Prog. Neuro-Peychopharmao. Vol. 1, pp. 235-247, 1977. Pergamon Press. Printed in Great Britain.
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)
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 acquisition; (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-psychotrnpic drugs.
3. The animal experimental results are thoroughly corroborated by the data obtained in clinical 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.
The term “nootropic” (noos = mind; tropein = towards) was proposed by us (Giurgea, 1972,
1973) to designate psychotropic drugs that characteristically interfere with the higher telencephalic 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 resistance of learned behaviours to agents that tend to impair them; (b) the facilitation of interhemispheric 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 efficacy of the tonic cortico-subcortical control mechanisms; and (e) the display of above mentioned activities by selective functional impact on higher integrative, telencephalic mechanisms, i.e. partial lack of usual psychological and general pharmacological activities.
Piracetam [ (oxo-2-pyrrolidinyl-1) 2 acetamide] seems to, up to now, correspond best to these definitions as far as animal pharmacology, clinical pharmacology and therapeutics are concerned and will be used as prototype for nootropic drugs.
Ip this review we shall present various features of the nootropic profile under three main headings; animal pharmacology, clinical pharmacology and pharmacotherepeutics. Some considerations to biochemical data and the classification of nootropic drugs will be given in the later part of the paper.
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. 1 and 2. Recent published data on nootropic drugs are presented in Table 1. One additional 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).
Nootropic effect on learning.
Experimental data and references in animal pharmacology
Figure 1 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 before the last retention test.
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 submitted 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 mg/kg).
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 statistically not different from that in test I.
For comparison (extreme right), a typical experiment in “enriched” non-injected rats illustrating 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’ administration (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 Wedl and Suchenwirth (1977) who have replicated a significant improvement of mental performance in a group of seventeen young healthy 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 (KVAT) and three paper and
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.
Chroma brain syndrome due to ageing
Stegink (1972), in a double blind study involving 196 elderly patients, has compared piracetam with a placebo in the treatment of psycho-organic symptoms occurring in the course of senile 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 improvement 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 at. (1974), Delwaide et ai. (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.
In acute alcohol withdrawal, Knott and Beard (1973),2 Petty (1973),2 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 earlier 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 electrical 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 hemidecortication.
Figure 3 illustrates one aspect of piracetam’s facilitating aspect of the writing-in callosal interhemispheric mechanism.
2.2.2, Clinical pharmacology
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.
Fig. 3. Effect of piracetam on monocular pattern discrimination learning (L) and on strength of resulting primary and secondary engrams revealed by hemidecorticated re-leaming (R). Brain schemes indicate conditions of experiment on days 1-3 (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 Dimond 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
Nootropic effect and its relationship to brain resistance. Experimental data and references in animal pharmacology
Enhanced cerebral resistance and mainly speeding-up of brain recovery (Criterium: EEG; species: rabbit)
Giurgea et al., 1970
Enhanced resistance to sub-cellular lesions (Criterium: electronic microscopy and histochemistry; species: rat)
Enhanced resistance to experimental high-altitude
(Criterium: convulsions; species: rat)
Quadbeck, 1970 (pers.comm.)
EEG protection and enhanced survival percentage (Species: cat, rat)
Moyersoons and Giurgea, 1974;
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-pic drugs. It can be seen that dexamphetamine, pyritinol and sulpiride are inactive (Giurgea, 1977).
Fig. 4. Experimental schedule of the “curare-like hypoxia” model.
Mice are given i.p. 3 mg/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 decurarizing agent, enhances the number of survivors because it confers a CNS protection during the short-lasting asphyxia induced by the curare-like agent.
Effect of piracetam and some other neuro-psychotropic drugs on “curare-like hypoxia” model
* 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 al. (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. Piracetam 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 hypoxic or toxic state, was also investigated.
Calliauw and Marchau (1975) in a double blind controlled trial demonstrated that, in comparison with placebo, piracetam significantly improved state of consciousness in deeply comatous hospitalised patients following head injuries.
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).
Effect of piracetam on the cortico-subcortical “control”
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, cortical KC1-application (Bures et at., 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 towards 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 at., 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-traumatic 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
effect as compared to placebo in patients with post-concussional syndromes, consisting of symptoms vertigo and headaches.
2.5. Lack of side effects
2.5.1. Animal pharmacology
Piracetam: Lack of usual pharmacological activity*
Piracetam, while active in previously described situations, is devoid of usual “routine” pharmacological activities even in high doses (Table 5). 3
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 neurochemical parameters, whereas in piracetam-treated rats there is a highly–significant speedup 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 (Schiller 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 selectively activates brain adenylatekinase (an enzyme facilitating ATP formation in anaerobic conditions) 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.
Fig. 5. The place of nootropic drugs in the classification of psychiatric drug.
In the light of previous considerations, the classification of psychotropic drugs is presented in Fig. 5.
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.
Inquiries and reprint requests should be addressed to:
Prof. Dr. C. Giurgea, Head of the Neuropharmacological Research Department.
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Partly supported by IRSIA research grant No. 20310.
2.3.1. Animal pharmacology
Table 2 summarizes the main existing data in this field.
See also Giurgea, (1976)
2.5.2. Clinical pharmacology
In normal subjects (Oswald and Lewis, 1972, pers. comm.; S. Jongers et at., 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 mads on the whole brain. It is therefore difficult to discuss them thoroughly in the light of the
We shall however briefly mention here the essential metabolic data and refer the interested reader to more specialised publications (Pede et at., 1971; Gobert 1972).
Three major points are to be emphasized:
(a) Piracetam in all animal species studied, including man, is practically not metabolised. About 96-98% 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