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.

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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?"