Headache and migraine are one of the most common neurological disorders affecting nearly 16% of the US population [1]. Migraine can be a severely debilitating condition and has been evaluated to be the 2nd highest cause of years lived with disability and 1st among women between the ages of 15 and 49 years old [2]. Headache is persistently one of the top five most common reasons for emergency department visits [3]. Furthermore, the annual direct health care costs for patients with migraine in the USA is estimated to be $22,364 per person, and a greater indirect total cost estimate of over 19 billion dollars [4]. While over the past several decades there has been advancement in understanding the pathophysiology of migraine, there is still much to be understood about this painful and disabling condition.

Management of headache disorders and migraine involves a multipronged approach, and can include lifestyle modifications, medications, procedures, as well as other therapeutic regimens. Common lifestyle modifications may be recommended by healthcare providers that include reducing stress, improving sleep habits, increasing exercise and altering dietary composition [5]. Historically, the relationship between diet and migraine and other headache disorders has been controversial and is frequently debated. Diets including a ketogenic diet, IgG-based elimination diet, high omega-3/low omega-6 diet, low glycemic index diet, and a vegan diet have been shown, through randomized clinical trials (RCTs), to reduce headache/migraine pain and/or severity [6,7,8,9,10]. Several studies have highlighted how the intake of certain foods and drinks may potentially be a trigger for headache disorders (Table 1) [11]. Many of these foods contain histamine, phenylethylamine, and tyramine, which are established headache triggers [12]. Of these reported triggers, Monosodium glutamate (commonly referred to as MSG) has garnered much controversy over evidence and history of its relation as not just a headache trigger, but a cause of numerous ailments such as indigestion, palpitations, chest pain/tightness, flushing, and dizziness [13]. In this paper, we review the history and evidence of MSG as a trigger for headache and migraine disorders, as well as assessing the negative associations of Asian cuisines for its use of MSG.

Table 1 Common self-reported dietary triggers of headaches and migraine
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MSG, an umami substance, is a sodium salt of glutamic acid. It is naturally found in certain meats, certain cheeses (Parmesan and Roquefort), and vegetables (mushrooms, tomatoes, and broccoli) [14,15,16]. MSG was first derived in 1908 by Kikunae Ikeda in Japan and contains ~ 80% glutamic acid, ~ 20% sodium, and ~ 1% of contaminants and water. At room temperature, it exists as an odorless, white powder that is soluble in both alcohol and water. Subsequent to its discovery in Japan, it became the most widely used food additive to provide a unique savory flavor to food products [17]. While MSG may classically be associated as being an additive in Asian cuisine, several other cuisines use it as a flavor enhancer. MSG can be found in popular fast-food dishes, potato chips, frozen meals, and seasoning blends [18]. However, years later, MSG would become widely labeled as a potential trigger for a plethora of symptoms and etiologies including migraines and other headache disorders [19].

Animal Studies

Numerous pre-clinical studies have been conducted measuring the neurological effects of MSG on mice and other rodents. Onaolapo et al. conducted a study on measuring the effect of low dose MSG on the neuronal morphology and antioxidant effects in mice. Six groups were given one of the following solutions orally: distilled water (control), L-glutamate at 10 mg/kg body, and MSG at 10, 20, 40, and 80 mg/kg of body weight for 28 days. They observed that relative brain weight increased in the mice who were given 40 and 80 mg/kg of MSG compared to distilled water. Histological samples of the mice brains’ found neuronal damage in the cerebellum, cerebrum, and hippocampus. Plasma glutamine and glutamine were elevated but no significant difference in total brain glutamine and glutamate levels were observed [20].

Sadek et al. conducted a study giving MSG and/or lycopene subcutaneously. Compared to placebo, those that received MSG were found to have increased levels of brain and serum cholinesterase, creatin phosphokinase, and lactate dehydrogenase, an increase in lipid peroxidation markers, and a decrease in glutathione [21]. Furthermore, msg was found to cause neuronal death via upregulation of pro-apoptotic Bax proteins. Swamy et al. and Shivasharan et al. assessed giving rats 2 g/kg MSG intraperitoneally. Both studies reported decreased glutathione, decreased locomotor activity, and altered hippocampal neuronal histology [22, 23].

Human Studies

Several studies have been conducted on the relation of MSG and headache in humans, primarily using two approaches with placebo: with and without simultaneous food intake (Table 2). Prawirohardjono et al. conducted a study providing healthy volunteers with either capsules of placebo or MSG (1.5 and 3.0 g/person) during breakfast. No statistically significant difference was seen in the incidence of headache among the treatment and control group [24]. In a similar study, Tarasoff and Kelly conducted a study where placebo and differing levels of MSG were administered before a standardized breakfast over 5 days. They too reported no statistically significant difference in headache incidence among the treatment and placebo groups [25].

Table 2 Studies conducted on the relation of MSG and headache in humans, primarily using two approaches with placebo: with and without simultaneous food intake
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Morselli PL and Garattini S, and Zanda et al. conducted studies providing 3 mg of MSG in 150 ml of beef broth with meals. The former reported no statistical difference in headache incidence, while the latter did report a statistically significant higher incidence of headache among women who received the MSG-containing broth [26, 29].

A number of studies have examined the effects of MSG when not combined with a meal; soda was the primary medium used for MSG administration. Comparable to the aforementioned MSG studies on humans, results were mixed. Studies noting statistical significant differences in headache incidence compared to a placebo include Geha et al. (5 g in 200 ml of citrus-flavored beverage), Baad-Hansel et al. (75 mg/kg or 150 mg/kg in 400 ml of sugar-free soda), and Shimada et al. (150 mg/kg in 200 ml of citrus flavored beverage) [32,33,34]. One of the initial studies examining the effect of MSG on headaches was conducted by Rosenblum et al. Subjects consumed 5 mg of MSG mixed with either tap water or chicken stock, had no significant statistically difference observed when compared to the placebo group [27]. Other studies, which noted no significant statistical difference among the MSG and control groups include studies by Tarasoff et al. (3.15 mg in 300 ml of soda), Gore et al. (1.5–6 g in 150 ml of tap water), and Kenney et al. (1–5 g of tomato juice) [25, 28, 30]. Yang et al. conducted a study providing participants with 1.25–5 g of MSG in 200 ml of a citrus-tasting beverage. While the 1.25 g dose was not found to have a significant statistical difference compared to the placebo, there was a difference with the 2.5 g and 5 g doses [31]. A possible explanation to how MSG could cause headaches includes an overstimulation of glutamate pathways as well as decreased γ-aminobutyric acid (GABA) levels [16].

While some of these aforementioned studies report negative outcomes, it should be noted that the amount of MSG provided is proportionally high compared to what the general public consumes. It has been previously suggested that studies using beverages as a vehicle may not have been properly blinded [35]. Additionally, none of the studies that had MSG administered with a meal reported a statistically significant difference in the incidence of headache. The average intake of food-added MSG in the USA, Europe, the UK is estimated to be 0.6 g/day [32, 36, 37]. MSG consumption in East Asia appears to be higher, with intake rates reported to be 1.1–1.6 g/day in Japan and 1.6–2.3 g/day in South Korea [38, 39]. Consumption of MSG has been linked to hypertension and obesity; however, these studies included participants who consumed higher than-average levels of MSG [40, 41]. Conversely, it is reported that MSGs dietary element may stimulate the intake of foods high in protein and bolster several physiological activities, such as intestinal motility [42].

For individuals who worried that MSG could be a trigger for headaches or migraines, an elimination diet might serve as an effective diagnostic method. An elimination diet involves the exclusion of a suspected dietary component for a period of 4–6 weeks to analyze how it affects an individual’s symptoms [43, 44]. If there’s no noticeable improvement in the individual’s headache symptoms after the removal of MSG, then it is likely that MSG is not a contributing factor to their headaches. It is paramount for the individual to ensure that their diet is free of MSG, as there might be various foods and/or additives containing it that they are unaware of.

Chinese Restaurant Syndrome

In 1968, Dr. Ho Man Kwok published a constellation of symptoms occurring after the consumption of Chinese food, dubbed Chinese restaurant syndrome (CRS) [45]. Symptoms included transient facial pressure, burning, chest pain, diaphoresis, palpitations, abdominal pain, headache, and/or nausea. This ill-defined syndrome was later connected with the consumption of MSG. Dr. Kwok, who is of Cantonese descent, would later stress that CRS was in regards specifically to American Chinese food, expressing that he never observed these symptoms prior to coming to the USA [46].

Since then, various publications, tabloids, and medical journals have published the dangers of CRS in the 1970s and 1980s [47]. Kerr et al. described as possible prevalence of CRS to be 1–2% [48]. Several articles describing the condition were published in Nature [49, 50]. Zautcke et al. described CRS as a “benign, self-limited process that has an excellent prognosis for immediate and rapid recovery” [51]. Articles about similar conditions, such as Chinese-Restaurant Asthma, were subsequently published [52]. Several of the aforementioned studies above, such as ones published by Morselli and Gartattini and Gore et al. used the term CRS [26, 30].

MSG was first described as a causative agent of CRS and headaches in 1969 by Schaumburg et al., where they conducted a small double blind experiment (n = 56) with soup, with varying amounts of MSG, and measuring the incidence of headaches following consumption [53]. While the relation of MSG and headaches is still debated, there is some evidence for it being a trigger of headache attacks. However, it is important that patients who believe MSG to be a trigger know what foods contain it. As previously mentioned, it is a common misnomer that Chinese and other Asian cuisines are the most common sources of MSG. Many fast-food and chain restaurants frequently contain MSG in their dishes [54]. MSG use in the USA is widespread and often found in frozen vegetables, condiments, breakfast cereals, and even baby food [16]. MSG can also be found in different spices such as Sazón, a popular seasoning used in Hispanic dishes [55]. Various articles and studies have been published on CRS since the late 1960s, even though MSG had historically been used in cooking much earlier [46]. Even as recent as 2023, there are still publications that use the term CRS and give reinforcement that it is still a legitimate condition associated solely with Chinese food [56]. In light of the increase in hate crimes against people of Asian, Asian-American, and Pacific Islander ancestry since the COVID-19 Pandemic, it is vital to debunk myths surrounding certain ethnic cuisines as being a trigger for discomforting symptoms.

Conclusion

In this narrative review, we reviewed the history of MSG, as well as the studies assessing the effects of MSG on animals and humans. While previously accused of causing various symptoms labeled as CRS, the evidence whether MSG may cause symptoms such as headache is mixed. Yet, there are several studies that demonstrate a statistically significant increase in headaches when compared against placebo. For individuals who are concerned how MSG may be a headache trigger, we recommend completing a thorough elimination diet of MSG. Further studies assessing the effects of MSG and headache are warranted.