JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Vol. XXIII, No.

8
Copyright © 1975 by the American Geriatrics Society Printed in U.S.A.

Effects of A Procaine Preparation

(Gerovital H3) in Hospitalized Geriatric
Patients: A Double-Blind Study
ISRAEL ZWERLING, MD*, ROBERT PLUTCHIK, PhD**, MARGARET HOTZ, RNt,
RUTH KLING, MD:j:, LEO RUBIN, MDII, JOEL GROSSMAN, PhD~ and
BARBARA SIEGEL, MA§

Hahnemann Medical College, Philadelphia, Pennsylvania, Albert Einstein College of Medicine,

and Bronx State Hospital, Bronx, New York

ABSTRACT: The effects of Gerovital H3 (a specially stabilized form of procaine

hydrochloride) on geriatric psychiatric patients were assessed in a double-blind study
at Bronx State Hospital. The mean age of the subjects was 73 years and the average
rating for the severity of organic symptoms was "moderate." During the first six
weeks of study, the patients were each given a 5-00 injection of either Gerovital or
placebo (saline) intramuscularly three times a week. This dosage was doubled to 10
ml per injection during the second six weeks. Nine Gerovital and 10 control subjects
completed the first six weeks; and 6 Gerovital and 7 control subjects completed the
entire 12-week study. Objective rating scales were used to evaluate patients on
measures of interpersonal functioning, cognitive ability, psychiatric symptoms, and
urine and blood chemical findings. All subjects were assessed before treatment and
at six weeks and twelve weeks of the study. Side effects were recorded at two-week
intervals.
On most measures the variability between subjects was quite large, whereas
differences between average scores for the two groups usually were small The few
significant differences showed no systematic pattern and would be expected to
occur by chance alone when so many statistical comparisons are made. The overall
results of this double-blind study strongly indicated that, among these hospitalized
geriatric patients with organic symptoms, Gerovital H3 had no ameliorative effect on
either psychologic or physiologic functioning.

The action of procaine hydrochloride as an
anesthetic and vasodilator is well known. More
controversial is its reported effect on the aging
process.
* Chairman, Department of Psychiatry, Hahnemann
Medical College, Philadelphia, PA.
** Correspondence to be addressed to: Robert Plut-
chik, PhD, Director of Program Development and Clini-
cal Research, Department of Psychiatry, Albert Ein-
stein College of Medicine, 1300 Morris Park Avenue,
Bronx, NY 1046l.
t Nurse Administrator, Bronx State Hospital.
:j: Chief of Service, Geriatric Unit, Bronx State Hos-
pital.
I Chief of Service, Medical-Surgical Unit, Bronx
State Hospital.
~ Psychologist, Geriatric Unit, Bronx State Hospital.
§ Psychologist, Psychiatry Department, Bronx Muni-
cipal Hospital Center.
355
Beginning in the late 1950's a series of re-
ports testified to the effect of procaine on
various aspects of aging such as loss of mem-
ory, skin disorders, parkinsonism, hyperten-
sion, and depression (1). The reports were criti-
cized by Chiu (2) because of the lack of place-
bos, control series, double-blind trials or statis-
tical analyses. The findings of subsequent stud-
ies have been inconsistent. For example, Bucci
and Saunders (3) observed some beneficial ef-
fects of procaine but did not use controls or
standardized measures. Kral et ale (4) used con-
trols, and noted a temporary decrease in de-
pressive symptoms in patients with arterioscle-
rotic brain disease. Four other investigative
groups (5-8) in controlled studies found no
 ZWERLING ET AL.
effect of procaine hydrochloride on medical
symptoms or on behavior, even when the pro-
caine was administered in "standard" dosages
for up to one year.
Despite these negative findings, interest in
procaine hydrochloride has continued. MacFar-
lane (9), in a recent biochemical study, showed
that Gerovital H3 (a specially formulated prep-
aration of procaine hydrochloride) is a more
effective inhibitor of monoamine oxidase in rat
brain than is commercial procaine hydrochlo-
ride, but a less effective inhibitor than ipronia-
zid. The belief that further investigation is jus-
tified has led the Food and Drug Administra-
tion to authorize several controlled research
studies on the effect of Gerovital H3 in geri-
atric patients. The present paper reports the
results of one such study.
MATERIAL AND METHODS
Gerouital
The effects of Gerovital H3 on geriatric inpa-
tients were assessed in a 12-week study at
Bronx State Hospital. This drug is a special
preparation of procaine hydrochloride manu-
factured in Romania and presently supplied in
the United States for research purposes. Each
5-ml ampule of Gerovital H3 contains 100 mg
of 2% procaine hydrochloride plus benzoic acid
(a preservative) and potassium metabisulfite
(an antioxidant). The pH level of Gerovital H3
is buffered to 3.3, whereas the pH level of
commercially available procaine hydrochloride
(Novocain) ranges between 5.5 and 7.6. Saline
solution in matching ampules was used as a
placebo.
Selection of patients
Before the study began, the patients were
selected to represent varying levels of organic
brain dysfunction. Voluntary consent forms
were signed by the patients or by their nearest
relatives. An attempt to select the subjects at
random proved unfeasible, since many patients
could not speak or write or had no available
relatives. Although the original protocol called
for the testing of 60 patients, only 19 were
able to complete the necessary forms and parti-
cipate in the program.
356
Vol. XXIII
Medication program
All drugs were discontinued for four weeks
before the beginning of the Gerovital H3 injec-
tions. Each patient in the drug group was given
a 5-ml injection of Gerovital H3 intramuscu-
larly three times a week during the first six
weeks of the study. During the second six
weeks the dose was doubled to 10 ml per
injection. In a double-blind procedure, each
control subject was given a fi-ml injection of
saline thrice weekly during the first six weeks,
and 10-ml injections during the last six weeks.
Nine drug patients and 10 controls completed
the first six weeks of the study; 6 drug patients
and 7 controls completed the second six weeks.
Description of patients
Initially there were 3 men and 6 women in
the drug group, and 5 men and 5 women in the
control group. The mean age for the drug
group was 74 years, and for the controls 72
years. The drug group had been hospitalized at
Bronx State for an average of twenty-eight
months, and the controls had been hospitalized
for an average of thirty-three months. On a
gross measure of severity of organic symptoms
("mild" rated 1, "moderate" 2, and "severe"
3) the mean organic disease rating was 1. 7 for
the drug patients and 2.1 for the controls.
Tests
Measures of interpersonal functioning, cog-
nitive ability, psychiatric symptoms, and lab-
oratory determinations (including urinalysis
and a complete blood count) were obtained
just before the study began (baseline) and after
six weeks and twelve weeks of the medication
program. T-tests were used to compare the
mean ratings of the drug and control groups on
each dimension. Comparisons of the mean
scores between the groups were made at the
baseline, at six weeks and at twelve weeks.
Mean difference· scores, indicating changes
within each group from baseline to six weeks
and baseline to twelve weeks, also were calcu-
lated. The presence or absence of side effects
was noted at the baseline and at two-week
intervals thereafter.
The following scales were used:
Geriatric Rating Scale (GRS) - to measure
competence in daily personal and interpersonal
August 1975 GEROVITAL H3 IN GERIATRICS

activities [Plutchik et al (10)]. The items assess
behaviors such as the ability to eat, dress or
walk without assistance, sociability, coopera-
tion, and productive activity. Ward behavior is
rated by aides or attendants on each of 31
items on a three-point scale in which 0 repre-
sents good functioning. The GRS score is the
sum of the patient's ratings on the 31 items. A
high overall score represents a high level of
dysfunction.
Geriatric Interpersonal Evaluation Scale
(G IES) - to provide an index of cognitive
behavior in terms of social interaction, orienta-
tion, recent and remote memory and vocabu-
lary [Plutchik et al. (11)]. The patient earns
one point for each correct response made dur-
ing a structured interview. Normative data are
available.
Brief Psychiatric Rating Scale - for a psychi-
atrist's evaluation of the patient in 18 symp-
tom areas (12). Each symptom is rated on a
seven-point scale ranging from 0 (not present)
to 6 (extremely severe). Mean ratings are com-
puted for each symptom separately. The 18
items are listed in Table l.
Side Effects Check List - covering 20 side
effects, e.g., drowsiness, insomnia, agitation,
nausea, or constipation. A physician rates each
side effect as 0 (not present), 1 (mild), or 2
(marked). Noncommunicative patients could
not be rated as regards side effects for which
detection depends upon the patient's self-re-
port. For each patient, a mean "side effect
index" was computed.
Laboratory data. Blood samples were taken
from each patient at baseline and at six weeks
and twelve weeks of the study. The blood was
subjected to standard laboratory tests including
a hemogram, and determination of cholesterol,
triglycerides, fasting blood sugar and blood
urea nitrogen values. Urinalysis was also carried
out at these times.
RESULTS AND DISCUSSION
Table 1 shows: 1) the psychiatrists' mean
ratings of the patients in both the drug and
control groups at baseline and at six-weeks and
twelve weeks; 2) the mean scores on the Geria-
tric Rating Scale, reflecting the patients' ward
behavior; and 3) cognitive functions as mea-
sured by the Geriatric Interpersonal Evaluation
Scale. Only the means are shown in Table l.
The variability of the data was quite large for
most measures, but the differences between the
means for the control and drug groups usually
were small.
Statistical comparisons (t-tests) were made

TABLE 1
Ward Behavior Ratings, Interview Ratings and Psychiatric Ratings for Drug and
Control Groups - Baseline, Six Weeks and Twelve Weeks

Baseline Six Weeks Twelve Weeks

Drug Control Drug Control Drug Control

N=9 N=10 N=9 N=10 N=6 N=7

GIES Scale 20.3 17.6 22.7 18.7 20.5 22.1

GRS Scale 20.8 19.1 19.4 17.9 14.8 13.7
Brief Psychiatric Rating Scale:
somatic concern 3.0 1.2 2.0 0.9 2.3 0.9
anxiety 3.5 3.0 2.9 2.4 3.2 1.4
emotional withdrawal 1.9 4.3 1.7 2.8 1.5 2.6
conceptual disorganization 3.0 3.8 3.3 3.8 2.5 2.1
guilt feelings 1.3 1.5 2.2 1.6 0.7 0.2
tension 3.0 3.9 3.4 3.7 3.7 2.4
mannerisms and posturing 1.6 1.9 1.9 2.0 1.8 1.6
grandiosity 0.9 0.6 1.1 0.7 1.8 0.6
depressive mood 3.1 3.0 2.7 2.1 2.3 1.7
hostility 1.9 1.1 2.6 1.3 2.0 0.3
suspiciousness 2.0 2.0 2.1 1.9 1.2 0.6
hallucinatory behavior 0.7 0.4 0.7 1.5 0.7 0.4
motor retardation 2.4 2.0 2.9 1.3 2.3 1.7
uncooperativeness 1.8 0.4 1.8 0.9 1.3 0.3
unusual thought content 1.6 2.4 1.5 2.7 0.6 1.8
blunted affect 2.0 3.8 1.6 3.1 1.7 3.2
excitement 2.1 2.2 2.8 2.4 2.2 1.9
disorientation 3.8 3.8 2.6 4.1 1.7 2.3

357
 ZWERLING ET AL. Vol. XXIII

between the drug and control groups at base-
line, and separately at six weeks and twelve
weeks during the study. With two exceptions,
the results of the t-tests comparing the drug
and control groups at baseline were not signifi-
cant. At six weeks there were no significant
differences, and at twelve weeks there was only
one significant difference (the drug group was
rated as more hostile than the control group).
These few significant differences, which
showed no systematic pattern, would be ex-
pected on the basis of chance when many tests
of significance are made. Therefore it is likely
that they simply reflected random variation.
A statistical analysis was made of change
scores. This was done to minimize the effects
of any differences between the groups at base-
line. The change in scores between the baseline
rating and the rating at six weeks or twelve
weeks constituted the primary index. Mean
change scores for the drug group were com-
pared with mean change scores for the control
group. No significant differences were found
for any of the psychologic measures or psychia-
tric ratings at the end of twelve weeks.
Because of the recent interest in Gerovital
H3 as an antidepressant, the items of the Brief
Psychiatric Rating Scale relevant to depression
(somatic concern, anxiety, emotional with-
drawal, guilt feelings, depressive mood, motor
retardation, and blunted affect) were also
studied separately. None of the items individ-
ually, nor the overall depression index based on
the sum of the seven items, discriminated sig-
nificantly between the Gerovital and the pla-
cebo patients. This lack of difference between
the two groups was found when the analyses
were based on actual rating scores as well as on
change scores.
Data on the side effects index and labora-
tory studies are listed in Table 2. The two
groups of subjects did not differ on the basis of
the number and severity of side effects. In both
groups the symptoms most often reported (agi-
tation, confusion and difficulty in walking) had
been present at baseline. These symptoms are
typical among geriatric populations and cannot
be considered to be side effects of the study
procedure.
In assessing the mean laboratory values (Ta-
ble 2), it should be remembered that sample
sizes were small and the variability within each
group was fairly high on most measures. No
significant differences between group mean val-
ues were found at six weeks or twelve weeks.
Comparisons based on change scores between
baseline and twelve weeks also were not signifi-
cant, with the exception of the values for tri-
glycerides. However, this apparent difference
was produced by a large fluctuation in one
patient. No differences were noted between the
two groups as regards urinalysis findings (in-
cluding albumin, sugar and acetone), erythro-
cyte counts and leukocyte counts.
The overall results were characterized "by
small and apparently random differences be-
tween the drug and control subjects. Although
the total number of patients was not large,
many different types of measures (e.g., ward
behavior, psychiatric ratings, side effects, blood

TABLE 2
Laboratory Measures and Side Effects Index for Drug and
Control Groups - Baseline, Six Weeks and Twelve Weeks

Baseline Six Weeks Twelve Weeks

Drug Control Drug Control Drug Control

N=9 N=lO N=9 N=lO N=6 N=7

Side Effects Index 0.3 0.2 0.2 0.1 0.6 0.6

Laboratory Studies:
blood urea nitrogen (rng/IOO ml) 21.0 20.3 22.6 21.0 20.0 19.8
fasting blood sugar (mg/100 ml) 98.8 100.2 91.2 93.1 '96.8 102.1
triglycerides (mg/100 ml) 70.3 137.0 53.1 114.8 198.8 160.0
cholesterol (mg/100 ml) 250.1 227.1 242.7 213.1 215.0 250.5
hemoglobin (gm/100 ml) 14.1 13.8 14.2 14.0 14.6 14.4
hematocrit (%) 42.7 40.8 43.0 41.7 44.3 42.7
leukocyte count (per cu mm) 6544.0 6480.0 6967.0 7000.0 7567.0 7857.0
polys (%) 63.9 60.9 63.2 55.0 60.5 57.9
lymphocytes (%) 30.9 33.8 32.3 38.6 35.0 36.6
monocytes (%) 1.4 3.1 2.6 2.8 1.0 2.4
eosinophils (%) 3.0 2.4 1.6 2.7 2.7 2.9

358
August 1975 GEROVITAL H3 IN GERIATRICS
chemical values) and a double-blind method
were used. In addition, dosage levels were in-
creased during the second six-week period to
twice the "standard" dosage. The fact that
there were no significant differences suggests
that Gerovital H3 had no therapeutic efficacy
in this sample of hospitalized geriatric patients
with organic symptoms.
Although this conclusion is consistent with
those reported by almost all Gerovital H3 re-
searchers who used controlled techniques, there
are two double-blind studies in the litera-
ture which claim beneficial effects from Gero-
vital therapy. In one of these studies (13),
Abrams et al. compared Gerovital H3, the
Romanian procaine hydrochloride preparation,
with an American commercially available prep-
aration of procaine hydrochloride without ad-
ditives. The study unfortunately had several
drawbacks: 1) one third of the 60 subjects
dropped out before completion of the study,
2) no objective tests were used, and the ratings
made by the psychologists, nurses and family
members are of unknown reliability, and 3)
post-treatment ratings were made five months
after treatment was terminated. Moreover,
when the two groups were compared on the
basis of a family questionnaire, a psychologic
evaluation, and a nurses' rating, there were no
significant differences between the two groups.
Only when an overall assessment was made,
based upon a combination of all ratings, was
any significant difference found between the
contrasted groups of patients.
In 1974, Zung et al. (14) reported a double-
blind study comparing the antidepressant ef-
fects of Gerovital H3 with those of imipramine.
The major focus was on geriatric outpatients
with mild depressions; excluded were patients
who were suicidal, severely demented, schizo-
phrenic, or incapable of spontaneous conversa-
tion and activity. Measures of change were
based upon a self-rating anxiety scale, a self-rat-
ing depression scale, a psychiatric rating of
depression and anxiety, and a clinical global
impression. Unfortunately, no reliability data
were given for the global impression. Although
an analysis of variance would have been the
most appropriate method of statistical com-
parison among the three groups, a series of
t-tests showed that depression was reduced
more significantly and frequently in both the
Gerovital and imipramine groups than in the
placebo group. No differences were found be-
tween the two active drugs on any of the
measures used. These results suggest that Gero-
vital H3 has some antidepressant effect on rela-
tively intact geriatric patients with mild depres-
sions.
In our study, no antidepressant effect of
Gerovital H3 was observed in a group of hos-
pitalized geriatric patients, nor was there any
effect on ward behavior, cognitive functioning,
memory, or various biochemical indices. The
differences between our findings and those of
Zung and associates are probably related to
differences in the type of patient studied, and
possibly to the types of assessment measures
used. Further research should be directed to-
ward the resolution of these inconsistencies.
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359