guy mixing shakeby: Jay McCombs

“Tonight at 10 on the local news, find out which ingredient in your diet Coke is going to give you cancer!” I don’t even have to watch. I know they are talking about aspartame and that the horse has long since been dead, yet still they continue to beat it. So what is the truth? Saccharine-containing products contain warning labels about causing cancer in animals, but saccharine is now absent from many lists of carcinogens—why? Aspartame has been reported to cause brain tumors and nearly every other disease known to man, yet it’s still an ingredient in nearly every “diet” food—why? What about the new guys like sucralose (Splenda)? Are they going to kill us? Well, I think the best place to start with every story is at the beginning.

Artificial sweeteners have been around since 1879, and for 90 years things were really, um, sweet. Then 1970 rolled around, and in the world of artificial sweeteners, the sky began to fall. Chicken Little reported the events and chaos ensued. To make a long story short, several countries (including the US) banned the use of cyclamate due to an article in Science that demonstrated rats fed the sweetener showed an increased risk of developing bladder cancer [1]. But wait, there’s more! After the review of a long-term study on primates that showed cyclamate conveyed no risk of cancer, although there was much debate about the validity of the experiment due to small sample size, many countries, under the advice of the WHO, repealed their bans (actually every country other than the US) [2]. Cyclamate was the first on the chopping block, but many others would follow.

Perhaps one of the best known, and most falsely maligned, sweeteners is saccharine. There is copious research on this compound and to cover it all in this text would be impractical. Instead I am going to try and hit the high points and focus on the widely publicized bladder cancer controversy.

Saccharine seemed safe in rat studies at first; however, when the progeny of rats fed cyclamate was also fed saccharine, several studies showed that the saccharine-fed rats had an increased risk of cancer (there are many studies on this topic, only the largest has been sited) [3]. As it turns out, the problem wasn’t so much with the saccharine as it was with the rats. Rats have higher osmolar urine, thus allowing for the formation of damaging crystals in the bladder [4]. Humans do not concentrate their urine as much and consequently do not have the same problem. There are, unfortunately, no direct studies on humans consuming saccharine and, therefore, I feel it is not worth mentioning the few descriptive studies that found saccharine benign.

Aspartame is another widely consumed first generation artificial sweetener. You can find it in everything from diet Coke to protein powders. There are lots of things people bring up about aspartame and the majority of them are not based on science. They are based on ideas that make some non-scientific assumptions. The best example is the brain tumor scare.

The trouble began on account of rats (again)—specifically, rats eating aspartame and subsequently developing brain tumors [5]. In addition, a study showed that nitrosated aspartame had mutagenic properties and it was possible that aspartame could be nitrosated in the gut (although there is no research to verify if this actually happens) [6]. Combine this with the rising rate of brain tumors since 1981 (the year aspartame was introduced) and you’ve got yourself a brain tumor scare [7]. Fact-twisting leaches, er, excuse me, the media, began to warn against the dangers of aspartame. Shortly thereafter my mom started calling me telling me how terrible aspartame was and Mercola recorded a gagillion hits to his website.

You want the truth? First the rats. Subsequent studies could not recreate and confirm the findings of the previous authors [8]. In the world of science, that means the study can’t be used to definitely pin the blame on aspartame and could involve some other unknown source of error. Next, the ensuing backlash from the scientific community. Basically, an editorial written by Ross stated (please allow me to paraphrase) that the argument was completely asinine due to the tremendous amount of other common things that were introduced in and around 1981 that could also be said to contribute to brain tumors using the same logic: VCR’s, computers, etc. [9]. And if editorial beat downs weren’t sufficient, the completion of a controlled study evaluating the potential link between brain tumors and aspartame in children pretty much put this one to bed [10]. They found no link to brain tumors secondary to aspartame consumption by children or by their mothers during gestation or breast feeding.

If you feel like you’ve read enough about aspartame skip ahead because I am tired of this beast rearing its ugly head. A website that spawns “the world’s most popular natural health newsletter” warns of the dangers of aspartame based on some pretty deceptive information (it would not be a stretch to say lies). First, the article creates the guise of being scientific using lots of esoteric words, scary medical conditions, and tactics such as putting numbers in parenthesis after particularly dramatic statements but failing to include a bibliography on the page. It makes it very, very difficult to verify the veracity of a work when the author doesn’t provide the sources he has used (some might even call this plagiarism); fortunately, I was up to the task. Bellow I’m going to try and deal with many of the common anti-aspartame arguments that I see on the internet.

1) Most sites point out a shocking revelation that 75% of the adverse reactions to food additives reported to the FDA were due to aspartame. We aren’t talking about death certificates after autopsy. We are talking about complaints to the FDA that anyone can make at anytime based on their own personal thoughts and experiences with no burden to prove them scientifically. In fact, a study that inspected people that claimed to have an allergy to aspartame found aspartame was no more likely than placebo to cause allergic reactions in said individuals [27].

I feel it important to mention something called the nocebo effect. Basically, when someone has negative expectations of a harmless substance they find themselves suffering from the negative symptoms they expected to experience, despite the innocuous nature of said substance. With the public media falsely reporting on the many dangers and side effects of aspartame, it is no wonder so many people feel they are suffering from its ill effects.

2) Aspartate and phenylalanine, amino acids, are two of the 3 components that aspartame is made from and completely broken down when ingested. The web critics try to paint this as something terrible, mentioning a disease called phenylketonuria (PKU) that causes permanent mental retardation. They also mention the damaging effects of glutamate and tell you that aspartame will raise blood levels to dangerous levels. One article points to some editorial letters written by Olney in 1975 [11, 12]. A strong part of said article’s argument seems to neglect current evidence that shows aspartame consumption has no dangerous effect on blood levels of aminos when taken alone or with meals, with MSG, after chronic consumption, and after abuse doses, even when looking at children and those heterozygous for the PKU gene defect or diabetics or people in liver failure [13-24].

Furthermore, research shows that aspartame consumption doesn’t negatively affect brain receptor chemistry [25, 26] nor does it cause seizures—even in individuals who anecdotally relate that aspartame is a trigger for their seizures [28, 29]. To go one step further it has been shown that cognitive function after chronic and acute use of aspartame remains unaffected, even in people heterozygous for the PKU defect. [30-32].

3) There is also the lesser constituent of aspartame, methanol, or “wood poison” as one anti-aspartame author refers to it. Methanol poisoning is very serious; however, becoming poisoned by methanol from aspartame would be quite challenging since aspartame doesn’t appreciably raise blood levels of methanol [20]. Not to mention many foods, like tomato juice, contain far more methanol than aspartame; however, some critics counter this with the argument that these foods also contain an “antidote,” ethanol. This is laughable and demonstrates a poor understanding of how ethanol acts as an antidote. Methanol itself isn’t toxic. It must be converted to a toxic substance, formestate, by alcohol dehydrogenase—an enzyme that also acts on ethanol. The way ethanol works as an antidote is by overwhelming the enzyme system with an alternative substrate. The medical dose of ethanol is 7.5 ml/kg. So unless you are drinking your glass of tomato juice with a fifth of vodka (Bloody Mary anyone?) you aren’t getting the antidote effects of ethanol.

Finally we come to the new kids on the block. Unfortunately there is a paucity of information on sweeteners such as sucralose (Splenda), acesulfame-K, and neotame. There are several animal studies, but few directly examining their effects on humans beyond those tests needed to receive the generally-accepted-as-safe (GRAS) stamp from the FDA. These tests are quite rigorous and leave little question as to the safety of the new sweetener. However, if you still feel apprehensive and would like to review the data yourself it is all on file with the FDA.

Artificial sweeteners have received criticism far beyond what they deserve. They offer safe ways for diabetics to sweeten foods and for the general public to reduce calorie consumption. A can of Coke contains about 36g of obesity-epidemic-driving, insulin-resistance-promoting, non-Adkins-approved sugar. A diet Coke, on the other hand, sweetened with aspartame contains no sugar and zero calories. Perhaps the critics of sweeteners could do more good for the public if they focused their zeal and energy on some of the more important scourges of society rather than getting worked up about fringe outliers in esoteric epidemiology studies.


1. Wagner, MW. Cyclamate acceptance. Science. 1970 Jun 26;168(939):1605 (PMID: 5420548)

2. Takayama S, Renwick AG, Johansson SL, Thorgeirsson UP, Tsutsumi M, Dalgard DW, Sieber SM. Long-term toxicity and carcinogenicity study of cyclamate in nonhuman primates. Toxicol Sci. 2000 Jan;53(1):33-9. (PMID: 10653518)

3. Squire RA. Histopathological evaluation of rat urinary bladders from the IRDC two-generation bioassay of sodium saccharin. Food Chem Toxicol 1985; 23: 491–497. (PMID: 4040097)

4. Cohen SM, Anderson TA, de Oliveira LM, Arnold LL. Tumorigenicity of sodium ascorbate in male rats. Cancer Res 1998; 58: 2557–2561. (PMID: 9635578)

5. Study E33-34 in Master file 134 on aspartame. On file at the FDA Hearing Clerk’s Office 2001

6. Shephard SE, Wakabayashi K, Nagao M. Mutagenic activity of peptides and the artificial sweetener aspartame after nitrosation. Food Chem Toxicol 1993; 31: 323–329.

7. Olney JW, Farber NB, Spitznagel E, Robins LN. Increasing brain tumor rates: is there a link to aspartame? J Neuropathol Exp Neurol 1996; 55: 1115–1123.

8. Anonymous. Aspartame. Review of safety issues. Council on Scientific Affairs. JAMA 1985; 254: 400–402.

9. Ross JA. Brain tumors and artificial sweeteners? A lesson on not getting soured on epidemiology. Med Pediatr Oncol 1998; 30: 7–8.

10. Gurney JG, Pogoda JM, Holly EA. Aspartame consumption in relation to childhood brain tumor risk: results from a case-control study [published erratum appears in J Natl Cancer Inst 1997; 89: 1460]. Natl Cancer Inst 1997; 89: 1072–1074.

11. Olney JW. Letter: 1-Glutamic and L-aspartic acids–a question of hazard? Food Cosmet Toxicol. 1975 Oct;13(5):595-6. PMID: 811518

12. Olney JW. Letter: Aspartame as a sweetener. N Engl J Med. 1975 Jun 5;292(23):1244-5. PMID: 1128585

13. Silva LC, Pires RF, Coelho JC, Jardim LB, Giugliani R. Evaluation of an aspartame loading test for the detection of heterozygotes for classical phenylketonuria. Clin Genet. 1997 Apr;51(4):231-5. PMID: 9184243

14. Stegink LD, Lindgren SD, Brummel MC, Stumbo PJ, Wolraich ML. Erythrocyte L-aspartyl-L-phenylalanine hydrolase activity and plasma phenylalanine and aspartate concentrations in children consuming diets high in aspartame. Am J Clin Nutr. 1995 Dec;62(6):1206-11.

15. Curtius HC, Endres W, Blau N. Effect of high-protein meal plus aspartame ingestion on plasma phenylalanine concentrations in obligate heterozygotes for phenylketonuria. Metabolism. 1994 Apr;43(4):413-6.

16. Hertelendy ZI, Mendenhall CL, Rouster SD, Marshall L, Weesner R. Biochemical and clinical effects of aspartame in patients with chronic, stable alcoholic liver disease. Am J Gastroenterol. 1993 May;88(5):737-43.

17. Gupta V, Cochran C, Parker TF, Long DL, Ashby J, Gorman MA, Liepa GU. Effect of aspartame on plasma amino acid profiles of diabetic patients with chronic renal failure. Am J Clin Nutr. 1989 Jun;49(6):1302-6.

18. Torii K, Mimura T, Takasaki Y, Ichimura M. Dietary aspartame with protein on plasma and brain amino acids, brain monoamines and behavior in rats. Physiol Behav. 1986;36(4):765-71.

19. Stern SB, Bleicher SJ, Flores A, Gombos G, Recitas D, Shu J. Administration of aspartame in non-insulin-dependent diabetics. J Toxicol Environ Health. 1976 Nov;2(2):429-39.

20. Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE, Tephly TR. Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. Metabolism. 1989 Apr;38(4):357-63.

21. Stegink LD, Wolf-Novak LC, Filer LJ Jr, Bell EF, Ziegler EE, Krause WL, Brummel MC. Aspartame-sweetened beverage: effect on plasma amino acid concentrations in normal adults and adults heterozygous for phenylketonuria. J Nutr. 1987 Nov;117(11):1989-95. PMID: 2890728.

22. Stegink LD, Filer LJ Jr, Baker GL. Plasma and erythrocyte concentrations of free amino acids in adult humans administered abuse doses of aspartame. J Toxicol Environ Health. 1981 Feb;7(2):291-305.

23. Stegink LD, Filer LJ Jr, Baker GL. Plasma amino acid concentrations in normal adults fed meals with added monosodium L-glutamate and aspartame. J Nutr. 1983 Sep;113(9):1851-60.

24. Stegink LD, Filer LJ Jr, Baker GL. Effect of aspartame and sucrose loading in glutamate-susceptible subjects. Am J Clin Nutr. 1981 Sep;34(9):1899-905. PMID: 7282615

25. Fernstrom JD. Dietary amino acids and brain function. J Am Diet Assoc. 1994 Jan;94(1):71-7. PMID: 7903674.

26. Reilly MA, Lajtha A. Glutamatergic receptor kinetics are not altered by perinatal exposure to aspartame. Neurochem Int. 1995 Mar;26(3):217-22.

27. Geha R, Buckley CE, Greenberger P, Patterson R, Polmar S, Saxon A, Rohr A, Yang W, Drouin M. Aspartame is no more likely than placebo to cause urticaria/angioedema: results of a multicenter, randomized, double-blind, placebo-controlled, crossover study. J Allergy Clin Immunol. 1993 Oct;92(4):513-20. PMID: 8409113

28. Rowan AJ, Shaywitz BA, Tuchman L, French JA, Luciano D, Sullivan CM. Aspartame and seizure susceptibility: results of a clinical study in reportedly sensitive individuals. Epilepsia. 1995 Mar;36(3):270-5. PMID: 761491

29. Dailey JW, Lasley SM, Burger RL, Bettendorf AF, Mishra PK, Jobe PC. Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame. Epilepsy Res. 1991 Mar;8(2):122-33. PMID: 1648476

30. Spiers PA, Sabounjian L, Reiner A, Myers DK, Wurtman J, Schomer DL. Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects. Am J Clin Nutr. 1998 Sep;68(3):531-7. PMID: 9734727

31. Trefz F, de Sonneville L, Matthis P, Benninger C, Lanz-Englert B, Bickel H. Neuropsychological and biochemical investigations in heterozygotes for phenylketonuria during ingestion of high dose aspartame (a sweetener containing phenylalanine). Hum Genet. 1994 Apr;93(4):369-74.

32. Stokes AF, Belger A, Banich MT, Bernadine E. Effects of alcohol and chronic aspartame ingestion upon performance in aviation relevant cognitive tasks. Aviat Space Environ Med. 1994 Jan;65(1):7-15. PMID: 8117231

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