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Does monosodium glutamate cause flushing (or merely “glutamania”)?
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Does monosodium glutamate cause flushing (or merely "glutamania") ? Jonathan K. Wilkin, M.D. Richmond, VA Monosodium glutamate is widely regarded as the provocative agent in the "Chinese restaurant syndrome," of which flushing is regarded as part of the reaction. Six subjects were monitored by laser Doppler velocimetry for changes in facial cutaneous blood flow during challenge with monosodium glutamate and its cyctization product, pyrogtutamate. Additionally, records of patients challenged with monosodium glutamate in the laboratory were reviewed. No flushing was provoked among the twenty-four people tested, eighteen of whom gave a positive history of Chinese restaurant syndrome flushing. These results indicate that monosodium glutamate-provoked flushing, if it exists at all, must be rare. Monosodium glutamate and its cyclization product, pyroglutamate, may provoke edema and associated symptoms. U AM AcAo DERMATOL15:225-230, 1986.)
Several Oriental groups have traditionally cooked food wrapped in seaweed to enhance the flavor. In 1910, Ikeda determined that the flavorenhancing agent in the marine alga Laminaria japonica is monosodium glutamate? Subsequently, monosodium glutamate has been employed as a flavor enhancer in amounts considerably greater thanthat obtainable by cooking with seaweed. ~ Thus alleged glutamate toxicity from culinarY exposure is only a recently described entity. in 1968, Kwok 2 described a constellation of e f fects beginning 15 to 20 minutes after the first dish was eaten in a Chinese restaurant. He Suggested that the high sodium content of Chinese food might be responsible. Particularly, the dissociation constant of an organic salt, monosodium glutamate, could make the symptoms more acute. Even From the Dermatology Section, McGuire Veterans Administration Medical Center, and the Departments of Pharmacology and Dermat0fogy, Medicat College of Virginia. Supported by a Veterans Adminish'at[on Merit Review Grant. Ace:epical for publication March 20. 1986. Reprint requests to: Dr. Jonathan K. Wilkin, Chief, Dermatology Section, McGuirc Veterans Administration Medical Center, t201 Broad Rock Rd., Richmond, VA 23249.
though Kwok did not list flushing as part of his reaction, flushing subsequently became included in the "Chinese restaurant syndrome.'"3-4 Although early accounts indicated a pharmacologic, or toxic, type of reaction, subsequent evidence introduced reasonable doubt. First, the symptoms cannot be directly related to the concentration of glutamate in blood. Peak plasma levels o f glutamate and areas under the time-concentration curves of subjects who developed symptoms are not statistically different from those of subjects tree from symptoms? Second, in some studies employing substantial amounts of monosodium glutamate, a toxic reaction to monosodium glutamate was not elicited. ~-8 Accordingly, several workers have speculated that the reaction is due to monosodium glutamate in the presence of another agent or is due solely to a second agent. 9 Such speculations have included the high sodium content of Oriental foods,' some ingredient in soy sauce,' ethanol t° (either consumed as a beverage or used in cooking), * the nonaleohol components of cooking wine, t preservatives, and myeotoxins, z* In sum, the presence of monosodium glutamate may be essential for the 225
226
Journal of the Amerfcan Academy of Dermatology
Wilkin
Table I. Chemicals tested for provocation of monosodium glutamate-like toxic reaction* Readion provoked
Monosodium L-glutamate Monopotassium L-glutamate L-Glutamic acid Monosodium oL-glutamate
I
No reaction provoked
Monosodi um /9-glutamate Monosodium L-aspartate Sodium chloride Sucrose Aspartame Glycine
*Data from Schaurnburg HH, Byck R, Gerstl R, Mashman JH: Science 163:826-828, 1969, and from Stegiak LD, Filer LJ, Baker GL: Am J Clin Nutr 34:1899-1905, 1981.
reaction but in some instances is not sufficient. Thus an additional factor must be considered. Two important lines of evidence emerge from laboratory studies of the glutamate-associated flushing reaction. First, the reaction most commonly occurs following the ingestion of clear soup or broth after fasting. La2 Second, the reaction may be provoked by monosodium L-glutamate, monopotassium L-glutamate, L-glutamic acid, or monosodium DL-glutamate?3 Monosodium D-glutamate, monosodium L-aspartate, sodium chloride, sucrose, aspartame, and glycine do not provoke the reaction 13't4 (Table I). Second, monosodium glutamate is often added to clear soups and broths in considerable quantities to obtain a pleasantly strong meat-flavor. 1 Typically, it is one of the first ingredients added to the soup, which may be brought to a boil several times as successive ingredients are added ~517 (Table II). Cyclization of the L-glutamate under these circumstances results in the formation of L-pyroglutamate. Although L-glutamic acid and its salt form, L-pyroglutamate, monosodium n-glutamate, which is ineffective in provoking the toxic reaction, would cyclize to a different isomer. Thus the restriction of agents capable of provoking the glutamate toxic reaction (Table I) to those which cyclize to L-pyroglutamate is compatible with the-hypothesis that L-pyroglutamate is important in the glutamate toxic reaction. Although the quantities of pyroglutamate formed in vivo are limited, L-glutamic acid readily
Table II, Synthesis of "three-flavor soup"* I. Cut the chicken, fish, and abalone into thin slices. 2. Wash the spinach and cut it into convenient pieces. 3. Beat the egg in a bowl; add the salt, sake, pepper, monosodium glutamate, and cornstarch; and coat the fish and chicken carefully in this mixture. 4. To four cups of soup stock, add the abalone, bamboo shoots, mushrooms, salt, sake, pepper, and monosodium glutamate, and bring the mixture to a boil. Add the chicken and fish, piece by piece. Season to taste. Add the spinach and, just before serving, sprinkle in a few drops of chicken fat. *Modified from Min CK: Practical Chinese cooking. Tokyo. 1969, Japan Publications, Inc.
cyclizes to L-pyroglutamic acid when boiled in solution over a wide pH range (4-10) 1~ or when autoclaved with an equal weight of water at 135 ° to 140° C t9 (Fig. 1). Furthermore, although glutamate has minimal peripheral effects on cardiovascular control ,20 this excitatory amino acid does act at central sites affecting cardiovascular control. 2~ Since atropine blocks the monosodium glutamate reaction, 4 and since atropine readily crosses the blood-brain bartier, these findings are compatible with a central site for the initiation of this toxic reaction. 4 Pyroglutamate crosses the blood-brain barrier with significantly greater ease than L-glutamate22 Thus I undertook this study to characterize the role of L-pyroglutamate in the provocation of the monosodium glutamate toxic reaction. Additionally, I reviewed the results of monosodium glutamate flushing challenges during clinical evaluations over the past 5 years in my laboratory. MATERIALS AND METHODS
Six clinically healthy men were recruited by word of mouth from the medical school and nearby laboratories. This study was approved by the local institutional review board. All subjects were requested to abstain from strenuous physical exertion and to take nothing by mouth except small quantities of water within 6 hours of the start of the study. All subjects denied taking prescription and over-the-counter medications during
Volume 15 Number 2, Part 1 August, 1986
Monosodium glutamate flushing L-Glutamate
Transitional S t a t e
H2~-- ~H2 o=c c H - c o o -
H~tC--iH2 H " O ~ ~' H--CO0.......o-''~ '~ I
t I HO INHs
227
L-Pyroglutamate (=L-5-Oxa-2-Pyr rolid~ne Carboxylic Acid) H2 C--CH2 I I o=c c . - - c o o -
"INHz
\N/ I H
Fig, 1. The cyclization of L-glutamate to t.-pyroglutamate H20 can occur during cooking. the l0 days before the study period and did not consume alcoholic beverages nor caffeine within the 24-hour period before each laboratory test. Each subject was seated individually in a laboratory where the temperature was maintained at 23.1 ° ± 1.2 ° C. On arriving at the laboratory, each subject was asked to go to the restroom and void the bladder. On returning to the laboratory, each subject was seated comfortably in a large recliaer chair. Facial cutaneous blood flow was monitored continuously from a probe placed on the left malar eminence at 2 cm below the infraorbital ridge, by means of methods described elsewhere.~ The results are expressed as ratios (CPI; cutaneous perfusion index) of the highest values attained during the 90 minutes after the test solution was ingested to the baseline values. Each subject was challenged at weekly intervals by L-glutamate and L-pyroglutamate given at 35.7, 71.4, 142.9, and 285.7 and at 7.1, 14.3, 28.6, and 71.4 mg/kg, respectively (Table llI). Although the L-glutamate and L-pyrogtutamale were presented randomly and in a double-blind manner, the doses of the provocative agents were increased sequentially within this design in order to ethically detect unpleasant side effects at the lowest possible dose. Prospectively, Subjects l, 2, and 3 recalled flushing after eating Chinese restaurant food. The remaining three subjects were uncertain on this point. Additionally, 1 reviewed the data obtained in the clinical evaluation of fifteen patients with flushing reactions. Among these fifteen subjects, there were twenty challenges, ~ each consisting of 3 gm of monasodium glutamate in aqueous solution. Twelve of these fifteen patients indicated that they had experienced flushing reactions after eating Chinese cuisine. Three additional subjects who described flushing reactions after eating Chinese cuisine were tested with 5 gm mannsodium glutamate in aqueous solution. These data were analyzed by calculating the 95% confidence interval for theoretical risk of a monosodiu m glutamate-provoked reaction. 2~,z~
Table I I I . Effect of L-glutamate and L-pyroglutamate on facial cutaneous blood flow Substance tested
L-Glutamate
Dose
Mean
(mg/kg)
CPI ± SEM
35.7 71.4 142.9 285.7
1.15 1.13 1.24 1.21
_ 0.05 _+__0.04 _ 0.09 ± 0.02
7.1 14.3 28.6 71.4
1.18 1.21 1.19 1.13
± 0.06 _+ 0.08 ± 0.05 _+ 0.06
L-Pyroglutamate
CPI: Cutaneous perfusion index,
In addition to monitoring for flushing reaction by laser Doppler velocimetry in the prospective study, I used the malar thermal circulation index method, described elsewhere, ~4m'2s in the retrospective portion of this study. Patients and subjects were asked to report during these studies when any unusual sensation occuffed to them, Study participants were again questioned on this point at the conclusion of each study. RESULTS No flushing was provoked by any of the four concentrations each of the monosodium L-glutamate and L-pyroglutamate (Table III). Values less than 1.80 indicated no flushing? 3 In tact, in none of the individual tests were any values greater than 1.67. Sensations of " p r e s s u r e " in the chest and " t i g h t n e s s " in the hands occurred after the high dose of m o n o s o d i u m glutamate and the high dose of pyroglutamate in one subject only. Two additional subjects described a puffiness of the fingers and thirst during the evening, approximately 6 hours after the tests with the high doses o f both agents. The m i n i m u m amount of monosodium glu-
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Journal of the American Academy of Dermatology
Wilkin
Table IV. Numbers of subjects tested* at three doses of monosodium glutamate (MSG) with corresponding upper 95% confidence limits for the probablility of MSG-provoked flushing Subjects with All subjects Amount of MSG (gin)
3 5 18.5
positive history
n
% Upper 95% confidence limit
n
% Upper 95% confidence limit
24 9 6
11.7 28.3 39.3
18 6 3
19.3 39.3 63.2
*None of the st)bjects tested had flushing.
tamate given to any subject at the highest challenge dose was 18.5 gm. A retrospective analysis of clinical laboratory records disclosed that flushing did not occur during twenty challenges of 3 gm monosodium glutamate among fifteen subjects nor after challenge with 5 gm monosodium glutamate in three alleged "Chinese restaurant flushers." Thus, at levels of 3 gm monosodium glutamate ..... no flushing reactions were elicited in twenty-fgur subjects, eighteen of whom were alleged Chinese restaurant flushers. At the level of 5 gm monosodium glutamate, there were no flushers among nine subjects, six of whom were alleged Chinese restaurant flushers. Finally, in the prospective study, no flushing reactions were elicited after 18.5 gm monosodium glutamate in six subjects, three of whom were alleged Chinese restaurant flushers. The upper 95% confidence limits for the probabilitY of monosodium glutamate-provoked flushing (in percentage) are calculated for each challenge dose of monosodium glutamate'-6.~7 (Table IV). DISCUSSION The failure to provoke flushing after 3 gm mOuo_ sodium glutamate rules out any long-term risk in the general adult population higher than 11,7% with 95% confidence. Among subjects who believed they had experienced components of the Chinese restaurant syndrome, a long-term risk
higher than 19.3% was ruled out (Table IV). These resutts contrast sharply with those of earlier studies in which the Chinese restaurant syndrome was thought to occur in 25% or more of the general adult public) 9"3~) Although pyroglutamate was not shown to be a cause of flushing in the present study, it did provoke sensations of burning, tightness, and puffiness at one-fourth the concentration of monosodium glutamate. Since monosodium glutamate is present in stock cubes for soups and may be maintained at high temperatures for prolonged periods of time, it is possible that pyroglutamate could be synthesized in the preparation of soups at Chinese restaurants. That pyroglutamate provokes symptoms at lower concentrations than monosodium glutamate may relate to the greater ease with which pyroglutamate traverses the blood-brain barrier) ~ This would support the postulated central site of activity of the offending agent in the provocation of the Chinese restaurant syndrome: It is also possible that some pyroglntamate is forined in vivo from glutamate? 1'32 Furthermore, all neutral salts do not have equal effects on the structure and solubility of proteins and other colloids? 3 Such osmotically active solutes, known as osmolytes, accumulate in cells during osmotic stress and prevent damage from cellular dehydration by balancing the osmotic strength of the cytoplasm with that of the environment. 34 In addition to functioning as osmotic balancing agents, these "osmoprotectants" may interact with crucial macromolecules of the cell to help modulate their biologic activity?4 Such molecules can be supplied exogenously to living systems with profound results?" Pyroglutamate is structurally related to molecules possessing potent osmotic activity?4 Thus edema and symptoms resuiting therefrom may occur in humans after oral challenge with pyroglutamate. At the very least, the edematous symptoms and signs are likely due to more than sodium, since glutamate and pyroglutamate can be osmotically active solutes. More recently, additional negative studies have been reported. Rosenblum et al~ could not identify even one subject who experienced burning sensations, chest pain, or palpitations among the
Volume 15 Number 2, Part 1 August, 1986
ninety-eight healthy men challenged with monosodium glutamate. Only lightheadedness and tightness o f the face appeared with greater frequency among the monosodium glutamate-treated subjects in comparison with control subjects. Morselli and Garattini, 7 using a double-blind crossover method, found no differences in subjective response to 3 gm monosodium glutamate, nor were there any changes in blood pressure. Bazzano et al ~ administered monosodium glutamate in quantities up to 147 gin/day without provoking the Chinese restaurant syndrome. Subsequently, K e n n e y 3-' reported that monosodium glutamate-induced symptoms are not accompanied by objective changes in skin temperature or brachial artery blood pressure and postulated that the sensations provoked by monosodium glutamate are visceral, perhaps esophageal, but not peripheral in origin. Accordingly, the burning sensation beginning over the face, reputed to be the first symptom of the Chinese restaurant syndrome, ~3 may not be a subjective indicant of flushing. In fact, Kerr et al 3'36 pointed to the imprecision and ambiguity in questionnaires, specifically citing the example o f " b u r n i n g " reported as nonspecific " f l u s h i n g . " Finally, in a reevaluation o f the evidence, Kerr et al ~'~C' lowered their estimate o f the prevalence rate of the Chinese restaurant syndrome in the general adult public downward to ] % to 2% of the general adult public. Such a risk rate is compatible with the results o f the present study. The statement that " a study of nonsusceptible subjects only will not reveal significant reactions ''37 has been used to counter previous, negative reports. No matter how many subjects we identify as having no flushing reactions after challenge with monosodium glutamate, we can never rule out the possibility that flushing could occur in a sensitive subject as a result of monosodium glutamate. However, significant flushing from monosodium glutamate, if it exists at all, must be limited to a small percentage o f the general adult public who are so exquisitely sensitive that they respond to anaounts encountered in usual culinary exposure. Furthermore, signs and symptoms related to tissue edema may result from glutamate, not only directly, but
Monosodium glutamate flushing
229
also indirectly from its conversion to pyroglutamate. REFERENCES
I. Reif-Lehrer L: Possible significance of adverse reactions to glutamate in humans. Fed Proc 35:2205-2211, 1976. 2. Kwok RHM: Chinese-restaurant syndrome. N Engl J Med 278:796, 1968. 3, Kerr GR, Wu-Lce M, EI-Lozy M, et al: Prevalence of the '°Chinese restaurant syndrome." J Am Diet Assoc 75:29-33, t979. 4. Ghadimi H, Kumar S, Abaci F: Studies on monosodium glutamate ingestion. Biochem Med 5:447-456, 1971. 5. Ghezzi P, Salmona M, Recchia M, et al: Monosodium glutamate kinetic studies in human volunteers. Toxicol Lett 5:417-421, 1980. 6. Bazzano G, D'Elia JA, Olson RE: Monosodium glutamate: Feeding of large amounts in man and gerbils. Science 169:1208-1209, 1970. 7. Morselli PL, Garattini S" Monosodium glutamate and the Chinese restaurant syndrome. Nature 227:61 t-612, 1970. 8. Rosenblum I, Bradley JD, Coulston F: Single and double blind studies with oral monosodium glutamate in man. Toxicol Appl Pharmaeol 18:367-373, 1971. 9. Gore ME, Salmon PR: Chinese restaurant syndrome: Fact or fiction? Lancet 1:251-252, 1980. 10. Sauber WJ: What is Chinese restaurant syndrome? Lancet 1:721-722, 1980. 11. Schaumburg H: Chinese restaurant syndrome, N Engl J Med 278:1122, 1968. 12. Reif-Lehrer L: A questionnaire study of the prevalence of Chinese restaurant syndrome. Fed Proc 36:1617- t 623, 1977. 13. Schaumburg HH, Byck RR, Gerstl R, Mashman JH: Monosodium L-glutamate: Its pharmacology and role in the Chinese restaurant syndrome. Science 163:826-828, 1969.
14. Stegink LD, Filer LJ, Baker GL: Effect of aspartame and sucrose loading in glutamate-susceptible subjects. Am J Clin Nutr 34:1899-1905, 198 I. 15. Hahn E: The cooking of China. New York, 1973, TimeLife Books, pp. 77-78. 16. Hahn E: Recipes: The cooking of China. New York, 1973. Time,Life Books. 17. Min CK: Practical Chinese cooking. Tokyo, t969, Japan Publications, p. 64. 18. Diem K, l.entner C, editors: Scientific tables, ed. 7. Basel, Switzerland, 1970, Ciba-Geigy, Ltd., p. 516. t9. Windholz M, editor: The Merck index, ed. 9. Rahway, NJ, 1976, Merck & Co., Inc., p. t038. 20. Kirkendol PL, Pearson JE, Robie NW: The cardiac and vascular effects of sodium glutamate. Clin Exp Pharmaco[ Physiol 7:617-625, 1980. 21. Chelly J, Kouyoumdjian JC, Mouille P, et aI: Effects of L-glutamic acid and kainic acid on central cardiovascular control. Eur J PharmacoI 60:91-94, 1979. 22. Caccia S, Garattini S, Ghezzi P, Zanini MG: Plasma and brain levels of glutamate and pyroglutamate after oral
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28. 29.
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monosodium glutamate to rats. Toxicot Lett 10:169-175, 1982. Wilkin JK: Quantitative assessment of alcohol-provoked flushing. Arch Dermatol 122:63-65, 1986. Wilkin JK: A quantitative, non-invasive method for the characterization of flushing reactions. J Invest Derrnatol 78:276-279, 1982. Ghadimi H, Kumar S, Abaci F: Studies on monosodium glutamate ingestion. Biochem Med 5:447-456, 1971. Hanley JA, Lippman-Hand A: tf nothing goes wrong, is evel"ything all right? JAMA 249:1743-1745, 1983. Wilkin JK: Chtorpropamide-a[cohol flushing, malar thermal circulation index, and baseline malar temperature. Metabolism 31:948-954, 1982. Wilkin JK, et al: Aspirin blocks nicotinic acid-induced flushing. Clin Pharmacol Ther 31:478-482, 1982. Kenney RA, Tit[bail CS: Human susceptibility to oral monosodium L-glutamate. Am J Clin Nutr 25:140-i46, 1972. Kerr GR, Wu-Lee M, El-Lozy M, et al: Objectivity of food-symptomatoiogy surveys. J Am Diet Assoc 71:263268, 1977. Barrett JG, Scott IR: Pyrrolidone carboxylic acid syn-
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thesis in guinea pig epidermis. J Invest Dermato181:122124, 1983. Marstein S: Studies on the accumulation of L-pyroglutamic acid in guinea pig epidernfis. J Invest DermatoI 74:135-138, 1980. Yancey PH, Clark ME, Hand SC, et al: Living with water stress: Evolution of osmolyte systems. Science 217: 1214-1222, 1982. LeRudulier D. Strum AR, Dandekar AM, et al: Molecular biology of osmoregalation. Science 224:1064-1068, 1984. Kenney RA: Placebo-controlled studies of human reaction Io oral moaosodium L-glutamate, in Filer LJ Jr, et al, editors: Glutamic acid: Advances in biochemistry and physiology. New York, 1979, Raven Press. Kerr GR, Wu-Lee M, Ei-Loz3, M, et al: Food-symptomatology questionnaires: Risks of demand-bias questions and population-based surveys, in Filer 1.2 Jr, et at, editors: Glutamic acid: Advances in biochemistry and physiology. New York, 1979, Raven Press. Himms-Hagen J: Chinese restaurant syndrome, Nature 228:97, 1970.
ABSTRACTS
Cutaneous T cell lymphoma Knobler RM, Edelson RL: Med Clin North AM 70:109138, 1986 A capable review of this impoctant uncologic matter comes from Columbia University. Philip C. Anderson. M.D. Metastatic melanoma, or is it? Back L, Brown A: Plast Reconstr Surg 77:138-149, 1986 Here is a healthy recognition that histotogic confirmation is useful in assessing metastasis. The familiar point is that melanin may collect in lymph nodes near a cutaneous melanoma, even without metastasis to the node. Surge,~ns seeing ~he pigmented lymph node may not assume thai melanoma is in the node. Philip C. Anderson, M.D.
The use of ketoconazole in the treatment of blastomycosis McManus E J, Jones JM: Am Rev Respir Dis 133:141-i43, 1986 The general rule i~ lhat if the blastomycosis is not widely disseminated and the patient is not immune-suppressed, then ketaconazole alone may he sufficient. Watch for a stable remission: otherwise
additional treatment with amphotedcin B is required. From Wisconsin come reports of many patients who have the disease. Philip C. Anderson, M.D.
Contact allergy to various components of topical preparations for treatment of external otitis Fraki ,IE, Kalimo K, Tuohimaa P, et al: Acta Otolaryngol (Stockh) 100:414-418, 1985 Briefly, allergic contact dermatitis of the ear canal is usually caused by the eardrops, often the rteomyc[n. Philip C. Anders~, M.D.
The day-care centre in the management of psoriasis Thirumoorthy T, Tan YC, Wong BY: Ann Acad Med Singapore 14:689-692, 1985 From Middle Road Hospita/ha Singapore come .some results ha treating psoriasis. About 80% success was accounted to the dithranolultraviolet B (UVB) combination (patients are 95% clear or better) while ordinary psoralens plus ultraviolet A (PUVA) tied with a rate of 77%. The PUVA plan required twenty-five treatment sessions; on the average, about 42 days and 346 oules/cm:. "REPUVA," that is, REti~oids and PUVA, gave 96% success with eighteen treatments, on the average, and used 142 joulest'cmL Philip C. Anderson, M.D.
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Does monosodium glutamate cause flushing (or merely "glutamania") ? Jonathan K. Wilkin, M.D. Richmond, VA Monosodium glutamate is widely regarded as the provocative agent in the "Chinese restaurant syndrome," of which flushing is regarded as part of the reaction. Six subjects were monitored by laser Doppler velocimetry for changes in facial cutaneous blood flow during challenge with monosodium glutamate and its cyctization product, pyrogtutamate. Additionally, records of patients challenged with monosodium glutamate in the laboratory were reviewed. No flushing was provoked among the twenty-four people tested, eighteen of whom gave a positive history of Chinese restaurant syndrome flushing. These results indicate that monosodium glutamate-provoked flushing, if it exists at all, must be rare. Monosodium glutamate and its cyclization product, pyroglutamate, may provoke edema and associated symptoms. U AM AcAo DERMATOL15:225-230, 1986.)
Several Oriental groups have traditionally cooked food wrapped in seaweed to enhance the flavor. In 1910, Ikeda determined that the flavorenhancing agent in the marine alga Laminaria japonica is monosodium glutamate? Subsequently, monosodium glutamate has been employed as a flavor enhancer in amounts considerably greater thanthat obtainable by cooking with seaweed. ~ Thus alleged glutamate toxicity from culinarY exposure is only a recently described entity. in 1968, Kwok 2 described a constellation of e f fects beginning 15 to 20 minutes after the first dish was eaten in a Chinese restaurant. He Suggested that the high sodium content of Chinese food might be responsible. Particularly, the dissociation constant of an organic salt, monosodium glutamate, could make the symptoms more acute. Even From the Dermatology Section, McGuire Veterans Administration Medical Center, and the Departments of Pharmacology and Dermat0fogy, Medicat College of Virginia. Supported by a Veterans Adminish'at[on Merit Review Grant. Ace:epical for publication March 20. 1986. Reprint requests to: Dr. Jonathan K. Wilkin, Chief, Dermatology Section, McGuirc Veterans Administration Medical Center, t201 Broad Rock Rd., Richmond, VA 23249.
though Kwok did not list flushing as part of his reaction, flushing subsequently became included in the "Chinese restaurant syndrome.'"3-4 Although early accounts indicated a pharmacologic, or toxic, type of reaction, subsequent evidence introduced reasonable doubt. First, the symptoms cannot be directly related to the concentration of glutamate in blood. Peak plasma levels o f glutamate and areas under the time-concentration curves of subjects who developed symptoms are not statistically different from those of subjects tree from symptoms? Second, in some studies employing substantial amounts of monosodium glutamate, a toxic reaction to monosodium glutamate was not elicited. ~-8 Accordingly, several workers have speculated that the reaction is due to monosodium glutamate in the presence of another agent or is due solely to a second agent. 9 Such speculations have included the high sodium content of Oriental foods,' some ingredient in soy sauce,' ethanol t° (either consumed as a beverage or used in cooking), * the nonaleohol components of cooking wine, t preservatives, and myeotoxins, z* In sum, the presence of monosodium glutamate may be essential for the 225
226
Journal of the Amerfcan Academy of Dermatology
Wilkin
Table I. Chemicals tested for provocation of monosodium glutamate-like toxic reaction* Readion provoked
Monosodium L-glutamate Monopotassium L-glutamate L-Glutamic acid Monosodium oL-glutamate
I
No reaction provoked
Monosodi um /9-glutamate Monosodium L-aspartate Sodium chloride Sucrose Aspartame Glycine
*Data from Schaurnburg HH, Byck R, Gerstl R, Mashman JH: Science 163:826-828, 1969, and from Stegiak LD, Filer LJ, Baker GL: Am J Clin Nutr 34:1899-1905, 1981.
reaction but in some instances is not sufficient. Thus an additional factor must be considered. Two important lines of evidence emerge from laboratory studies of the glutamate-associated flushing reaction. First, the reaction most commonly occurs following the ingestion of clear soup or broth after fasting. La2 Second, the reaction may be provoked by monosodium L-glutamate, monopotassium L-glutamate, L-glutamic acid, or monosodium DL-glutamate?3 Monosodium D-glutamate, monosodium L-aspartate, sodium chloride, sucrose, aspartame, and glycine do not provoke the reaction 13't4 (Table I). Second, monosodium glutamate is often added to clear soups and broths in considerable quantities to obtain a pleasantly strong meat-flavor. 1 Typically, it is one of the first ingredients added to the soup, which may be brought to a boil several times as successive ingredients are added ~517 (Table II). Cyclization of the L-glutamate under these circumstances results in the formation of L-pyroglutamate. Although L-glutamic acid and its salt form, L-pyroglutamate, monosodium n-glutamate, which is ineffective in provoking the toxic reaction, would cyclize to a different isomer. Thus the restriction of agents capable of provoking the glutamate toxic reaction (Table I) to those which cyclize to L-pyroglutamate is compatible with the-hypothesis that L-pyroglutamate is important in the glutamate toxic reaction. Although the quantities of pyroglutamate formed in vivo are limited, L-glutamic acid readily
Table II, Synthesis of "three-flavor soup"* I. Cut the chicken, fish, and abalone into thin slices. 2. Wash the spinach and cut it into convenient pieces. 3. Beat the egg in a bowl; add the salt, sake, pepper, monosodium glutamate, and cornstarch; and coat the fish and chicken carefully in this mixture. 4. To four cups of soup stock, add the abalone, bamboo shoots, mushrooms, salt, sake, pepper, and monosodium glutamate, and bring the mixture to a boil. Add the chicken and fish, piece by piece. Season to taste. Add the spinach and, just before serving, sprinkle in a few drops of chicken fat. *Modified from Min CK: Practical Chinese cooking. Tokyo. 1969, Japan Publications, Inc.
cyclizes to L-pyroglutamic acid when boiled in solution over a wide pH range (4-10) 1~ or when autoclaved with an equal weight of water at 135 ° to 140° C t9 (Fig. 1). Furthermore, although glutamate has minimal peripheral effects on cardiovascular control ,20 this excitatory amino acid does act at central sites affecting cardiovascular control. 2~ Since atropine blocks the monosodium glutamate reaction, 4 and since atropine readily crosses the blood-brain bartier, these findings are compatible with a central site for the initiation of this toxic reaction. 4 Pyroglutamate crosses the blood-brain barrier with significantly greater ease than L-glutamate22 Thus I undertook this study to characterize the role of L-pyroglutamate in the provocation of the monosodium glutamate toxic reaction. Additionally, I reviewed the results of monosodium glutamate flushing challenges during clinical evaluations over the past 5 years in my laboratory. MATERIALS AND METHODS
Six clinically healthy men were recruited by word of mouth from the medical school and nearby laboratories. This study was approved by the local institutional review board. All subjects were requested to abstain from strenuous physical exertion and to take nothing by mouth except small quantities of water within 6 hours of the start of the study. All subjects denied taking prescription and over-the-counter medications during
Volume 15 Number 2, Part 1 August, 1986
Monosodium glutamate flushing L-Glutamate
Transitional S t a t e
H2~-- ~H2 o=c c H - c o o -
H~tC--iH2 H " O ~ ~' H--CO0.......o-''~ '~ I
t I HO INHs
227
L-Pyroglutamate (=L-5-Oxa-2-Pyr rolid~ne Carboxylic Acid) H2 C--CH2 I I o=c c . - - c o o -
"INHz
\N/ I H
Fig, 1. The cyclization of L-glutamate to t.-pyroglutamate H20 can occur during cooking. the l0 days before the study period and did not consume alcoholic beverages nor caffeine within the 24-hour period before each laboratory test. Each subject was seated individually in a laboratory where the temperature was maintained at 23.1 ° ± 1.2 ° C. On arriving at the laboratory, each subject was asked to go to the restroom and void the bladder. On returning to the laboratory, each subject was seated comfortably in a large recliaer chair. Facial cutaneous blood flow was monitored continuously from a probe placed on the left malar eminence at 2 cm below the infraorbital ridge, by means of methods described elsewhere.~ The results are expressed as ratios (CPI; cutaneous perfusion index) of the highest values attained during the 90 minutes after the test solution was ingested to the baseline values. Each subject was challenged at weekly intervals by L-glutamate and L-pyroglutamate given at 35.7, 71.4, 142.9, and 285.7 and at 7.1, 14.3, 28.6, and 71.4 mg/kg, respectively (Table llI). Although the L-glutamate and L-pyrogtutamale were presented randomly and in a double-blind manner, the doses of the provocative agents were increased sequentially within this design in order to ethically detect unpleasant side effects at the lowest possible dose. Prospectively, Subjects l, 2, and 3 recalled flushing after eating Chinese restaurant food. The remaining three subjects were uncertain on this point. Additionally, 1 reviewed the data obtained in the clinical evaluation of fifteen patients with flushing reactions. Among these fifteen subjects, there were twenty challenges, ~ each consisting of 3 gm of monasodium glutamate in aqueous solution. Twelve of these fifteen patients indicated that they had experienced flushing reactions after eating Chinese cuisine. Three additional subjects who described flushing reactions after eating Chinese cuisine were tested with 5 gm mannsodium glutamate in aqueous solution. These data were analyzed by calculating the 95% confidence interval for theoretical risk of a monosodiu m glutamate-provoked reaction. 2~,z~
Table I I I . Effect of L-glutamate and L-pyroglutamate on facial cutaneous blood flow Substance tested
L-Glutamate
Dose
Mean
(mg/kg)
CPI ± SEM
35.7 71.4 142.9 285.7
1.15 1.13 1.24 1.21
_ 0.05 _+__0.04 _ 0.09 ± 0.02
7.1 14.3 28.6 71.4
1.18 1.21 1.19 1.13
± 0.06 _+ 0.08 ± 0.05 _+ 0.06
L-Pyroglutamate
CPI: Cutaneous perfusion index,
In addition to monitoring for flushing reaction by laser Doppler velocimetry in the prospective study, I used the malar thermal circulation index method, described elsewhere, ~4m'2s in the retrospective portion of this study. Patients and subjects were asked to report during these studies when any unusual sensation occuffed to them, Study participants were again questioned on this point at the conclusion of each study. RESULTS No flushing was provoked by any of the four concentrations each of the monosodium L-glutamate and L-pyroglutamate (Table III). Values less than 1.80 indicated no flushing? 3 In tact, in none of the individual tests were any values greater than 1.67. Sensations of " p r e s s u r e " in the chest and " t i g h t n e s s " in the hands occurred after the high dose of m o n o s o d i u m glutamate and the high dose of pyroglutamate in one subject only. Two additional subjects described a puffiness of the fingers and thirst during the evening, approximately 6 hours after the tests with the high doses o f both agents. The m i n i m u m amount of monosodium glu-
228
Journal of the American Academy of Dermatology
Wilkin
Table IV. Numbers of subjects tested* at three doses of monosodium glutamate (MSG) with corresponding upper 95% confidence limits for the probablility of MSG-provoked flushing Subjects with All subjects Amount of MSG (gin)
3 5 18.5
positive history
n
% Upper 95% confidence limit
n
% Upper 95% confidence limit
24 9 6
11.7 28.3 39.3
18 6 3
19.3 39.3 63.2
*None of the st)bjects tested had flushing.
tamate given to any subject at the highest challenge dose was 18.5 gm. A retrospective analysis of clinical laboratory records disclosed that flushing did not occur during twenty challenges of 3 gm monosodium glutamate among fifteen subjects nor after challenge with 5 gm monosodium glutamate in three alleged "Chinese restaurant flushers." Thus, at levels of 3 gm monosodium glutamate ..... no flushing reactions were elicited in twenty-fgur subjects, eighteen of whom were alleged Chinese restaurant flushers. At the level of 5 gm monosodium glutamate, there were no flushers among nine subjects, six of whom were alleged Chinese restaurant flushers. Finally, in the prospective study, no flushing reactions were elicited after 18.5 gm monosodium glutamate in six subjects, three of whom were alleged Chinese restaurant flushers. The upper 95% confidence limits for the probabilitY of monosodium glutamate-provoked flushing (in percentage) are calculated for each challenge dose of monosodium glutamate'-6.~7 (Table IV). DISCUSSION The failure to provoke flushing after 3 gm mOuo_ sodium glutamate rules out any long-term risk in the general adult population higher than 11,7% with 95% confidence. Among subjects who believed they had experienced components of the Chinese restaurant syndrome, a long-term risk
higher than 19.3% was ruled out (Table IV). These resutts contrast sharply with those of earlier studies in which the Chinese restaurant syndrome was thought to occur in 25% or more of the general adult public) 9"3~) Although pyroglutamate was not shown to be a cause of flushing in the present study, it did provoke sensations of burning, tightness, and puffiness at one-fourth the concentration of monosodium glutamate. Since monosodium glutamate is present in stock cubes for soups and may be maintained at high temperatures for prolonged periods of time, it is possible that pyroglutamate could be synthesized in the preparation of soups at Chinese restaurants. That pyroglutamate provokes symptoms at lower concentrations than monosodium glutamate may relate to the greater ease with which pyroglutamate traverses the blood-brain barrier) ~ This would support the postulated central site of activity of the offending agent in the provocation of the Chinese restaurant syndrome: It is also possible that some pyroglntamate is forined in vivo from glutamate? 1'32 Furthermore, all neutral salts do not have equal effects on the structure and solubility of proteins and other colloids? 3 Such osmotically active solutes, known as osmolytes, accumulate in cells during osmotic stress and prevent damage from cellular dehydration by balancing the osmotic strength of the cytoplasm with that of the environment. 34 In addition to functioning as osmotic balancing agents, these "osmoprotectants" may interact with crucial macromolecules of the cell to help modulate their biologic activity?4 Such molecules can be supplied exogenously to living systems with profound results?" Pyroglutamate is structurally related to molecules possessing potent osmotic activity?4 Thus edema and symptoms resuiting therefrom may occur in humans after oral challenge with pyroglutamate. At the very least, the edematous symptoms and signs are likely due to more than sodium, since glutamate and pyroglutamate can be osmotically active solutes. More recently, additional negative studies have been reported. Rosenblum et al~ could not identify even one subject who experienced burning sensations, chest pain, or palpitations among the
Volume 15 Number 2, Part 1 August, 1986
ninety-eight healthy men challenged with monosodium glutamate. Only lightheadedness and tightness o f the face appeared with greater frequency among the monosodium glutamate-treated subjects in comparison with control subjects. Morselli and Garattini, 7 using a double-blind crossover method, found no differences in subjective response to 3 gm monosodium glutamate, nor were there any changes in blood pressure. Bazzano et al ~ administered monosodium glutamate in quantities up to 147 gin/day without provoking the Chinese restaurant syndrome. Subsequently, K e n n e y 3-' reported that monosodium glutamate-induced symptoms are not accompanied by objective changes in skin temperature or brachial artery blood pressure and postulated that the sensations provoked by monosodium glutamate are visceral, perhaps esophageal, but not peripheral in origin. Accordingly, the burning sensation beginning over the face, reputed to be the first symptom of the Chinese restaurant syndrome, ~3 may not be a subjective indicant of flushing. In fact, Kerr et al 3'36 pointed to the imprecision and ambiguity in questionnaires, specifically citing the example o f " b u r n i n g " reported as nonspecific " f l u s h i n g . " Finally, in a reevaluation o f the evidence, Kerr et al ~'~C' lowered their estimate o f the prevalence rate of the Chinese restaurant syndrome in the general adult public downward to ] % to 2% of the general adult public. Such a risk rate is compatible with the results o f the present study. The statement that " a study of nonsusceptible subjects only will not reveal significant reactions ''37 has been used to counter previous, negative reports. No matter how many subjects we identify as having no flushing reactions after challenge with monosodium glutamate, we can never rule out the possibility that flushing could occur in a sensitive subject as a result of monosodium glutamate. However, significant flushing from monosodium glutamate, if it exists at all, must be limited to a small percentage o f the general adult public who are so exquisitely sensitive that they respond to anaounts encountered in usual culinary exposure. Furthermore, signs and symptoms related to tissue edema may result from glutamate, not only directly, but
Monosodium glutamate flushing
229
also indirectly from its conversion to pyroglutamate. REFERENCES
I. Reif-Lehrer L: Possible significance of adverse reactions to glutamate in humans. Fed Proc 35:2205-2211, 1976. 2. Kwok RHM: Chinese-restaurant syndrome. N Engl J Med 278:796, 1968. 3, Kerr GR, Wu-Lce M, EI-Lozy M, et al: Prevalence of the '°Chinese restaurant syndrome." J Am Diet Assoc 75:29-33, t979. 4. Ghadimi H, Kumar S, Abaci F: Studies on monosodium glutamate ingestion. Biochem Med 5:447-456, 1971. 5. Ghezzi P, Salmona M, Recchia M, et al: Monosodium glutamate kinetic studies in human volunteers. Toxicol Lett 5:417-421, 1980. 6. Bazzano G, D'Elia JA, Olson RE: Monosodium glutamate: Feeding of large amounts in man and gerbils. Science 169:1208-1209, 1970. 7. Morselli PL, Garattini S" Monosodium glutamate and the Chinese restaurant syndrome. Nature 227:61 t-612, 1970. 8. Rosenblum I, Bradley JD, Coulston F: Single and double blind studies with oral monosodium glutamate in man. Toxicol Appl Pharmaeol 18:367-373, 1971. 9. Gore ME, Salmon PR: Chinese restaurant syndrome: Fact or fiction? Lancet 1:251-252, 1980. 10. Sauber WJ: What is Chinese restaurant syndrome? Lancet 1:721-722, 1980. 11. Schaumburg H: Chinese restaurant syndrome, N Engl J Med 278:1122, 1968. 12. Reif-Lehrer L: A questionnaire study of the prevalence of Chinese restaurant syndrome. Fed Proc 36:1617- t 623, 1977. 13. Schaumburg HH, Byck RR, Gerstl R, Mashman JH: Monosodium L-glutamate: Its pharmacology and role in the Chinese restaurant syndrome. Science 163:826-828, 1969.
14. Stegink LD, Filer LJ, Baker GL: Effect of aspartame and sucrose loading in glutamate-susceptible subjects. Am J Clin Nutr 34:1899-1905, 198 I. 15. Hahn E: The cooking of China. New York, 1973, TimeLife Books, pp. 77-78. 16. Hahn E: Recipes: The cooking of China. New York, 1973. Time,Life Books. 17. Min CK: Practical Chinese cooking. Tokyo, t969, Japan Publications, p. 64. 18. Diem K, l.entner C, editors: Scientific tables, ed. 7. Basel, Switzerland, 1970, Ciba-Geigy, Ltd., p. 516. t9. Windholz M, editor: The Merck index, ed. 9. Rahway, NJ, 1976, Merck & Co., Inc., p. t038. 20. Kirkendol PL, Pearson JE, Robie NW: The cardiac and vascular effects of sodium glutamate. Clin Exp Pharmaco[ Physiol 7:617-625, 1980. 21. Chelly J, Kouyoumdjian JC, Mouille P, et aI: Effects of L-glutamic acid and kainic acid on central cardiovascular control. Eur J PharmacoI 60:91-94, 1979. 22. Caccia S, Garattini S, Ghezzi P, Zanini MG: Plasma and brain levels of glutamate and pyroglutamate after oral
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ABSTRACTS
Cutaneous T cell lymphoma Knobler RM, Edelson RL: Med Clin North AM 70:109138, 1986 A capable review of this impoctant uncologic matter comes from Columbia University. Philip C. Anderson. M.D. Metastatic melanoma, or is it? Back L, Brown A: Plast Reconstr Surg 77:138-149, 1986 Here is a healthy recognition that histotogic confirmation is useful in assessing metastasis. The familiar point is that melanin may collect in lymph nodes near a cutaneous melanoma, even without metastasis to the node. Surge,~ns seeing ~he pigmented lymph node may not assume thai melanoma is in the node. Philip C. Anderson, M.D.
The use of ketoconazole in the treatment of blastomycosis McManus E J, Jones JM: Am Rev Respir Dis 133:141-i43, 1986 The general rule i~ lhat if the blastomycosis is not widely disseminated and the patient is not immune-suppressed, then ketaconazole alone may he sufficient. Watch for a stable remission: otherwise
additional treatment with amphotedcin B is required. From Wisconsin come reports of many patients who have the disease. Philip C. Anderson, M.D.
Contact allergy to various components of topical preparations for treatment of external otitis Fraki ,IE, Kalimo K, Tuohimaa P, et al: Acta Otolaryngol (Stockh) 100:414-418, 1985 Briefly, allergic contact dermatitis of the ear canal is usually caused by the eardrops, often the rteomyc[n. Philip C. Anders~, M.D.
The day-care centre in the management of psoriasis Thirumoorthy T, Tan YC, Wong BY: Ann Acad Med Singapore 14:689-692, 1985 From Middle Road Hospita/ha Singapore come .some results ha treating psoriasis. About 80% success was accounted to the dithranolultraviolet B (UVB) combination (patients are 95% clear or better) while ordinary psoralens plus ultraviolet A (PUVA) tied with a rate of 77%. The PUVA plan required twenty-five treatment sessions; on the average, about 42 days and 346 oules/cm:. "REPUVA," that is, REti~oids and PUVA, gave 96% success with eighteen treatments, on the average, and used 142 joulest'cmL Philip C. Anderson, M.D.