Aspartame has been linked to an increased risk of developing anxiety behaviors

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Florida State University College of Medicine researchers have linked aspartame, an artificial sweetener found in nearly 5,000 diet foods and drinks, to anxiety-like behavior in mice.

Along with producing anxiety in the mice who consumed aspartame, the effects extended up to two generations from the males exposed to the sweetener.

The study is published in the Proceedings of the National Academy of Sciences.

“What this study is showing is we need to look back at the environmental factors, because what we see today is not only what’s happening today, but what happened two generations ago and maybe even longer,” said co-author Pradeep Bhide, the Jim and Betty Ann Rodgers Eminent Scholar Chair of Developmental Neuroscience in the Department of Biomedical Sciences.

The study came about, in part, because of previous research from the Bhide Lab on the transgenerational effects of nicotine on mice. The research showed temporary—or epigenetic—changes in mice sperm cells. Unlike genetic changes (mutations), epigenetic changes are reversible and don’t change the DNA sequence; however, they can change how the body reads a DNA sequence.

“We were working on the effects of nicotine on the same type of model,” Bhide said. “The father smokes. What happened to the children?”

The U.S. Food and Drug Administration (FDA) approved aspartame as a sweetener in 1981. Today, nearly 5,000 metric tons are produced each year. When consumed, aspartame becomes aspartic acid, phenylalanine and methanol, all of which can have potent effects on the central nervous system.

Led by doctoral candidate Sara Jones, the study involved providing mice with drinking water containing aspartame at approximately 15% of the FDA-approved maximum daily human intake. The dosage, equivalent to six to eight 8-ounce cans of diet soda a day for humans, continued for 12 weeks in a study spanning four years.

Pronounced anxiety-like behavior was observed in the mice through a variety of maze tests across multiple generations descending from the aspartame-exposed males.

“It was such a robust anxiety-like trait that I don’t think any of us were anticipating we would see,” Jones said. “It was completely unexpected. Usually you see subtle changes.”

When given diazepam, a drug used to treat anxiety disorder in humans, mice in all generations ceased to show anxiety-like behavior.

Researchers are planning an additional publication from this study focused on how aspartame affected memory. Future research will identify the molecular mechanisms that influence the transmission of aspartame’s effect across generations.

Other co-authors were Department of Biomedical Sciences faculty members Deirdre McCarthy, Cynthia Vied and Gregg Stanwood, and FSU Department of Psychology Professor Chris Schatschneider.


Aspartame is an artificial sweetener found in over 6,000 food items, and millions of American adults and children consume aspartame each day (Butchko & Stargel, 2001; Thomas, 2005; Whitehouse, Boullata, & McCauley, 2008). Aspartame was first approved by the US Food and Drug Administration (FDA) for limited use in solid food in 1981; it was approved as a general sweetener in 1996 (US Food and Drug Administration (FDA), 2006).

The World Health Organization (2004) and food regulatory authorities in Canada (Mortelmans, Van Loo, De Cauwer, & Merlevede, 2008) and Europe (Lean & Hankey, 2004) consider excessive intakes of aspartame as dosages above the acceptable daily intake (ADI) of 40 mg/kg body weight/day. The US FDA has set the ADI of aspartame at 50 mg/kg body weight/day (US FDA) and upholds the safety of aspartame consumption except for individuals with phenylketonuria, who should avoid using aspartame because phenylalanine is a metabolite.

Despite its widespread use, aspartame remains one of the most controversial food additives (Magnuson, 2010). Although some researchers have proposed that aspartame metabolites are responsible for adverse effects, such as headache, compromised memory, mood changes, and depression, others have not identified adverse effects of aspartame consumption. The purpose of this study, therefore, was to examine the neurobehavioral effects of consuming diets with higher (25 mg/kg body weight/day) and lower (10 mg/kg body weight/day) amounts of aspartame.

Pathophysiology of Aspartame Intake

Once ingested, aspartame is metabolized to yield aspartic acid, phenylalanine, and methanol (Humphries, Pretorius, & Naudé, 2008). Phenylalanine is involved in neurotransmitter regulation, and aspartic acid is an excitatory neurotransmitter (Caballero & Wurtman, 1988). Altered neurotransmitter regulation can result in neurobehavioral disturbances.

Some researchers have reported substantial increases in phenylalanine and aspartic acid, and subsequently reduced dopamine and serotonin production, following aspartame ingestion (Humphries et al., 2008; Rycerz & Jaworska-Adamu, 2013), which suggests aspartame metabolites may be responsible for neurobehavioral changes (Ekong, 2009).

Aspartame also compromises the blood–brain barrier, increasing its permeability and altering concentrations of catecholamines, such as dopamine, in the brain. Thus, aspartame ingestion may have a role in the pathogenesis of certain mental disorders (Humphries et al., 2008). Such claims have been refuted, however, by authors citing the high-aspartame concentrations needed for detrimental effects (Fernstrom, 2009).

Aspartame and Cognition

Recent reports comparing consumption of aspartame and sucrose sweeteners have raised questions regarding the relationship between aspartame consumption and cognitive function. For example, Konen et al. (2000) surveyed 90 university students who considered themselves either chronic aspartame users or non-users. The students completed nutrition surveys and memory questionnaires, in which they rated their perceived forgetfulness in the previous 6 months.

Compared to non-users, the aspartame users reported longer memory lapses. In a randomized double-blind study of 80 healthy young adults, Sunram-Lea, Foster, Durlach, and Perez (2002) reported better spatial memory, word recall, and reaction times in subjects who consumed drinks sweetened with 25 mg of glucose than in those who consumed a drink sweetened equally with aspartame. Harte and Kanarek (2004) also reported similar results when 14 healthy smokers drank 8 oz of a beverage containing either sucrose or aspartame and then chewed gum with or without nicotine.

Although nicotine had no effect on the participants’ memory and attention performance, those who consumed beverages with sucrose performed better on spatial memory and attention tasks than those who consumed beverages sweetened with 100 mg of aspartame (Harte & Kanarek, 2004). In these two studies, the effects may have been positive effects of sucrose rather than negative effects of aspartame, and aspartame and sweetener doses were administered only once and were the same regardless of body weight.

In contrast, in a double-blind study of 36 college students, attention and reaction times of participants did not differ among those who consumed a single can (250 ml) of Red Bull© energy drink, Red Bull© Sugar-Free (containing aspartame) energy drink, or a caffeine- and calorie-free placebo drink, and were tested once after drink consumption and again 1–10 days later (Gendle, Smucker, Stafstrom, Helterbran, & Glazer, 2009). As in previous studies, aspartame was given in a single dose that was not based on body weight.

Aspartame and Headaches

Although there are theoretical links between aspartame and headaches, evidence is limited. Dietary triggers may affect phases of the migraine process by influencing catecholamine and neuronal pathways (Millichap & Yee, 2003). In a review of evidence, large doses of aspartame (900 to 3,000 mg/kg body weight/day) were reported to trigger or exacerbate headaches in individuals susceptible to migraines (Sun-Edelstein & Mauskop, 2009).

Migraine as an allergic response to formaldehyde was proposed by Jacob and Stechschulte (2008), who found that in five patients reporting a history of migraines after aspartame consumption, patch-tests showed all had an allergic reaction to formaldehyde, an aspartame byproduct.

Despite counseling to avoid formadehyde- containing products, however, three of the five participants reported migraine recurrence when assessed 8–12 weeks later. In a randomized, double-blind, crossover study of 18 participants (aged 18–65 years), Van den Eeden et al. (1994) reported no significant differences in headache length or intensity after consumption of aspartame (30 mg/kg body weight/day) or placebo when aspartame was administered over four 7-day sessions after an initial week of placebo administration.

Aspartame, Mood, and Depression

The role of aspartame in depression and mood has been studied with mixed results. When 40 participants with depression and 40 participants without depression were given aspartame (30 mg/kg body weight/day) or confectioners’ sugar (Walton, Hudak, & Green-Waite, 1993) in a randomized, double-blind, crossover trial over 20 days with two 3-day washout periods and two 7-day treatment sessions and self-reported symptoms, the study was stopped by the institutional review board after only 13 participants completed the trial, due to the severity of adverse reactions in the depressed participants who consumed aspartame (Walton et al., 1993).

In contrast, when 133 women of normal weight (Reid, Hammersley, Hill, & Skidmore, 2007) and 53 overweight women (Reid, Hammersley, & Duffy, 2010) blinded to treatment condition who consumed standard doses of aspartame or sucrose-sweetened beverages over 4 weeks and completed a daily 10-item visual analog scale to measure mood, there were no differences in mood between those who drank aspartame-sweetened and sucrose-sweetened soft drinks.

The conflicting reports of the neurobehavioral effects (cognition, mood, depression, and headaches) of aspartame consumption may be due to study design issues including use of single doses of aspartame, placebo, or a sugar-based treatment, followed by a one-time assessment, without calculating dosages according to body weight or participant energy requirements, or only estimating dose by retrospective dietary recall.

No reports were found of indirect calorimetry to determine individual energy needs and portion sizes. We sought to control for these design limitations by using a crossover design and more rigorous measures to compare the neurobehavioral effects of consuming diets with high (25 mg/kg body weight/day) and low (10 mg/kg body weight/day) amounts of aspartame.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617129/


Original Research: Open access.
Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala” by Sara K. Jones et al. PNAS

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