Some Studies on Aspartame
Listed in reverse date order, linked to abstracts in MedLine:
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Cognitive and biochemical effects of monosodium glutamate and aspartame, administered individually and in combination in male albino mice, Abu-Taweel, Zyadah, Ajarem, Ahmad. Neurotoxicology and Teratology 42 (2014) 60–67
... Forty male Swiss albino micewere randomly
divided into four groups of ten each and were exposed to MSG (monosodium glutamate) and ASM (aspartame) through drinking water for one month.
Group I was the control and was given normal tap water. Groups II and III received MSG (8 mg/kg) and ASM
(32 mg/kg) respectively dissolved in tap water. Group IV received MSG and ASM together in the same doses.
After the exposure period, the animals were subjected to cognitive behavioral tests in a shuttle box and a
water maze. Thereafter, the animals were sacrificed and the neurotransmitters and oxidative stress indices
were estimated in their forebrain tissue. Both MSG and ASM individually as well as in combination had significant
disruptive effects on the cognitive responses, memory retention and learning capabilities of the mice in the order
(MSG+ASM) > ASM > MSG. Furthermore, while MSG and ASM individually were unable to alter the brain neurotransmitters
and the oxidative stress indices, their combination dose (MSG+ASM) decreased significantly the
levels of neurotransmitters (dopamine and serotonin) and it also caused oxidative stress by increasing the lipid
peroxides measured in the form of thiobarbituric acid-reactive substances (TBARS) and decreasing the level of
total glutathione (GSH). Further studies are required to evaluate the synergistic effects of MSG and ASM on the
neurotransmitters and oxidative stress indices and their involvement in cognitive dysfunctions
The carcinogenic effects of aspartame: The urgent need for regulatory re-evaluation., American Journal of Industrial Medicine. Soffritti M, et al., 2014 Apr;57(4):383-97
"Aspartame (APM) is an artificial sweetener used since the 1980s, now present in >6,000 products, including over 500 pharmaceuticals. 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.
Effect of Long Term Intake of Aspartame on Antioxidant Defense Status in Liver,
Abhilash M, Paul MV, Varghese MV, Nair RH.,
Food Chem Toxicol. 2011 Jun;49(6):1203-7.
The present study evaluates the effect of long term intake of aspartame, the artificial sweetener, on liver antioxidant system and hepatocellular injury in animal model. . . Rats that had received aspartame (1000 mg/kg b.wt.) in the drinking water for 180 days showed a significant increase in activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and y-glutamyl transferase (GGT). . . It can be concluded from these observations that long term consumption of aspartame leads to hepatocellular injury and alterations in liver antioxidant status mainly through glutathione dependent system.
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Sweet Debate: Do artificial sweeteners contribute to rather than combat obesity?
Lowen, Minnesota Medicine. 2011 Aug;94(8):20-3.
Results from several large-scale population
studies suggest that regular consumption of artificial
sweeteners such as aspartame and sucralose, particularly in
diet soda, may actually contribute to rather than combat
weight gain and type 2 diabetes."
EFSA: REPORT OF THE MEETINGS ON ASPARTAME WITH NATIONAL EXPERTS 2009 (full text)
Consequences of exposure to carcinogens beginning during developmental life.
Soffritti M, Belpoggi F, Esposti DD, Falcioni L, Bua L.
Basic & Clinical Pharmacology & Toxicology. 2008 Feb;102(2):118-24.
The increased incidence of cancer over the last 50-60 years may be largely attributed to two factors: the ageing of the population and the diffusion of agents and situations presenting carcinogenic risks. ... This paper reports a selection of studies conducted in the laboratories of the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation in which exposure to the chemical agents vinyl acetate monomer, ethyl alcohol and aspartame was started during developmental life and continued into adulthood. The results of these studies provide supporting evidence that lifespan exposure to carcinogenic agents beginning during developmental life produces an overall increase in the carcinogenic effects observed. Moreover, when comparing prenatal and postnatal exposure, the data demonstrate that the development of cancers may appear earlier in life.."
Carcinogenicity of aspartame in rats not proven., comment by Magnuson & Williams on Soffritti's 2007 study and Soffritti's answer.
Environmental Health Perspectives, 2008 Jun;116(6):A239-40; author reply A240.
... Data do not support the conclusions of Soffritti et al. (2007) that aspartame has carcinogenic potential at doses near the human level of exposure. The authors observed no significant effects at the low-diet level, and the actual dose is unknown. Also, no data were provided on in utero exposure. ..." [article at bottom of second page, and is followed by response from Soffritti]
Direct and indirect cellular effects of aspartame on
the brain Humphries P, Pretorius E, Naude H., European Journal of Clinical Nutrition, 62, p. 451-462.
... Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%).
Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an
excitatory neurotransmitter in the central nervous system. Glutamate, asparagines and glutamine are formed from their
precursor, aspartic acid. Methanol, which forms 10% of the broken down product, is converted in the body to formate, which
can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic
derivatives. Previously, it has been reported that consumption of aspartame could cause neurological and behavioural
disturbances in sensitive individuals. Headaches, insomnia and seizures are also some of the neurological effects that have been
encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include
norepinephrine, epinephrine and dopamine. The aim of this study was to discuss the direct and indirect cellular effects of
aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain
mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.
Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats.
Soffritti M, Belpoggi F, Tibaldi E, Esposti DD, Lauriola M.,
Environmental Health Perspectives, 2007 Sep;115(9):1293-7.
... The aim of this second study is to better quantify the carcinogenic risk of APM [Aspartame], beginning treatment during fetal life. ... CONCLUSIONS: The results ... confirm and reinforce the first experimental demonstration of APM's multipotential carcinogenicity at a dose level close to the acceptable daily intake for humans. Furthermore, the study demonstrates that when life-span exposure to APM begins during fetal life, its carcinogenic effects are increased."
First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats.
Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L, Tibaldi E, Rigano A.,
Environmental Health Perspectives, 2006 Mar;114(3):379-85.
"... APM [Aspartame] was administered with feed to 8-week-old Sprague-Dawley rats (100-150/sex/group), at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The treatment lasted until natural death, at which time all deceased animals underwent complete necropsy. ... The results of this mega-experiment indicate that APM is a multipotential carcinogenic agent, even at a daily dose of 20 mg/kg body weight, much less than the current acceptable daily intake. On the basis of these results, a reevaluation of the present guidelines on the use and consumption of APM is urgent and cannot be delayed."
Chronic aspartame affects T-maze performance, brain cholinergic receptors and Na+,K+-ATPase in rats.,
Christian B, McConnaughey K, Bethea E, Brantley S, Coffey A, Hammond L, Harrell S, Metcalf K, Muehlenbein D, Spruill W, Brinson L, McConnaughey M., Pharmacology, Biochemistry & Behavior. 2004 May;78(1):121-7.
This study demonstrated that chronic aspartame consumption in rats can lead to altered T-maze performance and increased muscarinic cholinergic receptor densities in certain brain regions. Control and treated rats were trained in a T-maze to a particular side and then periodically tested to see how well they retained the learned response. Rats that had received aspartame (250 mg/kg/day) in the drinking water for 3 or 4 months showed a significant increase in time to reach the reward in the T-maze, suggesting a possible effect on memory due to the artificial sweetener. . . . In aspartame-treated rats, there was a significant increase in muscarinic receptor densities in the frontal cortex, midcortex, posterior cortex, hippocampus, hypothalamus and cerebellum of 80%, 60%, 61%, 65%, 66% and 60%, respectively. . .It can be concluded from these data that long-term consumption of aspartame can affect T-maze performance in rats and alter receptor densities or enzymes in brain.
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Comments on the purported generation of formaldehyde and adduct formation from the sweetener aspartame. ,
Life Sci 1999;65(13):PL157-60
"A recent paper by Trocho et al. (1) describes experiments meant to show that formaldehyde adducts are formed when rats are
administered the sweetener aspartame. ... In this letter, studies which have been published
previously and which were not cited by these authors are reviewed in order to put into perspective the disposition of methanol and
formaldehyde in monkeys and humans, species relevant to the toxicity of methanol and its toxic metabolite, formic acid."
Formaldehyde derived from dietary aspartame binds to tissue components in vivo. ,
Trocho C, et al.,
Life Sci 1998;63(5):337-49
"Adult male rats were given an oral dose of 10 mg/kg aspartame 14C-labelled in the methanol carbon. At timed intervals of up to 6
hours, the radioactivity in plasma and several organs was investigated. ... The specific radioactivity of tissue protein, RNA and DNA was quite uniform. The protein label was concentrated in amino acids,
different from methionine, and largely coincident with the result of protein exposure to labelled formaldehyde. ... It
is concluded that aspartame consumption may constitute a hazard because of its contribution to the formation of formaldehyde adducts."
Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects.,
Spiers PA, et al., American J of Clinical Nutrition, 1998 Sep;68(3):531-7.
This study sought to determine whether aspartame can disrupt cognitive, neurophysiologic, or behavioral functioning in normal individuals.
Forty-eight healthy volunteers completed a randomized, double-blind, placebo-controlled, crossover study. ...
Plasma phenylalanine concentrations increased significantly during aspartame treatment....
Large daily doses of aspartame had no effect on neuropsychologic, neurophysiologic, or behavioral functioning in healthy young adults."
Supported by a grant from the NutraSweet Corporation
Phenylalanine concentrations increased significantly.
The volunteers were healthy adults. This cannot be generalized to diabetic adults, adults whose PKU scores were borderline, adults with any chronic illness, or children.
Erythema nodosum: 112 cases. Epidemiology, clinical
aspects and histopathology, Bohn S, Buchner S, Itin P, Schweiz Med Wochenschr 1997 Jul 8;127(27-28):1168-76
"... The commonest cause of
erythema nodosum [multiple, tender nodules most often occurring on the shins] was infection. Other etiologic factors were adverse drug reactions . . . and aspartame..."
Increasing brain tumor rates: is there a link to aspartame?
, Olney JW, Farber NB, Spitznagel E, Robins LN. J Neuropathol Exp Neurol 1996 Nov;55(11):1115-23
... we analyzed these data from 1975 to 1992 and found that the brain tumor increases in the United States occurred in two distinct phases, an early modest increase that may primarily reflect improved diagnostic technology, and a more recent sustained increase in the incidence and shift toward greater malignancy that must be explained by some other factor(s). ... Evidence potentially implicating aspartame includes an early animal study revealing an exceedingly high incidence of brain tumors in aspartame-fed rats compared to no brain tumors in concurrent controls, the recent finding that the aspartame molecule has mutagenic potential, and the close temporal association (aspartame was introduced into US food and beverage markets several years prior to the sharp increase in brain tumor incidence and malignancy). We conclude that there is need for reassessing the carcinogenic potential of aspartame.
Aspartame ingestion and headaches: a randomized crossover
trial. Van den Eeden SK, Koepsell TD, Longstreth WT Jr, van Belle G, Daling JR, McKnight B, Neurology 1994 Oct;44(10):1787-93
"...It appears that some people are
particularly susceptible to headaches caused by aspartame and may want to limit their consumption."
Neuropharmacological evaluation of movement disorders that
are adverse reactions to specific foods. Gerrard JW, Richardson JS, Donat J, Int J Neurosci 1994 May;76(1-2):61-9
Three cases are reported of patients who had episodic movement disorders triggered by foods or components of the diet. [aspartame was one] ... These observations suggest that, in susceptible individuals, foods can trigger movement disorders through an action on dopamine and other neurotransmitter pathways in the brain."
Adverse reactions to aspartame: double-blind challenge in
patients from a vulnerable population. Walton RG, Hudak R, Green-Waite RJ, Biological Psychiatry 1993 Jul 1-15;34(1-2):13-7
"...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."
Aspartame exacerbates EEG spike-wave discharge in
children with generalized absence epilepsy: a double-blind
controlled study., Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S, Weaver DF. Neurology 1992 May;42(5):1000-3
" Following aspartame compared with sucrose, the number of spike-wave discharges per hour and mean length of spike-wave discharges increased but not to a statistically significant degree. However, the total duration of spike-wave discharge per hour was significantly increased after
aspartame (p = 0.028), with a 40% +/- 17% (SEM) increase in the number of seconds per hour of EEG recording that the children spent in spike-wave discharge. Aspartame appears to exacerbate the amount of EEG spike wave in children with absence seizures..."
Oral administration of aspartame is not proconvulsant in rats.
Tilson HA, Thai L, Zhao D, Sobotka TJ, Hong JS.
Neurotoxicology 1989 Summer;10(2):229-38
These experiments examined the potential for single or repeated doses of aspartame to exacerbate or facilitate the production of seizures in Fischer-344 rats. ... In a second series of studies, young male and female rats were dosed with 1,000 mg/kg of aspartame on day 3-13 or 21-35 of age. Prior exposure to aspartame had no significant effect on the rate of kindling at 90 days of age. These experiments indicate that aspartame does not act a pro-convulsant in rats.
Effect of aspartame on seizures in various models of experimental epilepsy.
Guiso G, Caccia S, Vezzani A, Stasi MA, Salmona M, Romano M, Garattini S.
Toxicol Appl Pharmacol 1988 Dec;96(3):485-93
... Aspartame (0.75-1.0 g/kg), given orally as a single bolus to 16-hr fasted animals 60 min before metrazol, significantly increased the number of animals showing clonic-tonic seizures. ... A similar increase in seizure susceptibility was observed with 0.25-0.5 g/kg of the aspartame's metabolite phenylalanine.... Plasma and brain levels of phenylalanine and tyrosine significantly raised after both 1 g/kg aspartame as a single bolus ... or in three divided doses ...
Administration of aspartame potentiates pentylenetetrazole- and fluorothyl-induced seizures in mice.
Pinto JM, Maher TJ.
Neuropharmacology 1988 Jan;27(1):51-5
... Doses of aspartame were used which increased phenylalanine more than tyrosine in brain, as occurs in humans after the consumption of any dose of aspartame. Pretreatment with aspartame significantly increased the percentage of animals convulsing after administration of pentylenetetrazole and significantly lowered the CD50 for this convulsant. ... The seizure-promoting effect of aspartame could be demonstrated 30, 60 or 120 min after the 1000 mg/kg dose. The seizures induced by either convulsant were potentiated by equimolar amounts of phenylalanine, a major endogenous metabolite of aspartame, while the other metabolites, aspartic acid and methanol, were without effect. ..."
Possible neurologic effects of aspartame, a widely used food
additive, Maher TJ, Wurtman RJ, Environmental Health Perspectives 1987 Nov;75:53-7
"... Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine . . . the frequency of seizures . . . is enhanced. ... Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research."