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Division of Immunology, Children’s Hospital and Department of Pediatrics, Harvard University, Boston, MA;
*
Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA; Divisions of
Allergy-Immunology and
**
General Internal Medicine, Northwestern University, Chicago, IL; and
Division of Clinical Immunology and Allergy, University of California, Los Angeles, CA
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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KEY WORDS: • monosodium glutamate • Chinese Restaurant Syndrome • double-blind, placebo-controlled
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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Monosodium glutamate (MSG) is used worldwide as a flavor enhancer. L-Glutamic acid is the amino acid component of MSG, and has a long history of use in foods as a flavor enhancer. It is added either as the purified monosodium salt or as a component of a mix of amino acids and small peptides resulting from the acid or enzymatic hydrolysis of proteins. This amino acid is a major constituent of food proteins (in some foods comprising 20% of the total amino acid content), a pivotal metabolic intermediate in amino acid metabolism and a major energy source for cardiac myocytes. Regardless of dietary source (protein, protein hydrolysates or salts of free glutamic acid, including the monosodium salt MSG), all glutamate molecules entering the circulation from the gastrointestinal tract are structurally identical.
The average daily intake of MSG is estimated to be 0.3–1.0 g in
industrialized countries, but can be higher occasionally, depending on
the MSG content of individual food items and an individual’s taste
preferences. In the United States, the Food and Drug Administration
(FDA) has classified MSG as generally recognized as safe (GRAS).
Nevertheless, MSG has been alleged to cause many ills. The complex of
symptoms that follow ingestion of a Chinese meal and consist of
numbness at the back of the neck and arms, weakness and palpitations
was first described in 1968. MSG was suggested to trigger these
symptoms, which were referred to collectively as Chinese Restaurant
Syndrome (CRS). More recently, in its 1995 report, the Federation of
American Societies for Experimental Biology (FASEB) proposed the term
MSG symptom complex to denote the reactions alleged to occur after the
consumption of MSG. In addition to the MSG symptom complex, ingestion
of MSG has been alleged to cause or exacerbate numerous conditions,
including asthma, urticaria, atopic dermatitis, ventricular arrhythmia,
neuropathy and abdominal discomfort. An ongoing debate exists
concerning whether MSG indeed causes any of the alleged reactions and,
if so, the prevalence of reactions to MSG. For example, in the case of
asthma, MSG was reported in a single-blind challenge to exacerbate
symptoms (Allen 1987). This study suffered from
severe methodologic flaws in patient selection, use of bronchodilator
during the control period but not during the challenge, drug withdrawal
from the patients during the challenge period and, in fact, lack of
true single blinding. Using the same protocol, Manning and Stevenson (1991)
were not able to confirm asthmatic reactions
due to MSG in patients who experienced asthma within 12 h after
ingesting MSG in restaurants. Schwartzstein et al. (1987)
used a double-blind crossover protocol and did not
see any decrease in pulmonary function after MSG challenge in 12
patients. Simon (1986)
also reported not finding
asthmatic reactors to MSG in double-blind challenges; however, one
reactor was found in a single-blind challenge.
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Epidemiologic surveys of reactions to MSG. |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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). A questionnaire study in a
medically oriented population indicated that the prevalence of
CRS-sensitive people was as high as 25% (Reif-Lehrer 1977
). This study was criticized for many methodological
problems such as demand bias in questionnaire design and population
bias in survey technique. In a 1977 questionnaire survey, Kerr et al. (1977)
showed that, in a medical school community, no
one reported experiencing the triad of symptoms for CRS and that 3–7%
of subjects could be classified as having experienced "possible
CRS." This figure was increased to 31% when demand-biased
questions were introduced. To determine the incidence of CRS symptoms
in the general population, Kerr conducted a survey utilizing the
National Consumer Panel of the Market Research Corporation of America.
Of 3222 respondents, 43% recalled experiencing one or more unpleasant
symptoms associated with the consumption of food sometime in their
past. The symptoms were relatively nonspecific in nature, and there
were no responses that could be categorized as "definite CRS" or
"probable CRS." Only 1.8% of responses could be considered to
represent "possible CRS," and these symptoms associated with
Chinese food were linked to only 0.19% of the respondents according to
the authors (Kerr et al. 1979
). A questionnaire survey
in Thailand also showed "no correlation between susceptibility to CRS
and MSG intake" (Pothisiri 1983
). |
Clinical studies with MSG ingested with food. |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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). The only biochemically
demonstrable effect was a reduction in serum cholesterol and
ß-lipoprotein levels. Supplements of glutamate as high as 100 g/d
showed no toxic manifestations (Bazzano et al. 1970
).
When 3 g MSG was administered in 150 mL of beef bouillon at lunch
time to 73 healthy subjects either in an open label or double-blind
design with each subject acting as his or her own control, no
differences in symptomatology were found between the control and
MSG-treated groups (Morselli and Garattini 1970
,
Zanda et al. 1973
). In a study to examine the absorption
of glutamic acid from solutions of MSG or a casein hydrolysate, 60 mg
MSG/kg casein hydrolysate or a mixture of the two were administered to
12 healthy adults; no general ill effects were observed (Marrs et al. 1978
). In other studies, 60–150 mg MSG/kg body weight
was given to 14 adults and 13 infants with a typical Chinese rice
porridge meal. No adverse reactions were observed (Tung and Tung 1980
). |
Clinical studies with MSG ingested without food. |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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. In that study, it was found that intravenous or
oral administration of MSG could cause dose-dependent symptoms in
nearly all six individuals tested. The symptoms of burning, facial
pressure and chest pain were reported, and headache was reported to
occur in a small number of the individuals. The challenges were open,
or when blinded, did not take into consideration the taste of MSG.
In single- and double-blind studies, a total of 169 doses of up to
12 g were given in 99 subjects. Only subjective symptoms of
lightheadedness and tightness in the face appeared significantly more
often in the MSG group than in control. No subjects reported the triad
of symptoms of CRS, and objective measurements of blood pressure, pulse
and serum chemistries were not significantly different between the two
groups. The samples were osmotically matched, but the tastes were not
disguised (Rosenblum et al. 1971
).
In a placebo-controlled study in 77 subjects, it was found that
symptoms were felt after MSG ingestion but that the classic CRS
combination was rare. There was no correlation between the appearance
of symptoms and blood glutamate concentrations (Kenney and Tidball 1972
). In a nonblind study, 15 subjects were given 100
mg MSG/kg and six subjects reported subjective symptoms. The occurrence
of the symptoms was not related to plasma glutamate levels (Hsu and Huang 1985
).
In a study to test the effect of aspartame on CRS sufferers, six
individuals were found who reported one or more CRS symptoms after
drinking tomato juice containing 150 mg MSG/kg but not after drinking
tomato juice with 10 mg NaCl/kg. The solutions were administered in a
double-blind manner, but the tastes of the substances were not
disguised (Stegink et al. 1981
).
In a double-blind study with 55 subjects, a significant number
reacted more frequently to MSG than placebo, but none complained of any
of the classic CRS symptoms. It was noted that there were significant
differences in taste and aftertaste of the MSG samples compared with
placebo (Gore and Salmon 1980
). To test whether CRS
symptoms were caused specifically by MSG, symptoms experienced after
the ingestion of various common food items were examined. Of 60
subjects tested, it was found that all materials provoked symptoms and
that symptoms of burning, tightness or pain in the chest, neck, face or
arms, or numbness were reported in response to coffee in six subjects
and spiced tomato juice in six subjects, and in two subjects after the
ingestion of a 2% MSG solution. MSG was found not to be unique in
producing discomfort after eating (Kenney 1980
).
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The Chinese Restaurant Syndrome (CRS) or MSG symptom complex |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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).
The syndrome was called "Chinese Restaurant Syndrome (CRS)" and
numerous reports, most of them anecdotal, were published after the
original observation. Some reported symptoms similar to the original
report, whereas others reported symptoms differing from those
originally reported. The range of symptoms described in these reports
included numbness, headache, migraine, palpitations, tightness,
weakness, aching, flushing, sweating, fasciculation, lacrimation,
syncope, dizziness, shudder attacks, paresthesias, arrhythmias and
tachycardia. Further uncontrolled study indicated that a triad of
symptoms, differing from those originally described, of "burning,
facial pressure and chest pain" could be induced in individuals given
high doses of MSG and that there was a dose response (Schaumburg et al. 1969
).
Since then, clinical studies on these acute, temporary and "self-limited" adverse reactions have been performed by numerous groups, with varying degrees of rigor in experimental design ranging from uncontrolled open challenges to DBPC studies. DBPC challenge of individuals believing to be MSG sensitive did not confirm their sensitivity, and studies indicate that the symptoms observed in some experiments are not specific to MSG ingestion and can also be elicited by other foods. Studies in which MSG was administered in food rather than in pure form have generally shown a lack of symptoms altogether. Thus, a causal relationship between MSG and acute, temporary and "self-limiting" adverse reactions is far from established.
Proposed mechanisms to explain MSG symptom complex.
Numerous mechanisms have been proposed for CRS but none has been
proven. Restriction of circulation by the application of an axillary
cuff confined burning sensation to the arm after MSG injection; thus
the stimulation of peripheral receptors was proposed as the mechanism
for CRS (Schaumburg et al. 1969
).
The symptoms of CRS were noted to be similar to those observed after
acetylcholine administration. Glutamate can be converted to
acetylcholine via the tricarboxylic acid (TCA) cycle, and experiments
indicated that drugs affecting the cholinergic mechanisms could
modulate CRS symptoms; thus it was proposed that CRS was a form of
acetylcholinosis (Ghadimi et al. 1971
). However, it
should be noted that this should be true for any TCA cycle
intermediate.
The symptoms and regions of the body affected by CRS were noted to be
similar to those of pain referred from the upper esophagus. Studies
indicate that individuals purportedly reacting to MSG may react to
concentration rather than dose; furthermore, the same dose of MSG taken
in capsules is associated with fewer reactions. Because MSG was found
not to be unique in producing CRS symptoms, it was proposed that CRS
may be a manifestation of esophageal irritation (Kenney 1986
).
Plasma sodium levels were found to be increased after a Chinese meal,
and the high sodium content of Chinese restaurant meals was suggested
to be the cause of CRS (Smith et al. 1982
).
Folkers and colleagues suggested that subjects experiencing CRS
symptoms did not do so after vitamin B-6 supplementation and proposed
that CRS was a manifestation of vitamin B-6 deficiency (Folkers et al. 1984
).
The symptoms of CRS were suggested to be similar to those of histamine
intoxication. When the histamine content of ingredients used in Chinese
cooking was measured, it was found that some Chinese meals could
contain levels of histamine close to the toxic threshold established by
the FDA for histamine in foods, leading the authors to propose that CRS
may be caused by histamine (Chin et al. 1989
).
MSG challenge studies in subjects claiming to be MSG sensitive.
A drink vehicle with a novel taste that could effectively mask the
taste of MSG was used to challenge individuals who believed themselves
to be MSG sensitive. Of >30 such individuals with whom contacts were
made, only six agreed to be tested. When these individuals were
challenged with 6 g of MSG in a double-blind,
placebo-controlled manner, it was found that four of the six did not
react to either substance, whereas two reacted to both MSG and placebo.
Of the subjects who reacted, one reported tingling of hands and warmth
behind the ears after both MSG and placebo; the other subject
experienced tightness of the face after ingesting either substance. The
remaining four individuals who had ascribed their previous symptoms
such as headache, nausea, tongue swelling and uncontrollable coughing
to MSG ingestion, did not react to either substance (Kenney 1986
).
In a study designed to monitor flushing, which study participants felt
was caused by MSG ingestion, 24 subjects, including 18 who had a
history of subjective flushing symptoms after eating Chinese food were
challenged with 3–18.5 g MSG. No one reported flushing sensations. Six
subjects, three with a history of flushing, were challenged with
35.7–285.7 mg MSG/kg body weight or 7.1–71.4 mg pyroglutamate/kg body
weight. None reported flushing sensations and no significant changes in
cutaneous blood flow occurred (Wilkin 1986
).
Yang et al. (1997)
recently conducted a DBPC study of 61
self-identified MSG-sensitive subjects. The subjects were
challenged with 5 g MSG or placebo, and a positive reaction was
defined as the occurrence of two or more symptoms among 10 symptoms
described to occur after MSG ingestion. The rates of reaction to
placebo and MSG were not significantly different. Upon rechallenge with
placebo and increasing doses of MSG (1.25, 2.5 or 5 g), the
frequency and severity of the responses increased with increasing
doses, reaching significance for headache, muscle tightness, flushing,
general weakness and numbness/tingling.
We recently conducted a multicenter DBPC multiple challenge study with
a crossover design to evaluate reactions allegedly due to the
consumption of MSG in 130 self-identified subjects who believed
they had had reactions to MSG (Geha et al. 1998
). In
three of four protocols (A-D), MSG was administered without food. A
"positive response" was defined as the presence of at least two of
10 symptoms reported to occur after ingestion of MSG-containing
foods. In Protocols C and D, a "reproducible response" was defined
as the same two or more symptoms among those listed in the enrollment
inclusion criteria that were reproducible in separate challenges, with
no symptoms produced by placebo.
All subjects who satisfied the inclusion/exclusion criteria were enrolled in Protocol A. Subjects were randomized to receive placebo on d 1 and 5 g MSG (in a citrus-flavored beverage) on d 2 (Arm 1) or 5 g MSG on d 1 and placebo on d 2 (Arm 2). Prior testing on normal volunteers established that the citrus flavor effectively masked the taste of MSG. Subjects who responded with two or more symptoms to at least one test article in Protocol A were eligible to be enrolled in Protocol B. Protocol B was initiated immediately after completion of Protocol A and consisted of four challenges, each on a separate day. Each subject was administered randomly four test articles consisting of placebo, 1.25 g, 2.5 g or 5 g of MSG in 200 mL citrus-flavored beverage. Subjects who responded with two or more symptoms to 5 g MSG but not to placebo in both Protocols A and B were eligible to be enrolled in Protocol C. Subjects were randomly assigned to receive 5 g MSG or placebo first in each of two sets of challenges administered on two separate days. Subjects who responded to 5 g MSG but not to placebo in both sets of challenges in Protocol C were eligible to be enrolled in Protocol D. Protocol D consisted of six challenges each performed on a separate day. Each subject randomly received three times capsules containing 5 g MSG and three times capsules containing placebo (5 g sucrose) during a cereal breakfast consisting of Frosted Flakes.
In Protocol A, 50 (38.5%) of 130 subjects reported two or more symptoms ("positive response") during the MSG challenge and had no symptoms or one symptom after placebo. Nineteen subjects (14.6%) reported two or more symptoms to both MSG and placebo, whereas 17 subjects (13.1%) reported two or more symptoms to placebo and no symptoms or one symptom after MSG. Forty-four subjects (33.8%) reported no symptoms or one symptom to both MSG and placebo. Administration of 5 g MSG was associated with a significantly higher frequency of response, i.e., of occurrence of two or more symptoms and with significantly higher frequency of occurrence of four of the 10 symptoms.
Eighty-six subjects who responded to at least one of the two challenges in Protocol A were eligible for Protocol B. Of these 86 subjects, 17 either chose not to participate or did not complete Protocol B; 69 subjects completed Protocol B. Administration of 1.25, 2.5 and 5 g of MSG was associated with significantly increased frequency of response. There was no significant increase in frequency of response for any of the 10 symptoms with 1.25 g MSG. An increased frequency of response was observed only for numbness/tingling with 2.5 g MSG and for six of 10 symptoms (general weakness, muscle tightness, flushing, sweating, headache/migraine, numbness/tingling) with 5 g MSG. Nineteen subjects responded to 5 g MSG but not to placebo in both protocols A and B.
Twelve of the 19 eligible subjects participated in Protocol C and underwent two challenges (C1 and C2), each with 5 g MSG vs. placebo. Only two of the 12 subjects responded to MSG and not to placebo in both challenges. However, in none of these subjects did the symptoms in Protocols C1 and C2 reproduce those observed in Protocols A and B.
Subjects who report reactions allegedly caused by MSG ingest MSG in food. It was therefore important to ask whether the two subjects who had responded to 5 g MSG but not to placebo in protocols A through C would react to the same dose of MSG administered with food. Both subjects who responded to MSG in protocol C enrolled in protocol D, which consisted of six challenges, three with 5 g MSG and three with placebo, in which the test articles were administered in the middle of a standard breakfast and the subjects were asked to report their symptoms. Each subject responded to only one of the three MSG challenges with two or more symptoms. In both subjects, the symptoms reported differed from those reported in the previous three protocols.
The data from the study suggest that large doses of MSG given without
food may elicit more symptoms than a placebo in individuals who believe
that they react adversely to MSG. However, neither persistent nor
serious effects from MSG ingestion were observed and the frequency of
the responses was low. More importantly, the responses reported were
inconsistent and were not reproducible. The responses were not observed
when MSG was given with food (Geha et al. 1998
).
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FDA position on MSG |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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SUMMARY |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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FOOTNOTES |
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2 Supported by a grant from the International Glutamate Technical Committee.
4 Abbreviations used: CRS, Chinese Restaurant
syndrome; DBPC, double-blind, placebo-controlled; FASEB, Federation
of American Societies for Experimental Biology; FDA, Food and Drug
Administration; GRAS, generally recognized as safe; MSG, monosodium
glutamate; TCA, tricarboxylic acid.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONEpidemiologic surveys of...Clinical studies with MSG...Clinical studies with MSG...The Chinese Restaurant Syndrome...FDA position on MSGSUMMARYREFERENCES |
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