EAL

UM: Monosodium Glutamate (MSG) and Adverse Effects (2013)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To address the validity of the symptom complex referred to as the Chinese Restaurant syndrome and not to assess alleged reactions such as anaphylaxis or asthma in self-identified MSG-sensitive subjects.

Inclusion Criteria:

Between the age of 18 and 60 years
Received financial compensation
Had to have within three hours of a meal alleged to have contained MSG, two or more of the following symptoms:
- Feeling of general weakness
- Feeling of muscle tightness
- Feeling of muscle twitching
- Feeling of flushing
- Sweating sensation
- Burning sensation
- Headache or migraine
- Chest pain
- Palpitation or heart pounding
- Feeling of numbness or tingling
- One of these symptoms and at least one additional symptom the subject attributed to MSG.

Exclusion Criteria:

Pregnant or nursing
Had an unconscious episode after ingestion of MSG or any unexplained loss of consciousness
Described symptoms that suggested sensitivity as judged by an investigator
Were receiving beta-blocker therapy
Had uncontrolled hypertension or had significant medical disease
Subjects who were unable to comply with study procedures or provide informed consent
Employees and their relatives of companies that manufacture MSG or of the International Glutamate Technical Committee.

Description of Study Protocol:

Recruitment

Newspaper advertisements between March 14 and November 2, 1993 requested replies from persons who believed they had reactions to MSG. Respondents were screened by telephone to ascertain inclusion and exclusion criteria and eligible subjects were invited to participate in the study.
A sample size calculation was conducted prior to enrollment:
- 27 needed for 5% placebo, 40% MSG
- 43 for 5% placebo, 30% MSG
- 38 for 10% placebo, 40% MSG
- 71 for 10% placebo, 30% MSG
A sample size of 60 was chosen.

Design

Double-blind, placebo-controlled, randomized study
Method of randomization was not given.

Blinding Used

Double-blinded.

Intervention

Two-phase study.

Initial Challenge

Placebo: 200ml citrus-flavored beverage
MSG: 5g in placebo beverage.

Re-challenge with Subjects Who Responded to One But Not Both Challenge Doses

Placebo
MSG: 1.25, 2.5 or 5g.

Statistical Analysis

Statistical analyses were done with non-parametric tests suitable for the testing of proportions or ordered variables with non-normal distributions and included the McNemar change test, Cochran Q-test, Friedman two-way analysis of variance by ranks and Wilcoxon paired and unpaired tests
A Bonferroni adjustment was made for multiple comparisons
A conditional logistic model was used to evaluate the relative risk of responding to placebo versus MSG
All analyses were done with the SAS and Systat computer programs (Systat Inc.).

Data Collection Summary:

Timing of Measurements

All subjects underwent an initial challenge in which they ingested on an empty stomach 5g of MSG or placebo in random order on different days, with the intent to screen out negative and ambivalent responders
Subjects were questioned about symptoms every 15 minutes and vital signs were recorded every 30 minutes. Subjects who did not have any symptoms were released from the clinic after two hours of observation. Subjects with symptoms were followed up longer. Subjects were challenged the next day with an alternate agent and observed as on the first day.
The interval between the tests was never less than one day and depended on the availability of the subject
Subjects who responded to neither test agent or to both were concluded to be non-responders or inconsistent responders and did not undergo further study
Subjects returned to the clinic for further challenges until all test procedures were completed
Reports of symptoms were elicited by asking subjects whether they were experiencing anything unusual. The severity of a symptom was rated as one (mild, but noticeable) to three (severe, having significant impact on the subject).

Dependent Variables

Adverse Symptomology

Positive reaction to a test dose was defined as the occurrence of equal to or higher than index symptoms:

General weakness
Muscle tightness
Muscle twitching
Flushing
Sweating sensation
Burning sensation
Headache or migration
Chest pain
Palpitation or pounding heart
Numbness or tingling
One of above symptoms and at least one additional symptom the subject attributed to MSG.

Independent Variables

Placebo
MSG: 1.25, 2.5 or 5g.

Description of Actual Data Sample:

Initial N: 110 eligible subjects
Attrition (final N): 61 subjects (25% male)
Age: Mean age was 38±9 years
Other relevant demographics: 34 (58%) had a history of atopy
Anthropometrics: Mean weight 75±17kg
Location: Ottawa, Ontario, Canada.

Summary of Results:

Key Findings

Pre-challenge vital signs (pulse, blood pressure, temperature) were within normal limits and remained unchanged during and after MSG and placebo challenges
No subjects had adverse reactions including hives, wheezing, vomiting or diarrhea on challenge.

Initial Challenge

61 subjects entered the study and on the initial challenge, 18 (29.5%) responded to neither MSG nor placebo, 6 (9.8%) to both, 15 (24.6%) to placebo and 22 (36.1%) to MSG (P=0.324)
There was a non-statistically significant increase in report of symptoms after MSG ingestion compared with placebo
Flushing was increased (P>0.05) after MSG ingestion compared with flushing after placebo ingestion
Total and average severity of symptoms after ingestion of MSG (374 and 80) were greater than respective values after placebo ingestion (232 and 56; P=0.026 and 0.018, respectively)
An unbalanced response to placebo was observed indicating sequence of administration impacted results.

Re-challenge

No effect (P>0.05) of sequence administration
Re-challenge revealed an apparent threshold dose for reactivity of 2.5g MSG
Headache (P<0.023), muscle tightness (P<0.004), numbness or tingling (P<0.007), general weakness (P<0.040) and flushing (P<0.016) occurred more frequently after MSG than placebo ingestion.

Author Conclusion:

The results of this study suggest that sensitivity to MSG exists, at least in the clinical setting described and is characterized by unpleasant reactions such as numbness, tingling, headache, muscle tightness, general weakness and flushing. Future challenges of MSG with food will provide further insights into the mechanism of MSG-associated symptoms and the entity known as the MSG symptom complex.

Funding Source:

Other:

International Glutamate Technical Committee

Reviewer Comments:

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes