104 Yang: The neurobiology of sugar cravings But do artificial sweeteners actually help re- duce weight? Surprisingly, epidemiologic data sug- gest the contrary. Several large scale prospective cohort studies found positive correlation between artificial sweetener use and weight gain. The San Antonio Heart Study examined 3,682 adults over a seven- to eight-year period in the 1980s [18]. When matched for initial body mass index (BMI), gender, ethnicity, and diet, drinkers of artifi- cially sweetened beverages consistently had higher BMIs at the follow-up, with dose de- pendence on the amount of consumption. Average BMI gain was +1.01 kg/m2 for con- trol and 1.78 kg/m2 for people in the third quartile for artificially sweetened beverage consumption. The American Cancer Society study conducted in early 1980s included 78,694 women who were highly homoge- nous with regard to age, ethnicity, socioeco- nomic status, and lack of preexisting conditions [19]. At one-year follow-up, 2.7 percent to 7.1 percent more regular artificial sweetener users gained weight compared to non-users matched by initial weight. The difference in the amount gained between the two groups was less than two pounds, albeit statistically significant. Saccharin use was also associated with eight-year weight gain in 31,940 women from the Nurses’ Health Study conducted in the 1970s [20]. Similar observations have been re- ported in children. However, childhood studies often were complicated by the more dynamic growth-associated diet changes. Consumption of both sugar-sweetened and artificially sweetened soda increased and milk consumption decreased with age [21]. A strict differentiation between artificial sweetener users and non-users was not pos- sible. A two-year prospective study involv- ing 166 school children found that increased diet soda consumption was associated with higher BMI Z-scores at follow-up, indicat- ing weight gain [22]. The Growing Up Today Study, involving 11,654 children aged 9 to 14 also reported positive associa- tion between diet soda and weight gain for boys [23]. For each daily serving of diet beverage, BMI increased by 0.16 kg/m2. The correlation was not significant for girls. The National Heart, Lung, and Blood Institute Growth and Health Study followed 2,371 girls from age 9 to 19 for 10 years [24]. Both diet and regular soda drinking was associ- ated with increase in total daily energy in- take. Soda intake also predicted the greatest increase in BMI, although the correlation between diet soda and BMI was not signifi- cant. A cross-sectional study looking at 3,111 children and youth found diet soda drinkers had significantly elevated BMI [21]. In addition, consensus from interven- tional studies suggests that artificial sweet- eners do not help reduce weight when used alone [2,25]. BMI did not decrease after 25 weeks of substituting diet beverages for sugar-sweetened beverages in 103 adoles- cents in a randomized controlled trial, except among the heaviest participants [26]. A dou- ble blind study subjected 55 overweight youth to 13 weeks of a 1,000 Kcal diet ac- companied by daily capsules of aspartame or lactose placebo. Both groups lost weight, and the difference was not significant. Weight loss was attributed to caloric restriction [27]. Similar results were reported for a 12-week, 1,500 Kcal program using either regular or diet soda [28]. Interestingly, when sugar was covertly switched to aspartame in a meta- bolic ward, a 25 percent immediate reduction in energy intake was achieved [29]. Con- versely, knowingly ingesting aspartame was associated with increased overall energy in- take, suggesting overcompensation for the expected caloric reduction [30]. Vigilant monitoring, caloric restriction, and exercise were likely involved in the weight loss seen in multidisciplinary programs that included artificial sweeteners [31,32]. EXPERIMENTAL STUDIES ON ARTIFICIAL SWEETENERS AND ENERGY Preload experiments generally have found that sweet taste, whether delivered by sugar or artificial sweeteners, enhanced human appetite. Aspartame-sweetened water, but not aspartame capsule, increased subjec-