- Click here for explanation of classification scheme.

To evaluate reactions reported to occur after the consumption of monosodium glutamate (MSG) in self-identified subjects who believed they had experienced reactions to MSG.

• Report of at least two of the following complaints within four hours of a meal reported to contain added MSG:
  • Feeling of general weakness
  • Feeling of muscle tightness
  • Feeling of muscle twitching
  • Feeling of flushing
  • Sweating sensation
  • Burning sensation
  • Headache or migraine
  • Chest pain
  • Palpatations and feeling of numbness or tingling
• Subjects signed an informed consent.

• Report of life-threatening reactions associated with ingestion of MSG-containing meals
• Age less than 18 or greater than 60 years
• Pregnancy
• History of:
  • Unexplained loss of consciousness
  • Uncontrolled hypertension
  • Heart disease evidenced by angina
  • Congestive heart failure
  • History of myocardial infarction
  • Heart surgery
  • Pulmonary disease
  • Oxygen treatment
  • Steroid-dependent asthma
  • Hospitalization for pulmonary disease in the past year
  • Chronic neurologic diseases (ie, seizure, stroke or  multiple sclerosis)
  • AIDS
  • Cancer
  • Other chronic illnesses
• Employment at companies that manufacture MSG and being a relative of employees of companies that manufacture MSG
• Member of the International Glutamate Technical Committee and being a relative of members of the International Glutamate Technical Committee.

Recruitment

• Subjects were recruited from responses to advertisements in local newspapers placed by the three study centers in Boston, Chicago and Los Angeles
• Subjects received financial compensation.

Design

• The study design was a multi-center, randomized, double-blind, placebo-controlled, multiple-challenge crossover design. The study was performed in the outpatient clinic at each of the three study centers and was conducted in four consecutive phases, each with its own protocol (A, B, C and D). The study was approved by the institutional review board or research ethics committee at each study center.
• A stratified randomization was used and separate randomization schemes were developed for each site-sex stratum.

Criteria for a Response

A positive response was defined as the occurrence of any two or more symptoms among the 10 symptoms listed in the enrollment inclusion criteria.

Reproducibility

• In protocols C and D, the reproducibility of the response to MSG was also assessed according to the recommendations of the 1995 FASEB report on MSG, which became available after completion of protocols A and B
• For confirmation of the symptom complex, double-blind placebo controlled challenges on separate occasions must reproduce symptoms with the ingestion of MSG and produce no response with placebo.

Protocols

• Protocol A:
  • All subjects (N=132) were enrolled in protocol A after an overnight fast
  • Subjects were randomized to receive either placebo on day one and MSG on day two (arm one) or MSG on day one and placebo on day two (arm two)
  • Permuted blocks of four were used for randomization
  • The test articles in protocol A were 200ml of citrus-flavored beverage containing 0g (placebo) or 5g of MSG.
• Protocol B:
  • Subjects who responded with two or more symptoms to at least one article in protocol A were eligible to enroll in protocol B (N=75). Protocol B was begun after completion of Protocol A and before the blinding codes of A were broken.
  • Four challenges for each subject, with each challenge performed on a separate day
  • A 4x4 Latin square design was used to assign the order of challenges for the four doses compared
  • Each subject was randomly administered test articles consisting of 0g (placebo), 1.25g, 2.5g or 5 g of MSG in 200ml of citrus flavored beverage.
• Protocol C:
  • Subjects who responded with two or more symptoms to 5g of MSG but not placebo in protocols A and B were eligible to be enrolled in protocol C (N=12)
  • In protocol C, subjects were randomly assigned to either placebo or MSG first in each of two sets of challenges administered on four separate days
  • Stratified randomization was not used because of the small number of subjects expected
  • The test articles in protocol C were opaque capsules containing 5g of sucrose (placebo) or 5g MSG taken with 200ml of bottled water
• Protocol D:
  • Subjects were responded to 5g of MSG but not placebo in both sets of challenges in protocol C were eligible to be enrolled in protocol D (N=2)
  • Protocol D consisted of six challenges, each performed on a separate day
  • Subjects were randomly assigned to receive capsules three times containing 5g of sucrose (placebo) or 5g of MSG along with 200ml of bottled water during a standardized breakfast consisting of Frosted Flakes and 2% cow's milk
  • Stratified randomization was not used because of the small number of subjects expected.

Blinding Used

Each protocol was conducted as a double-blind study.

Intervention

• Protocol A: 0g or 5g of MSG in 200ml of citrus-flavored beverage
• Protocol B: 0g, 1.25g, 2.5g and 5g of MSG in 200ml of citrus-flavored beverage
• Protocol C: 0g or 5g of MSG in capsule form
• Protocol D: 0g or 5g of MSG in capsule form during a standardized breakfast.

Statistical Analysis

• In protocols A and B, relative risk (RR) was used to describe the crude effect of MSG versus placebo on individual symptoms and on the overall response
• The McNemar test for correlated proportions was used to perform significance testing
• In protocol A, stratification by site, sex, age groups and challenge order (arm one or two) was used to describe and test for treatment effects within strata. Homogeneity of the effect of MSG among the strata was assessed by using the Breslow-Day test. Results were tested separately for the two challenge days. Each challenge day's analyses are based on the entire set of patients, half of whom received MSG and half of who received placebo. RRs are presented, and X² tests and Fisher exact tests were used where appropriate for significance testing. All subjects who completed protocol B were analyzed by using conditional logistic regression with dummy variables.
• Statistical testing was not performed on data collected in protocols C and D because of the small sample size.

Timing of Measurements

• All challenges began in the morning between 8:00 a.m. and 9:00 a.m.
• No food was ingested starting the preceding midnight and for two hours after the challenge, except in Protocol D
• Pulse was- measured every 30 minutes
• Blood pressure was measured every 30 minutes
• Respiratory rate was measured if respiratory symptoms were reported
• Temperature was timing of measurement not specified
• In Protocols A and B, subjects were queried about symptoms using a checklist every 15 minutes after ingestion of MSG
• In Protocols C and D, subjects were given blank sheets of paper and asked to record any symptoms every 15 minutes for two hours after ingestion of MSG
• Subjects were allowed to leave two hours after MSG ingestion unless they were complaining of symptoms in which they were not allowed to leave until clearing of all symptoms (always less than four hours).

 Dependent Variables

List of 10 symptoms from the inclusion criteria:

• General weakness
• Muscle tightness
• Muscle twitching
• Flushing
• Sweating
• Burning Sensation
• Headache or migraine
• Chest pain
• Palpitations
• Numbness or tingling
• At least two symptoms.

Independent Variables

•  Protocol A:
  • Control beverage: 200ml citrus-flavored
  • MSG beverage: 5g in control beverage
• Protocol B:
  • Control beverage: 200ml citrus-flavored
  • MSG: 1.25g, 2.5g or 5g in control beverage
• Protocol C:
  • Control capsule: 5g sucrose
  • MSG capsule: 5g MSG
• Protocol D:
  • Control capsule: 5g sucrose with standardized breakfast
  • MSG capsule: 5g MSG with standardized breakfast.

 Initial N

132 subjects enrolled in the study.

Attrition (final N)

• Protocol A: 130 subjects (46 male, 84 female) completed protocol A
• Protocol B: 69 subjects completed protocol B
• Protocol C: 12 subjects completed protocol C
• Protocol D: Two subjects completed protocol D.

Age

• 54 subjects were 30 years old or less
• 50 subjects were 31 to 45 years old
• 26 subjects were 46 years old or older.

Location

• Boston
• Chicago
• Los Angeles.

Key Findings

• Protocol A:
  • 17 (13.1%) responded to placebo but not to MSG
  • 50 (38.5%) responded positively to MSG but not to placebo
  • 19 (14.6%) responded to both placebo and MSG
  • 44 (33.8%) responded to neither placebo nor MSG
  • The administration of 5g of MSG was associated with a greater (P<0.05) frequency of response (two or more symptoms) and with a greater frequency of occurrence of four of the 10 symptoms
  • No increase (P>0.05) in heart rate or blood pressure over baseline after challenge with either placebo or MSG
  • No increase (P>0.05) in heart rate over baseline when subjects who reported palpitations were analyzed separately
  • No reports of wheezing and no changes in the physical exam
• Protocol B:
  • Administration of 1.25g, 2.5g, and 5g of MSG was associated with increased (P>0.05) frequency of response
  • No increase (P>0.05) in frequency of response for any of the 10 symptoms after ingestion of 1.25g of MSG
  • After ingestion of 2.5g of MSG, there was an increased (P>0.05) frequency of response for numbness or tingling
  • After ingestion of 5g of MSG, there was increased (P>0.05) frequency of response for six of 10 symptoms (general weakness, muscle tightness, flushing, sweating, headache or migraine, and numbness or tingling). Occurrence of symptoms other than the 10 listed was also greater (P>0.05) with 5g of MSG.
  • 19 subjects reported two or more symptoms; in 14 of the 19 subjects, the response was reproducible (same two or more symptoms in both protocols A and B)
• Protocol C:
  • Two or 12 subjects reported two or more symptoms after 5g of MSG but not after placebo
  • Neither of these subjects reported the same two or more symptoms during the MSG challenge in protocols A through C
• Protocol D:
  • Each of the two subjects reported two or more symptoms in one one of the three MSG challenges
  • They symptoms reported differed from those reported in the previous three protocols.

 Protocol A

Frequency of Symptoms Reported
Symptom	Placebo	MSG	RR (*P<0.005)
General weakness	0.14	0.30	2.17*
Muscle tightness	0.18	0.34	1.83*
Muscle twitching	0.06	0.13	2.13
Flushing	0.08	0.25	3.30*
Sweating	0.04	0.07	1.80
Burning sensation	0.05	0.14	3.00
Headache or migraine	0.28	0.54	1.89*
Chest pains	0.02	0.06	2.67
Palpitations	0.04	0.10	2.60
Numbness or tingling	0.20	0.28	1.38
At least two symptoms	0.27	0.53	1.97*

 *P<0.05.

 

Frequency of Occurrence of Two or More Symptoms
	N	Placebo	MSG	RR (*P<0.05)
Site
Boston	44	0.18	0.43	2.38*
Chicago	39	0.28	0.41	1.33
Los Angeles	47	0.34	0.72	2.13*
Sex
Female	83	0.29	0.52	1.79*
Male	47	0.26	0.55	2.17*
Age (year)
30 or less	54	0.24	0.44	1.85*
31 to 45	50	0.32	0.52	1.63
46 or more	26	0.27	0.73	2.71*
Challenge arm
One (placebo-MSG)	64	0.38	0.50	1.33
Two (MSG-placebo	66	0.18	0.56	3.08*

 

Protocol B

Number of Subjects Who Responded
	Number of Subjects	Placebo	1.25g MSG	2.5g MSG	5.0g MSG
Boston	23	3	7	8	9
Chicago	18	5	7	5	12
Los Angeles	28	8	14	19	18
Total	69	16	28	32	39
RR (*P<0.05)			1.75*	2.00*	2.44*

 

Reproducibility of Symptoms in Protocols A and B

 

Number of Subjects
	Responded to MSG But Not Placebo In Protocol A and Completed Protocol B	Responded to MSG But Not Placebo In Both Protocols A and B	Reproducible Reactions Across Protocols A and B
Boston	15	7	2
Chicago	8	5	5
Los Angeles	14	7	7
Total	37	19	14

 

Protocol C

Number of Subjects
	Responded To MSG But Not Placebo In Protocol C1	Responded To MSG But Not Placebo In Protocol C2	Responded To MSG But Not Placebo In Both Protocols C1 and C2	Reproducible Responses In Protocols A Through C
Boston (N=4)	1	2	1	0
Chicago (N=4)	2	1	1	0
Los Angeles (N=4)	1	0	0	0
Total	4	3	2	0

 

Protocol D

	Placebo Challenges: Number of Symptoms Reported with Each Challenge			MSG Challenges: Number of Symptoms Reported with Each Challenge			Number of Reproducible Responses
	1	2	3	1	2	3
Boston (N=1)	0	0	0	0	0	3	0
Chicago (N=1)	0	0	1	2	0	1	1

 

• Limitations as noted by authors:
  • Possible demand bias
  • Decreasing sample size with progression of protocols
• Subjects who appear to consistently respond to MSG in the absence of food may not do so when MSG is administered in food
• Large doses of MSG given without food may elicit symptoms more than placebo in individuals who report they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion were observed and the responses were not consistent on re-testing.

Industry:

International Technical Glutamate Committee Other:

• Study population were not well described
• Very small sample size for protocols C and D; unable to perform statistical testing
• Not clear when physical examination was performed and at what frequency.
• Possibility that there is a sub-group better at detecting the taste of MSG than the general population cannot be ruled out.