Connections Between Food Additives and Psychiatric Disorders
Source: Psychiatric Times /image: Adobe Stock /Author: Ruo-Gu Xiong、Jiahui Li、Hua-Bin Li, PhD
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SPECIAL REPORT: PSYCHIATRY & THE ENVIRONMENT
Psychiatric disorders such as anxiety and depression have gradually become a major public health concern with 1 of every 8 individuals worldwide experiencing a mental disorder.1,2 Various and individual psychological, biological, and environmental risk factors can influence brain structure and function and contribute to the development of mental health disorders.3,4 Recently, the connections between food additives and mental health disorders have gained increasing attention.
Food additives are used to prevent food spoilage and/or to enhance food color and flavor. The results of several studies have indicated, however, that excessive use of certain food additives (eg, sweeteners, preservatives, and emulsifiers) may trigger mental disorders including anxiety, depression, and attention-deficit/hyperactivity disorder (ADHD).5-7
An increasing number of studies suggested that ingestion of specific food additives can disrupt neurotransmitters and the hippocampus and induce neuroinflammation and gut microbiota dysbiosis, leading to anxiety and depression.8,9
Natural and Nonnutritive Sweeteners
Consumption of sweeteners widely used in the food industry has been connected to a variety of mental health issues and conditions in research. Results of a study based on 18,838 participants found a positive correlation between the consumption of non-nutritive sweeteners and major depression in both men and women.10 Another study involving 227 college students showed a potential link between reduced artificial sweetener intake and lower stress levels.11
An in vivo study in mice demonstrated that the consumption of aspartame, 0.015% or 0.03%, in drinking water induced anxiety-like behaviors by disrupting gene expression in the amygdala and specifically upregulating the mRNA levels of glutamate N-methyl-D-aspartate receptor subunit 2D (GRIN2D) and metabotropic receptor 4 (GRM4) and downregulating the mRNA level of GABA-A receptor-associated protein (GABARAP).12
In contrast, in a diabetic mouse model, chronic exposure to sucrose increased depression- and anxiety-like behaviors along with brain abnormalities. Results of this study also revealed that saccharin ingestion mitigated brain abnormalities and alleviated anxiety and depression in diabetic mice, suggesting that it could be a substitute for sucrose in diabetic patients.13
Another nonnutritive sweetener, stevioside, was proven to ameliorate prenatal obesity-induced postpartum depression in C57BL/6J mice by attenuating neuronal damage, decreasing oxidative stress, inhibiting inflammation, and restoring intestinal barrier damage.14
Essentially, use of the natural sweetener sucrose and the nonnutritive sweetener aspartame may have negative effects on mental health—however, the nonnutritive sweeteners saccharin and stevioside have shown potential for attenuating depression in mice. This suggests that different nonnutritive sweeteners may have varying effects. It is important for individuals to be careful when using both natural and nonnutritive sweeteners until further clarification from research results is provided.
Preservatives
Preservatives are used in the food industry to extend food shelf life. Parabens are one commonly used preservative in food. A study conducted in Canada based on a prospective observational pregnancy cohort found that the presence of paraben methylparaben in meconium was linked to ADHD in children aged 7 to 8 years (OR, 2.33; 95% CI, 1.45-3.76).15
However, in individuals with late-life depression, the consumption of 250 to 1500 mg of the preservative sodium benzoate reduced perceived stress, improved cognitive function, and enhanced treatment adherence.16 Additionally, several epidemiological studies found that sodium benzoate consumption alleviated positive symptoms in schizophrenia.17,18
Animal studies have also reported effects of preservatives on mental disorders. For example, exposing zebrafish embryos to methylparaben temporarily increased cortisol levels, reduced AChE activity, induced anxietylike behaviors, and decreased exploratory behavior in a dose-dependent way.19
Furthermore, butylparaben and propylparaben induced anxiety-like behaviors in zebrafish larvae by causing oxidative stress-induced apoptosis in the brain.20
Similarly, sodium benzoate given at a dose below the US Food and Drug Administration (FDA) safety limit induced delayed hatching, oxidative stress, and anxiety-like behaviors in zebrafish larvae.21 In a rat model, sodium benzoate consumption induced anxiety and motor impairment.22
However, in another rat model with chronic, unpredictable, mild stress-induced depression, administration of 400 and 899 mg/kg of sodium benzoate alleviated depression by downregulating D-amino oxidase activity and increasing the levels of BDNF and protein kinase A in the prefrontal cortex region of the brain.23
In short, the results of both epidemiological and animal studies suggest that preservatives—and particularly parabens—may contribute to anxiety, depression, and ADHD. The effects of sodium benzoate on different mental disorders remain unclear; however, they may be influenced by several factors, including dosage, duration, and the specific animal models used.
Emulsifiers and Flavoring Agents
Other food additives, such as emulsifiers and flavoring agents, may also have negative effects on mental health. For example, administration of 2 emulsifiers—carboxymethylcellulose and polysorbate 80—altered gut microbiota and the expression of anxiety-related neuropeptides in a sex-dependent manner, leading to anxiety-like behaviors in male mice and reduced social behaviors in female mice.24
Moreover, exposure to monosodium glutamate (MSG) during pregnancy dramatically decreased exploratory behavior and induced depressionlike behaviors, possibly due to increased expression of the K+/Cl− cotransporter KCC2.25
Another study reported that administration of MSG caused neuronal lesions in neonatal rats and induced anxiety in adult rats.26 Furthermore, repeated exposure to MSG was associated with oxidative stress, neuroinflammation, and ADHD-like behaviors in rats.27 Food-grade titanium dioxide use also has led to increased anxiety-like behaviors.28
In short, use of emulsifiers (eg, carboxymethylcellulose, polysorbate 80) and flavoring agents (eg, MSG) may contribute to or induce mental disorders including anxiety, depression, and ADHD.
Concluding Thoughts
Consumption of some food additives (eg, aspartame, parabens, polysorbate 80, and MSG) has been associated with increased risk of mental disorders, including anxiety, depression, schizophrenia, and ADHD. The mechanisms of action in the associated studies were related to disruption of neurotransmitters and hippocampus, oxidative stress, neuroinflammation, gut microbiota dysbiosis, and changes in synthesis of ion channels; further effects will be determined in future research.
Use of other food additives (eg, sodium benzoate) may have more mixed effects on mental disorders, whereas administration of other additives (eg, saccharin and stevioside) may exert a protective or ameliorating effect.
However, most of the studies were conducted in zebrafish, mice, rats, and other animals. One should hesitate when extrapolating these animal-based results to human beings while also being mindful of their implications if confirmed.
In different studies, consumption of several healthy vegetables, fruits, and spices and their bioactive compounds (eg, apple phenolic extract, ascorbic acid, gallic acid, melatonin, and curcumin) and of probiotics has shown significant preventive and therapeutic effects against mental disorders induced by food additives.4,29,30 These foods can be recommended by clinicians without doing harm to patients; their consumption may help to mitigate any potential damage related to the use of food additives.
Ms Xiong is a postgraduate in the School of Public Health at Sun Yat-sen University in Guangzhou, China. Ms Li is a research assistant in the School of Chinese Medicine at The University of Hong Kong in Hong Kong, China. Dr Li is a professor in the School of Public Health at Sun Yat-sen University.
References
1. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137-150.
2. Kang S, Eum S, Chang Y, et al. Burden of neurological diseases in Asia from 1990 to 2019: a systematic analysis using the Global Burden of Disease Study data. BMJ Open. 2022;12(9):e059548.
3. Arango C, Dragioti E, Solmi M, et al. Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas. World Psychiatry. 2021;20(3):417-436.
4. Wu SX, Li J, Zhou DD, et al. Possible effects and mechanisms of dietary natural products and nutrients on depression and anxiety: a narrative review. Antioxidants. 2022;11(11):2132.
5. Carocho M, Morales P, Ferreira I. Natural food additives: quo vadis? Trends Food Sci Technol. 2015;45(2):284-295.
6. Sambu S, Hemaram U, Murugan R, Alsofi AA. Toxicological and teratogenic effect of various food additives: an updated review. Biomed Res Int. 2022;2022:6829409.
7. Stevenson J. Recent research on food additives: implications for CAMH. Child Adolesc Ment Health. 2010;15(3):130-133.
8. Aparna S, Patri M. Benzo[a]pyrene exposure and overcrowding stress impacts anxiety-like behavior and impairs learning and memory in adult zebrafish, Danio rerio. Environ Toxicol. 2021;36(3):352-361.
9. Ong-Artborirak P, Boonchieng W, Juntarawijit Y, Juntarawijit C. Potential effects on mental health status associated with occupational exposure to pesticides among Thai farmers. Int J Environ Res Public Health. 2022;19(15):9654.
10. Yu ZM, Parker L, Dummer TJB. Associations of coffee, diet drinks, and non-nutritive sweetener use with depression among populations in eastern Canada. Sci Rep. 2017;7(1):6255.
11. Miller B, Branscum P. Evaluating the association between artificial sweetener intake and indicators of stress and anxiety. Community Health Equity Res Policy. 2023;43(3):339-342.
12. Jones SK, McCarthy DM, Vied C, et al. Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala. Proc Natl Acad Sci U S A. 2022;119(49):e2213120119.2022.
13. Kumar M, Chail M. Sucrose and saccharin differentially modulate depression and anxiety-like behavior in diabetic mice: exposures and withdrawal effects. Psychopharmacology (Berl). 2019;236(11):3095-3110.
14. Ye J, Shi RJ, Fan H, et al. Stevioside ameliorates prenatal obesity induced postpartum depression: the potential role of gut barrier homeostasis. Mol Nutr Food Res. Published online December 15, 2023.
15. Baker BH, Wu H, Laue HE, et al. Methylparaben in meconium and risk of maternal thyroid dysfunction, adverse birth outcomes, and attention-deficit hyperactivity disorder (ADHD). Environ Int. 2020;139:105716.
16. Lin CH, Wang SH, Lane HY. Effects of sodium benzoate, a D-amino acid oxidase inhibitor, on perceived stress and cognitive function among patients with late-life depression: a randomized, double-blind, sertraline- and placebo-controlled trial. Int J Neuropsychopharmacol. 2022;25(7):545-555.
17. Baker A, Clarke L, Donovan P, et al. Cadence discovery: study protocol for a dose-finding and mechanism of action clinical trial of sodium benzoate in people with treatment-refractory schizophrenia. Trials. 2021;22(1):918.
18. Seetharam JC, Maiti R, Mishra A, Mishra BR. Efficacy and safety of add-on sodium benzoate, a D-amino acid oxidase inhibitor, in treatment of schizophrenia: a systematic review and meta-analysis. Asian J Psychiatry. 2022;68:102947.
19. Luzeena Raja G, Divya Subhashree K, Lite C, et al. Transient exposure of methylparaben to zebrafish (Danio rerio) embryos altered cortisol level, acetylcholinesterase activity and induced anxiety-like behaviour. Gen Comp Endocrinol. 2019;279:53-59.
20. Lite C, Guru A, Juliet M, Arockiaraj J. Embryonic exposure to butylparaben and propylparaben induced developmental toxicity and triggered anxiety-like neurobehavioral response associated with oxidative stress and apoptosis in the head of zebrafish larvae. Env Toxicol. 2022;37(8):1988-2004.
21. Gaur H, Purushothaman S, Pullaguri N, et al. Sodium benzoate induced developmental defects, oxidative stress and anxiety-like behaviour in zebrafish larva. Biochem Biophys Res Commun. 2018;502(3):364-369.
22. Noorafshan A, Erfanizadeh M, Karbalay-Doust S. Sodium benzoate, a food preservative, induces anxiety and motor impairment in rats. Neurosci. 2014;19(1):24-28.
23. Guo F, Zhang Z, Liang Y, et al. Exploring the role and mechanism of sodium benzoate in CUMS-induced depression model of rats. Neuro Endocrinol Lett. 2020;41(4):205-212.
24. Holder MK, Peters NV, Whylings J, et al. Dietary emulsifiers consumption alters anxiety-like and social-related behaviors in mice in a sex-dependent manner. Sci Rep. 2019;9(1):172.
25. Biney RP, Djankpa FT, Osei SA, et al. Effects of in utero exposure to monosodium glutamate on locomotion, anxiety, depression, memory and KCC2 expression in offspring. Int J Dev Neurosci. 2022;82(1):50-62.
26. Rosa SG, Quines CB, Stangherlin EC, Nogueira CW. Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters. Physiol Behav. 2016;155:1-8.
27. Abu-Elfotuh K, Abdel-Sattar SA, Abbas AN, et al. The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/β-Catenin signaling pathways in rat model. Biomed Pharmacother. 2022;155:113799.
28. Medina-Reyes EI, Delgado-Buenrostro NL, Díaz-Urbina D, et al. Food-grade titanium dioxide (E171) induces anxiety, adenomas in colon and goblet cells hyperplasia in a regular diet model and microvesicular steatosis in a high fat diet model. Food Chem Toxicol. 2020;146:111786.
29. Xiong RG, Li JH, Cheng J, et al. New insights into the protection of dietary components on anxiety, depression, and other mental disorders caused by contaminants and food additives. Trends Food Sci Technol. 2023;138:44-56.
30. Xiong RG, Li JH, Cheng J, et al. The role of gut microbiota in anxiety, depression, and other mental disorders as well as the protective effects of dietary components. Nutrients. 2023;15(14):3258.