PART 2: GLUTAMATE SENSITIVITY REAL? MYTHS ABOUT GLUTAMATE, MSG AND MORE

Medically Reviewed by Dr. Sony Sherpa, (MBBS) - September 10, 2024

This article aims to review the current literature available to disentangle fact from fiction regarding dietary glutamates, MSG, and glutamate sensitivity:

• Part 1 introduces glutamate and its functions in the body, possible benefits, and myths pertaining to MSG consumption.
• Part 2 (below) covers the safety and toxicity of glutamate, possible side effects, risk factors, and tips for supporting optimal glutamate metabolism.

Toxicity & Safety: Are There Side Effects to Consuming Glutamate?

Excessive glutamate consumption has been associated with adverse effects. However, most people do not consume it in sufficient quantities to experience problems. At acceptable concentrations, studies confirm that it is safe.

Added free glutamate in the form of MSG, hydrolyzed proteins, protein isolates, maltodextrin, and yeast extracts typically increase concentrations above that found in natural whole foods. Therefore it is reasonable to conclude that a diet high in these refined products may contain sufficient levels of free glutamates to pose a risk to health. This is especially true of susceptible individuals and infants.

Safe and Toxic Glutamate Concentrations

It’s difficult to say for sure at what dose free glutamate may be unsafe to consume, both as a once-off amount and chronically. MSG is one of the most studied forms of free glutamate and is also often a by-product present in other refined flavor-enhancing agents and protein formulations.

Evaluations for MSG toxicity concluded^[1]:

• At doses of up to 5000mg per kg of body weight per day, there were no adverse effects in rats over a short-term period.
• Once off administration was confirmed as safe for doses under 5250mg per kg of body weight in rats.
• The spleen and kidneys of test subjects were shown to be enlarged when fed short-term daily doses of 939mg per kg body weight for male rats and 1039mg per kg body weight for female rats. These effects were not associated with increased risk for disease until dosage exceeded safe levels.
• Infantile rats were shown to be the most vulnerable to potential adverse effects of MSG.

Levels considered safe to consume and implemented in food additive legislation are set at a fraction of those found to be toxic in animal studies. Average daily MSG consumption across the population has been estimated at roughly 0.3-1g; well below the doses administered in studies. Infants that consume protein-rich baby formulas are perhaps at the highest risk for glutamate overload^[2] and potential adverse developmental effects.

More studies are required on the long-term effects of chronic consumption of free glutamates, at low quantities in healthy subjects, as well as on high-risk sensitive individuals with health conditions.

9 Potential Side Effects of Free Glutamate Overload

MSG has generated many inconsistent results across studies, some of which point towards potential for adverse effects. This highlights the need for more research to clarify interindividual differences regarding free glutamate consumption.

Potential side effects elicited by MSG may include:

1. Ferroptosis. In vitro, MSG is capable of promoting ferroptosis, which is a specific type of cell death pertaining to iron overload. Ferroptosis is most relevant to red blood cells, however, studies show that MSG can induce it in neurons.^[3]
2. Blood Pressure. High-dose MSG consumption has been associated with elevated blood pressure in both healthy people and those with hypertension, over a 5-year period.^[4] Rat studies confirm these observations, revealing that MSG reduces vasodilation, increases blood clotting factors, and promotes an increase in blood sodium levels.^[5]
3. Taste Perception and Craving. A diet high in MSG over the course of a month was shown to diminish the perception of umami taste, the flavor that MSG is able to enhance. This diminishing return was accompanied by a reduced craving for savory foods.^[6]
4. Hypothalamic Lesions. A number of studies have made mention of hypothalamic lesions that developed in lab rats treated with MSG. One study revealed that a small portion of hypothalamic neurons live just outside the blood-brain barrier and that these neurons are susceptible to MSG-induced neurotoxicity.^[7] Toxicity has been linked with MSG-induced reductions in Brain Derived Neurotrophic Factor (BDNF) in the hypothalamus^[8]. These neurons were shown to rapidly repair in the week following toxicity, growing in number after insult.
5. Improper Development. Infantile rats given MSG have been shown to be at a greater risk for developing obesity, neurological deficits, visual problems, and reproductive disorders during their adult lives. During infancy, the blood-brain barrier has not developed properly, and a greater diversity of molecules are able to pass. Furthermore, developmental outcomes may be a result of the effects of MSG on the developing pituitary-hypothalamus axis^[9], which has been shown to induce knock-on effects in the thyroid^[10], thymus, liver, adrenal glands^[11], and reproductive organs.
6. Innate Immune Suppression. The innate immune system characterizes the local defense systems of every cell in the body. MSG may be able to inhibit innate allergic reactions and immune reactions towards foreign material, as shown in vitro in the spleen cells of mice and rats. The regenerative capacity of these cells was also hampered.^[12]
7. Immune Cell Aggravation. High-dose MSG administration in vitro and in animal studies has proven to promote an inflammatory immune cell profile while reducing the immune production of anti-inflammatory compounds. At large enough concentrations, results reveal that MSG is capable of inducing gene damage in lymphocytes and eventual cell death. Treated animals displayed an increased rate of thymus atrophy, indicative of age-related immune changes.^[13]
8. Insulin Resistance. While not documented in all rat studies, some studies revealed that MSG can induce insulin resistance, accompanied by faulty fat metabolism, and abnormal growth of pancreatic cells.^[14][15] This suggests that free glutamate may increase the risk of diabetes and other metabolic disorders in some individuals.
9. Oxidative Stress and Inflammation. In animal studies and in vitro, MSG has been shown to promote oxidative stress and related inflammation in a number of tissues. These include the brain, liver, kidney^[16], spleen, and thymus.^[17] In large doses, the inflammation is capable of inducing pathological changes in these tissues. However, nutrients have been shown to offset the inflammation induced by high-dose MSG through increasing cellular antioxidant levels.^[18]

Risk Factors for Glutamate Sensitivity

Any factor that disrupts the regulation of glutamate in the body can serve as a risk factor for glutamate sensitivity and eventual toxicity.

Ultimately, glutamate’s required use is the factor that regulates its levels across tissues^[19]. If it cannot perform a function due to a deficiency of another cofactor in a reaction, there will be an excess of glutamate available. This may then lend itself to promoting an imbalance in another area of cellular metabolism. In neurons, that may manifest as glutamate-induced excitotoxicity. In other body tissues, it may promote an increase in cellular activity that eventually generates excessive inflammation or growth.

Small increases and decreases in glutamate levels are natural and not likely to be of any concern unless fluctuations fall outside of healthy ranges. Chronic cellular deficits in metabolism can eventually promote excesses and deficits in glutamate that predispose individuals to glutamate sensitivity.

Glutamate Sensitivity Risk Factors may include:

• Folate deficiency may increase the risk for glutamate sensitivity, as folate utilization in the nervous system requires glutamate, and folate deficiency is associated with excessive glutamate levels.^[20] Severe folate deficiency can increase homocysteine levels and promote blood-brain barrier permeability^[21], potentially allowing for blood glutamate to enter the brain. Folate reduces homocysteine levels and has been shown to protect against glutamate-induced excitotoxicity^[22]. Folate and glutamate are usually coupled together in dietary sources to maintain a healthy balance, yet fortification of foods with MSG may offset this ratio.
• Glutamine Deficiency. Body glutamate is additionally regulated by glutamine. Elevated glutamine is associated with lower glutamate and better overall health status. Glutamine deficiency is known to promote glutamate excess and is associated with: all-cause mortality^[23], alcoholic liver diseases^[24], diabetes risk^[25], worse prognosis for those with cancer or cardiovascular conditions^[26], and eventual heart failure^[27]. Those deficient in glutamine may be more sensitive to free dietary glutamates. Luckily, the majority of ingested glutamate is bound and likely to be converted into glutamine or other beneficial amino acids in the intestine.
• Hyperammonemia. A diet high in glutamate may be contraindicated in those with hyperammonemia, who are prone to having excess glutamate in the liver and bloodstream. Glutamate is essential for generating ammonia and urea from protein. Excessive dietary intake is likely to contribute significantly to symptoms of hyperammonemia. More research is required before conclusions can be drawn.
• Symptomatic Individuals. There is a trend for participants across studies to respond negatively to MSG if they already suffered from symptoms known to the MSG symptom complex. For instance, frequent migraine sufferers were more likely than other participants to acquire a headache from consuming MSG-enriched foods. This suggests that MSG may increase the nature of a pre-existing problem or may be unrelated. While further research is required to clarify this concern, those who suffer from frequent headaches, gastrointestinal upsets, skin and respiratory ailments, as well as musculoskeletal disorders may be at an increased risk for glutamate sensitivity.
• Neurodegenerative Diseases. As explained above, dietary-free glutamate may be problematic for patients with neurodegenerative disorders. In some individuals, MSG has the potential to promote a rise in blood glutamate concentrations. Coupled with altered brain glutamate metabolism and increased blood-brain permeability common to these diseases, elevations of blood glutamate are likely to exacerbate neurodegenerative processes. In individuals with a compromised blood-brain barrier, consumption of free glutamates is likely to increase the risk of developing a neurological condition.
• Insulin Resistance. As mentioned above, those with diabetes, metabolic syndrome, or who are at a higher risk for developing insulin resistance (e.g. those with hyperlipidemia, hypercholesterolemia, stress disorders, etc) may wish to moderate consumption of free glutamates; particularly if they experience symptoms post consumption of meals high in free glutamate.
• Liquid Administration. While most results have been inconclusive, limited evidence indicates that liquid administration of MSG may have a higher propensity for eliciting adverse reactions in sensitive individuals, at lower quantities. Liquids are known to pass more easily over into the spleen and be more bioavailable than solids in general, yet no comparison has ever been tested with regard to MSG fortification.
• Infrequent Consumption. One study revealed that sensitive individuals who suffered an initial reaction to MSG became more resilient in response to a second dose^[28]. Thus it may be that frequent consumers of MSG manage it better than those who avoid it. More research is required to fully understand this finding.
• Age and Gender. Of those affected across studies, females appeared to react more to MSG than males on average. In animal studies, infantile and aged specimens were at a higher risk for developing adverse effects from MSG administration, with infants being the most vulnerable.

Supporting Optimal Glutamate Metabolism

Dietary glutamate cannot be avoided entirely without promoting severe nutritional deficiencies. Added glutamate also need not be avoided completely, if one leads a healthy lifestyle that supports optimal glutamate metabolism throughout the body. This implies consuming a balanced diet plan that enhances health and well-being.

A few specific nutrients that were proven to protect against MSG toxicity include:

• Optimal omega-3:omega-6 ratio. Supplementation of omega-3 and 6 in the right ratios to breast-feeding rats protected suckling offspring from MSG-induced obesity, metabolic imbalances, and developmental deficits.^[29]
• Tannins were shown to protect against MSG-induced cellular inflammation^[30]. Red wine, teas, and some herbs are particularly rich in tannins.
• Alpha-tocopherol is possibly protective against MSG-induced kidney inflammation and toxicity.^[31] Dietary sources include nuts and seeds.
• Dietary GABA is able to pass the blood-brain barrier in small quantities and is protective against glutamate-induced toxicity^[32]. It’s produced by the gut microbiome and can be found in fermented products, butter, and whole foods containing bound glutamates.
• Floral extracts may offset some of the adverse effects of MSG-induced neuroinflammation in rats.^[33] Some floral extracts, such as chamomile, serve to activate GABA receptors, mimicking the effects of dietary GABA.

Alongside antioxidant nutrients that appear to regulate free glutamate, fruits and vegetables contain higher concentrations of less bioavailable forms of glutamate which serve to minimize potential reactions. Therefore, trading refined sources of glutamate for natural whole food sources may prove helpful for sensitive individuals.

Conclusion

Glutamate is a protein salt vital to regulating many bodily functions and can be found prolifically throughout the human diet in both free and bound forms. The majority of those consuming glutamates do not experience adverse reactions, irrespective of dose, delivery, or frequency.

Free glutamates, inclusive of MSG, are associated with inducing allergenic symptoms in sensitive individuals, who comprise a small subset of the population. The symptoms and their severity are not predictable, and neither are the conditions giving rise to them. Adequate nutrition status appears to regulate dietary and body glutamate, as does optimal metabolic health. Infants as well as those with neurological, metabolic, or cardiovascular diseases and/or nutritional deficiencies may be at an increased risk for glutamate sensitivity.

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