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COMMENTARY

Artificially Sweetened BeveragesCause for ConcernDavid S. Ludwig, MD, PhD

THE TASTE RECEPTOR FOR SWEETNESS, T1R2/R1R3,1

can detect sugar at a concentration as low asabout 1 part in 200, whereas some bitter sub-stances can be detected in the range of a few

parts per million, perhaps explaining why most individu-als prefer foods with high sugar content but little bitter-ness. However, this innate preference for sweetness does

not necessarily lead to obesity or other diet-related dis-eases because sugar-containing foods in their naturalform tend to be highly nutritious. For instance, an 8-ozapple contains beneficial vitamins, minerals, and phyto-chemicals but fewer calories than a 2-oz portion of bread.Most fruits elicit a high level of satiety relative to caloriesingested due to their low-energy density, high-fiber con-tent, and low glycemic index.2

Problems occur when sugarschiefly sucrose and thechemically similar product, high-fructose corn syruparerefined, concentrated, and consumed in large amounts.Without the protection confer red by an intact, natur alfood containing fiber and antioxidants, these refined

sugars increase blood glucose and insulin levels rapidlyafter consumption, increasing concentrations of triglycer-ides, inflammatory mediators, and reactive oxygenradicals.2 In contrast to whole fruit, intake of refined car-bohydrate increases risk for diabetes, cardiovascular dis-ease, and other chronic illness.3 Sugar-sweetened bever-ages may have an especially adverse effect on body weightbecause of the exceptionally low-satiety value of sugars inliquid form.

One proposed solution to the problems caused by over-consumption of these fattening, empty calories is artificialsweeteners. Presently, 5 such products have US Food andDrug Administration (FDA) approval: saccharin, acesul-

fame, aspartame, neotame, and sucralose. (Stevia, a naturalextract from the plant Stevia rebaudiana, received FDAapproval in 2008.) These synthetic substances are hun-dreds to thousands of times more potent than sucrose andelicit an intense sensation of sweetness in trace concentra-tions.

As suggested by the term diet with which these productsare marketed, foods and beverages with artificial sweeten-ers are intended to produce a sweet taste comparable with

their sugar-containing counterparts but with fewer calo-ries, thereby promoting weight loss when substituted forcalorie-containing products. Short-term clinical trials pro-vide some evidence for this effect. For example, obeseadults who consumed an average of 600 kcal/d of sucrose,mostly in the form of beverages, for 10 weeks showedincreased body weight, blood pressure, and inflammatorymarkers compared with a control group given artificialsweeteners.4,5

However, body weight is regulated by complex and re-

dundant biological and behavioral pathways. Calories dis-placed by artificial sweeteners may be replaced over timefrom other sources;the nature andcompleteness of this com-pensation would therefore determine the ultimate effects onbody weight and other health outcomes. In addition, over-stimulation of sugar receptors by frequent consumption ofhyper-intense sweeteners may cause taste preferences to re-main in, or revert to, an infantile state (ie, with limited tol-erance for more complex tastes). Individuals who habitu-ally consume artificial sweeteners may find more satiatingbut less intensely sweet foods (eg, fruit) less appealing andunsweet foods (eg, vegetables, legumes) less palatable, re-ducing overall diet quality in ways that might contribute to

excessive weight gain.Diet drinks may comprise a special and particularly con-

cerning case. Diet drinks have essentially no calories,unlike most artificially sweetened solid foods that typicallycontain other nutrients. Moreover, diet drinks are oftenconsumed in the absence of other foods, producing a dis-sociation between sweet taste and calorie intake. One con-cern is that the dissociation of these physiological eventsmight disrupt the hormonal and neurobehavioral path-ways regulating hunger and satiety. In support of this pos-sibility, Swithers and Davidson6 reported that rodents fedsaccharin compared with those fed glucose showed dimin-ished calorie compensation ability, increased calorie

intake, and increased body weight. In a study of pharma-cological reward, Lenoir et al7 gave rodents the mutuallyexclusive choice of intravenous cocaine or an oral saccha-rin solution. They found that most animals, including

Author Affiliations: Optimal Weight for Life Program, Department of Medicine,Childrens Hospital, Boston, Massachusetts.Corresponding Author: David S. Ludwig, MD, PhD,Department of Medicine, Chil-drens Hospital Boston, 300 Longwood Ave, Boston, MA 02115 (david.ludwig@childrens.harvard.edu).

2009 American Medical Association. All rights reserved. (Reprinted) JAMA, December 9, 2009Vol 302, No. 22 2477

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those with prior cocaine exposure, selected the lever thatdispensed saccharin over the lever that dispensed cocaineand suggested that [t]he absolute preference for tastesweetness may lead to a re-ordering in the hierarchy ofpotentially addictive stimuli, with sweetened diets . . . tak-ing precedence over cocaine and possibly other drugs of

abuse.No long-term studies of diet drink consumption andbody weight have been conducted in humans. Amongobservational studies, the San Antonio Heart Study founda dose-response relationship between diet drinks andmeasures of adiposity over a 7-year period among 5158adults.8 Consuming more than 21 servings of diet drinksper week vs none was associated with a 2-fold increasedrisk of developing overweight or obesity. In the Multi-Ethnic Study of Atherosclerosis,9 daily consumption of dietdrinks was associated with a 36% increased risk for meta-bolic syndrome and a 67% greater risk for type 2 diabetesamong 6814 adults. These studies must be interpreted cau-tiously because excessive weight gain may prompt some

individuals to increase diet drink consumption, producingreverse causation.

Artificial sweeteners have been used for a century andhavereceived considerable scientific scrutiny. Recurring ques-tions about cancer risk, as they relate to the 5 products withcurrent FDA approval, have been largely dismissed. How-ever, increasing concern about the health effects of refinedsugar has driven a marked increase in the consumption ofartificial sweeteners, especially in liquid form. Per capita dietdrink intake has increased from less than 1 oz per day inthe 1960s to about 4 oz per day this decade.10 Among regu-lar consumers of diet drinks, intake now totals more thanthree 8-oz servings per day.10 If trends in consumption con-

tinue, the nation will, in effect, have embarked on a mas-sive, uncontrolled, and inadvertent public health experi-ment. Although many synthetic chemicals have been addedto the food supply in recent years, artificial sweeteners inbeverages stand out in their ability to interact with evolu-

tionarily ancient sensorineural pathways at remarkably highaffinity.

Ultimately, high-quality, long-term clinical trials com-paring all 3 beverage types are needed: sugar sweetened,artificially sweetened, and unsweetened. Even if dietdrinks produce long-term weight loss when substituted

for sugar-sweetened beverages, they might cause weightgain when consumed instead of unsweetened drinks. Fornow, diet drinks may best be considered an aid in transi-tioning from high-calorie beverages to traditional, mini-mally sweetened beverages like water, mineral waters,teas, and coffee with no more than 1 g of sugar per oz (ie,2 teaspoons per 8-oz cup).

Financial Disclosures: Dr Ludwig reported receiving royalties from a book aboutchildhood obesity, andgrantsfrom foundations andthe National Institutes of Healthfor obesity-related research, mentoring, and patient care.Funding/Support: Dr Ludwig is supported in part by a career award grant fromthe NationalInstituteof Diabetes andDigestiveand Kidney Diseases (K24DK082730).

REFERENCES

1. Li X, Staszewski L, Xu H, DurickK, ZollerM, Adler E. Humanreceptors forsweetand umami taste. Proc Natl Acad Sci U S A. 2002;99(7):4692-4696.2. Ludwig DS. The glycemic index: physiological mechanisms relating to obesity,diabetes, and cardiovascular disease. JAMA. 2002;287(18):2414-2423.3. Mann J. Dietary carbohydrate: relationship to cardiovascular disease and dis-orders of carbohydrate metabolism. Eur J Clin Nutr. 2007;61(suppl 1):S100-S111.4. Raben A, Vasilaras TH, Moller AC, Astrup A. Sucrose compared with artificialsweeteners: different effects on ad libitum food intake and body weight after 10wk of supplementation in overweight subjects. Am J Clin Nutr. 2002;76(4):721-729.5. Srensen LB, Raben A, Stender S, Astrup A. Effect of sucrose on inflammatorymarkers in overweight humans. Am J Clin Nutr. 2005;82(2):421-427.6. Swithers SE, Davidson TL. A role for sweet taste: calorie predictive relations inenergy regulation by rats. Behav Neurosci. 2008;122(1):161-173.7. Lenoir M, Serre F, Cantin L, Ahmed SH. Intense sweetness surpasses cocainereward. PLoS One. 2007;2(1):e698.8. Fowler SP, Williams K, Resendez RG, Hunt KJ, Hazuda HP, Stern MP. Fuelingthe obesity epidemic? artificially sweetened beverage use and long-term weight

gain. Obesity (Silver Spring). 2008;16(8):1894-1900.9. Nettleton JA, Lutsey PL, Wang Y, Lima JA, Michos ED, Jacobs DR Jr. Diet sodaintake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2009;32(4):688-694.10. Mattes RD, Popkin BM. Nonnutritive sweetener consumption in humans: ef-fects on appetite and food intake and their putative mechanisms. Am J Clin Nutr.2009;89(1):1-14.

COMMENTARY

2478 JAMA, December 9, 2009Vol 302, No. 22 (Reprinted) 2009 American Medical Association. All rights reserved.