybe that aura of mistrust that surrounds artificial sweeteners—maybe it’s not justified by the science at all.

TWILLEY: But both Vasanti and Barry agree that there’s just not very much science—just a handful of studies that really tease out these confounding effects and reverse causation. So we can’t really say for sure.

GRABER: And there’s another possible issue with artificial sweeteners. And a possible explanation for why studies might be showing that people gain weight from drinking diet sodas.

TWILLEY: Remember, these artificial sweeteners are a lot sweeter than sugar—hundreds, even thousands of times sweeter.

MALIK: And so for that reason there’s concern, particularly among children, that repeat consumption of these beverages might habituate a person towards sweets.

GRABER: In this scenario, you get so used to things being super sweet that you just crave more and more sweets. But Rick Mattes says that’s not the only way these calorie-free sweeteners might be tricking our bodies.

MATTES: So, for example, we have throughout evolutionary time associated sweetness with the ingestion of carbohydrate. And we have learned that an appropriate response to eating something sweet is to secrete insulin.

TWILLEY: The theory here is that you drink your diet soda or eat your NutraSweet gumball and your body is like, whoa baby, here comes the sugary goodness! Hey pancreas, you better pump out some insulin to keep the old blood sugar levels steady.

GRABER: But wait. There’s no sugar in your blood. That insulin has nothing to do. Your hormone and blood sugar levels get all out of whack. And so maybe one response would be—you’re still hungry, you still crave actual calories, so you go and eat more.

TWILLEY: Either way, whether it’s just that you get used to sweet and crave it more, or whether the diet soda actually makes you hungry physically, this is how people think that possibly artificial sweeteners might contribute to weight gain and heart disease

GRABER: Barry Popkin studied whether artificial sweeteners make you eat more sweets. He found that people who drank diet sodas actually ate slightly fewer sweet treats than people who drank water.

TWILLEY: And that is pretty much the best evidence we have right now—but it’s one study.

BARRY POPKIN: We don’t have these kind of research on these studies on children. And the fear still is, the big unknown, will diet beverage consumption or diet foods enhance the sweetness preference of young children? And we do not have an answer to that question.

TWILLEY: And as for the question of whether artificial sweeteners make you hungry by messing with your metabolism and raising your insulin—that is even more of a mystery right now. Scientists are studying it, sure, but there’s not enough research to say one way or other.

GRABER: But then Rick told us something that complicates the matter even more. Throughout this episode, all the scientists we’ve spoken to talked about all these sweeteners, Equal and Splenda and Saccharin, they’ve talked about them as if they’re all basically the same thing.

MATTES: From a consumer use and clinical prescription and policy practice we tend to just lump all of them together and say, oh yes, the low calorie sweeteners. And we assume that they all work by a common mechanism. But, you know, if you think about it kind of carefully, one could start to question that. So, for example, they are all very distinct chemical structures.

TWILLEY: This is one of those insights that is completely obvious and also hadn’t occurred to me at all. But of course—they are all different chemical structures. And Rick has actually spent a lot of time showing exactly how these structural differences create different effects in our bodies. So the first thing is—they all taste slightly different. They taste sweet because they bind to the sweet receptor—but they all bind to it in slightly different places and in slightly different ways.

MATTES: So some have a very abrupt rise in sweetness and an abrupt fall. So the duration of the sensation is short. Others, like Neotame, for example, has a very long persistent sweet taste, which is why it’s a good sweetener to use for example in chewing gum where you’d like to keep the sweetness level high for an extended period of time.

GRABER: Saccharin has a bitter aftertaste, as we’ve already discussed. One called glycorisin has a slight licorice flavor. But another thing—these sweet chemicals all affect the brain differently. They light up regions of the brain’s reward center in different ways.

MATTES: But how that translates into actual sensation or behavior is still very much up in the air. We really don’t know that. All we can say at this point is that with exposure to these compounds we get a different signal.

TWILLEY: This is kind of amazing. Your brain looks different on Diet Coke than on sugarfree gum.

GRABER: On top of this—if you heard our episode Hacking Taste, you might remember that we have sweet receptors throughout our body, not just on our tongues.

MATTES: It’s in our intestines, it’s in our bones. It’s all over the body. And so we used to think that low-calorie sweeteners would elicit a sweet taste when they were in the oral cavity, but once we swallowed them they were basically inert. We would just excrete them.

TWILLEY: But we were wrong. Artificial sweeteners trigger those sweet receptors wherever they find them—in the intestines, in the bones, in the liver—wherever.

GRABER: So, for instance, if the sweet receptor is on a particular type of cell in the pancreas called a beta cell, if it’s triggered, the beta cell doesn’t send a sweet taste to your brain—but instead, that sweet chemical spurs the beta cell to release insulin.

TWILLEY: And so here is where things get really interesting. Because all these artificial sweeteners are different chemical structures, they reach different places in our body. So that means they’re all switching on a slightly different set of cells.

MATTES: So some sweeteners enter the blood supply and so would have access, for example, to the brain and to the beta cell. Others are not. Aspartame will never get into the bloodstream, for example. So each of these sweet compounds can be expected to have a different effect throughout the body based on how they’re digested, absorbed, and excreted.

GRABER: This is shocking. Artificial sweeteners are different at every level—how we taste them, how they affect our brains, how we digest them, what our body does in response to the sweetener.

MATTES: So one might fully well expect that they have a different outcome on body weight. So we did a trial.

TWILLEY: Rick got a bunch of volunteers and divided them into five different groups. And each of the groups had to drink a daily fruity drink sweetened with a different sweetener.

MATTES: So the sweeteners were sucrose, aspartame, saccharin, stevioside, and sucralose.

TWILLEY: If you were in the sucrose group—that’s the control, because sucrose is sugar—you drank a sugar-sweetened fruit drink every day for 12 weeks. If you were in the sucralose group—that’s Splenda—you drank that every day. And so on.

GRABER: Rick and his colleagues measured everything they could measure about the participants in the study. They measured how many calories the volunteers were burning. They measured their body composition and their blood sugar levels. The volunteers had to record their food intake. They had to rate their appetite.

MATTES: And what we found—and really very much to our surprise—was that sucrose consumption led to an increase in body weight. That actually was not a surprise to us—that is what we would have predicted. But saccharin behaved very similarly to the sucrose.

TWILLEY: And that’s the surprise. Saccharin contains no calories. And yet in Rick’s trial, the people drinking sugary fruit juice and the people drinking saccharin fruit juice ended up gaining pretty much the same amount of weight.

GRABER: People who drank the Splenda-sweetened drinks lost the most weight. People whose drinks were sweetened with Stevia and NutraSweet basically stayed the same. No change.

TWILLEY: Rick said that he checked—the change wasn’t due to people eating differently—so it wasn’t like a situation where the saccharin folks got more hungry or craved more sweet foods. So what did cause this difference?

MATTES: What that suggests is that there is another mechanism at play.

GRABER: And Rick thinks that mechanism might just be the microbes living in our guts. The gut microbiome.

TWILLEY: Microbes! Drink!

MATTES: I hate to default to that but given the evidence, which I think is very sound, that selected low-calorie sweeteners will make it to the colon and very likely do alter the relative proportions of different gut bacteria.

TWILLEY: Given those changes—is it possible that some sweeteners—like say, maybe, saccharin—are boosting the kind of gut microbes that are especially good at getting calories out of food? And might that explain why the saccharin fruity drink drinkers gained weight? Maybe?.

GRABER: Conveniently for us, there is actually a researcher in Israel at the Weizmann Institute named Eran Elinav. And he is studying this very thing.

TWILLEY: Eran didn’t start out looking at the effect of artificial sweeteners on the microbiome—he was actually doing a personalized nutrition study. But he sort of came across artificial sweeteners by accident, when he looked at his results.

GRABER: Eran and his team were studying how different foods affected blood sugar in people. And they noticed something weird—it looked like some people would get a blood sugar spike after a diet soda, and some people didn’t. And that didn’t make any sense.

ERAN ELINAV: Yes, this result was very surprising and at first I didn’t believe it in fact, not only because I was a heavy consumer of these compounds, but because, you know, the logic was exactly the opposite.

GRABER: Nobody should have gotten a blood sugar spike, because there was no sugar in these drinks!

TWILLEY: So Eran started up a side project, trying to figure out what the hell was going on.

GRABER: Eran did a bunch of different studies with mice. And he’s been able to show that—at least in mice—some artificial sweeteners changed the populations of gut microbes and favored ones that grab more calories from the food passing through.

TWILLEY: Just like Rick speculated.

GRABER: This sounds pretty convincing—but a lot of studies in mice don’t necessarily translate to us humans. So now of course Eran is studying this in people.

ELINAV: I cannot tell you the answers because I don’t know them yet. This is work in progress.

TWILLEY: This research is super interesting, but we have to point out—it is not yet news you can really use. One day, we might know whether different people have the kind of microbes that respond to certain sweeteners with a blood sugar spike

GRABER: Or which artificial sweeteners are the ones that change your gut microbes to make them better at harvesting calories, and which ones don’t do that.

TWILLEY: But really, right now, Eran is the first to say we don’t fully understand what’s going on.

GRABER: Barry Popkin agrees it is far too early to say anything definitive.

POPKIN: The initial work that Eran presented is very, very preliminary. He right now has a study that will be completed in about a year where he is actually following a thousand people with the diet sweeteners and a thousand without. That study will give us some meaningful results.

TWILLEY: This is something we kept hearing. We just don’t know enough—yet—about what these artificial sweeteners are really doing in our bodies.

MATTES: We have almost all of it yet to learn.

GRABER: But, as we discussed with Carolyn, there are already a lot of these sweeteners in the food supply.

TWILLEY: So much so that Eran has really struggled finding people for his trials that haven’t already eaten artificial sweeteners.

ELINAV: It is super difficult. I didn’t think it would be that difficult but, you know, when you start questioning people, artificial sweeteners are so well-integrated into into our diet in many different food products—you know, 0% yogurt and so on and so forth—that it was really hard to find these individuals.

GRABER: And in fact there will soon be even fewer people who are artificial sweetener virgins. We talked about this in our soda wars episode—with the tiered tax in the UK, companies are using more artificial sweeteners so that they don’t have to pay as high a sugar tax. And this is happening in Chile, too, because of their warning labels.

TWILLEY: All this reformulation—it’s making some scientists kind of nervous. Even Barry, who is all about doing whatever it takes to lower sugar consumption.

POPKIN: It’s a huge global experiment that’s going on and I fear these when we don’t have the kind of research to go behind them. It’s not all that different than when everybody came out against total fat long ago and they added tons of sugar to the diet and we found we had very adverse effects to that.

GRABER: The scientists all do think there’s a place for diet sodas today. If you’re someone who drinks a lot of regular soda, and if you’re someone who’s trying to manage your weight.

MATTES: I think that they can be used effectively. Now, they are not necessarily magic bullets. You can’t just add them to your diet and expect weight to disappear.

TWILLEY: Here’s the thing. To channel Donald Rumsfeld, since he’s already popped up this episode—the known knowns about obesity and diabetes are much more significant than the semi-known unknowns of what artificial sweeteners might be doing to your personal gut microbe community.

GRABER: This is where most scientists seem to fall on this question: they’re not huge fans of artificial sweeteners, they’re a little wary, they’d rather we just switch to unsweetened drinks—but they think artificial sweeteners can be a useful tool for people who need them to cut down on sugar.

TWILLEY: So when we started making this episode, I thought we were going to find all this science that showed that artificial sweeteners were bad for you—physically speaking.

GRABER: Right. I thought we’d get to the bottom of whether or not they were unsafe. And we kind of did.

TWILLEY: Which is that they’re not, really. They might not be helpful—we’re not sure, the research is still being done.

GRABER: But they don’t seem to be particularly harmful for you. They don’t seem to cause cancer or heart attacks or strokes. They might mess with our gut microbiome, and even our metabolism, scientists are still trying to figure that out. But that’s just on an individual level—

TWILLEY: Because it turns out that where artificial sweeteners are definitely bad for us is in a bigger picture way, as a society—in how we eat and how we think about eating.

GRABER: This is the conclusion that Carolyn Thomas came to.

THOMAS: I grew up in a house where my mom was always on a diet. you know Weight Watchers or Jenny Craig. NutraSweet was all around me, when I was growing up. We had Crystal Light in the fridge and Diet Pepsi. And, as I became older, I just was so curious. You know, how did we have all of these NutraSweet sweetened foods, but yet my mom was still always on a diet? It never really led to a time when she felt good about her weight or in control of what she was eating. She was always sort of up and down and back and forth. So I think it’s, for me, these products are ways that people could consume more and feel good about consuming more. So it didn’t decrease the amount of sugar people consumed. it just added a new category of sweet.

TWILLEY: Thanks so much this episode to Carolyn Thomas, her book is called Empty Pleasures and you can find a link at gastropod dot com.

GRABER: Thanks also to Rick Mattes, Vasanti Malik, Barry Popkin, and Eran Elinav. We have links to their work as well at at gastropod.com.

TWILLEY: And, of course, thanks to the Alfred P. Sloan Foundation for the Public Understanding of science, technology, and economics, as well as the Burroughs Wellcome Fund, for supporting this episode.

GRABER: Finally, thanks to listener Elizabeth Preston, who suggested we do an episode on artificial sweeteners. Apparently her husband’s cousin said that aspartame was the fecal matter of bacteria. As it happens, today aspartame is indeed excreted by special bacteria that were genetically modified to do so. So, kind of?