Over 30 years have passed since the "Nootropic
Revolution" quietly began with the development of Piracetam in the late
medical efficacy with a virtual absence of toxicity and side
effects; something rarely seen with more standard medical
More importantly, they offered promise not only in the realm of
fighting disease, but also in the virtually unexplored realm of drugs that could not only
postpone or even reverse "normal" brain aging, but could even make
"normal" brains work better!
The Piracetam-nootropics have been
exhaustively researched; since the first scientific studies
on Piracetam in the late 1960's over 1000 scientific papers on Piracetam,
Oxiracetam, Pramiracetam, and Aniracetam have been published with about two thirds of them on Piracetam.
The action of the Piracetam-nootropics has been studied in a broad
range of animals; goldfish, mice, rats, guinea pigs, rabbits,
cats, dogs, marmosets, monkeys and humans.
The toxicity of Piracetam and its
"cousins" is amazingly low- almost non-existent. In acute toxicity
studies, intravenous doses of Piracetam given to rats (8g/ Kg bodyweight) and
oral doses given to mice, rats, and dogs (10g/ Kg or more) produced no toxicity.
This would be equivalent to 560-700 grams (1.23
to 1.54 pounds) for a 154 pound human. Rats given 100-1000mg/ Kg orally for 6
months and dogs given 10,000mg/ Kg orally for one year showed no toxic effect, a
teratogenic (birth defect causing) effects were found, either (Tacconi and
The four main commercially available "racetam"
nootropics all share a pyrrolidine nucleus, while Piracetam, Oxiracetam, and
Pramiracetam, also share an acetyl group. The racetams (especially
Piracetam and Oxiracetam) are closely related in structure to the amino acid
Pyroglutamic Acid. Pyroglutamic Acid has been shown in some studies to have weak
nootropic activity (Gouliaev and Senning 1994). Pyroglutamic Acid is naturally present
in many human foods, as well as the mammalian brain.
The concept and definition of a "nootropic
drug" was first proposed in 1972 by C.E. Giurgea, the principal Piracetam
researcher and research coordinator for UCB, the Belgian company that launched
Piracetam. "The main features... defining a nootropic drug are
(A) the enhancement, at least under some
conditions, of learning acquisitions as well as the resistance of learned
behaviors to agents that tend to impair them;
(B) the facilitation of interhemispheric flow of
(C) the partial enhancement of the general
resistance of the brain and particularly its resistance to physical and chemical
(D) the increase in the efficacy of the tonic
cortico-subcortical control mechanisms; and
(E) [absence of the usual negative pharmacologic
effects of psychotropic drugs].
Giurgea and Salama 1977). Giurgea derived the
term "nootropic" from the words "noos" (=mind) and "tropein"
(=to turn toward).
Schaffler and Klausnitzer (1988) have given an
excellent brief overview of some of the chief effects of the Piracetam-nootropics. "From animal biochemistry it is known that
enhance brain metabolism by stimulation of oxidative catabolism, increase of
ATP-turnover and cAMP levels, enhancement of phospholipid-metabolism and protein
biosynthesis. [Piracetam-nootropics have] an impact on the hippocampal release
of acetylcholine and on the dopaminergic turnover, too. Pharmacologically there
exist protective effects with regard to several noxes [harmful agents] and an
impact on the associative cortical sphere and on hippocampal structures, which
are related with learning and memory, especially when the respective functions
are impaired. The performatory enhancements are related with an increased
arousability of hippocampal pyramid cells, facilitated transmission of the
thalamic afferences, increased release of hippocampal acetylcholine and enhanced
The clinical biochemistry indicates enhancing functions on the
utilization of oxygen and glucose under the conditions of decreased brain metabolism, as
well as improvements in local perfusion. Due to this profile [Piracetam-nootropics] can
be expected to be of value in the treatment of disease which are related to impairments in
the above mentioned features, such as several types of senile dementia, (e.g. Primary
Degenerative Dementia= Alzheimers type: Multi Infarct [stroke] Depantia), ischaemic
[poor brain blood flow] insults, hypoxia, anoxia and toxicologically or dietary based
deficiencies." (Footnotes in the original text omitted here).
From the beginning of Piracetam research, the ability of the Piracetam-nootropics to partly or completely prevent or reverse the toxic action of a broad array
of chemicals and conditions has been repeatedly demonstrated. Aniracetam reverses the
memory impairment in rats induced by Clonidine. Piracetam, Oxiracetam,
Aniracetam all antagonize the normally lethal neuromuscular blockade induced by
Hemicholinium-3 (HC3) in mice. Piracetam, Oxiracetam, and Aniracetam have all attenuated
or reversed the Scopalamine (anticholinergic agent)- induced amnesia in rats and mice
under a broad range of experimental conditions.
Oxiracetam has reversed the typical "spaced out"
electroencephalogram of healthy humans given Valium, restoring a normal vigilance
electroencephalogram while maintaining Valium's anti-anxiety effects. Piracetam and Aniracetam have
ameliorated the amnesia produced by the protein synthesis inhibitor
Piracetam, Oxiracetam, Pramiracetam, and Aniracetam all attenuate or
reverse the amnesia in mice and rats induced by electroconvulsive shock treatment
both passive and active learning conditions.
When mice were given Oxydipentonium, a short acting curare-like agent
which induces asphyxia, at a dose sufficient to kill 90-100% of the placebo treated
controls, the two groups of Piracetam treated mice had a 90 and 100% survival rate.
When humans, rats, mice and rabbits have been put under diverse hypoxic
experimental conditions, Piracetam, Oxiracetam, and Aniracetam have acted to attenuate or
reverse the hypoxia-induced amnesia and learning difficulties. as well as to speed up
recovery time from hypoxia and reduce the time needed to renormalize the
electroconvulsive shock treatment (Gouliaev and
Senning Giurgea and Salama 1977).
A classic series of experiments on the protective power of Piracetam
against barbiturate poisoning was reported by Moyersoons and Giurgea in 1974. Rabbits connected to electroconvulsive shock treatment machines were given either Piracetam or saline injections before
intravenous (I.V.) administration of the fast acting barbiturates-Secobarbital.
When Piracetam was given I.V. one hour before Secobarbital, 10/10 rabbits
survived versus 3/10 survivors given saline. Electroconvulsive shock treatment records showed only minimal abnormalities
in the Piracetam rabbits, while the saline rabbits showed massive
electroconvulsive shock treatment silence, rapidly
followed by death. When given only one-half hour before Secobarbital, 7/11 Piracetam rabbits
survived versus 3/11 control rabbits.
Electroconvulsive shock treatment records of the Piracetam rabbits showed somewhat more abnormalities
than those given one hour Piracetam pre-treatment, but still far more normal appearing
than the saline control rabbits' electroconvulsive shock treatment. Piracetam was also given orally one hour before
Secobarbital. 8/9 Piracetam rabbits survived while only 3/9 controls survived. The
electroconvulsive shock treatment records of
both groups were similar to those of the rabbits given Piracetam and saline I.V. one hour
The experiments then treated Piracetam against a more slow acting
barbiturate Allobarbital, giving the Piracetam I.V. two minutes after the Allobarbital
infusion 11/13 Piracetam rabbits survived, while only 2/13 saline control rabbits survived
electroconvulsive shock treatment. Records of the Piracetam rabbits again showed electrical silences to be almost absent,
and if present, to be shorter and appear later than in the control animals.
In the Allobarbital experiment, one of the two surviving control rabbits
actually presented a more normal electroconvulsive shock treatment after
Allobarbital than did one of the survivors eleven Piracetam survivors.
Yet an electroconvulsive shock treatment recorded the next morning (about 18 hours later) showed that
the control was still asleep, and it was not aroused by a loud noise. The Piracetam
rabbit, however, was well awake, behaved normally, moved around and its
electroconvulsive shock treatment was normal.
Thus, whether given I.V. or orally, and before or after general lethal
(to controls) barbiturate infusion, Piracetam served to protect both life and brain
structure and function, as evidenced by electroconvulsive shock treatment records and post recovery behavior.
The rabbit experiments just described are hardly unusual. The Piracetam-nootropics routinely show an ability to
stabilize or normalize the
electroconvulsive shock treatment's of humans and
animals under a broad range of experimental and medical conditions.
The electroconvulsive shock treatment records the electro-chemical activity of large groups of
cortical neurons, and thus provides a "macro" picture of brain activity.
dementia, hypoxia and benzodiazepines all promote a similar shift in
electroconvulsive shock treatment frequency
Low frequency delta waves (0-4 cycles per second) and theta waves (4-8
cps) are increased, while alpha waves (8-12 cps) and beta waves (beta-1; 12-20 cps, beta
2; 20-32 cps) diminish. The average frequency of the delta and alpha waves also drops, as
compared to healthy normal subjects.
Nootropics - clinical studies
Giaguinto and colleagues (1986) gave 12 healthy humans 5mg Valium
orally at 10PM the night before their experiment. The next morning they were given either
I.V. Oxiracetam or saline in a double blind crossover experiment. Oxiracetam strongly
decreased the excessive delta activity while simultaneously strongly increasing alpha
activity, and also induced a modest increase in beta activity. Thus Oxiracetam restored
the electroconvulsive shock treatment to a pattern indicating increased vigilance and alertness, yet without destroying
Valium's anti-anxiety effect.
Itil and co-workers (1986) treated four groups of 15 patients suffering
mild to moderate dementia with either Oxiracetam or placebo for three months.
blind study used Oxiracetam in doses of 800, 1600 and 2400mg daily. Quantitative
electroconvulsive shock treatment data
indicated that in patients with dementia, Oxiracetam had a mode of action similar to other
vigilance enhancing compounds. The majority of patients who had abnormal slow
electroconvulsive shock treatment patterns
before treatment showed a "normalization" of their brain waves- i.e. a decrease
in slow (delta and theta) and an increase in alpha waves. Saletu and colleagues (1985)
conducted a four week double blind trial of Oxiracetam (2400 mg per day) or placebo in 40
patients (mean age; 80 years) suffering from the "organic brain syndrome of late
life." Their results showed a clear trend towards a decrease in delta and theta wave
activity, an increase in alpha and beta wave activity, as well as an increase in the
dominant frequency and the centroid of alpha activity after Oxiracetam treatment. Their
report noted: "The attenuation of the slow activity and the elevation of the alpha
and/or slow wave beta activity after [Oxiracetam - other studies have shown similar
results with Piracetam and Aniracetam] reflect CNS changes that are just oppositional to
those seen in normally and pathologically aging subjects... The increase in delta and
theta activities and decrease in alpha activity in normal and pathological aging are due
to deficits in the vigilance regulatory systems which can be counteracted by nootropic
Nootropics - and the healthy
Piracetam-nootropics have also shown the ability to improve learning
and memory in healthy individuals not suffering from disease or severe age-related
degeneration. In 1976 Dimond and Brouwers reported the results of some of a series of
seven double blind trials, involving 16 second and third year college students "in
excellent health and good physical and mental condition."
Subjects received either 4.8 grams a day Piracetam or placebo for 14
days. In three different measures of verbal learning and memory, the results showed
a highly significant difference in favor of the Piracetam students over the controls, with
confidence levels of P=.01, P=.02 and P=.01. The authors stated "the fact is that
Piracetam improves verbal learning and in this it would appear to be a substance which
is.. capable of extending the intellectual functions of man.. our subjects were not
senile, suffering from generalized brain disorder, confusional states, or any other
pathology of the brain... It is therefore possible to extend the power which [individuals
gifted with high intelligence and good memory] possess to still higher levels despite the
fact that the range of their achievement is a high."
Giurgea and Salama report the confirmation of Dimond/ Brouwer's work by
Wedl and Suchenwirth in 1977. Wedl found significant improvement in mental performance in
a group of 17 healthy young volunteers given 3.2 grams per day Piracetam for five days.
Mindus and colleagues (1976) reported the results of a double blind
crossover trial with 18 healthy middle aged people (median age 56), with no evidence of
somatic or mental disease, based on medical records and administration of several
intelligence tests (group mean IQ; 120 plus or minus 11).
Most of the subjects were in intellectually demanding jobs, but had
reported a slight reduction for some years in their capacity to retain or recall
After four weeks of 4.8 grams per day Piracetam, Piracetam subjects
were switched to placebo for four weeks, while the original placebo group then received
Piracetam for four weeks.
Results of a series of paper and pencil tests, as well as computerized
tests to measure perceptual motor reactions, showed a clear benefit of Piracetam over
The three different paper and pencil tests showed superior effects on
performance compared to placebo, with confidence levels of P<.001, P<.001 and
P<.05. In four of the six computerized tests Piracetam showed a significant effect over
placebo, with confidence levels of P<.05 for three and P<.029 for the fourth.
A fifth test showed a clear trend in favor of Piracetam, with P<.10.
Wilsher and co-workers (1979) related their results with 4.8 grams per day Piracetam in a
double blind, crossover trial to study the benefits of Piracetam for dyslexic students.
Interestingly, the 14 healthy student controls, matched for IQ with the
dyslexic subjects, demonstrated a significantly better result on a test measuring ability
to memorize nonsense syllables while using Piracetam as compared to placebo.
Their improvement from baseline was a 19.5% decrease in the number of
trials needed to learn the nonsense syllables while using Piracetam, versus a 10.9%
decrease from baseline while using placebo. P<.05. Piracetam-nootropics may increase
learning and memory in healthy individuals, where they are not merely attenuating or
reversing pathology, through their distinctive power to promote what has been termed
The cerebral cortex in humans and animals is divided into two
hemispheres- the left and right cortex. In most humans the left hemisphere (which controls
the right side of the body) is the language center, as well as the dominant hemisphere.
The left cortex will tend to be logical, analytical, linguistic and sequential in its
information processing, while the right cortex will usually be intuitive, holistic,
picture oriented and simultaneous in its information processing. Research has shown most
people favor one hemisphere over the other, with the dominant cortex being more
electrically active and the nondominant cortex relatively more electrically silent (when
the person is being tested or asked to solve problems, or respond to information). The two
cortical hemispheres are linked by a bundle of nerve "cables"; the corpus
callosum and the anterior commisure. In theory these two structures should unite the
function of the two hemispheres; in practice they act more like a wall separating them.
This "functionally-split" neurology produces a parallel set of dichotomies in
consciousness; logic vs. intuition; reason vs. emotion; analysis vs. synthesis; parts vs.
whole; words vs. pictures; science vs. art and religion, etc. As noted earlier, the word
"nootropic" is derived from the Greek word "nous" (the more standard
philosophical spelling). Yet in the philosophy of Plato and Aristotle, "nous"
did not simply mean "mind." In ancient Greek philosophy, "nous"
referred to the faculty of "higher mind" or "reason," as opposed to
the more concrete, sensory oriented mind which humans share even with the lower animals.
And "reason" did not merely mean logic or analysis.
The Greek philosophers saw the role of philosophy to be a method of
developing and perfecting nous/ reason. They understood nous/ reason to be the integrative
mind, where logic works complementarily with intuition, and reason and emotion are in
harmony. With a developed nous, one could clearly see and understand "the forest and
the trees" simultaneously. From a modern neurological perspective it is obvious that
the cerebral basis for a well-functioning nous would be the effective, complementary,
simultaneous integrated function of cortical hemispheres, with neither hemisphere being
automatically dominant or silent.
This in turn would require the corpus callosum and anterior commisure
to optimize information flow between the two hemispheres. Research has shown the
Piracetam-nootropics to facilitate such intercebral information transfer- indeed, it's
part of the definition of a "nootropic drug."
Giurgea and Moyersoons reported in 1970 that Piracetam increased by
100% the transcallosal evoked responses elicited in cats by stimulation of one hemisphere
and recorded from a symmetrical region of the hemisphere.
Buresova and Bures (1976) in a complex series of experiments involving
monocular (one-eye) learning in rats, demonstrated that "...Piracetam enhances
transcommisural encoding mechanisms... and some forms interhemispheric transfer..."
Dimond (1976, 1979) used a technique called "dichotic
listening" to verify the ability of Piracetam to promote interhemispheric transfer in
humans. In a dichotic listening test, different words are transmitted simultaneously into
each ear by headphone. In most people the speech center is the left cortex, because the
nerves from the ears cross over to the opposite side of the brain, most people will recall
more of the words presented right ear than the left ear. Words received by the right ear
directly reach the left cortex speech center, while words presented to the left ear must
reach the left cortex speech center indirectly, by crossing the corpus callosum. Dimond's
experiments with young healthy volunteers showed that Piracetam significantly improved
left ear word recall, indicating Piracetam increased interhemispheric information
Okuyama and Aihara (1988) tested the effect of Aniracetam on the
transcallosal response of anaesthetised rats. The transcallosal response was recorded from
the surface of the frontal cortex following stimulation of the corresponding site on the
opposite cortical hemisphere. Aniracetam at two different I.V. doses (10 mg and 30mg per
Kg) significantly increased the amplitude of the negative wave compared to its level prior
to drug, P<.01 and P<.001. The researchers stated that "the present results
indicate that Aniracetam ...increased the amplitude of the negative wave, thereby
facilitating interhemispheric transfer... Thus, it is considered that the functional
increase in interhemispheric neurotransmission by nootropic drugs may be related to the
improvement of the cognitive function."
In spite of the many and diverse neurological and psychological
benefits they have shown in human, animal and cell studies, the Piracetam-nootropics are
generally considered NOT to be major agonists or inhibitors of the synaptic action of most
neurotransmitters. Thus, major nootropic researchers Pepeu and Spignoli (1990) state;
"the pyrrolidinone derivatives [Piracetam-nootropics] show little or no affinity for
CNS receptors for dopamine, glutamate, serotonin, GABA, or benzodiazepine... So far, little
effect of nootropic drugs has been demonstrated on brain monoamine and amino acid
neurotransmitters' metabolism and release."
They also note however that "... a number of investigations on the
electrophysiological actions of nootropic drugs have been carried out... Taken together,
these findings indicate that the nootropic drugs of the [Piracetam-type] enhance neuronal
excitability within specific neuronal pathways."
Gouliaev and Senning similarly state "... we think that the
racetams exert their effect on some species [of molecule] present in the membrane of all
excitable cells, i.e. the ion carriers or ion channels and that they somehow accomplish an
increase in the excitatory response... It would therefore seem that the racetams act as
potentiators of an already present activity (also causing the increase in glucose
utilization observed), rather than possessing any activity of their own, in keeping with
their very low toxicity and lack of serious side effects. The result of their action is
therefore an increase in general ne sensitivity towards stimulation."
Thus the Piracetam-nootropics would NOT be prone to the (often serious
effects of drugs which directly amplify or inhibit neurotransmitter c e.g. MAO inhibitors,
Prozac-style "selective serotonin reuptake inhibitors, tricyclic antidepressants,
amphetamines, benzodiazepines, etc.
The notable absence of biochemical, physiological, neurotogical, psychological side effects, even with high dose and/ or long
term nootropic use, is routinely
attested to in the vast literature on them. Thus in their 1977 review Giurgea and Salama
point out: "Piracetam active in previously described situations, is devoid of usual
're pharmacologic activities even in high doses... In normal subjects.. no side effects or
'doping' effects were ever observed. Nor did Piracetam induce any sedation,
tranquillization. locomotor stimulation or psychodysleptic symptomatology.."
Itil and co-workers reported in 1983 that "This investigation has
confirmed that [Pramiracetam] is a safe and well tolerated compound that can be given in
dosages up to 1500 mg without significant side effects. In fact side effects were reported
more frequently following both placebo and... phenelzine sulfate [an 'active control'
drug] than following any of the four doses evaluated."
After a major 12 week study with 272 Alzheimer and stroke dementia
patients, Maina and colleagues (1989) reported; "Thirty five minor side effects
were recorded in 30 patients on [Oxiracetam] and 33 unwanted effects in 26 patients on placebo,
but none of these was withdrawn from the study... As far as tolerability is concerned,
clinical assessments and laboratory evaluations did not reveal any difference between
treatment and placebo]."
Moglia and co-workers (1986) concluded from a study of 43 organic
syndrome patients that "side effects during [Oxiracetam] treatment headache (3
cases), constipation (1 case), sleep disturbances (1 Side effects during placebo treatment
were headache (2 case constipation (1 case). The side effects spontaneously disappears
required neither medication nor treatment interruption. No significant [adverse] change in
neurological and laboratory ex( lions, ECG and EEG could be detected at the end of
treatment, both in the [Oxiracetam] and in the placebo groups." When side effects are
occasionally reported in the clinical literature on Piracetam-nootropics. they are usually
of a type to suggest slight over-stimulation, mainly headaches, agitation, insomnia and
irritability. Yet other studies find these same symptoms to be improved by
Piracetam-nootropics when these symptoms are pre-existing in the patients. Thus Itil
(1986) notes, "...[ Piracetam] showed more improvement than [Oxiracetam] in factors
of paranoid delusion and agitation." Maina (1989) noted that "[Oxiracetam] does
not act only by increasing arousal and alertness. If this were the case, there would
probably be a worsening of the IPSC-E anxiety and tension [scores]. However, in our study
there was actually a decrease in anxiety and tension." Branconnier (1983), reporting
on his group's study of Pramiracetam in 32 Alzheimer patients noted that after four weeks'
treatment, there was a significant decrease in anxiety-tension (P=.004) and hostility
(P=.03), and a clean trend over placebo (P=.08) for Pramiracetam to improve existing sleep
One potentially limiting factor in obtaining clinical benefit from
Piracetam-nootropics has been bought to light through the research of Mondadori (1992) on
steroid interactions with nootropics. Mondadori has shown that either deficient or
excessive levels of adrenal steroids can block the memory benefits of Piracetam-nootropics
in animals. High doses of either corticosterone or aldosterone abolish the memory
enhancing benefits of Piracetam-nootropics, while giving corticosterone or aldosterone to
rats with no adrenals restores the positive memory effects of nootropics. Mandadori also
notes that cortisol levels are frequently elevated in Alzheimer patients, which might
explain the inconsistent results obtained with nootropics in different Alzheimer clinical
Nootropics - Synergy.
Since Piracetam-nootropics act (in part) through subtly amplifying neuronal electrical
excitability, they will tend to increase the activity of other drugs that modify neural
activity taken simultaneously. This in turn may increase both the positive action of the
other drug, as well as possibly lead to the occasional nootropic over-stimulation effects.
Thus even caffeine may be sufficiently stimulating to bring on the "nootropic over
stimulation effect," especially in those very sensitive to caffeine. A key normal
regulator of neuronal sensitivity is the essential mineral, Magnesium. Dietary
surveys in the Western world routinely show most people to be at least marginally Mg
deficient, with many getting half or less of the recommended dietary Magnesium intake
Thus, the occasional over stimulation seen with Piracetam-nootropics
may simply evidence an undetected synaptic Magnesium deficiency, and Magnesium supplementation may
provide a natural remedy to minimize such over stimulation Piracetam-nootropics have been
combined in many clinical and experimental situations with other drugs, almost always with
a positive, synergistic effect. Many clinical experiments have demonstrated Piracetam and
Oxiracetam to synergize with anti-epileptic medications, especially carbamazepine
(Tegretol). A simultaneous enhancement of the anti-epileptic drug's anti-seizure activity,
combined with improvement or elimination of the memory, alertness and comprehension
cognitive deficits induced 1: anti-epileptic drug, have been found in multiple studies
(Chaudhry Piracetam combined with Pentoxifylline (a caffeine analogue cerebral flow
enhancer) increased both "psycho-intellectual performance measures of cerebral blood
flow), significantly more than place either drug alone (Parnetti 1985).
Human and animal studies have shown increased benefit from combining
Piracetam with Choline, the raw material for neuronal production of be neurotransmitter
Acetylcholine, as well as Phosphatidylcholine, a fluidizing component of cell membranes
(Ferris 1982). When Piracetam was combined with Hydergine in experiments with mice
both brain survival time and learning/ memory deficits induced poxia, it was noted that
"The effect of the combination was greater than the sum of the effects of the
individual agents and indicates that synergism had occurred" (Berga 1986). A 1994
report looked at the synergy between Piracetam and intensive speech therapy given to
post-stroke aphasic patients; "In general, changes under [Piracetam] were 160% of the
changes observed in patients receiving placebo, while getting the same intensive speech
therapy" (Di 1994).
Those wishing to get the maximum benefit from Piracetam-nootropics may
to include in their regimen nutrients known to enhance brain structure function in various