Artificial sweeteners have been controversial for almost as long as they’ve been around. As early as 1906, President Theodore Roosevelt was compelled to defend the world’s first no-calorie sweetener. “Anybody who says saccharin is injurious to health,” he said, "is an idiot!”

The debate rages on today. Some dietitians and nutritional scientists go to bat for artificial sweeteners like sucralose and stevia as a safe way to enjoy sweet drinks and foods while avoiding the calories. Other scientists believe they play a role in the obesity and metabolic disease epidemics because they confuse the brain and the body about the caloric value of sweet foods. A lot of consumers — especially those trying to lose weight — end up confused.

Enter Dana Small, a neuroscientist at Yale University, whose research, published Thursday in Current Biology, promises to change not only our understanding of sweeteners, but of sweetness itself.

How Small discovered something baffling about sweetness

Small did not set out to test the healthfulness of artificial sweeteners. Rather, she was exploring a more fundamental question: Is the rewarding character of sweet foods due to the calories those foods contain?

To test her hypothesis, Small created five beverages. All were sweetened using the identical amount of sucralose, an artificial sweetener, so that they tasted about as sweet as a drink containing about 75 calories of sugar. But then Small varied the calories using a tasteless carbohydrate called maltodextrin. The small army of beverages she produced — each with its own distinctive color and flavor — were all equally sweet, but contained the following calories: zero, 37.5, 75, 112.5, 150.

After subjects had consumed each drink six times over a period of weeks — twice in the lab and four times at home — Small used fMRI brain scanning to see how each drink affected brain reward circuits. Her prediction: The more calories, the greater the reward.

The results were nothing like she envisioned. The most “reinforcing” drink was the 75-calorie one. It generated a stronger brain response than the 0-calorie drink, but it also generated a stronger brain response than the 150-calorie drink.

This made no sense. If calories were what made sweet foods appealing, why would a 75-calorie drink be more rewarding than a 150-calorie drink? But if calories had nothing to do with it, what made the 75-calorie drink more desirable than the zero-calorie drink?

It took Small two years to unravel these baffling results — with more experiments and analysis. In one experiment, she measured the body’s metabolic response, which is the energy the body expends to process calories. Once again, the results repeated themselves. The metabolic response to the high-calorie drink was lower than it was for the medium-calorie drink, a result that made Small think, “Holy cow, what’s going on?”

Diet soda may do more harm when consumed with carbohydrates

Eventually, she pieced it all together. Sweetness, she realized, plays a role in how the body responds to food. “It regulates the metabolic signal,” Small says.

When sweetness and calories were matched, it all ran as expected: the 75-calorie drink produced not only the largest metabolic response but also the largest brain response — because the calories matched the taste.

But when there was a “mismatch” between sweetness and calories, the response was strangely muted. “It’s like the system threw up its hands and didn’t know what to do,” Small explains.

The findings present certain troubling questions. For example, what happens to all those “mismatched” calories that don’t get metabolized? “We know it’s not being used as a fuel” Small says. “What’s happening to it?”

Those extra calories, she says, are probably being stored, either in muscle, in the liver, or in fat, none of which is desirable. “If sweeteners are disrupting how carbohydrates are being metabolized, then this could be an important mechanism behind the metabolic dysfunction we see in diets high in processed foods.”

The findings also suggest that whatever benefit or harm there may be to artificial sweeteners is context dependent. A diet drink consumed by itself and on an empty stomach may be far less harmful than one consumed with carbohydrates — with a sandwich, say, or a bag of chips.

But what’s troubling is that in an effort to reduce added sugars, food companies are now designing all sorts of products that contain blends of sweeteners and carbohydrates that could be disrupting the body’s metabolic response. The sports drink Powerade, Small notes in her paper, contains the sugars glucose and fructose alongside the artificial sweeteners sucralose and Acesulfame K. A yogurt product made by Chobani called Simply 100 similarly contains 14 grams of carbohydrate (six of which are from sugars) as well as stevia leaf extract.

This may also explain why the existing body of research on artificial sweeteners is so mixed. For example, a study published in The New England Journal of Medicine in 2012 found that Dutch children who consumed a single artificially sweetened beverage each day for 18 months gained less weight and less fat than children who drank a single sugar-sweetened beverage each day.

And yet, in much of the observational research — in which scientists look at large populations — people who consume artificially sweetened drinks, especially those who consume them a lot, appear to be at an alarmingly high risk for obesity, Type 2 diabetes, and cardiovascular disease.

Defenders of artificial sweeteners attribute this to “reverse causation.” Obese people, they point out, are already at a higher risk for obesity and metabolic disease. And since obese people are likely to turn to artificial sweeteners to lose weight, these studies just make it appear as though the artificial sweeteners are putting them at higher risk. (These studies, in other words, can make correlations look like causes.) Critics of artificial sweeteners counter that they still look bad even when you adjust for BMI, and that rats fed artificial sweeteners have been found to gain more weight than rats who are not.

In the Dutch study, when the children consumed their beverages at school, it was during morning break. The paper does not indicate whether or not food was consumed alongside them, and if so what kind of food.

Small’s research suggests this could be an important variable. Similarly, habitual users who drink, say, three or more artificially sweetened beverages a day may be more likely to consume them in combinations with food that are problematic.

It’s pretty much impossible to detangle taste from nutrition and metabolism

Ultimately, Small’s research attests to how difficult it is to disentangle taste and deliciousness from nutrition and metabolism. Behind the universal love of sweet foods lies a nest of complex body-brain systems that are partly driven by metabolism, but also regulate it.

“Taste,” Small says, “can change the metabolic fate of calories.”

In other words, the dream of foods that taste great but have none of the calories may be just a dream.

Mark Schatzker is the author of The Dorito Effect: The Surprising New Truth About Food and Flavor. He last wrote for Vox about tomato flavor.