EFFECT
OF
GLUTAMIC
ACID
ON
MENTAL
FUNCTION
Pilot
Study
By WILLIAM
J.
KERR, JR.,M.D.,
AND S. A. SZUREK,M.D.
San Francisco
S
INCE the observation of Price, Waelsch and Putnam1 that glutamic acid, given to control epileptic seizures, caused ‘‘a degree of improvement in mental efficiency{
that] could not be correlatcd with the incidence of seizures, much attention has been focused on the effect of the drug on mental function generally. Zimmerman, Burgemeisterand Putnam2’ :t have been giving glutamic acid to groups of children with normal, sub-normal and supernormal intelligence. They feel that there is definite improvement in the
mental function of the retarded group ; that there is evidence of improvement in the other
two groups of a less degree. Further evidence that glutamic acid may have a specific effect on
the brain is presented by Weil-Malherbe4 who showed that glutamic acid was the only
amino acid that could replace glucose as a substrate for brain slice respiration. Later
work by Nachmansohn5 showed that choline acetylase, an enzyme present in neural
tissue, inactivated by dialysis was reactivated almost completely by glutamic and citric
acids. Citric acid has not been tried clinically but is probably much too readily oxidized.
Because of the professional and lay interest in the potential value of this drug, the
present study has been carefully conducted as a supervised experiment in an effort to
evaluate therapy.#{176} A small group (four) participated in the controlled group (Group A).
One of these was removed from the hospital before the six months’ period had elapsed.
Another group of five children (one inpatient and four outpatients) were followed
without control (Group B) . The drug used was the laevo (plus) form of glutamic
acid.t This is to be differentiated from glutamic acid hydrochloride, a racemic mixture
of glutamic acid used principally as a source of hydrochloric acid. This latter drug was
tried initially in experimental work on intelligence, but caused excessive gastric irritation
in doses much above 5 gm. a day. A placebo was prepared from glycine with suflicient
tartaric acid to duplicate closely the taste of the glutamic acid. Tablets were of the same
size, shape and color; were packaged in identical bottles-only the child’s name appeared
on the label. Only the three physicians in charge of the program and the pharmacist
knew which child received which drug. This was done in an effort to eliminate any
factor of attitudinal effect on the part of the psychologists or, even more important, the
nursing staff. Dosage began at 5 gm./day and was increased by 1#{189}gm. every 7 to 10
days so that the final dosage was 33 gm/day for the inpatient group. This dosage was
well tolerated by all the children. The outpatients received from 22.5 to 37 gm. as
From the Children’s Division of Langley Porter Clinic and the Department of Pediatrics of the University of California Medical School, San Francisco, Calif.
(Received for publication July 12, 1949.)
* Dr. Robert E. Harris, Mrs. Elaine W. Barron and Dr. Clare Wright Thompson, of the Langley Porter Clinic Psychology Department, aided in designing the experiment and supervising the intelli-gence testing.
t Purchased from Parke-Davis Company.
The late Mr. Julian M. Wells, Chief Pharmacist of the University of California Hospital,
assisted in the preparation of the placebo.
646 WILLIAM
J.
KERR, JR., AND S. A. SZUREKmaximal dosage. One of the Group A children, receiving only placebos, vomited once
at a relatively low dosage; later he took large doses without difficulty. A child in Group
B developed gastritis on a relatively high dose but similarly took even greater amounts
after a brief rest. No increase in muscular activity as described by Zimmerman was
noted, although the average daily dose was as high as, and the final dose higher than,
those reported by him.2’ 3
The children in Group A all fell within the normal range as regards testable
intel-ligence. Actually, inpatient children in a psychiatric hospital are ill in a way which makes
it extremely difficult to be certain that they are participating adequately in a mental test
situation. Of the children for whom it was possible to calculate an I.Q., there were four
who could be divided into two pairs of the same sex and of approximately equal age
and I.Q. One of each of these pairs (experimental) received glutamic acid; the other
TABLE I
(1) (2) (3)
IQ after 3 Mo. IQ after 6 Mo.
IQ before --
____________
Treatment Mean Change Mean Change
from (1) from (1)
Group A
Glutamic Acid Male, 13 yr. Male, 5yr.
98 112
92
975 -10 ‘5 99 + 2 0
Placebo Male, 10 yr. Male, 7yr.
105 92
97
985 - 1 .0
108 +3.0
All Glutamic Acid-No Placebos Group B
Inpatient
Male, 6 yr. Est. 50-70 Est. 50-70 None Est. 50-70 None
Outpatients
Male, 4 yr. Est. 35-40 36 None 39 None
Male, 6 yr. 40 361 37
Female, 13 yr. 61 68 + 2.3 60 -2.3
Female, 10 yr. 55
59J
52* This 17 point gain loses some of its weight, not only because the other child in the group lost 13
points, but because this same boy had gained 18 IQ points in the 5 mo. prior to glutamic acid therapy. On every occasion but the last, the examiner estimated the true intelligence to be higher than the test
results.
(control) received placebos. Those in Group B were in the range from 35 to 70 and
showed no evidence of marked emotional disturbance. These children were brought to
the clinic by their parents in an effort to obtain glutamic acid therapy and not because
of neurotic or hyperaggressive behavior. Unfortunately, an inpatient group of low
intel-ligence was not available, but it was felt that the normal group would serve as a
satis-factory pilot group since definite improvement had been reported2’ in groups at all
intel-ligence levels. Patients were tested on the Revised Stanford-Binet Intelligence Test, with
after beginning therapy. More frequent testing is felt to give excessive “practice effect.”
A different examiner, unfamiliar with the previous test results, saw the child at each
test. The results are as shown in Table 1.
CONCLUSION
Administration of large doses of laevo (plus) glutamic acid to two children of
normal intelligence produced no significant change in testable intelligence as compared
with those receiving a placebo (glycine and tartaric acid) . The average gain of those
in Group A receiving glutamic acid was 2.0 I.Q. points ; of those receiving the placebo,
3.0 points. This is close to the test-retest gain made by the group on which the scale was
standardized by Terman and Merrill.8 The members of the Terman-Merrill group, aged
5 to 16 years, gained 2.0 I.Q. points on the average from the administration of one form
of the test to the administration of the alternate form
two
weeks later. Only estimates ofpretreatment ability were available for two members of the low intelligence group.
Tested after six months of therapy, they show no measurable change in intelligence with
increasing age. The three other members of the low intelligence group after six months
of therapy show a mean loss of 2.3 I.Q. points. (See Table I.) Children at this intelligence
level frequently show some loss of measured intelligence with increasing age.9
SUMMARY
These results do not substantiate previous reports that glutamic acid will increase
measurable intelligence. Attitudinal effect on the part of nurses, psychologists and
psychotherapists, which might influence the results, has been minimized by the use of
careful controls and different psychologists in each test situation.
Because of the small number of cases here reported, further studies are needed on
larger groups using similar controls. A hospital with a large stable population of children
with low testable intelligence would be preferable to the Langley Porter Clinic. One
such study is soon to be reported. The results are in essential agreement with these.1#{176}
REFERENCES
1. Price, J. C., Waelsch, H., and Putnam, T. J., Dl-glutamic acid hydrochloride in treatment of petit mal and psychomotor seizures, J. A. M. A. 122:1153, 1943.
2. Zimmerman, F. T., Burgemeister, B. B., and Putnam, T. J., Effect of glutamic acid upon mental functioning in children and in adolescents, Arch. Neurol. & Psychiat. 56:489, 1946.
3. Zimmerman, F. T., Burgemeister, B. B., and Putnam, T. J., Group study of effect of glutamic
acid upon mental functioning in children and adolescents, Psychosom. Med. 9:175, 1947.
4. Weil-Malherbe, H., Studies on brain metabolism: Mechanism of glutamic acid in brain, Biochem. J. 30:665, 1936.
5. Nachmansohn, D., Cox, R. T., Coates, C. W., and Machado, A. L., Action potential and enzyme activity in electric organ of Electrophorus electricus: Phosphocreatine as energy source of action
potential, J. Neurophysiol. 6:383, 1943.
6. Nachmansohn, D., John, H. M., and Waelsch, H., Effect of glutamic acid on formation of acetylcholine, J. Biol. Chem. 150:485, 1943.
7. Nachmansohn, D., and Machado, A. L., Formation of acetylcholine: New enzyme; “choline acetylase,” J. Neurophysiol. 6:397, 1943.
S. Terman, L. M., and Merrill, M. A., Measuring intelligence, Boston, Houghton Muffin Company,
1937, p. 43.
9. Kuhlmann, F., Results of repeated mental re-examination of 639 feeble-minded over period of 10
years, J. Appl. Psychol. 2:195, 1921.
648 WILLIAM
J.
KERR,
JR.,
AND
S. A.
SZUREK
SPANISH ABSTRACT
Efecto del Acido Glutimico en La Funci6n Mental: Estudio Piloto
La administraci#{243}n de grandes dosis de #{225}cidolaevoglut#{225}mico a nifios de inteligencia normal no produjo ning#{252}n cambio de significancia en Ia inteligencia de prueba comparada con aquellos que recibieron un placebo (glicerina y #{225}cidotart#{225}rico).
Nuestros resultados no soportan informes anteriores de que el #{225}cidoglut#{225}mico aumenta Ia
in-teligencia mensurable. El efecto de actitud de parte de enfermeras, psic#{243}logos y psicoterapeutas, que pueden influenciar los resultados, han sido reducidos a! minimo por el uso de cuidadosos controles y
diferentes psic#{243}logos en cada situaci#{243}n de ensayo,
A causa del pequeflo n(imero de casos reportados aqul, se necesitan m#{225}sestudios en grupos m#{225}s grandes usando controles similares. Un hospital con una poblaci#{243}n grande y estable de ni#{241}oscon
baja inteligencia ensayable serla preferible a la Clinica Langley Porter. Tal estudio ser#{225}reportado pronto. Los resultados est#{225}nde acuerdo con los nuestros.
