EAL

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

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to investigate the influence of oral administration of MSG to healthy young male volunteers on the occurrence of headache, sensitivity to pressure pain in masseter and temporalis muscles, blood pressure, heart rate and the occurrence of side-effects.

Inclusion Criteria:

Healthy, pain-free young men over 18 years of age
No history of adverse effects to MSG
Subjects recevied financial compensation.

Exclusion Criteria:

Pain and headache conditions (tension-type headache, migraine)
Serious illness, e.g., uncontrolled hypertension, heart disease, pulmonary disease
Allergy or adverse effects to MSG
Diabetes mellitus
Asthma.

Description of Study Protocol:

Recruitment

Men were recruited from the School of Dentistry Aarhus, Denmark.

Design

Three session, randomized, double-blinded, placebo-controlled crossover study
Randomization by computer program.

Blinding Used

Double-blinded
The single-examiner and all subjects were blinded with regard to the sequence of the sessions until after finishing data collection.

Intervention

Placebo beverage: Soda (Sprite Zero, sugar-free) containing carbon dioxide, citric acid, sodium citrate, aromas, artificial sweeteners (aspartame, acesulfame potassium) and sodium benzoate plus 24mg per kg of bodyweight NaCl
Low MSG beverage: Soda plus 75mg MSG per kg
High MSG beverage: Soda plus 150mg MSG per kg.

Statistical Analysis

The number of subjects was based on a paired-design sample size calculation, which gave a minimum of 10 healthy subjects
Results are presented as means plus or minus standard error of the mean (SEM)
The Tukey Honestly Significantly Difference test was used for post hoc analyses
The frequency of each specific side-effect was compared between sessions with McNemar's tests
Values of P<0.05 were considered statistically significant.

Data Collection Summary:

Timing of Measurements

Subjects fasted overnight and no food or drinks other than water were ingested for two hours after each drink
At baseline, a blood sample was taken and the following parameters were evaluated: Spontaneous pain on a zero-to-10 visual analog scale (VAS), pressure pain threshold (PPT) and pressure pain tolerance (PPTol) and pressure pain tolerance with a pressure algometer at four sites [right masseter muscle, left masseter muscle, right anterior temporalis muscle and left anterior temperalis muscle (TAR)]
Measurements were also taken at 15, 30, 45, 60, 90 and 120 minutes after MSG or placebo ingestion.

Dependent Variables

Occurrence of headache, sensitivity to pressure pain in masseter and temporalis muscles, blood pressure, heart rate and the occurrence of side-effects: Subjects were asked to spontaneously report if they had any sort of side-effects and at time-points 15, 30, 45, 60, 90 and 120 minutes after MSG or placebo ingestion; spontaneous pain; PPT measured once at each of the four sites mentioned above; SBP, DBP and HR were measured
Systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) with the use of a digital blood pressure monitor were measured at the most prominent part of the masseter muscles and at the anterior part of the temporalis with a one-cm diameter probe and a rate of increase in pressure of 30kPA
Plasma glutamate concentrations were measured using an enzyme-based assay. The plasma glutamate concentrations at 30 minutes after ingestion in the two MSG sessions are given as a percentage of the plasma glutamate concentration at 30 minutes in the placebo session
During the measurements, the subjects sat comfortably in a dental chair in a quiet room and the head of subjects was gently supported by the opposite hand of the examiner
Subjects were instructed to keep their teeth slighty apart to avoid contraction of the jaw-closing muscles during pressure stimulation.

Independent Variables

Placebo
Low MSG: 75mg per kg
High MSG: 150mg per kg.

Control Variables

A control experiment to rule out sodium-loading as an explanation for any change in blood pressure was conducted with five healthy male subjects: Subjects ingested the same beverage containing an equimolar dose to high MSG of NaCl 52mg per kg bodyweight (equivalent to 0.89mmol Na per kg) and the SBP, DBP and HR were followed over two hours as the study sessions.

Description of Actual Data Sample:

Initial N: 14 men
Attrition (final N): 14 men
Age: Mean, 24.1±2.8 years
Ethnicity: NA
Other relevant demographics: NA
Anthropometrics: Mean bodyweight, 80.9±10kg
Location: Aarhus County, Denmark.

Summary of Results:

Key Findings

Headache

None of the subjects had spontaneous pain at baseline on the days of the study
Four subjects experienced headache during the low MSG session. They scored 4, 4, 1 and 1 on the zero-to-10 VAS. One of these subjects experienced headache (VAS, 3.5) in the high MSG session.
No spontaneous pain was experienced during the placebo session
Headache occurred more in the low MSG session, compared with high MSG and placebo (P=0.045).

Pressure Pain Threshold and Pressure Pain Tolerance

The normalized pressure pain thresholds at the four muscle sites were not significantly influenced by MSG ingestion (P>0.089)
Overall, the normalized pressure pain tolerances at the four muscle sites were not significantly different between sessions (P>0.073).

Autonomic Parameters

Systolic BP was elevated in the high MSG session, compared with low MSG and placebo (P<0.036). BP was also greater (P<0.003) in the high MSG, compared with the low MSG.
Diastolic BP was greater (P<0.035) 15 minutes after MSG ingestion, compared with the other time-points
Normalized HR was not affected (P=0.321) by MSG ingestion
In the control experiment, BP and HR were not influenced (P>0.327) by ingestion of 52mg per kg bodyweight of NaCl (equivalent to high MSG).

Side Effects

The mean number of side-effects reported by each subject in the three sessions were 2.4 ± 0.4 (high MSG), 1.8 ± 0.3 (low MSG) and 0.4 ± 0.2 (placebo).
Stomach ache (P=0.014), the feeling of pressure/tenderness i the zygomatic region (P=0.008) and tender masseter muscles (P=0.045) were reported more frequently in the high MSG compared with the control and low MSG.
Other side effects such as burning skin or facial flushing were not greater (P>0.157) after MSG ingestion.

Other Findings

The mean baseline glutamate level in the three sessions was 4.2±0.7uM. At 30 minutes after ingestion, plasma glutamate concentrations were significantly (P<0.001) increased by 556% in the high MSG session and by 395% in the low MSG session, compared with baseline. High MSG was greater (P=0.010) than the low MSG. In the placebo session, plasma glutamate concentrations were 97.5% of the baseline level.
Spontaneous remarks noted by the examiner indicated that a salty taste was reported by two to three subjects in each session and bad taste was reported by five to seven subjects in each session.

Author Conclusion:

Although no spontaneous pericranial muscle pain or statistically significant reductions in Pressure Pain Threshold levels due to MSG ingestion were detected, there was an increased occurrence of headache and side-effects such as subjectively reported muscle tenderness located in the craniofacial region
Based on the findings from this study, additional studies on the effect of systemic MSG on pericranial muscle sensitivity should be performed in women and in patients with chronic musculoskeletal pain, e.g., temporomandibular disorder or fibromyalgia.

The authors also noted the following in their discussion:

The lack of oveall mechanical sensitization suggests that the 150mg perkg doses of MSG may not have raised skeletal muscle interstitial glutamate concentrations sufficiently to cause mechanical sensitization in their healthy male subjects
It may be that some individuals are more sensitive to the effects of elevated glutamate concentrations than others, as witnessed by the variability in adverse effects such as headache and craniofacial sensitivity.

Funding Source:

Other:

Danish Dental Association

Reviewer Comments:

The authors noted that the study group consisted of healthy young men alone and the results may not be reflective of the response to MSG in the general population.

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?	No
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?	Yes
	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?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	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)?	No
	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