Since its discovery in 1965, and its first approval by the US Food and Drugs Administration (FDA) in 1981, the safety of APM, and in particular its carcinogenicity potential, has been controversial. The present commentary reviews the adequacy of the design and conduct of carcinogenicity bioassays on rodents submitted by G.D. Searle, in the 1970s, to the FDA for market approval. We also review how experimental and epidemiological data on the carcinogenic risks of APM, that became available in 2005 motivated the European Commission (EC) to call the European Food and Safety Authority (EFSA) for urgent re-examination of the available scientific documentation (including the Searle studies). The EC has further requested that, if the results of the evaluation should suggest carcinogenicity, major changes must be made to the current APM specific regulations.
Taken together, the studies performed by G.D. Searle in the 1970s and other chronic bioassays do not provide adequate scientific support for APM safety. In contrast, recent results of life-span carcinogenicity bioassays on rats and mice published in peer-reviewed journals, and a prospective epidemiological study, provide consistent evidence of APM's carcinogenic potential. On the basis of the evidence of the potential carcinogenic effects of APM herein reported, a re-evaluation of the current position of international regulatory agencies must be considered an urgent matter of public health.  PMID:  24436139

This study was designed to ascertain whether individuals with mood disorders are particularly vulnerable to adverse effects of aspartame. Although the protocol required the recruitment of 40 patients with unipolar depression and a similar number of individuals without a psychiatric history, the project was halted by the Institutional Review Board after a total of 13 individuals had completed the study because of the severity of reactions within the group of patients with a history of depression.
In a crossover design, subjects received aspartame 30 mg/kg/day or placebo for 7 days. Despite the small n, there was a significant difference between aspartame and placebo in number and severity of symptoms for patients with a history of depression, whereas for individuals without such a history there was not.
We conclude that individuals with mood disorders are particularly sensitive to this artificial sweetener and its use in this population should be discouraged.  [Biol Psychiatry. 1994]  PMID:  8373935

Administration of the artificial sweetener aspartame (L-aspartylphenylalanylmethyl ester; 200 mg/kg) by gavage to rats caused large increments in brain and plasma levels of phenylalanine and its product tyrosine. Glucose administration (3 g/kg, by gavage, a dose sufficient to cause insulin-mediated reductions in plasma levels of the large neutral amino acids leucine, isoleucine, and valine) also elevated brain phenylalanine and tyrosine, and enhanced the increments caused by the aspartame, nearly doubling the rise in brain phenylalanine.
Each animal's brain phenylalanine or tyrosine levels were highly correlated (r = 0.97 and 0.99, respectively) with its plasma phenylalanine or tyrosine ratios, affirming that aspartame's effects on the brain amino acids result from the changes it produces in plasma composition.
As described previously, glucose consumption increased brain tryptophan levels, and consequently, brain levels of the 5-hydroxyindoles serotonin and 5-hydroxyindoleacetic acid.
Aspartame alone had no effect on these compounds but completely blocked the changes in 5-hydroxyindoles caused by glucose. Each animal's brain level of tryptophan (r = 0.89) and 5-hydroxyindoles (r = 0.74) was also significantly correlated with its plasma tryptophan ratio, affirming that the effects of glucose or aspartame on these brain constituents also result from the changes they produce in plasma composition.
The aspartame-glucose combination also reduced brain levels of leucine, isoleucine, and valine to a significantly greater extent than aspartame or glucose alone.
These observations indicate that high aspartame doses can generate major neurochemical changes in rats, especially when consumed along with carbohydrate-containing foods. However, they should not in any way be interpreted as demonstrating that aspartame significantly affects the human brain.  PMID:  620452

Although undoubtedly well intentioned, any attempt to replace sugared beverages with aspartame containing diet products will, in my opinion, have a devastating impact on the health of our children and adolescents. The alarming increase in obesity, type II diabetes, and a wide variety of behavioral difficulties in our children is obviously attributable to multiple factors, but I am convinced that one powerful force in accentuating these problems is the ever increasing use of aspartame.

Aspartame is a multipotential toxin and carcinogen. The dipeptide component of the molecule can alter brain chemistry, significantly changing the ratio of catecholamines to indolamines, with resultant lowering of seizure threshold, production of carbohydrate craving and in vulnerable individuals leading to panic, depressive and cognitive symptoms.

The methyl ester component of aspartame is metabolized to methanol, which in turn is broken down into formic acid and formaldehyde. Methanol can lead to serious eye problems, formic acid and formaldehyde are potent carcinogens. The diet food industry and the F.D.A. are fond of saying that aspartame is "the most studied product in history" with an outstanding safety record. In fact, however, virtually all of the studies in the medical literature attesting to its safety were funded by the industry, whereas independently funded studies, now numbering close to 100, identify one or more problems. It would be especially tragic if an attempt to improve the health of our children led to even greater exposure to this highly toxic product. Thank you for your attention to this urgent public health issue.

European Journal of Clinical Nutrition (2012) 66, 972; doi:10.1038/ejcn.2012.47; published online 16 May 2012  GUT bacteria and aspartame: why are we surprised?  E Pretorius  Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

The artificial sweetener aspartame (APM; L-aspartyl-L-phenylanaline methyl ester) has been the subject of many debates since its initial approval for human consumption in 1974. However, these sweeteners are frequently used as part of a weight control regime, despite research indicating the negative effects on the body.

In a Science article late in 2011, Wu et al. discussed the fact that various dietary factors have an impact on gut bacteria, including the controversial dietary sweetener, APM.

Recently, in the October 2011 Science Perspective Section, Uri Gophna commented on this observation, stating that it is surprising that even minor concentrations of the artificial sweetener APM, can modify bacterial communities. The observations by Wu et al., however, should not be ‘surprising’, as APM has, over the past 20 years, frequently been under vigorous scientific discussion.

Currently, it is still approved by the FDA, as well as the EFSA; even though on consumption, each molecule of APM releases a molecule of methanol, which metabolizes into a molecule of formaldehyde. Formaldehyde (which is a highly reactive substance) is classified as a known human carcinogen, with no safe level of consumption. Therefore, it is not unexpected that very small amounts of the sweetener can modify bacterial communities, as these bacteria acts as the first line of intestinal defense and are therefore in direct contact with the sweetener and its metabolic compounds.

During obesity or periods of weight management regimes, where patients might use APM (as part of their management program), it is perhaps more crucial to have optimum bacterial community functioning in the intestines.

The observations of Wu et al., as well as a renewed interest in the APM debacle, spurred on by a new prepublication book released by Woodrow Monte, entitled ‘While Science Sleeps: A Sweetener that Kills’ might urge scientists and regulatory bodies to look at APM again.