Choosing to have diet drinks with your meals could lead to weight gain, scientists believe.
Many people choose beverages with artificial sweeteners rather than the 'full-fat' sugar versions to watch their waistlines.
But research found that when consumed with a carbohydrate, such as fries, the body's metabolism is impaired.
The brain's ability to perceive sweet taste also changed, which, over time, may damage how the body copes with real sugar.
Sweetened drinks on their own had no negative effect, the study on 45 people over two weeks showed.
There has been a long-standing debate about whether diet sodas, filled with sweeteners such as sucralose, are as healthy as they seem.
The latest findings suggest its not consumption of sweeteners, but what they are consumed with, that affects the body.
Professor Dana Small, who led the study at the University of Yale, said: 'Our findings suggest that it's OK to have a Diet Coke once in a while, but you shouldn't drink it with something that has a lot of carbs.
Ordering a diet drink with your fries could lead to weight gain, scientists believe
'If you're eating French fries, you're better off drinking a regular Coke or better yet water.
'This has changed the way that I eat, and what I feed my son. I've told all my friends and my family about this interaction.'
Previous research has suggested that drinking diet drinks may make people more likely to gain weight because people who have them feel they deserve a sweet treat afterwards.
And the chemicals in artificial sweeteners may change the bacteria in the gut and make people more likely to gain weight or develop diabetes, experts have previously said.
The latest study was designed to test whether or not repeated consumption of an artificial sweetener would damage how the brain perceives sweet taste.
The theory is called 'uncoupling', and suggests consuming sweet foods without any real calories reduces the body's response to real sugar.
It could potentially mean that people put on weight easier, develop glucose intolerance or even get diabetes.
The study suggests that drinking diet drinks on their own does not appear to affect the body's response to sugar. Instead, this effect was only observed when the drinks were consumed with a carbohydrate.
Sweetened drinks on their own had no negative effect, the study on 45 people showed
Adults who have at least one diet drink a day are three times more at risk from a stroke or dementia, research revealed in 2017.
Scientists said the sugar-free drinks should no longer be regarded as the healthier alternative and urge the public to stick to water or milk.
Their study of almost 4,400 adults also suggests diet drinks are more likely to cause strokes and dementia than those full of sugar.
There was no link between sugary beverages and either of the illnesses - although the researchers aren't encouraging people to drink them either.
The team of scientists from Boston University believe the artificial sweeteners including aspartame and saccharine may affect the blood vessels, eventually triggering strokes and dementia.
Diet drinks account for a quarter of the sweetened beverages market but there is growing evidence they are not as healthy as previously thought.
The study enrolled 45 people between the ages of 20 and 45 who didn't normally have low-calorie sweeteners.
All of them were healthy and had no problem with their metabolism, according to paper published in the journal Cell Metabolism.
They each consumed seven low-calorie drinks in a lab over a two week period. Each drink contained sweeteners the equivalent of two sachets of Splenda.
Some of the volunteers had a powdered carbohydrate, called maltodextrin, added to their drinks. This was intended to serve as a control.
But to the researchers' surprise, the control group showed the observed decreases the brain's response to sweet taste, as measured by MRI scans.
The body's insulin sensitivity, which is how efficient the body uses insulin, and glucose metabolism, which is how the body breaks down sugar to use for energy, was also impaired.
Taking this into account, the researchers added a second control group where those taking part were given drinks with only maltodextrin in.
There was no evidence that having these drinks affected insulin sensitivity or glucose metabolism.
Professor Small said: 'When the drink was consumed with just the low-calorie sweetener, no changes were observed; however, when this same amount of low-calorie sweetener was consumed with a carbohydrate added to the drink, sugar metabolism and brain response to sugar became impaired.
'This would be important because sweet-taste perception might lose the ability to regulate metabolic responses that prepare the body for metabolizing glucose or carbohydrates in general.'
Professor Small speculated as to why the drinks with both sweeteners and maltodextrin may have produced the observed effects.sonos sonos One (Gen 2) - Voice Controlled Smart Speaker with Amazon