Prog. Newo-Peychopharnm. Vol. 1, pp. 235-247, 1977. Pergamon Press. Printed in Great Britain.

NOOTROPIC DRUGS*

C. GIURGEA and M. SALAMA

Neuropharmacological Research Department, UCB-Dipha, and
Clinical Development, UCB-Dipha, Brussels, Belgium;
University of Louvain, Belgium

(Final form, July 1977)

Abstract
1. Nootropic drugs were proposed as a class of psychoactive drugs that selectively improve
efficiency of higher telencephalic integrative activities.
2. The main features of the nootropic profile consist of: (a) enhancement of learning acqui-
sition; (b) .resistance to impairing agents; (c) facilitation of interhemispheric transfer
of information; (d) enhanced resistance to brain "aggressions"; (e) increased tonic, cor-
tico-subcortical "control"; and (f) absence of usual pharmacological effects of neuro-
psychotropic drugs.
3. The animal experimental results are thoroughly corroborated by the data obtained in clini-
cal pharmacology and pharmacotherapeutics supporting the concept that nootropic activity
is based on a functional telencephalic selectivity.
4. The basic mechanism of action at molecular and cellular levels of nootropic drugs is not
yet known. Some recent data emphasized a possible role for cerebral ATP.

Keywords: psychotropic drugs, nootropics, piracetam, integrative telencephalic mechanism,

learning, brain injury, hypoxia, interhemispheric transfer.

1. Introduction

The term "nootropic" (noes = mind; tropein = towards) was proposed by us (Giurgea, 1972,
1973) to designate psychotropic drugs that characteristically interfere with the higher telen-
cephalic integrative activity by a direct and selective action.

The main features we presently consider important in defining a nootropic drug are: (a) the
enhancement, at least under some conditions, of learning acquisitions as well as the resistancs
of learned behaviours to agents that tend to impair them; (b) the facilitation of interhemis-
pheric flow of information; (c) the partial enhancement of the general resistance of the brain
and particularly its resistance to physical and chemical injuries; (d) the increase in the ef-
ficacy of the tonic cortico-subcortical control mechanisms; and (e) the display of above men-
tioned activities by selective functional impact on higher integrative, telencephalic mechan-
isms, i.e. partial lack of usual psychological and general pharmacological activities.

Piracetam [ (oxo-2-pyrrolidinyl-I) 2 acetamidel seems to, up to now, correspond best to these

definitions as far as animal pharmacology, clinical pharmacology and therepeutics are con-
cerned and 'will be used as prototype for nootro.lic drugs.

CH,-CO -NH,
Piracetam

113 this review we shall present various features of the nootropic profile under three main
headings; animal pharmacology, clinical pharmacology and pharmacotherepeutics. Some considera-
tions to biochemical data and the classification of nootropic drugs will be given in the later
part of the paper.

*Partly supported by IRSIA research grant No. 20310.

236 C. Giurgea and M. Salama

2. Nootropic Profile

2.1. Enhancement of learning acquisition and resistance to impairing agents

2.1.1. Animal pharmacology

The various data regarding the animal pharmacology are summarized in Table 1 as well as in
Figs. I and 2. Recent published data on nootropic drugs are presented in Table I. One addition-
al very recent contribution of Danielle Lefevre of our laboratory* is given here as an example
of piracetam's beneficial effect in early sensory deprived rats (Giurgea 1977).

Table 1
Nootropic effect on learning.
Experimental data and references in animal pharmacology

Modality Test/Agent Species Reference

water-maze rat Giurgea and

Mouravieff-Lesuisse
1972
Facilitated "Y" -maze rat Wolthuis, 1971
acquisition "drinking" test rat Wolthuis, 1971
spinal fixation rat Giurgea and
Mouravieff-Lesuisse,
1971
active goldfish
avoidance Bryant et at., 1973

hypoxia rat Giurgea et al., 1971

Sara and Lefevre,
1972
Gouret and Raynaud,
Enhanced 1976
resistance
to learning ECS rat Giurgea, 1972
impairment Sara and David
Remacle, 1974
Matthies and Ott
1975
age rat Giurgea and
Mouravieff-Lesuisse,
1972
chemicals (8-AZA) rat ibid., 1971, 1972
sensory Myslivicek and
rat Hassmanova, 1973
deprivation Myslivicek, 1975
Lefevre, 1975 (in
Giurgea, 1976a)

Figure I gives the general schedule of the study on passive avoidance performance (PAP) in
differential environment.
Figure 2 illustrates that rats reared in isolation show impaired-retention of PAP as seen
by its time decay, and that piracetam readily improves learning performances when injected

* Institute of Experimental and Compared Psychology, University of Louvain, Belgium.

 Nootropic drugs 237

before the last retention test.

PASSIVE 3&H %H
*TEST I ) TEST II
AVOIDANCE wmmlbu CACES
. %kEY

Fig. 1. Effect of rearing in differential environment in rats as regards

passive avoidance performance (experimental schedule).

Litter-mates Wistar rats are kept at weaning for 6 weeks in sensory "impoverished" (isol.)
or "enriched" (enr.) environment. Both groups are kept in isolation for 24 hr and then submit-
ted to passive avoidance one-trial learning. They are tested for retention 24 hr later (test I)
and 96 hr after test I (test II). Thirty minutes before test II (arrow), rat received i.p.
saline or piracetam (120 rug/kg).

mr.
no- inj.
100

90 isod. l-lo- isol.sol. isol

inj.
r
t
noJ.
$ O--
.-
& 60-.
SO..

3
2 LO..
s 30..

20

10

Fig. 2. Effect of piracetam on the deterioration of passive avoidance

performance (PAP) in isolated-reared rats.

From left to right: isolated, non-rejected rats show good avoidance in test I but performance
in test II is almost,absent; saline-injected rats achieved very poor avoidance score in test
II; in the piracetam-group, performance in test II, though very well maintained, was statisti-
cally not different from that in test I.

For comparison (extreme right), a typical experiment in "enriched" non-injected rats illus-
trating excellent maintenance of avoidance performances from test I to test II is shown.

2.1.2. Clinical pharmacology

Dimond and Brouwers (1976) studied the effect of piracetam (4.8 g/day) in a double blind
versus placebo investigation, on sixteen healthy student volunteers. After a 2 weeks' admini-
stration (i.e. the second test session under drug), the drug treated group showed an important
and significant improvement as compared to the control group both of direct or delayed recall
of verbal learning.

Recent confirmation of those conclusions is provided by Wed1 and Suchenwirth (1977) who have
replicated a significant improvement of mental performance in a group of seventeen young heal-
thy volunteers (3.2 g/day piracetam for 5 days).

Mindus et al. (1976) studied eighteen middle-aged subjects, mentally healthy, but all of
them complaining of some memory decline. Piracetam (4.8 g/day) was given for 4 weeks, versus
placebo, in a double blind design. By means of a battery of perceptual and psychomotor tests
(such as Critical Flicker Fusion (CFF), Krakau Visual Acuity Test (RVAT) and three paper and
238 Cd. Giurgea and M. Salama

pencil tests), the authors concluded that mental performance in these almost normal middle-
aged subjects was significantly improved by the-drug.

2.1.3. Therapeutic data

The therapeutic indications reporting an improvement of mental performances and vigilance

are numerous and diverse.

Chzwnic brain syndrome due to ageing

Stegink (1972), in a double blind study involving 196 elderly patients, has compared pirac-
etam with a placebo in the treatment of psycho-organic symptoms occurring in the course of se-
nile involution. Piracetam was administered in a dose of 800 mg, t.i.d., for 8 weeks.

The overall mental condition of the patients treated with piracetam showed a significant im-
provement as compared to that of the placebo group; statistically significant differences were
found for such parameters as disorders of alertness, asthenia, and psychomotor agitation.

Feruglio et al. (1974), Delwaide et al. (1975), Guilmot and Van Ex (1975), Eckmann (1976) in
double blind controlled investigations versus placebo, confirmed these results. Heinitz (1975),
Plauchu et al. (1974), Voelkel (1975) and Baving (1975) have also published similar results.

Chronic atcoholism

In acute alcohol withdrawal, Knott and Beard (1973),* Petty (1973),* Weckroth (1975) and Week.
roth and Mikkonen (1972), have demonstrated in controlled double blind studies the advantage
of piracetam over placebo. The piracetam-treated patients experienced at a significantly ear-
lier stage an improvement of their state of alertness and mental performances.

Binder (1974)) in a controlled study versus placebo, came to the same conclusion in chronic
alcoholics who had been hospitalised for long-terms.

2.2. Facilitation of interhemispheric transfer of information

2.2.1. Animal pharmacology

In curarised rats, piracetam selectively facilitates transcallosal evoked potentials on el-

ectrical stimulation of the associative, suprasylvian cortex (Giurgea and Moyersoons, 1972,
1974).

Buresova and Bures (1973, 1976) found that in rats interhemispheric transfer of lateralised
visual engrams, acquired during functional hemidecortication, was facilitated by piracetam
which also facilitated formation of a secondary engram during monocular learning without hemi-
decortication.

Figure 3 illustrates one aspect of piracetams facilitating aspect of the writing-in callo-
sal interhemispheric mechanism.

2.2.2. Clinical pha-rmacology

Dimond (1975) tried and succeeded in obtaining human data that are in good agreement with
the previously reported animal findings. Indeed, in healthy young volunteers submitted to di-
chotic listening of verbal messages, it was found:
(a) that verbal capacity was significantly improved; and
(b) that this was due mainly to increased response to information presented to the left ear.

* Personal communications.
 Nootropic drugs 239

S P

SL R R PL R R
1 2 3 1 2 3

Fig. 3. Effect of piracetam on monocular pattern discrimination learning

(L) and on strength of resulting primary and secondary engrams
revealed by hemidecorticated re-learning (R). Brain schemes in-
dicate conditions of experiment on days l-3 (occluded eye and
depressed hemisphere black).
P: rats treated with piracetam; S: rats treated with saline.
Ordinate: average number of trials to criterion.
Vertical traces denote SEM-values. (Courtesy of Buresova and
Bures, 1976).

The brain, concludes Dimond, seems to be super-connected by the drug.

2.2.3. Therapeutic data

The improved interhemispheric transfer and the subsequent improved cortical integration,
as seen in the Dlmond study (1975), may be particularly important for the understanding of
the enhancement of the vigilance as well as of the mental performances that were discussed
previously.

2.3. Enhanced brain resistance to physical and chemical injuries

2.3.1. Animal pharmacology

Table 2 summarizes the main existing data in this field.

240 C. Giurgea and M. Salama

Table 2
Nootropic effect and its relationship to brain resistance.
Experimental data and references in animal pharmacology

Agent Modality References

Enhanced cerebral resist- Giurgea et at.,

ante and mainly speeding- 1970
up of brain recovery
(Criterium: EEG; species:
rabbit)

Enhanced resistance to Schiller, 1974

Hypoxia sub-cellular lesions
(Criterium: electronic
microscopy and histo-
chemistry; species: rat)

Enhanced resistance to Quadbeck, 1970

experimental high-alti- (pers.comm.)
tude
(Criterium: convulsions;
species: rat)

Chemicals EEG protection and en- Moyersoons

(barbiturates, hanced survival percen- and Giurgea,
phenothiazines, tage (Species: cat, rat) 1974;
cyanides Hoyer, 1975
(pers.comm.)

Figure 4 shows the "curare-like hypoxia" model developed with J. Dauby, using a short-acting
curare-like agent, the oxydipentonium.

In Table 3 are presented the results obtained with piracetam and some other neuro-psychotro-
pit drugs. It can be seen that dexamphetamine, pyritinol and sulpiride are inactive (Giurgea,
1977).

Curare * hypoxia
mice Ll? or l?O.

DRUG CUQARE x/10

b
us treated
IT ,, lh. TT lh. y
AL Ah
x
L
*? 9-340
SA INE CURARE saline
or i.47
ATER

# oxydipentonium chloride ( short -actin

curare-like B

Fig. 4. Experimental schedule of the "curare-like

hypoxia" model.
 Nootropic drugs 241

Mice are given i.p. 3 s&kg of oxydipentonium chloride, a short-acting curare-like agent.
It is assumed that an active drug (i.p. or p.o.), provided it is not a simple decurarising
agent, enhances the number of survivors because it confers a CNS protection during the short-
lasting asphyxia induced by the curare-like agent.

Table 3
Effect of piracetam and some other neuro-psychotropic
drugs on "curare-like hypoxia" model

Survival
Drugs wdkg placebo drug Activity*
i.p.

Centrophenoxine 294 2110 7110 +

94 O/10 7110 +

29 2110 8110 +

Dexamphetamine 55 2110 Of10 0

5.5 2110 2110 0

0.55 l/10 3110 0

Piracetam 800 l/l0 lO/lO +

454 o/10 9110 +

142 2110 6110 0

Pyritinol 459 l/10 3110 0

46 l/10 2110 0

Sulpiride 109 3110 3110 0

34 l/10 3110 0 a

11 3110 2110 0

* Activity is established by the ratio between the number of survivors

in drug treated groups and in the placebo group; + means p ~0.05
(Fisher Yates).

2.3.2. Clinical pharmacology

Lagergren and Levander (1974), Cronholm et at. (1975) studied the effect of piracetam in
twelve patients who had a heart pace-maker and in whom they were able to induce a moderate,
brief and reversible bradycardia. Piracetsm was given p. o., (4.8 g/day) for 9 days, in a
cross-over double blind study using a placebo.

Among several perceptual and psychomotor tests that responded positively to piracetam, the
results of the Critical Flicker Fusion tests can be taken to imply that piracetam counteracts
the impairment in performance associated with cerebral hypoxia caused by lowering of heart
rate. Isaksson et al. (1975, 1976) analysed the same patients and found by quantitative EEG
studies that piracetam, both in normal and bradycardic situations, enhanced the alpha-power
spectrum, thus tending to normalise the EEG.

2.3.3. Therapeutic data

The effect of piracetam on cerebral distress consecutive to brain injury, or due to a hyp-
oxic or toxic state, was also investigated.

Calliauw and Marchau (1975) in a double blind controlled trial demonstrated that, in compar-
ison with placebo, piracetam significantly improved state of consciousness in deeply comatou8
hospitalised patients following head injuries.
242 -C. Giurgea and M. Salama

Roquefeuil et al. (1975) measuring some biochemical parameters, showed the improvement of
the brain metabolism. Schulte-am-Esch and Pfeifer (1974) and Ciocatto and Bava (1974) have
published similar clinical data.

2.4. Increased cortico-subcortical control

2.4.1. Animal pharmacology

Piracetam shows a clear effect in two experimental models that require integration at CNS
subcortical levels.

As seen in Table 4, piracetam inhibits central nystagmus, i.e. the nystagmus obtained in the
awake rabbit by electric stimulation of a diencephalic structure (lateral geniculate body).
On the other hand, piracetam facilitates acquisition of an experience at spinal level probably
because it shortens the spinal fixation time (Table 4).

Table 4
Effect of piracetam on the cortico-subcortical control

Piracetam: Enhanced tonic control

Modality Species Reference

Central (LGB) nystagmus: rabbit Giurgea et al., 1967

inhibited

Spinal fixation: rat Giurgea and Mouravieff-

facilitated Lesuisse, 1971

N. B. Cortical spreading depression (Giurgea, 1972) facilitates central

nystagmus and inhibits spinal fixation.

It is important to understand in these two particular preparations the cortico-subcortical

inter-relationships, especially the descending ones. As compared to the ascending, cortico-
petal relationship, the cortico-fugal neurophysiological tonic regulating influences are widely
considered more important (Narikashvili, 1970).

To approach this problem we have used the functional decortication produced by local, cort-
ical KCI-application (Bures et al., 1974). Cortical spreading depression (CSD) as seen in
Table 4 facilitates central of nystagmus and inhibits spinal fixation. One can argue therefore
that the functional, tonic cortical control is inhibiting towards LGB and facilitating to-
wards the particular spinal memory consolidation.

Thus the activity of piracetam is equivalent to an enhancement of the cortical tonic control
since it inhibits central nystagmus and facilitates spinal fixation.

2.4.2. Clinical pharmacology

In 1967, Oosterveld (see Giurgea et al., 1967) has demonstrated in healthy volunteers that
piracetam significantly inhibits the so-called torsion swing nystagmus. Later on, Boniver
(1974) showed that a caloric nystagmus was also inhibited by piracetam in normal subjects.

2.4.3. Therapeutic data

The remote effects of head injuries have also been studied, and the significant superiority
of piracetam as compared to a placebo has been evidenced, e.g. in the treatment of post-trau-
matic vertigo; this activity may be correlated with the one found for nystagmus.

Aantaa and Meurman (1975), Hakkarainen (1976, pers. comm.), and Ferrey and Bouttier (1972)
in controlled double blind studies, have shown that piracetam has a significantly superior
 Nootropic drugs 243

effect as compared to placebo in patients with post-concussional syndromes, consisting of symp-

toms vertigo and headaches.

2.5. Lack of side effects

2.5.1. Animal pharmacology

Piracetam, whiie active in previously described situations, is devoid of usual "routine"

pharmacological activities even in high doses (Table 5).

Table 5
Piracetam: Lack of usual pharmacological activity*

Behavioral Sedation Giurgea et al., 1967

Stimulation Wolthuis, 1971
Locomotion in Overton, 1974 (pers. comm.)
general
Toxicity, etc.
Electro- EEG (cortical, Stumpff, 1975 (pers.conuo.)
subcortical)
physiological Giurgea, 1972-76
Limbic
Giurgea, 1972-76
excitability
Autonomic Cardiovascular Giurgea, 1972-76
system
Respiratory
system
Gastrointestin-
al system

* See also Giurgea, (1976)

2.5.2. Clinical pharmacology

In normal subjects (Oswald and Lewis, 1972, pers. comm.; S. Jongers et al., 1975) no side
effects or "doping" effects were ever observed. Nor did piracetam induce any sedation, tran-
quillisation, locomotor stimulation or psychodysleptic symptomatology in the more important
patient material for whom reliable data are available.

3. Biochemical Considerations.

Currently available CNS biochemical data for piracetam are derived mainly from studies made
on the whole brain. It is therefore difficult to discuss them thoroughly in the light of the
telencephalic hypothesis.

We shall however briefly mention here the essential metabolic data and refer the interested
reader to more specialised publications (Pede et aZ., 1971; Gobert 1972).

Three major points are to be emphasized:

(a) Piracetam in all animal species studied, including man, is practically not metabolised.
About 96-982 of the administered substance, by any route of administration, is eliminated
mostly in the urine and secondarily in the faeces.
(b) The plasma half-life of piracetam is about 2.5 hr in the dog and about 4.5 hr in
man.
244 C. Giurgea and M. Salama

(c) Piracetam readily passes such physiological barriers as the blood-brain barrier and the
placental barrier. From the biochemical pharmacology data, an interesting EEG-biochemical
correlation is noted. Indeed, as we have described above, piracetam significantly enhanced
EEG recovery after nitrogen hypoxia in the rabbit. Using similar experimental.conditions,
it was observed that in the saline-treated rats, it takes about 2 hr to recover normal neuro-
chemical parameters, whereas in piracetam-treated rats there is a highly-significant speed-
up recovery. Electronic microscopy studies have also shown that hypoxia-induced polysomial
damage in the rat brain and a few other organs was prevented in piracetam-treated animals
@chiller 1974).

As to the intimate mechanisms responsible for the functional telencephalic neuro-pharmacolo-

gical selectivity of piracetam, we do not have as yet, as mentioned before, comprehensive,
causal interpretation in molecular terms of its therapeutic efficacy.

Recently, however, Nicholson and Wolthuis (1976a, b) claimed that piracetam rather select-
ively activates brain adenylatekinase (an enzyme facilitating ATP formation in anaerobic con-
ditions) and inhibits cortical release of proline (a putative inhibitory neuro-transmitter).
Should those findings be enlarged, and confirmed, they might provide a starting point for a
deeper understanding of the way in which nootropic drugs act.

4. Problems of Classification

It seems obvious that, if one takes into account the WHO classification of psychotropic
drugs (Shepherd, 1972), nootropic drugs should be considered as a new class independent of
neuroleptics, anxiolytic sedatives, antidepressants, psychostimulants or psychodysleptics.

If, however, one keeps to the Delay-Deniker classification, nootropic drugs should be looked
upon (as suggested by Boissier, pers. comm.) as a distinct class among the psycho-analeptics
which, by definition, includes all drugs that somehow enhance mental efficiency.

In the light of previous considerations, the classification of psychotropic drugs is pres-

ented in Fig. 5.

Fig. 5. The place of nootropic drugs in the classification of psychiatric

drug.

Acknowledgements

The authors are indebted to J. Polderman, M.D. for his assistance in the updating of the
bibliography.

The competent secretarial work of Mrs. S. Tourtois is also acknowledged.

Inqwities and reprint requests should be addressed to:

Prof. Dr. C. Giurgea, Head of the Neuropharmacological Research Department.
UCB-Dipha,
Brussels, Belgium.
 Nootropic drugs 245

Reference5
AANTAA, E. and MFURMAN, I.H. (1975). The effects of piracetam (Nootropil - ucb 6215) upon the
late symptoms of patients with head injuries. J. Intern. Med. Ree. 3: 352-355.
BAVING, G. (1975). Untersuchungen Uber Piracetam bei station&en PatTenten mit cerebro-vascu-
1Xr bedingten geistiger Leistungsminderung schwerer obstruktiver Emphisembronchitis und ar-
terieller Rypoxie. Therapiewoche. 25: 2421-2427.
BINDER, S. (1974). Die Wirkung des Gotropikums Piracetam auf die kortikale Leistungsfahig-
keit chronische Alkoholiker. Munch. Med. Wschr. 116: 2127-2130.
BONIVER, R. (1974). Influence du piracetam sur le fonctionnement du syst&me vestibulaire.
Quelques reflexions sur l'interference m6dicamenteuse au niveau du syst&me vestibulaire avec
les m&anismes responsables du nystagmus. Acta O.R.L. Belg. 28: 293-299.
BRYANT, R.C., .PETTY, F. and BYRNE, W.L. (1973). Effects of pirzetam (SKF 38462) on acquisi-
tion, retention and activity in the goldfish. Psycho$azwzzc. (Bed) 29: 121-130.
BURES, J., BURESOVA, 0. and KRIVANEK, J. (1974). The mechanism and applzations of Lego's
spreading depression of electroencephalographic activity. Academia Prague. pp. 140.
BURESOVA, 0. and BURES, J. (1973). Mechanisms of interhemispheric transfer of visual infow
ation in rat. A&u Neurobiol. Exp. 33: 673-688.
BURESOVA, 0. and BURES, .I. (1976). PiEcetam-induced facilitation of interhemispheric trans-
fer of visual information in rat. Psychophamnac. (Bert.! 46: 93-102.
CALLIAUW, L. and MARCRAU, M. (1975). Clinical trials of pirzetam in disorders of conscious-
ness due to head injury. Acta Anaesth. Belg. 26: 51-60.
CIOCATTO, E. and BAVA, G.L. (1974). Utilita den'impiego di un farmaco nootropo (Piracetam)
nella rianimazione degli stati di coma. Clin. Terapeutica.
CRONROLM, B., SCRALLING, D. and LEVANDER, S. (1975). On models and measures of alertness and
noetic functions. 3rd Congress of the Intern. College of Psychosomatic Medicine, Rome.
DELWAIDE, P.J., YLIEFF, M., GYSELYNCK-MAMBOURG, A.M., DIJEUK, L. and BURLET, A. (1975). Ef-
fets du piracetam sur la demence s&rile. M&i. Hyg. 33: 1150-1158.
DIMOND, S.J. (1975). The effects of a nootropic substance on the capacity for verbal memory
and learning in normal man. 3rd Congress of the Intern. College of Psychosomatic Medicine,
Rome.
DIMOND, S.J. and BROUWERS, E.Y.M. (1976). Increase in the power of human memory in normal man
through the use of drugs. Psychophamrzc. (Bert.) 49: 307-309.
ECKMANN, F. (1976). Klinische Untersuchungen mit Pirzetam. Munch. med. We&r. 118: 957-958.
FERREY, G. and BOUTTIER (1972). Controlled study of 50 cases of post-traumatic subjective
headache syndromes. Congres des Psychigtres et Neurologistes de langue francaise, LKK&me
Seance, Tunis.
FERUGLIO, F.S., MACCBIONE, C. and MOLASCRI, M. (1974). I1 2-pirrolidone-acetamide (Piracetam)
nella sindrome psico-organica senile. Cl&. Tezupeutica 51-52.
GIURGEA, C. (1972). Vers une pharmacologic de l'activitd intggrative du cerveau. Tentative
du concept nootrope en psychopharmacologic. Actual Phannac. 25e se'rie: 115-156. Mssson,
Paris.
GIURGRA, C. (1973). The "nootropic" approach to the pharmacology of the integrative activity
of the brain. Cond. Reflex 8: 108-115.
GIURGEA, C. (1976). PiracetamT Nootropic pharmacology in neurointegrative activity. In:
Current Developments in Psychopha~ology, Vol. III, pp. 223-273. Spectrum, New York.
GIURGEA, C. (1977). The pharmacology of-nootropic drugs: Geropsychiatric implications. In:
Neuro-Psychopharmacology, PKG. 10th Congress of the Collegiwn Internationale Newo-Psycho-
phannacologicwn, Deniker, P., Radouco-Thomas, C. and Villeneuve, A. (eds.) Pergamon Press,
Oxford.
GIURGEA, C., LEFEVRE, D., LBSCRENIER, C. and DAVID-REMACLE, M. (1971). Pharmacological pro-
tection against hypoxia-induced amnesia in rats. Peychophazmac. (Bert.) 20: 160-168.
GIURGEA, C. and MOURAVIEFF-LESUISSE, F. (1971). Pharmacological studies onan elimentary
model of learning. The fixation of an experience at spinal level: Part I. Pharmacological
reactivity of the spinal cord fixation time. Arch. Int. Phamnacodyn. 191: 279-291.
GIURGEA, C. and MOURAVIEFF-LESUISSE, F. (1972). Effet facilitateur du -acetam sur un app-
rentissage rlpdtitif chex le rat. J. P-C. (P&S). 3: 17-30.
GIURGEA, C., MOURAVIEFF-LESUISSE, F. and LEEMANS, R. (19707. Corrdlations blectropharmacolo-
giques au tours de l'anoxie oxyprive ches le lapin en respiration libre ou artificielle.
Rev. Neural. (Paris). 122: 484-486.
GIURGEA, C. and MOYERSOOK F. (1972). On the pharmacology of cortical evoked potentials.
Arch. Int. Pharmacodyn. -199: 67-78.
246 I Giurgea and M. Salama

GIURGEA, C. and MOYERSOONS, F. (1974). Contribution B l'etude Olectrophysiologique et pharma-

cologique de la transmission calleuse. Colloque Internationale "Les syndromes de disconnexion
calleuse chez l'homme", Lyon.
GIURGEA, C., MOYERSOONS, F. and EVRAERD, A. (1967). A GABA-related hypothesis on the mechanism
of action of the anti-motion drugs. Arch. Int. Pharmacodyn. 166: 238-251.
GOBERT, J.G. (1972). Genese d'un medicament: le piracetam. M6txlisation et recherche bio-
chimique. J. Pharm. Belg. 27: 281-304.
GOURET, C. and RAYNAUD, G. (1976). Utilisation du test de la boite B deux compartiments pour
la recherche de substances protlgeant le rat contre l'amn&ie par hypoxie. IntdrOt et limites
de la m6thode. J. Pkamwc. (Paris). 7: 161-175.
GUILMOT, P.H. and VAN EX, R. (1975): Effets du piracetam sur certain6 sympt8mes-cibles de la
senescence. Ars. Medici. 30: 791-803.
HEINITZ, M. (1975). Neue Azekte zur Therapie der zerebralen Insufficienz durch Piracetam.
Fortschr. Me&sin. 93: 293-298.
ISAKSSON, A., LAGERGREK K. and WENNBERG, A. (1975). Interaction between heart rate and spec-
tral parameters of the EEG. A pilot study on piracetam-treated patients with cardiac pace-
maker. In: Quantitative Anabsis of the EEGMethods and Avvlicationa. Proc. 2nd Svmnosium
of the Study Group for EEG-M&hodoiogy, pp. 149-157, Telef;nken-AEG, Constanz, DBR.-
ISAKSSON, A., LAGERGREN, K. and WENNBERG, A. (1976). Visible and non visible EEG changes
demonstrated by Spectral Parameters Analysis. EZectroencepkal. Clin. Neuropkysiol. -41:
225-226.
LAGERGBEN, K. and LEVANDER, S.E. (1974). Effect of piracetam upon performance at varied heart
rate. Psychoptic. (Berl.) 39: 97-104.
MATTHIES, II. and OTT, T. (1975).- Differentiation of substances influencing acquisition or re-
tention of learned behavior. Abstr. 6th Intern. Congress of Pharmacology, Helsinki, Finland,
p. 370, communication number 878.
MINDUS, P., CRONHOLM, B., LEVANDER, S.E. and SCHALLING, D. (1976). Piracetam-induced improve-
ment of mental performance. Acta Psychiut. Stand. 54: 150-160.
MOYERSOONS, F. and GIURGEA, C. (1974). Protective efzct of piracetam in experimental barbi-
turate intoxication: EEG and behavioral studies. Arch. Int. Phannacodyn. 210: 38-48.
MYSLIVICEK, J. (1975). The effect of piracetam on cortical evoked responsesx rats stimulated
at different post-natal periods. Activ. nerv. sup. &&a). 17: 303-304.
MYSLIVICEK, J. and HASSMANOVA, J. (1973). Early sensory deprivzion treated with piracetam
(ucb-Dipha 6215) in young rats. Activ. nerv. SUP. (Prakal. 15: 151-153.
NARIKASHVILI, S.P. (1970). Direct and indirect cortical influences on thalamic nuclei. In:
EZectrwphysiology of the Central Nervous System, Rusinov, V.S. (ed.), pp. 287-298. Plenum
Press, New York.
NICHOLSON, V.J. and WOLTHUIS, O.L. (1976a). Effect of the acquisition enhancing drug pirac-
etam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine.
Biochem. P-c. 25: 2241-2244.
NICHOLSON, V.J. and WXTHUIS, O.L. (1976b). Differential effects of the acquisition enhancing
drug pyrrolidone acetamide (piracetam) on the release of proline from visual and parietal
cerebral cortex in vitro. Bmin Res. 113: 616-619.
PEDE, J.P., SCHIMPFESSEL, L. and CROKAERCR. (1971). The action of piracetam on the oxydat-
ive phosphorylation. Arch. Int. Physiol. Biochem. 79: 1036-1037.
PLAUCHU, M., NOVE-JOSSERAND, G., BRESSOT, C. and SOUTr%AND, P. (1974). Action du Nootropyl
(oxo-2-pyrrolidyne-acetamide) dans les Btats confusionnels chez des malades hospitalis&
dans une service de mgdecine inteme. Lyon M&i. 232: 105-108.
ROQUEFEUIL, B., ESCURET, E. and VIGUIE, E. (1975). Etude mdtabolique du piracetam en rean-
imation neuro-chirurgicale. AgressoZogie 16: 43-62.
SARA, S. and LEFEVRE, D. (1972). Hypoxia-inxced amnesia in one-trial learning and pharma-
cological protection by piracetam. Psyckopkarmac. (Berl.). 25: 32-40.
SARA, S.J. and DAVID-REMACLE, M. (1974). Recovery from electrzonvulsive shock-induced am-
nesia by exposure to the training environment. Pharmacological enhancement by piracetam.
Psyckopharmac. (Berl.1 36: 59-66.
SCHILLER, E. (1974). ElekGomikroskopische und mikro-interferometrische BeitrRge sum Wirk-
ungsmechanismus von Piracetam. Verk. Dtsch. Ges. Path. 58: 578.
SCHULTE-AM-ESCH, J. and PFEIFER, G. (1974). Vorllufige Erfahrungen mit Piracetam in der
Intensivtherapie schwerer SchBdel-Him-Verletzungen. Me&z. KZin. 69: 1235-1238.
SHEPHERD, M. (1972). The classification of psychotropic drugs. Psyckx. Med. 2: 96-110.
'S JONGERS, J.J., GOLARD, G., MISERQUE, P., THIEBAULD, C., VOGELAERE, P., POLDE-&fAN, J. and
SEGERS, M. (1975). Effets cardio-circulatoires et neuromusculaires du piracetam, au repos
et B l'effort, chez des jeunes sujets bien portants. Brux.-M&d. 55: 117-140.
STEGINK, A.J. (1972). The clinical use of piracetam, a new nootropic drug. Arsneim. Forsch.
(Drug Research) -22: 975-977.
 Nootropic drugs 247

VOELREL, A. (1975). Ueber der Wirkungsprofil von Piracetam bei Psychosyndromen und symptoma-
tischen Psychosen. Arzneim. Forech. (Drug Research) 24: 1127-1129.
WECRROTH, J. (1975). On the effect of piracetam after prolonged use of alcohol on certain
performance traits and traits of subjectively rated mental states. Proc. 31st Intern. Con-
gress on Alcoholism and Drug Dependence, Bangkok.
WECRROTH, J. and MIRRONEN, H. (1972). On the effect of ucb 6215 on certain intellectual
perceptual and psychomotor performance traits and traits of subjectively rated mental states,
Proc. 30th Intern. Congress on Alcoholism and Drug Dependence, Amsterdam.
WRDL, W. and SUCBBNWIRTB, R.M.A. (1977). Eigenwirkungen des GABA-Abk8aunlings Piracetam im
doppelten Blindversuch bei gesunden Probanden. Nervenamt 48: 58-60.
WOLTBUIS, 0. (1971). Experiments with ucb 6215, a drug whichynhances acquisition in rats;
its effects compared with those of metamphetamine. Eur. J. Phamac. -16: 283-297.