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______________________________________________________________________________
Analyzing the Monosodium and Dietary Glutamate Model of Depression: A Narrative Review
Olaitan Olabiyi1, Ayomide Ajibewa1, Abayomi Ajayi2.
Published online: December 2025
  © The Author(s) 
Abstract
Background: This narrative review aimed to explore the scientific understanding of the role of monosodium glutamate and dietary glutamate in depressive-like phenotypes. It illuminated the findings that are linked to the monosodium glutamate (MSG) model of depression, curating recent literature on MSG-induced depression and the closely related sphere of MSG induced neurotoxicity.
Methodology: A comprehensive search of the literature from 2010 to 2025 was conducted using Google Scholar, PubMed, and Scopus databases, focusing on peer-reviewed studies with definite outcomes. A narrative review was done due to the limited number of eligible studies.
Results: A comprehensive search of relevant databases having studies of MSG induced neurobehavioral and pathophysiological changes in depression was conducted with preference for recency of studies (up to two decades back). Supraphysiological doses and/or the parenteral route of monosodium glutamate can consistently induce depressive-like phenotypes in animal models. The limitations of the MSG model of depressive-like behavior were also critically analyzed. Three thousand five hundred and eighty results came from the searches, with sixty-three studies adjudged to meet the inclusion criteria.
Conclusion: The monosodium glutamate model of depression provides a valuable approach to understanding the multifaceted nature of depression. Future endeavors should focus on the standardization of methodological processes and the incorporation of the evaluation of the chronic effects of monosodium glutamate in human studies.
Keywords: Monosodium Glutamate (MSG), Dietary Glutamate, Depressive-like Phenotypes, Monosodium Glutamate Induced Depression, Neurotoxicity, animal Models, Supraphysiological Doses.
Corresponding Author: olaitanolabiyi40@gmail.com

Introduction
Major depressive disorder encompasses a host of causative factors, including environment, genetics, stress, and diet. The World Health Organization (WHO) statistics reveal that 4% of the world population experience symptoms consistent with depression, with women more affected than men (WHO 2023). This condition can be debilitating, severely affecting key aspects of life at home, in the workplace, and in school. Hence, this portends a great burden of the disorder worldwide. At this time, developing countries such as Nigeria are becoming increasingly cognizant of the link between mental health disorders, such as depression, and the socioeconomic status and quality of life generally (Imbur 2024). This has led to increased exploration of some key aspects of depression, including dietary influences that underlie these disorders.
Glutamate, a major excitatory neurotransmitter, has been implicated in the pathophysiology of depression, with increasing evidence (Niciu et al., 2014; Onaolapo & Onaolapo, 2021; Boyko et al., 2023). Its importance in the mediation of learning and cognition, which are critical brain functions, cannot be overstated; on the other hand, its propensity for overstimulating functional brain neurons cannot be ignored in the etiology of various neurological conditions, including depression. Glutamate may also stimulate peripheral glutamate receptors in the gut and still affect CNS functions, with interaction between receptors and afferent nerve fibers (Uneyama et al., 2006). This is a result of an imbalance of glutamate levels or dysregulation of glutamate homeostasis in the body. 
Glutamate can be of an endogenous or exogenous source. The latter is commonly derived from diets containing monosodium glutamate and from natural food sources, such as those found in many foods, including meat, fish, and aged cheese. Despite that monosodium glutamate, a worthy representative of dietary glutamate, is generally recognized as safe (GRAS) by the FDA (Dal et al., 2017; Bayram et al., 2023), concerns and anecdotal reports still endure regarding its systemic and neurological effects (Umukoro et al., 2015; Rosa et al., 2016; Kumar et al., 2021; Brandley et al., 2022). 
The synthesis of MSG has evolved from a costly and patient protein source to bacterial fermentation, which helped to augment production considerably (Samuels 1999; Ault 2004). This, coupled with increasing acceptance of the flavor-improving characteristic, has increased profitability in the glutamate industry. Despite its widespread use, the exact effect of MSG and dietary glutamate on mental health, especially how they contribute to the pathophysiologic mechanisms of depression, is still a subject of debate, with inconsistent and mixed findings in scientific studies. 
This narrative review explores the empirical evidence surrounding the monosodium and dietary glutamate model of depression. It evaluates key biological and neurotoxic aspects of the monosodium glutamate model of depression, a departure from the psychological and social factors that cause depression. We want to analyze the current mechanistic understanding, methodology of extant research, and attempt to identify salient gaps for future investigations.
Methods
Data Sources and Searches
An extensive literature search was done utilizing Google Scholar, PubMed, and Scopus Databases. The keywords used in the search were “MSG”, “monosodium glutamate”, “depression”, “depressive-like”, and “neurotransmitters”. Boolean connectors were employed by two independent reviewers for these keywords. The search was conducted between March 2025 and May 2025. In ensuring a robust search, Boolean connectors were used to combine items such as “monosodium glutamate” OR “MSG” with “depression” OR “depressive-like” OR “neurotransmitters”. The review process was in accordance with the PRISMA 2020 guidelines for transparency and reproducibility.
Inclusion Criteria:
Titles, abstracts, and full texts were thoroughly examined to determine eligibility. Studies were included if:
I. They were original research articles published in peer-reviewed journals or relevant review articles that are pointers to relevant original studies.
II. Written and expressed in the English Language and available as full-text PDFs.
III. They investigated the effect of monosodium glutamate administration on depressive-like behaviors in models of depression and closely related spheres of neurotoxicity.
IV. They employed validated behavioral tests, especially in animal models.
V. They included studies with relevant neurochemical changes that pertain to depressive-like behaviors or depression.
VI. Studies between 2010- early 2025, before March 2025.
Exclusion Criteria:
Studies were excluded if:
I. They were not published in English or were not accessible as full-text PDF documents
II. They were articles that had not been subject to peer review or lacked sufficient data to make a specific outcome analysis.
III. They lacked validated behavioral tests and/or studies with relevant neurochemical changes that pertain to depressive-like behaviors or depression.
Data Collection and Extraction
	Collected data points included: subjects that were administered monosodium glutamate; dose & route of administration; key neurochemical and behavioral findings; the authors and publication year. 
Assessment of Methodological Quality and Risk of Bias
The primary studies were subject to critical appraisal, despite that this was a narrative review. This was to make sure that the finding was interpreted correctly and consistently. The Office of Health Assessment and Translation (OHAT) Risk of Bias Tool was employed to determine the internal validity of both human and animal studies. These provided qualitative judgements for specific bias domains, with the observation that all biases are not equal in impact.
The assessment of the study was done by two independent reviewers. Objectivity and consistency were ensured. A consensus was reached by reviewers for the final rating, with a third reviewer stepping in to resolve conflicts.
Monosodium Glutamate and Dietary Glutamate: Sources and Metabolism in the Body.
Monosodium glutamate, MSG, a sodium salt of glutamic acid, is named sodium-2-aminopentedioate reflective in line with the IUPAC nomenclature. Hence, it is ionized in solution to give the individual sodium ion and glutamic acid (Kayode et al., 2023). Monosodium glutamate is often referred to as the fifth taste; the other four being salt, sweet, sour, and bitter. It gives the free form of glutamate, the same as endogenously active ones. Umami depicts the monosodium glutamate taste mediated by the GPCR, T1R1, and T1R3 subunits. The heterodimer receptor formed by these subunits binds to umami substances such as L-glutamate, causing a series of reaction cascades that help in the perception of the distinct umami taste (Servant & Frerot, 2021; Diepeveen et al., 2022). 5´-ribonucleotides are important in this process as they help in stabilizing the heterodimer receptor in an active conformation, sensitive to glutamate. Monosodium glutamate could lose the umami taste upon undergoing various degradative reactions, but it assumes a flat configuration to attach to the umami receptors (Diepeveen et al., 2022).
 A walk back into history shows that glutamic acid was discovered in the late 19th century by the German chemist Karl Heinrich upon adding sulfuric acid to wheat gluten (Sano 2009). In 1908, isolated glutamic acid was obtained from the seaweed by an extraction and crystallization process. Moving on from the acid hydrolysis of wheat gluten, the increased demand for MSG's appetizing and palatability characteristics led to a delve into fermentation and chemical production (Kazmi et al., 2017). Fermentation remains the current method of production, usually utilizing genetically engineered bacteria that secrete glutamic acid through their cell wall. The process of bacterial fermentation closely mimics that of making yoghurt and vinegar. As of today, monosodium glutamate is commercially produced on a large scale in a cheap and consumer-friendly way. Its palatability and appetizing attributes make it the darling of fast food and the commercial food industry worldwide, and this wide acceptability in Asia has been replicated in other continents of the world.
Glutamate is either free (not bound to a protein) or bound (bound to a protein that will release it subsequently in free form). In human beings, the average daily intake of total glutamate is 10 g, while that of free glutamate is greater than 1000 mg (Beyreuther et al., 2007). Dietary sources of monosodium glutamate, including sausages, hamburgers, barbecues, and bodybuilding proteins, are reflective of urbanization trends. Other sources that give free glutamate include proteins such as meat, fish, eggs, and even tomatoes. Some foods on a commercial scale have been found to flout the limit of monosodium glutamate in some countries (Lavine 2007). This brings to the fore the need for tighter regulations on the production and labelling of monosodium glutamate-containing food. However, when monosodium glutamate is consumed with food, even at high doses, there is a form of tolerance such that it will not sufficiently cause brain lesions (Fernstrom 2018). This may be due to factors including the dilution of the concentration of the monosodium glutamate, reduction of influence on taste and satiety, and protein-umami synergism on appetite regulation. In addition, excessive consumption of MSG may portend a decrease in appetite resulting from a decrease in palatability (Loliger 2000). This may be protective, as humans will find food containing high levels of MSG to be unattractive. A reduced consumption of monosodium glutamate well below critical limits signifies a reduced risk of the untoward effect of monosodium glutamate.
Despite that monosodium glutamate is recognized as safe, giving it the GRAS status with the FDA, its presence and usage in a variety of food products may not be explicitly defined, thereby exceeding daily standard intake (Maluly et al., 2017; Wijayasekara, 2017). A certain author advocated for its outright ban since it imbibes the cardinal sins of deception and adulteration (Samuels 2013). Its meaty flavour may encourage consumption of less expensive protein, and it is said to make food appear or taste better than it is (Samuels 2013). Another risk is that of adulterated and substandard MSG in the market. It is now considered misinformation that MSG is unsafe at acceptable limits. This overrides the previous misconception that it caused a cluster of symptoms, often called "Chinese restaurant syndrome," which included headaches, anxiety-like behaviors, palpitations, and obesity linked to MSG consumption. Several studies depict no such effects when MSG is combined with food in normal concentrations, and remain inconclusive for large concentrations of MSG (US FDA 2012; Obayashi and Nagamura 2016; Henry-Unazeze 2017). 
The toxicity profile of MSG to the brain and body often depends on the species involved, age at dosing, dose, and the route of administration (Hassan et al., 2019). For instance, adult rodents (mice and rats) may show similar levels of MSG in the blood. Guinea pigs may show significantly higher levels, which translates to higher impacts (Bizzi et al., 1977). Younger mice are significantly more affected by MSG administration than older ones, as many of the protective barriers are not yet fully formed. The parenteral route for MSG administration in pre-clinical studies may not reflect the typical oral consumption process in humans. Hence, there is a significant challenge to extrapolating results in young rodents or for the parenteral route in either an age-dependent Alzheimer’s disease or a non-age-specific one like depression (Roberts et al., 2018; Hassan et al., 2019) since the body can easily metabolize glutamate (Samuels, 1999; Rivera-Cervantes et al., 2004).
Monosodium glutamate is metabolized similarly to glutamate from other sources. It is reduced to glutamate and sodium in body fluids, followed by absorption. Glutamate also has a crucial impact on energy production and metabolism, exchanging with α-ketoglutarate (AKG) through the glutamate pyruvate transaminase or glutamate oxaloacetate transaminase (Xiao et al., 2016). Astrocytic conversion of glutamate to glutamine occurs via glutamine synthetase. Normal dietary consumption of glutamate shows a breakdown to carbon dioxide by the GIT. However, if MSG is consumed in overwhelming proportions, ATP may be generated or conversion may be done to other amino acids. These include ornithine, glutamine, and aspartate (Kazmi et al., 2017). 
Figure 1: Biological Etiologies of Depressive Phenotypes





Depression and the Role of Endogenous Glutamate
Traditionally, major depression is usually treated with a sequence of single antidepressants. However, provided that the key improvement in clinical symptoms and tolerable side effects is not established, a second agent could then be added (Bennabi et al., 2019). There are a number of grey areas that increasingly demarket this approach. First, studies have shown that anti-depressants may paradoxically worsen depression too (Damluji 1988; Benazzi 2003). Then, conventional management of depression, which employs the same principle of dosing and agent as treatment of other chronic diseases like hypertension, often causes disappointing remission rates for the first line, making each subsequent antidepressant treatment administered, remission rates progressively decreased (Stahl, 2010). Take into account that the majority of conventional antidepressant agents have the underlying monoamine deficit principle in part or in whole. Therefore, it is logical to consider pathophysiologic factors and, by extension, the potential pharmacotherapeutic interventions for depressive disorder. This brings us to the need to further study the glutamate model of depression.
An understanding of the exact mechanisms of glutamate action in depression may illuminate certain pathophysiologic core of the disorder (Asejeje et al., 2024). In essence, the gut-brain axis and glutamatergic signaling in the brain and gut play crucial roles in depression. Glutamate is a key excitatory neurotransmitter that facilitates fast synaptic impulses of memory and learning in the brain. It is a potent excitotoxin that is found to play a role in the pathophysiology of depression, with increasing evidence (Hashimoto 2009; Mitchell et al., 2010; Niciu et al., 2014). It may exert its actions at different cell compartments, including presynapse, postsynapse, and glia. Glutamate stimulates extra synaptic NMDA in the subgenual cingulate area either to cause depression alone or co-morbid depression in glutamate-associated diseases (Onaolapo & Onaolapo 2021).
L-glutamate abounds inside the brain more than outside, lending credence to its central function. Although the extracellular fluid concentration of glutamate is kept within an acceptable range of 0.5 to 2 µm by the excitatory amino acid transporters (Hawkins 2009; Zhou and Danbolt 2014), peripheral glutamate may distort the blood-brain barrier and significantly affect brain concentrations (Xhima et al., 2016). 
Results
	Initially, we selected 63 studies out of the total 3,580 results to meet the inclusion criteria. Upon examining the abstract and full text, 19 studies met the criteria perfectly and were suitable for further in-depth analysis. The majority of studies examined were on animal models, while only two were returned for human studies.
Evidence for Monosodium Glutamate-Induced Depressive-Like Behaviors in Animal Models
Previous studies in the last one and a half decades have significantly demonstrated that the administration of monosodium glutamate can evidently cause changes in behaviors that are consistent with depression in animal models (Umukoro et al., 2015; Quines et al., 2016; Yang et al., 2020).  They have generated pivotal empirical evidence for the use of monosodium glutamate to induce depressive-like phenotypes, while making use of standardized behavioral tests to depict these characteristics.
In a study by Quines et al. in 2014, male and female newborn Wistar rats received a daily subcutaneous dose of monosodium glutamate at 4 g/kg/day from postnatal day 1 to day 5. There was a significant increase in immobility time in the forced swim paradigm. Similarly, there was an increased freezing reaction in the contextual fear conditioning. The uptake of serotonin in the cerebral cortices of rats increased, which was positively correlated with the degree of immobility. This uptake was, however, negatively correlated with the Na+ K+ ATPase activity. These proofs of depressive-like behaviors delineate the underlying mechanisms, including a dysregulation of the serotonergic system and neuronal excitability. Impairment of the HPA axis regulation also contributes to anxiety-like behaviors. 
Rosa et al. 2016 found a downregulation in serotonin levels with concomitant GABA increase following a similar dose of 4 g/kg per day from the 1st to 10th postnatal day in female Wistar rats. For Abu-Taweel et al., 2014 and Abdel Moneim et al., 2018, a significant decrease in serotonin levels in the brain was found. Dopamine was also significantly downregulated in the Abu Taweel study at a dose of 8 mg/kg monosodium glutamate orally for one month in male albino mice.
Further lending to the evidence, Umukoro et al. 2015 demonstrated that oral administration of monosodium glutamate at the highest dose of 500 mg/kg daily for 21 days in mice elicited depressive-like behaviors in the forced swim test. The lower doses used in the study did not produce considerable behavioral abnormalities, suggesting a dose-dependent effect. There was no significant perturbation of memory in the Y maze however. This study makes use of an oral route of administration, which is more predictive of typical human dietary consumption than parenteral routes. There is the argument that the utilization of a parenteral route in such animal studies could jeopardize the extrapolation of the animal data to humans (Reeds et al., 1996) since the body can effectively bio-transform added glutamate (Samuels, A. 1999; Rivera-Cervantes et al., 2004). 
The administration of monosodium glutamate has also been linked with neurotoxic effects or general malaise, including a significant reduction in spontaneous locomotor activity (Zhao et al., 2019), aggressive behavior, and loss of muscle strength (Nishigaki et al., 2018). There have also been reports on the affective potential of monosodium glutamate administration on cognitive abilities, including exploratory behaviors and short-term working memory (Fahmy et al., 2023).
Zebra fish behavioral models are becoming widely accepted since, compared to pre-clinical studies, they present a cheap, yet accurate and easy to maintain alternative, and can be correlated to human disease pathologies. A study by Devaraj et al. 2020 evaluated the effect of monosodium glutamate on both phenotypic changes and brain neurotransmitters in Danio rerio. Levels of dopamine, norepinephrine, and serotonin were found to drop as monosodium glutamate dosage increased (100 mg/L, 150 mg/L, and 200 mg/L). A corresponding increase in glutamate and GABA was also found. 
The induction of depressive-like characteristics by MSG depends on the dose, route of administration, and age of animals at dosing. The parenteral route, while not a good predictor of human depressive phenotype, appears to consistently induce these behaviors in animals, even at orally ineffective doses. Some studies making use of the oral route have given rise to antidepressant-like effects in some behavioral despair paradigms. This reflects a considerable difference in methodology in which the parenteral exposure in neonates leads to much higher levels during critical windows of development. The oral administration in adults, on the other hand, suggests extensive gut metabolism and a restrictive blood-brain barrier (O’Hara et al., 1977). Different administration methodologies may mimic distinct etiologies of depression, suggesting a need for careful assessment of experimental protocol when interpreting and analyzing results. 
Finally, various studies have consistently linked the monosodium glutamate-induced depressive-like and anxiety-like phenotypes. This portends that the pathophysiological and neurobiological impacts of monosodium glutamate encompass broader pathways involved in mood and anxiety disorders. Furthermore, the mechanistic effects of monosodium glutamate are not depression-specific alone, especially in animal studies. Hence, the monosodium glutamate model, already a veritable model of obesity for instance (Bunyan et al., 1976), may be utilized to better understand the joint neurobiological influences that underly co-occurring psychiatric conditions or co-occurring metabolic and psychiatric conditions.
Evidence for Monosodium Glutamate-Induced Depressive-Like Behaviors in Clinical Models. 
A study by Brandley et al., 2022, evaluating how much low glutamate affected anxiety, post-traumatic stress disorder (PTSD), and depression in veterans with Gulf War illness, had some revealing results. The study reported that monosodium glutamate significantly worsened anxiogenic behavior in the most severe group, with no effect on depression or PTSD symptoms. It also postulated that a low glutamate diet may effectively manage depressive-like and anxiety-like symptoms, even though glutamate only directly caused symptoms in anxiety. Underlying nutrient intake was also found to prevent negative psychiatric effects from glutamate exposure.
Furthermore, Kumar et al., in a cross-sectional study in 2021, reported the correlation between dietary intake of glutamic acid and increased depressive symptoms among non-obese subjects with a schizophrenia spectrum disorder. There is a paucity of clinical and human-based studies on monosodium glutamate effects. Hence, there is a need for large-scale clinical trials worldwide.
Specific Neurobehavioral Tests Employed in MSG Depression Models
These tests typically measure behavioral parameters that could be extrapolated to human depressive symptoms, including anhedonia, behavioral despair, and changes in locomotor activity. 
· Forced Swim Test (FST): It is a commonly utilized animal model to evaluate depressive-like behavior (Slattery et al., 2012). Here, the active swimming phase is juxtaposed with the passive immobile phase of rodents when they are forced to swim in a cylinder without any means of escape (Slattery et al., 2012). It has its basis on the principle that when an animal is placed in an inescapable water environment, it floats with minimal movement to keep its head above water. This is a form of despair or helplessness. It is a widely accepted model for pre-screening antidepressant drugs.
· Tail Suspension Test (TST): This is used in screening products for possible antidepressant activity, and overall, it determines how depressive-like behaviors are manipulated. There is a suspension by the tail, thereby preventing rodents from holding on to surfaces or escaping. Escape targeted behaviors are determined and recorded. Like FST, it is invaluable for high-throughput screening of prospective antidepressant compounds (Can et al., 2012). 
· Sucrose Preference/ Splash Test: Anhedonia is the inability to experience pleasure from rewarding or enjoyable activities and is a core symptom of depression. This is a reward-based test used as an indicator of anhedonia (Serchov et al., 2016).
· Contextual Fear Conditioning: It is used to evaluate anxiogenic behaviors, which often co-exist with depressive states. It evaluates an animal’s fear response to a specific context, which has been learned (Rudy et al., 2004).
· Open Field Test: This test determines the general locomotor activity and anxiety-like behavior in rodents. In this test, the number of pecks and the space explored are predicted. In assessing behavior in the open field test, the constellation of behavioral signs should be taken into cognizance (Perals et al., 2017). Reduced locomotor activity likely indicates depressive-like states.












Table 1: Key Animal Studies on MSG-Induced Depressive-Like Behaviors (2010-Present)[footnoteRef:1] [1:  Kumar et al., 2021 involved human subjects, not animal models, for dietary correlation] 

	Study
	Species/Strain/Model
	MSG Dose
	Route of Administration
	Duration of Administration
	Relevant Behavioral Tests Used
	Key Depressive-like and Neurobiological Findings

	1) Abdel Moneim et al., 2018



2) Abu-Taweel et al., 2014




3) Rosa et al., 2016










4) Quines et al., 2014






5) Umukoro et al 2015






6) Biney et al., 2021




7) Sriram et al., 2024



8) Hamza et al., 2019





9) Kardesler and Baskale 2017







10) Yang et al., 2020







11) Salem et al., 2022





12) Zhao et al., 2019




13) Zhu et al., 2020




14) Rodrigues et al., 2021





15) Abdehamid et al., 2023




16) Devaraj  et al., 2020



17) Fahmy et al., 2023



18) Merispour et al., 2019




19) Kumar et al., 2021













	Male Albino Rats




Male Albino mice




Male and female Wistar rats






Newborn Wistar Rats




Male Swiss Mice



Female inbred imprinting control region (ICR) mice

Male Wistar Albino Rats


Adult male rats




Neonatal Male Wistar Rats





Newborn Sprague Drawley Rats




Young Wistar Rats




Neonatal Male Wistar Rats



Neonatal Sprague-Drawley Rats


Male Wistar Rats




Male Albino Rats



Zebrafish




Male Albino Wistar Rats


Two age groups of mice (4-5 weeks; 9-10 weeks)

Human schizophrenic subjects
	1.66 g/kg/day




8 mg/kg MSG together with Aspartame


4 g/kg/day







4 g/kg/day





500 mg/kg




4 g/kg





500 mg/kg



6 or 17.5 mg/kg



50 mg/kg/day, 100 mg/kg/day and 200 mg/kg/day




4 mg/kg/day





0.4 g/kg





4 mg/g




4 mg/g 




4 g/kg




600 mg/kg/day



100 mg/L 150 mg/L and 200 mg/L


2 mg/kg




2.5 g/kg and 5 g/kg




Dietary

	Oral gavage




Orally in drinking water



Subcutaneous injection






Subcutaneous injection




Orally




Orally, In utero




Orally 


Orally





Intraperitoneally






Subcutaneously






Oral





Subcutaneously



Subcutaneously



Subcutaneously




Orally



Orally




Oral Gavage




Orally




Oral (dietary intake)

	Thirty days





One month




1st to 10th post-natal day






1st to 5th post-natal day




Daily for 21 days




Post natal day 43




21 days


30 days





One day on one day off, eight times in total





First five postnatal days





8 weeks





Alternate days after birth from day 2 to day 10


Every two days for 10 days


Post natal day 60-76




28 days



14 days




10 days




Singled dose or repeated dosing for seven/fourteen days




	Eight-arm radial maze






 


Spontaneous locomotor activity, Elevated plus and contextual fear conditioning.

Forced swim test and spontaneous locomotor test


Forced swim test


















8-arm radial maze setup





Open field test, sucrose preference test and forced swim test








Open field test




Open field test, forced swim test


Open field test, forced swim test.








T-maze test










Forced swim test



Beck Depression Inventory Scores
	Decrease in brain serotonin in brain tissue as well as serum. Increased total time taken to enter the food containing arms

Reduction in levels of brain neurotransmitters (dopamine and serotonin).


Increased serotonin and GABA uptake in rat’s hippocampus. Increase in behavioral anxiety-like parameters in the behavioral tests.




Increased serotonin uptake. Increased immobility time in the forced swim test.



Depressive-like behavior in the forced swim test. Increased brain oxidative stress parameters


Increased expression of KCC2. Effect on locomotion and depression-like behaviors,

IL-6 levels increased and BDNF levels downregulated

Reduction of catecholamine levels (dopamine, serotonin and norepinephrine). BDNF decreased at lower dose and increased at higher dose of MSG.


Difference in catecholamine levels






Upregulation of caspase-1 and GSDMD mediated pyroptosis. Reduced locomotor activities and increased anhedonia. 


Increased glutamate, decreased brain monoamines, increased oxidative stress, decreased BDNF.


Decreased dopamine, GABA and serotonin levels. This was ameliorated by escitalopram. Reduced locomotor activity

Decrease in BDNF/TrkB pathway–dependent GR phosphorylation. Increased immobility time in the FST after pretest. Shorter time in centre
Increased immobility time. Stimulation of Na+/K+-ATPase and AChE in cerebral cortex and hippocampus

Reduced DA and DOPAC; reduced 5-HT and 5-HIAA; reduced NE levels. Increased oxidative stress

Decreased dopamine, norepinephrine and serotonin. Increased glutamate. Decreased GABA levels. Increased response latency.

Reduced dopamine and serotonin receptors (S-2A). Increased caspase-3. Increased oxidative stress parameters

Increased immobility time in younger mice with single dose and repeated dosing.

Proportionality between dietary glutamate consumption and depressive symptoms in normal subjects. No link between dietary glutamate and BDI scores in obese patients.












Discussion
This review reveals that there are important neurobiological mechanisms underlying MSG-induced depression. These mechanisms usually involve a complex interplay including oxidative stress production and neuroinflammation, glutamatergic excitotoxicity, a deficit in the neurotransmitter system, and the metabolic/endocrine pathways. Understanding the gut-brain axis communication is key to unraveling dietary impacts on depression.
On oxidative stress and neuroinflammation, the administration of monosodium glutamate may cause a dose-dependent free radical production in the brain. This is indispensable in the neurogenerative process since the brain has a modest antioxidant system. Upregulated oxidative stress markers, such as lactate dehydrogenase and malondialdehyde, and downregulated endogenous antioxidants such as catalase and glutathione-S transferase (GST) may accompany the administration of monosodium glutamate in rodents (Hazzaa et al., 2020; Adelakin et al., 2024; Kesherwani et al., 2024). In the liver, monosodium glutamate may precipitate a buildup of ammonium ions and, consequently, free radicals. This combines with the prominent polyunsaturated fatty acids of the cell membrane, thereby causing further oxidative stress damage in the power house of the cell. This appears to cause geometric increase in the levels of monosodium glutamate, further enhancing neurotoxic effects. In a study by Essawy et al., 2025, the impact on the polyunsaturated fatty acids, PUFAs, particularly in the brain, may be ameliorated by omega-3 polyunsaturated fatty acid administration. Deficiencies in these fatty acids may result in behavioral changes and cognitive impairment.
Monosodium glutamate exposure has also been implicated in the induction of the hypothalamic pituitary adrenal (HPA) axis as well as the body’s stress response machinery (Torrezan et al., 2019; Atteia et al., 2024). This could potentiate systemic inflammatory response. Neuroinflammation, a key component of the pathophysiology of depression, involves glial cell activation, dysregulation of the blood-brain barrier, and abnormal cytokine signaling. However, in a study reported by Seo et al. (2010), long-term administration of monosodium glutamate under chronic variable stress of day-to-day life has led to inhibition of the HPA axis.
Dietary monosodium glutamate does not typically cause a proportionate increase in brain level of glutamate like it does in plasma (Fernstrom 2018). Therefore, there is a reduced possibility of the induction of profound histopathological alterations in the brain by lower and orally administered doses. Monosodium glutamate usually gives the free glutamate, similar to the endogenous ones (Seo et al., 2010). However, at high doses, the balance of glutamate/GABA is deranged giving rise to anxiety-like effects.  Furthermore, in neonatal rodents, the developing blood-brain barrier is less restrictive, thereby explaining the possibility of the potentiation of monosodium glutamate-induced excitotoxicity and depressant-like effect (Nemeroff et al., 1978). Some population might be at greater risk of significant monosodium glutamate adverse effects, despite its GRAS status. They may have monosodium glutamate symptom complex, pre-existing health conditions that directly affect monosodium glutamate metabolism, and potential interaction with other substances (Kumar et al., 2021). Certain stressful conditions with or without the administration of monosodium glutamate may cause excessive NMDA receptor stimulation and result in depression from the disruption of the gut-brain axis.
Furthermore, on the effect on neurotransmitters, particularly monoamines, supraphysiological doses of monosodium glutamate have been associated with a downregulation of serotonin levels in the blood and the brain. Many reports have linked high doses of monosodium glutamate with a considerable decline in brain and serum serotonin levels beyond depressant-like effects, to entrench memory dysfunction (Rosa et al., 2016; Abdel Moneim et al., 2018). Some studies have also found increased uptake of other monoamines like norepinephrine and dopamine (Abu-Taweel et al., 2014; Hamza et al., 2019). The effect of monosodium glutamate on GABA and the glutamate/GABA balance has been nuanced. In a study by Kardesler and Baskale 2017, as monosodium glutamate dosage increased in neonatal rats, levels of GABA was reduced. Glutamate levels also increased relative to the dosage. When monosodium glutamate plummets GABA levels, it can elicit an upregulation of dopamine levels since both GABA and dopamine have a modulating effect on each other in certain brain regions. Specifically, GABAergic neurons inhibit dopamine release.
An early 2000s hypothesis of the pathophysiology of depression that deals with the reduction of Na+-K+ ATPase expression and function also deserves a mention (de Lores Arnaiz and Ordieres 2014).  This reduction is induced by monosodium glutamate (Quines et al., 2015). Reduced Na+- K+ ATPase activity affects mood disorders by manipulating neuronal excitability and neurotransmitter release.
The metabolic and endocrine pathways may be intertwined, with the administration of monosodium glutamate eliciting effects that may affect their similar mechanistic pathway processes. The gut-brain axis and glutamatergic signaling could play crucial roles in depression. Nutritional psychiatry emphasizes the two-way communication between the gut and the brain. Monosodium glutamate, a significant model of obesity (Nagata et al., 2006; Bautista et al., 2019), may help elucidate the pathophysiological mechanisms of neurological disorders such as depression, which is increasingly associated with dietary modifications. 
First, monosodium glutamate has been linked to a significant perturbation in the HPA axis, which controls bodily stress response. Secondly, monosodium Glutamate levels in the hypothalamic or circumventricular region of the brain, which does not have a structured blood-brain barrier, could increase proportionally with plasma glutamate concentration from monosodium glutamate administration. Hence, administration of supraphysiological doses of monosodium glutamate to neonatal rodents may cause neuronal necrosis of the hypothalamic sections of the brain, causing depressive-like symptoms (Nemeroff et al., 1977; Poon and Cameron, 1978). 
Reduced levels and hypoactivity of glutamate, as opposed to the excitotoxicity, have been linked to depression too (Onaolapo and Onaolapo 2021). High intake of monosodium glutamate, as a dietary factor, may modify the structure and composition of the gut microbiota. This may be from modifying the actions of certain probiotics and beneficial microorganisms that can release glutamate. Recent evidence points to the involvement of this gut microbiota in the regulation of brain neurotransmitters such as GABA, glutamate, and the monoamines (Strandwitz 2018; Huang & Wu 2021; Dicks 2022). Probiotics may influence gut-brain microbiome to affect some of the construct validity associated with clinical depression, such as anhedonia (Onaolapo and Onaolapo 2021). There is a critical need for the characterization of a depression-linked gut microbiome profile (Du et al., 2020). Furthermore, microbiome-targeted therapies need to be investigated more in clinical studies.


Figure 2: Links between monosodium glutamate administration and depressive like behavior. 

Depressive-like and neurotoxic symptoms
Mitochondrial toxicity
Calcium influx


Oversaturation of meagre brain antioxidant defense system
Lipid Peroxidation and neuronal damage

Neuroinflammation and immune cell activation







Critical Assessment of the MSG Model of Depression
Several authors have defined a list of criteria of validity that focuses on human disease states, including depression. However, over the years, there has been a tilt towards the criteria of external validity, and less towards internal validity. Internal validity imparts the design of the experiment: reproducibility, inter-observer reliability, randomization, etc. External validity, on the other hand, determines how the results of a study can be extrapolated to a general population, for instance, the feasibility and suitability of animal models of depression. (McKinney and Bunney 1969). 
Limitations of the Review Process/ Included Studies
The current review is limited by the predominant inclusion of animal studies at the preclinical level.  Although they can offer valuable insights into the mechanistic pathways of depression, caution should be exercised in the direct interpretation and translation of findings to the complex human pathophysiology of depression. The use of supraphysiological doses beyond the usual human dietary intake levels contributes to this limitation. This is, however, in spite of a sufficient symptomatic or behavioral isomorphism in animal studies. In addition, as stated previously, the effects of oral monosodium glutamate can differ significantly from the parenteral route of administration. This suggests that the validity of the monosodium glutamate model of depression relies on the specific administration protocol, which brings about the pathophysiological effects. Finally, there remains a paucity of clinical studies evaluating the direct effects of monosodium glutamate on depression. Even the limited studies have been inconsistent.
The predominantly short-term period of the included studies does not directly assess the chronic effects of monosodium glutamate. Therefore, there is a need to assess the long-term impact (up to 90 days) of monosodium glutamate consumption in inducing depressive phenotypes, especially at lower doses.
Confounding Factors
Supraphysiological doses of monosodium glutamate may cause a broad spectrum of neurotoxicity beyond specific depressive-like characteristics. These include neurodegeneration, memory impairment, aggressive behaviors, etc. This can confound the interpretation of monosodium glutamate as a specific model of depression, as observed depressive-like phenotype may be secondary to the neurotoxicity spectrum.
In a similar vein, monosodium glutamate, particularly at high doses, may be linked with a range of metabolic disorders such as impaired glucose tolerance, obesity, and liver damage (Adeleke et al., 2022; Abdou et al., 2025). These co-morbidities may complicate the depressive phenotypes since they are established risk factors for depression. There is a need for further research into the alignment of metabolic and neuropsychiatric disorders, and monosodium glutamate may be a very efficient biochemical tool to study this comorbidity.
Conclusion and Future Directions
These recent studies provide significant preclinical evidence that supraphysiological doses and/or the parenteral route of monosodium glutamate can consistently induce depressive-like phenotypes in animal models. The neurobiological mechanisms include oxidative stress and neuroinflammation; glutamate excitotoxicity; neurotransmitter system dysfunction, etc. The involvement of the gut-brain axis and its increasing understanding point to the fact that changes in the gut microbiota due to the effect of dietary glutamate may affect mood disorders by affecting neurotransmitter regulation. 
The monosodium glutamate-induced model incorporates aspects of neurologic, metabolic, and inflammatory pathways in the understanding of depression. It reinforces that future therapeutic strategies for depression could make use of a multi-target approach to enhance efficacy. This model also helps to understand the profound impact of early life stressors on long-term mental health. This forms the neurodevelopmental basis of depression.
Future research should be focused on methodological standardization, improved translational relevance, evaluation of chronic effects, better delineation of mechanistic effects, robust human studies, and adoption of more protective interventions in the still evolving monosodium glutamate model of depression.








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High doses of MSG and/or Parenteral  route


Build up of ammonium ions in metabolic organs


Exacerbation of Metabolic disorders


Accumulation of ROS


Accumulation of glutamate and overstimulation  of  glutamate receptors



Depression


Deficits in Monoamine Levels


Deranged HPA Axis/ Stress Response


Abnormal Glutamate transmission and others


Brain Structure Dysfunction and Neurotrophic Factor Dysregulation


2

