Monosodium glutamate: Review on clinical reports

ABSTRACT

Monosodium glutamate is made up of nutritionally indispensable amino acids and used as flavour enhancer worldwide. Monosodium glutamate is believed to be associated with different health problems. This study is aimed to shed light on the available literature from last 25 years about different clinical trials which had been carried out on animal and human models regarding possible effects of monosodium glutamate. Google scholar, NCBI, PUBMED, EMBASE, Wangfang databases, and Web of Science databases were used to retrieve the available studies. Literature showed that monosodium glutamate was associated with adverse side-effects particularly in animals including induction of obesity, diabetes, hepatotoxic, neurotoxic and genotoxic effects. Different reports revealed increased hunger, food intake, and obesity in human subjects. Limited studies have been carried out on humans to check possible hepatotoxic, neurotoxic, and genotoxic effects of monosodium glutamate. Available literature showed that increased consumption of monosodium glutamate may be associated with harmful health effects. So, it is recommended to use common salt instead of it. Furthermore, intensive research is required to explore monosodium glutamate–related molecular and metabolic mechanisms.

KEYWORDS:

• Diabetes
• Hepatotoxicity
• Monosodium glutamate
• Neurotoxic
• Obesity

Introduction

Monosodium glutamate (MSG) is one of the most abundantly found amino acid in nature. It is present in heterogeneous group of foods as a flavour enhancer and used either as food additive (E621) in the form of hydrolysed protein or as purified monosodium salt.^[1] For the first time (1908), MSG was discovered in Japan from seaweed as a flavour enhancer and in pesticide/fertilizer as AuxiGro WP Metabolic Primer (AuxiGro). At earlier times, MSG and glutamic acid was produced by extraction, which was a slow and costly method. It was first introduced in the United States in the late 1940s. Later on (1956), large-scale production of MSG and glutamic acid was successfully achieved by fermentation. Since 1957, in the United States MSG, was produced by bacterial fermentation involving genetically modified bacteria which secrete glutamic acid through their cell walls.

Figure 1. Metabolic cycle of dietary glutamate and α-ketoglutarate in the intestinal enterocyte^[16].

Figure 2. Metabolic cycle of dietary glutamate in the intestine^[16].

In 1960s MSG had become a household word. Hydrolyzed protein products such as vegetable protein, sodium caseinate, and autolysed yeast become much popular. Every hydrolysed protein product contains processed free glutamic acid. It had same neurotoxic properties and flavour-enhancing potential just like processed free glutamic acid present in MSG. In the early 1970s, manufacturing companies voluntarily replaced MSG with hydrolysed vegetable protein and autolysed yeast in baby food. All MSG-containing ingredients were eradicated from baby food but remained in infant formula in the late 1970s. Because in early ages, MSG usage was responsible for increasing temperature, decreasing body mass, and less production of fat tissues. In the last 30 years, MSG usage has greatly increased. Now it is found in frozen entrees, crackers, canned tuna, soups, processed meats, cosmetics, dietary supplements, infant formula, salad dressings, vaccines, and in many other food products.^[2] Concentrations of MSG in different foods are listed in Table 1.^[3,4]

Table 1. Concentration of MSG in a variety of common foods^[3,4].

Food	Concentration (mg/100 g)
Cow milk	2
Apple	13
Human milk	22
Eggs	23
Beef	33
Chicken	44
Almond	45
Carrot	54
Onion	118
Garlic	128
Potato	102
Walnut	757

Monosodium glutamate usage in varied cultures

MSG is used by consumer and institutional food service providers in a negligible amount in animal feed, food processing industry, and restaurants. Now, a new chelating agent, glutamic acid N,N-diacetic acid tetrasodium salt (GLDA), is also used in some countries. According to a report (2014), Asia was the largest producer of MSG, accounting for approximately 94% of worlds’ MSG production capacity. High demand, economic and abundant workforce, and its use in feed stocks might be the reasons behind its large-scale production in Asia. Taiwan, Indonesia, China, Thailand, and Vietnam are the major MSG producers. China is one of the top producer (65%), consumer (55%), and exporter (44%) of MSG worldwide. Indonesia is the second largest (16%) exporter of MSG. It was reported that Middle East and Africa consumed 4%, Europe 3%, North America 2%, and central and South America 2% MSG.^[5] Some of the reasons behind twofold increased in MSG consumption worldwide are as follows.

• In Asian countries, MSG demand was increased because of changed dietary patterns, increased urbanization, improved living standards, and continuous development in food processing industry.

• Another reason of increased MSG consumption in West Africa may be its common use in their diet like soup, rice, noodles, and potatoes.

• Increased participation of women at work place, expansion of the middle class, and busier lifestyles are considered to be the possible causes behind increased MSG consumption in Brazil and many other countries.

Contrary to this, MSG was forbidden in some countries like the United States, Mexico, and Canada due to increasing concerns about obesity. Some advantages of MSG usage are as follows: (i) its taste is umami; (ii) it reduced the use of salts and fats without altering the taste; (iii) due to the presence of one-third of sodium, it can be used as a substitute of table salt; (iv) it is used in some patient’s (who have lost the apatite) diet to develop favourable taste; (v) MSG consumption increased in food industry due to its easy availability, consumer likeness, and cost-effectiveness;^[6] (vi) it is used as a fuel for digestive system to enhance body metabolism.

Biochemistry of monosodium glutamate inside human body

Glutamate is the main excitatory neurotransmitter in the body. Multiple glutamate transporters and receptors are found in our gastrointestinal tract and nervous system. Gut, particularly intestine, is the major site for several amino acids’ catabolism, mainly nonessential amino acids like glutamine, glutamate, and aspartate. In liver, large amount of ATP is produced by the conversion of amino acids into glucose.^[7,8] Evidence from human and animal studies showed that glutamate was extensively oxidized in gut and intestine. It is metabolized in enterocytes. First, glutamate is transported from intestine to lumen across the apical membrane. Main transporters of glutamate and glutamate–aspartate are EAAC-1, GLT-1, and GLAST-1. Among these transporters, EAAC-1 expression is restricted mainly to small intestine, and GLAST and GLT-1 expressions are restricted in various cell compartments within the stomach.^[9–11] Once inside the intestinal enterocyte, catabolism starts in cytosol and mitochondria by a process called transamination with the help of aspartate aminotransferase, alanine aminotransferase, branched-chain aminotransferase, and glutamate dehydrogenase (GDH) enzymes. α-Ketoglutarate is the end product. It is then metabolized to carbon dioxide by entering the tricarboxylic acid cycle. The un-oxidized carbon atoms are released into portal circulation after being converted into arginine, citrulline, alanine, ornithine, and proline.^[12–14]

It was found that in enterocytes glucose had little effect on glutamine oxidation, whereas glutamine effectively suppressed the oxidation of glucose.^[15] Carbon dioxide production is much less in case of glucose as compared with glutamate or glutamine, because they are channelled towards mitochondria (Fig. 1)^[16] In mitochondria, glutamate is transported by means of glutamate carrier proteins. These carrier proteins act as mitochondrial antiporters for protons or aspartate.^[17]

Several studies indicated that under normal dietary conditions most of the dietary glutamate is either metabolized or oxidized to carbon dioxide by the gut in first pass. However, if glutamate intake is increased to 3–4-fold, then it is mainly used in ATP generation or in conversion of other amino acids. Other than carbon dioxide production, ornithine, glutamine, and aspartate (non-essential amino acids) are the main products of glutamate metabolism (Fig. 2)^[16] Glutamate oxidation affects the oxidation of leucine because of same reaction proximity, that is, gut.^[16]

Evidence of side-effects of monosodium glutamate (MSG) in animal trials

Monosodium has been proved to be toxic for both humans and experimental animals.^[18] Side-effects reported by various studies can be summarized as appearance of anomalies of metabolic/digestive, respiratory, circulatory, and nervous systems.^[19] It was found that exposure of rats to MSG at neonatal stage can severely damage their hypothalamic nuclei (arcuate nucleus and ventromedial nucleus), which results in increased body weight, fat deposition, decreased motor activity, and secretion of growth hormone.^[20]

Induction of obesity and diabetes in MSG-treated rodents

Human diabetic condition had been studied intensively through various experimental models since decades. Diabetes was artificially induced by using different chemicals. In the light of reported literature, MSG appears to be a suitable candidate for inducing obesity which leads to diabetes. In a recent study conducted by Nagata et al.,^[21] it was found that newborn male and female mice injected with (2 mg/g) doses of MSG developed glycosuria and other symptoms by 29 weeks of age.

The MSG-treated mice showed increased blood glucose, insulin, triglycerides, and cholesterol levels as compared with control animals. The pancreatic islets of both male and female mice showed hypertrophy which was considered as progression of diabetes mellitus. MSG-induced diabetic condition in mice was strikingly similar to human type 2 diabetes mellitus. Therefore, these mice were not only considered as ideal models for studying diabetes but also to verify the potential side-effects of MSG treatment in animal trials.

Another experimental study performed on rats confirmed that MSG was a potent chemical for diabetes induction.^[22] Moreover, it was found that potency of MSG as an obesity inducing agent is higher in hypertensive (SHR) rats as compared with normotensive (WKY) Wistar Koyoto rats. Newborn rats were intraperitonially injected with 4 mg/kg of MSG dose for 5 days which resulted in more advanced obesity and higher triglyceride levels in SHR rats as compared with WKY.^[23]

MSG-induced hepatotoxicity and oxidative stress

As liver was involved in detoxification and metabolism, so it may be directly affected by toxic chemicals or their metabolites, for example, MSG. According to Onyema et al.,^[24] rats treated with MSG (0.6 mg/g body weight) for consecutive 10 days start to develop symptoms of liver damage. Significant increase in lipid peroxidation (LPO) and activities of liver enzymes including glutathione-s-transferase (GST), catalase, and superoxide oxidase (SOD) in rat livers were observed. In addition, level of reduced glutathione (substrate for GST) was decreased in liver due to increased activity of GST. It confirms the progression of oxidative damage caused by the production of reactive oxygen species (ROS). Similarly, MSG administration also elevated the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT) in serum.

Tawfik and Al-Badr^[18] also reported similar results with MSG-treated rats (0.6 and 1.6 mg/g body weight) for 2 weeks. Significant increase in the body weight along with relative weight of liver and kidney was observed. Activities of liver enzymes including ALT and GGT were increased, while serum total protein, albumin and bilirubin levels were significantly decreased. Therefore, it can be concluded that MSG treatment might impair hepatic and renal functions by increasing oxidative stress and altering the anti-oxidant enzyme activities.

Neurotoxic effects of monosodium glutamate

Since glutamate was known as an important excitatory neurotransmitter in the central nervous system, its excess leads to excitotoxicity which may cause severe neuronal damage and other complications. Common disorders include ischemia and traumatic brain injury; however, it may result in chronic conditions like amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson’s disease.^[25] A laboratory trial on neonatal rats revealed over-activation of glutamate receptors in brain induced by subcutaneous administration of MSG solutions. The altered biochemical environment also affected total content of all amino acids which collectively induced the behavioural changes including screeching, tail stiffness, head nodding, and generalized convulsions or seizure-like condition in animals.^[26] In another study, Beas-Zarate et al.^[27] investigated the excitotoxic effect of l-glutamate during neonatal periods in Wistar rats. Neuronal degeneration and cyto-architechtural changes in the hippocampal CA1 field were focused. Treated rats showed cellular degeneration of 11.5% in hippocampus as compared with untreated control animals. Furthermore, alterations were observed in dendritic spine density and arborisation resulting in increased proportion of thin and mushroom-shaped spines and decreased occurrence of stubby spines. These modifications suggested the cyto-excitotoxic effect of MSG which ultimately results in altered hippocampal integrity.

Dief et al.^[28] also evaluated the neurodegenerative effect of oral/subcutaneous treatment of MSG in male Wistar rats (aged 5 weeks). It was illustrated that cyclic-AMPK level was reduced in hippocampus by 43% and 31% in orally and subcutaneously treated rats, respectively. In addition, apoptosis-mediating substance known as Fas ligand showed a twofold increase in same region. Thus, it was concluded that MSG acts as a potent neurotoxin by affecting the chemical composition of hippocampus which activates neurodegenerative pathways. Likewise, toxic effects of MSG were monitored in cerebellar cortex of male albino rats. It was found that treated rats with 3 g/kg/day develop areas of degeneration in cortex which were surrounded by granule cells and pyknotic Purkinji.^[29]

Genotoxic effects of monosodium glutamate

Farombi and Onyema^[30] investigated the potential genotoxicity of dietary MSG mediated by oxidative damage in intraperitonially treated rats at dose of 4 mg/g body weight. Significant increase in malondialdehyde (MDA) formation was observed in organs like liver, brain, and kidney, whereas glutathione levels were markedly decreased with an increase in the activity of glutathione-S-transferase enzyme. This was an indication of increased oxidative stress which might have played a mediatory role in exerting the toxic effect at genetic level.^[31] In addition, genotoxic effect was monitored as formation of micronucleus in rat bone marrow cells.

Similar findings were obtained in another study in which MSG-induced oxidative stress mediated apoptosis in thymus cells of rat. It was noted that intraperitonially administered MSG (4 mg/g of body weight) results in enhanced apoptotic rate of thymocytes. An increase in the antioxidant activity of MDA and Xanthine oxidase was also observed. It illustrated significant increase in oxidative stress which might have induced the DNA damage leading to early cell death.^[32] Though, previous animal studies had reported toxic effects of MSG on various physiological aspects. However, literature was deficient in investigations related to its genotoxic effects in animal models.

Clinical trials related to MSG effects on humans

First incidence of side-effects after eating MSG was reported in 1968 and it was called as Chinese restaurant syndrome (CRS). Symptoms included numbness at the back of neck and arms, weakness, and strong rapid heartbeat (palpitations) after ingestion of Chinese meal.^[19] Average intake of MSG in European and Asian countries is generally 0.3–0.5 g/day and 1.2–1.7 g/day, respectively. MSG intake of 16.0 mg/kg of body weight is generally regarded as safe.^[33]

Effect of MSG on hunger and food intake

Many studies had reported increased food intake by adding MSG as flavouring agent. Human subjects (36 volunteers) were given soups with different concentrations of MSG and no MSG and results about hunger and food intake were measured. It was revealed that soups with MSG were called “pleasant,” “more delicious,” and “more satisfying.”^[34] French men (100) were given MSG-added diet (soup and vegetables), and a marked increase in food intake was observed. Increased intake of calcium, magnesium, and fat was also thought to be related to MSG-added food. This might be related with intake of particular kind of food. It was reported that MSG was a palatability enhancer in diet.^[35] Similar results were obtained from another study where 32 volunteers were evaluated for effect of MSG on food intake. They were given soups with and without MSG, and it was noticed that MSG added soups not only increased pleasantness and flavour but also significantly related with increased hunger and intake of food.^[36]

MSG-induced obesity

Numerous animal studies^[37–39] had indicated that MSG performed a potent role of inducing obesity in mice. A study was conducted (752 healthy Chinese) to find relationship between MSG intake and obesity in humans. It was found to be positively correlated with increased body mass index (BMI). MSG users had reportedly increased weight as compared with non-users, which was a finding independent of physical activity and total energy intake.^[40]

While another study indicated that MSG intake was not related to weight gain for the period of 5 years. Without adjusting the parameters of food items and rice eating, a 5% increase in weight was found, but when these factors were also adjusted, obesity due to MSG intake was diminished.^[41] A study conducted on 349 human subjects from Thai population indicated that high doses of MSG caused metabolic syndrome and obesity which was independent of other major factors like total energy intake and level of physical activity.^[42] Another study conducted on German military personnel about morbid obesity indicated that morbid obesity has direct correlation with short stature. Oral administration of MSG on pregnant rats indicated reduction in birth weight of offsprings. It was showed that glutamate maintains its toxicity even upon oral administration. It has been reported that neuronal toxicity, voracity, and altered growth hormone secretion were some of the serious side-effects caused by MSG. Therefore, it was suggested that MSG addition as flavouring agent in food must be avoided.^[43]

Hepatotoxicity

A study was conducted on mice to check the liver inflammation caused by MSG and revealed that all mice developed non-alcoholic fatty liver disease and non-alcoholic liver inflammation with fat accumulation (steatohepatitis). Condition of 12–month-old mice with steatohepatitis was similar with human steatohepatitis to an extent that it was difficult to differentiate between the two conditions. Nakanishi and coworkers^[44] suggested withdrawing of MSG from food chain and re-examination of its safety profile.

Allergic reactions

Schaumburg et al.^[45] reported that MSG triggers different symptoms like headache, chest pain, burning sensation, and facial pressure. Another double-blind clinical trial of 61 subjects was carried out and showed statistically significant complex symptoms after ingestion of MSG as compared with placebo. MSG symptom complex included headache, muscle tightness, numbness tingling, general weakness, and flushing. Severity and frequency of symptoms both were greater as compared with placebo.^[46] Some of the reactions after eating MSG includes abdominal discomfort, urticaria (skin rashes), ventricular arrhythmia (abnormal heart rhythms in ventricles), asthma, neuropathy (dysfunction of peripheral nerves particularly numbness and weakness), and atopic dermatitis (inflammation of skin resulting in itchy, red, swollen, and cracked skin). Study with 130 subjects indicated that when MSG was given without food it triggered some reactions, while these reactions abolished in the presence of food. Different epidemiologic surveys which were carried out to find the association between MSG intake and CRS indicated a very low or negligent relation between the two variables. From 3222 subjects only 1.8% responses can be classified as possible CRS.^[19] Matthew Freeman^[47] has reviewed seven different studies about MSG causing asthma symptoms or not and concluded that these studies cannot be a substantial evidence for potent role of MSG in asthma because of smaller subject size and objectionable study design.

Conclusion

It was concluded that MSG was used as a flavour enhancer in heterogeneous food groups including food industry and common household. No doubt it is wonderful in taste and induces urge to eat more food and particularly helps to eat food in some patients facing loss of appetite. The Food and Drug Administration (FDA) declared it safe for limited usage and enlist several potential side-effects linked to increased MSG consumption. Cardiac, circulatory, gastrointestinal, muscular, and neurological disorders are some of the common examples. All existing MSG forms cause these problems in MSG-sensitive individuals. Clinical trials of human and animal subjects also suggested various potential health hazards and the extrapolation of animal model results to humans is much demanding and strenuous. Excess of everything was bad, so MSG utilization up to certain level does not have any adverse effects because glutamate is a nutritionally indispensable amino acid. Therefore more detailed and vigorous studies are required to check the underlying cause of aforementioned drastic health effects. Studies should be designed to reveal the truth behind the complexity of MSG-related regulatory mechanisms.

Acknowledgements

We are thankful to Dr. Naila Safdar (Fatima Jinnah Women University, The Mall, Rawalpindi) for her useful discussions related to this review article.

Funding

No support or funding is available for this study.

Additional information

Funding

No support or funding is available for this study.