Summary of findings
1. (-1 limitations) we were uncertain of methods for randomisation
2. (-1 indirectness) participants are different in each trial (Schwartzstein 1987: chronic asthma and Woods 1998: people who perceived themselves MSG-intolerant) and we would not expect the same treatment effect in these two trials (unless the treatment is ineffective)
3. (-1 imprecision) small trials with few events
Monosodium glutamate (MSG), a flavour enhancer, is the sodium salt of the non-essential amino acid, glutamic acid. Glutamate is present in almost all proteins, and it plays an essential role in human metabolism as a key component of metabolic cycles (Filer 1994). Because there is no chemical difference between the MSG we find in foods and the MSG manufactured through fermentation by micro-organisms, the effects of MSG on the body are the same.
Kwok 1968 originally noted that MSG may cause adverse reactions; he wrote a letter to the New England Journal of Medicine to explain how he felt after eating MSG in a Chinese restaurant. The symptoms were tightness, burning or numbness in the face, neck and upper chest. This syndrome was named "Chinese Restaurant Syndrome". Kwok hypothesised that this syndrome could be due to MSG, sodium or some other unidentified substance. In 1981, Allen and Baker reported two cases of asthma and proposed an association between asthma and MSG (Allen 1981). Over the last two decades there have been a number of studies investigating whether MSG ingestion can induce an asthmatic response, but results are conflicting.
Although there are hypotheses about the mechanisms of MSG-induced asthma, for example, mediated by immunoglobulin E (IgE; a class of antibody found in mammals) or acetylcholine, findings are inconclusive. Yoneda 2011 investigated the effects of MSG on bronchial inflammation; they measured cytological, histological and functional changes in an ovalbumin-induced asthma mouse model, but found no acute effects on lung inflammation or airway hyper-responsiveness.
The objectives of this review were to:
- identify randomised controlled trials (RCTs) of monosodium glutamate (MSG) ingestion and asthma response in adults and children older than two years of age with asthma;
- assess the methodological quality of these trials; and
- determine the effect of MSG ingestion on asthma outcomes.
Criteria for considering studies for this review
Types of studies
We included RCTs only, with either parallel or cross-over design. We preferred double-blind trials, but we also reviewed single-blind and open studies for possible inclusion. We did not limit inclusion of trials by their duration.
Types of participants
We included adults and children older than two years with a diagnosis of asthma. We accepted trialist-defined asthma and recorded both the definition of asthma and the entry criteria used for each trial. We excluded studies on patients with acute asthma or exercise-induced bronchospasm because it is difficult to identify whether the attack of asthma is caused by MSG. We considered studies which included patients with other conditions only if the results for subjects with asthma could be identified separately. We excluded studies in children less than two years of age.
Types of interventions
We included studies involving either a challenge of MSG to the diet, manipulation of dietary intake of MSG, or both. We considered only the oral route of administration (for example, capsule or liquid etc). We included placebo and untreated control groups.
Types of outcome measures
We anticipated that not all studies would have results pertaining to the entire outcome measures listed below, but included all outcomes that were reported or available through contact with the authors.
- Lung function measurements, such as forced expiratory volume in one second (FEV
1), peak expiratory flow (PEF) or forced vital capacity (FVC)
- Hospital admissions
- Asthma symptom scores
- Bronchial hyper-responsiveness (BHR)
- Soluble inflammatory markers, such as eosinophil cationic protein (ECP) and/or tryptase
- Asthma medication usage
Search methods for identification of studies
We searched the Cochrane Airways group "Asthma and Wheez* RCT" ProCite Specialised Register, with no language restrictions. We performed the latest search in May 2012.
We used the following search terms:
MSG or "monosodium glutamate*" or monoglutamate or monosodiumglutamate or *sodium or sodium* or glutam* or Glutavene or L-glutamic or L-glu or accent or vestin or (food* and (salt* or additive* or flavour* or flavor*)).
Searching other resources
We searched bibliographies of existing trials and approached primary authors of eligible trials and MSG manufacturing companies to ask if they were aware of any other published or unpublished trials. We also searched trial registries for current or recently completed trials.
Data collection and analysis
Selection of studies
Two review authors (YZ, MY) reviewed the title and abstract of references returned by the searches to identify potentially relevant trials for full review. Then we independently read the abstract and methods sections of the papers to select the trials for inclusion in this review. We resolved differences between reviewer authors by consensus.
Data extraction and management
Two review authors (YZ, MY) independently extracted data for inclusion in the Characteristics of included studies tables. We contacted the principal investigators of included studies, when necessary, to request additional data or confirm methodological aspects of their study. We combined trials using Review Manager 5.1 software (RevMan 2011).
Assessment of risk of bias in included studies
We assessed the risk of bias in the included studies as either 'high', 'low' or 'unclear' using the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2011a) under the following headings: 1) sequence generation; 2) allocation concealment; 3) blinding; 4) incomplete outcome data; 5) selective outcome reporting; and 6) other potential bias.
Measures of treatment effect
Lung function measurements included the forced expiratory volume in one second (FEV
Unit of analysis issues
We planned to combine data from cross-over studies using generic inverse variance in Review Manager 5.1 software (RevMan 2011).
Dealing with missing data
We requested information from the trial authors when sufficient details were not available in the published reports to conduct analyses.
For binary outcomes, we used data from intention-to-treat analyses. If intention-to-treat data were not available in the publications, we used 'on-treatment' data (i.e. the data of those who complete the trial) and indicated it as such.
Assessment of heterogeneity
We had planned to measure statistical variation between studies using the I
Assessment of reporting biases
We had planned to visually inspected funnel plots to test for publication bias if we had found sufficient trials on a single meta-analysis.
We had planned to combine data in Review Manager 5.1 (RevMan 2011) using a fixed-effect mean difference (MD) and the 95% confidence intervals (CIs) for continuous variables measured on the same scale. We would have calculated the standardised mean difference (SMD) and 95% CIs for variables measured on different scales. We had planned to use a fixed-effect odds ratio (OR) for dichotomous variables. We had planned to compare random-effects and fixed-effect models; if we found a major difference in the pooled effect sizes and their 95% CIs, we would have opted for the random-effect model.
Subgroup analysis and investigation of heterogeneity
We had planned to perform the following subgroup analyses if we had found sufficient data:
- MSG versus placebo:
- MSG versus no treatment;
- low dose versus high dose; and
- adults versus children.
We had planned to perform sensitivity analyses if we had found sufficient included trials to explore the influence of the:
- risk of bias for allocation concealment; and
- risk of bias for outcome evaluation.
Description of studies
Results of the search
From the preliminary searches (latest search May 2012) we found a total of 86 references. By searching bibliographies of existing trials, we identified five additional studies. After removing 15 duplicate references from the searches, we identified 76 studies as potentially relevant; only two of these studies met the entry criteria and we included them in this review.
Both studies that met the inclusion criteria were double-blind, randomised, cross-over trials that recruited adult participants (Schwartzstein 1987; Woods 1998). Full details of these included studies can be found in the Characteristics of included studies section.
The purpose of the Schwartzstein 1987 trial was to study the effect of oral MSG on airway function in 12 subjects with a history of chronic asthma (diagnosed using criteria from the American Thoracic Society). Participants had a history of food sensitivity, or not, and they were clinically stable. Clincal stability was defined as: 1) no increase in symptoms requiring medical attention within the past month; 2) no participants receiving corticosteroid therapy for at least one month; and 3) being able to discontinue medications for at least 12 hours without adverse effects. The article did not report how the participants were recruited. The participants (eight men and four women) were 22 to 44 years old (mean 28 years), and the mean duration of asthma was 16 years (3 to 30 years). None of the participants used bronchodilators within 12 hours of the challenges. Two participants had a history of milk sensitivity, and only one subject believed that she was MSG-sensitive. Six subjects were receiving bronchodilator therapy on a daily basis. The interventions were MSG (25 mg/kg) versus sodium chloride (equimolar to MSG), given in identical capsules. Subjects fasted for at least six hours prior to study visits. The forced expiratory volume in the first second (FEV
The main purpose of the Woods 1998 trial was to determine if MSG would induce bronchoconstriction in adults with asthma who perceived they were MSG-sensitive. Twelve participants were recruited through The Alfred Hospital Asthma and Allergy Clinic, from patients registered on a computer database, between March 1995 and September 1996. The participants were aged between 19 and 57 years (mean 35.3 years), and seven (58%) of them were female. All of the participants had a history of reversible airway obstruction, however, they had been clinically stable without any change in their regular asthma medications in the past four weeks before the study. The study exclusion criteria were: 1) a previous life-threatening attack of asthma; 2) life-threatening anaphylaxis; 3) females who were pregnant or lactating or 4) a baseline FEV
We excluded 74 references for the following reasons.
- The studies did not examine the relationship between MSG and asthma (N = 45).
- They were review articles (N = 10), rather than trials.
- The studies were not randomised (N = 9).
- The studies involved subjects with diseases other than asthma (N = 10).
Full details can be found in the Characteristics of excluded studies table.
Risk of bias in included studies
We judged risk of bias in included studies as unclear using the Cochrane Collaboration's 'Risk of bias' tool (see Figure 1, Figure 2). Our judgement of each risk of bias can be found in Characteristics of included studies.
|Figure 1. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.|
|Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.|
Both studies (Schwartzstein 1987; Woods 1998) were reported as randomised, but gave no information of the methods used, and we therefore judged them to be at unclear risk of bias. Schwartzstein 1987 did not describe the allocation concealment, but there was reference to personnel carrying-out the randomisation in Woods 1998, and so we judged the latter as low risk of bias. Subjects and investigators were blinded as to the identity of the medications. Because of the unique flavour of MSG, capsules were used in both studies so that participants were unable to tell the difference between a capsule containing MSG and one containing placebo. All of the outcomes were reported according to the protocol. Schwartzstein 1987 was supported in part by the International Glutamate Technical Committee, and we are unsure if such sponsorship would influence the result.
Effects of interventions
Two cross-over trials involving a total of 24 subjects were included, with all subjects being exposed to MSG and control interventions. Both reported changes in FEV
We were unable to perform meta-analyses because of the heterogeneity of the studies. The participants in included studies were different; Schwartzstein 1987 included people with chronic asthma, with or without a history of food sensitivity, and Woods 1998 included people with clinically documented asthma and who perceived themselves MSG-intolerant). Furthermore, to be able to combine dichotomous data from cross-over studies, we would need to know the number of participants who form discordant pairs, but this information was not reported in Schwartzstein 1987. Hence, we presented the results in narrative form.
Primary outcome: lung function
In Woods 1998, eight out of 12 people experienced a fall in FEV
Schwartzstein 1987 gave only one MSG challenge of 25 mg/kg. Schwartzstein 1987 reported the mean FEV
In summary, there was no statistically significant difference between MSG and placebo for a positive FEV
Woods 1998 reported that there were no statistically significant differences in daytime or night time symptom scores between placebo and 1 g MSG challenges (P = 0.5 and P = 1.0, respectively), placebo and 5 g MSG challenges (P = 1.0 and P = 1.0, respectively), or 1 g and 5 g MSG challenges (P = 0.25 and P = 1.0, respectively). Schwartzstein 1987 reported the number of participants who had unusual sensations (two in the MSG group and two in the placebo group), but did not score the symptoms.
Non-specific bronchial hyper-responsiveness
Woods 1998 found that there was no evidence of MSG affecting non-specific BHR.
Eosinophil cationic protein levels in peripheral blood
Woods 1998reported that five participants had elevated ECP levels following the MSG challenge, however, baseline ECP levels were elevated in four participants. In the fifth subject, the ECP level was raised after both the 1 g and 5 g MSG challenge (the level was higher after the 1 g than the 5 g MSG challenge), but was normal after the placebo challenge.
Tryptase levels in peripheral blood
Woods 1998 found that the only elevated tryptase level occurred on a baseline sample.
This review summarises evidence from two small clinical trials assessing the effects of the MSG challenge on short-term physiological, symptomatic and biomarker outcomes. Long-term dietary avoidance has not been addressed in any clinical trials involving asthma patients to date. The evidence from this review, which found no difference in outcomes following MSG or control exposure, does not provide a reliable basis for recommendations on avoidance of MSG.
There are two reasons for this. First of all, only two small trials met the eligibility criteria of the review. The sample sizes of both studies were small and identical in number (n = 12), and the quality of one study was poor. As data from the included studies were limited, no firm conclusions can be drawn from this review regarding the effects of MSG in asthma. Secondly, the participants recruited had been clinically stable; those with a baseline FEV
The dose of MSG in studies is reasonable. The average daily MSG intake in Western countries is 0.3 g to 1 g, but it may be as high as 4 g to 6 g in a highly seasoned restaurant meal (Allen 1987). The doses in the studies were 0.3 g to 7.5 g (0.3, 1, 2.5, 5, 6, 7.5) (Raiten 1995), and the dosage used most frequently was 2.5 g. The doses used in challenges in the included studies are similar to quantities in meals, which means that it is unlikely that the absence of effect is due to under dosing.
Another limitation of this review is the lack of numerical outcome data on clinical scores such as symptoms, for which we were unable to extract raw data from trials assessing these outcomes.
We did not find any RCTs assessing the effects of MSG in children, so were unable to explore the relationship between childhood asthma and MSG.
Implications for practice
Limited evidence from people with stable chronic asthma did not provide any evidence that MSG could pose a risk. However, this review has not been able to establish the effect of MSG exposure on people with stable chronic asthma, as data were limited by small sample sizes. Because of the lack of data, these results cannot be applied to people with severe or unstable asthma, nor children since both trials recruited only adult patients.
Implications for research
There is a need for large, placebo-controlled randomised trials that would address as many MSG-related symptoms as possible, and researchers should pay attention to other aspects such as psychological factors. There is a need for further studies in children.
We are grateful to Jo Picot and Toby Lasserson for their help. We'd like to thank Elizabeth Stovold for searching studies for us. We would like to thank the referees for their helpful comments and Ryan Westhoff for his suggestions in writing the review.
Sponsored by the Chinese Cochrane Center.
Data and analyses
This review has no analyses.
Last assessed as up-to-date: 2 May 2012.
Contributions of authors
Yan Zhou selected the trials, extracted data, performed analyses, and wrote the review.
Ming Yang selected the trials.
Birong Dong gave advice on methodology.
Richard Wood-Baker edited the review and revised text.
Declarations of interest
There are no known conflicts of interest.
Sources of support
- No sources of support supplied
- Chinese Cochrane Centre, China.
Medical Subject Headings (MeSH)
MeSH check words
* Indicates the major publication for the study