More bad news for people who consume a lot of artificial sweeteners.

Consumption of artificial sweeteners such as sucralose and aspartame actually led to an increase in body mass index, according to a new review of trials and studies involving more than 400,000 participants and published in the peer-reviewed Canadian Medical Association Journal. “Evidence from randomized controlled trials does not clearly support the intended benefits of nonnutritive sweeteners for weight management,” the study found. The regular consumption of low-calorie sweeteners “may be associated with increased BMI and cardio-metabolic risk.”

This supports a laboratory experiment released earlier this year and presented at the Endocrine Society’s annual meeting in Orlando, Fla., which found low-calorie sweeteners actually promote fat accumulation in the body. “There is increasing scientific evidence that these sweeteners promote metabolic dysfunction,” said Sabyasachi Sen, an associate professor of medicine and endocrinology at George Washington University, and the principal investigator. Sucralose is the chemical used in Splenda, while aspartame is used in the brand Equal.

Diet soda sales have tumbled as consumers, turned off by studies on artificial sweeteners, have switched to bottled water, teas and energy drinks, instead. Bottled-water consumption in the U.S. hit 39.3 gallons per capita last year, while carbonated soft drinks fell to 38.5 gallons, marking the first time that soda was knocked off the top spot, according to recent data from industry tracker Beverage Marketing Corp. Sales of diet soda drinks have dropped by nearly 20% since 2009, according to market research group Euromonitor.

Researchers are divided over whether diet soda actually helps people lose weight. Swapping sugary drinks for diet drinks that contain artificial sweeteners may condition the body to expect calories, which makes people feel hungrier. Diet soda confuses our bodies, says Susan Swithers, a professor of psychological sciences and a behavioral neuroscientist at Purdue University in West Lafayette, Ind. who has reviewed studies on diet soda. She says diet soda “produces physiological responses — increasing metabolism and releasing hormones — to anticipate the arrival of sugar and calories.”

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And artificial sweeteners are popular, even if diet soda drinks have fallen in popularity. One-quarter of children and more than 41% of adults reported consuming low-calorie sweeteners in food, packets and beverages, a March 2017 study published in the Journal of the Academy of Nutrition and Dietetics. Most of these consumers reported consuming artificial sweeteners once daily (80% of children, 56% of adults) and frequency of consumption increased with body weight in adults, according to the study, which surveyed nearly 17,000 people.

The Food and Drug Administration has ruled that artificial sweeteners are safe, and sucralose, which was accidentally discovered by U.K. scientists while they were developing new insecticides, remains the biggest sugar substitute on the market, according to retail tracking service Infoscan Reviews and Information Resources, Inc. Aspartame is made from two amino acids, while sucralose is a modified form of sugar with added chlorine. One 2013 study, however, found that sucralose may alter glucose and insulin levels and may not be a “biologically inert compound.”

The Calorie Control Council, a trade group for manufacturers of artificial sweeteners including sucralose and aspartame, said the latest study linking weight gain and heart disease with low calorie sweeteners paints with too broad a brush. “Obesity is a complex condition with numerous causes and associations,” the statement said. Robert Rankin, president of the Calorie Control Council, said, “Individualized strategies are critical for successful body weight management and should address not only dietary preferences.” Also, correlation is obviously different from causation.

In response to the April study, the Calorie Control Council said the research was not preliminary and doses were not “physiologically relevant,” and noted that the study contradicts previous research that shows sucralose does not accumulate in the body. It cautioned against accepting research conclusions based on unpublished data. “It is critical to understand that plasma levels of sucralose, and many other compounds, are not similar to levels in human tissue,” the statement added. “Therefore, the doses utilized throughout this study have no physiological relevance.”