102 Yang: The neurobiology of sugar cravings Figure 1. Time line of arti- ficial sweetener use and obesity trends in the United States. Middle line: changes in the percentage of the population who are obese (BMI >30) from 1961 to 2006. Source: National Health and Nutrition Exami- nation Survey [57]. Bottom line: changes in the per- centage of the population who are regular artificial sweetener users from 1965 to 2004. Source: National Household Survey [2]. Top line: changes in the number of new artificial sweetener containing food products in- troduced to the American market from 1999 to 2004. Source: Mintel Market Analysis [14]. Bars below the time axis indicates the type and availability of artifi- cial sweeteners in the United States over time. Source: Kroger et al [9]. 300 times sweeter than sucrose but has a bit- ter aftertaste. Cyclamate, which was discov- ered in 1937 by Michael Sveda at the University of Illinois [8], was often blended with saccharin to improve the taste. Both compounds were deemed “generally recog- nized as safe” in the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetics Act. After the Food and Drug Ad- ministration (FDA†) banned cyclamate in 1969 because of its carcinogenic potentials, concern about saccharin’s safety also inten- sified. Eventually, the FDA announced its intention to ban saccharin in 1977. Avid con- sumer protests led to a moratorium from Congress on the final ban decision. A warn- ing label was nonetheless required on all saccharin products. Subsequent studies re- futed the link between cyclamate and cancer [9]. Bladder cancer associated with saccha- rin ingestion was also found to be specific to rodent physiology [9]. Cyclamate contin- ues to be marketed in about 50 countries, in- cluding Canada. The saccharin warning label was removed in 2000. Even though saccharin stayed on the U.S. market, regular artificial sweetener users were relatively few until the next gen- eration of compounds arrived (Figure 1, bot- tom line) [2]. Rigorous safety testing pre- ceded FDA approval for those new artificial sweeteners. In 1965, James Schlatter at Searle discovered aspartame [10]. He was trying to make new ulcer drugs. Aspartame consists of two amino acids, phenylalanine and aspartate, linked to a methanol backbone (Figure 2). Unlike the other artificial sweet- eners that are usually excreted unchanged, aspartame can be metabolized. Therefore, it is not strictly non-caloric (4 Kcal/g) and for- bidden in people with phenylketonuria [9]. Aspartame is about 200 times sweeter than sucrose. Due to the small amount ingested at a time, its caloric contribution is negligible. The FDA approved aspartame first for use in dry foods in 1981, then as a general sweet- ener in 1996. Monsanto bought Searle and converted it into NutraSweet in 1984. The patent on aspartame expired in 1992. Amid competition from generic manufacturers, NutraSweet engineered neotame, which was approved in 2002 [11]. Neotame is the most potent sweetener on the market, at 7,000 times the sweetness of sucrose. Acesulfame potassium resembles sac- charin and cyclamate in structure and taste