- Smart Drugs
Nootropics - Reviewing The Smart-Drugs
By James South MA
Over 30 years have passed since the "Nootropic
Revolution" quietly began with the development of Piracetam
(PIR) in the late 1960's. The second wave of this pharmacologic
revolution occurred in the late 1970's with the development of
Oxiracetam (OXR), Pramiracetam (PRM) and Aniracetam
The PIR-nootropics were revolutionary in at
least two ways. They combined physiological and medical efficacy
with a virtual absence of toxicity and side effects, something
rarely seen with more standard medical drugs. 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 PIR-nootropics have been exhaustively researched,
since the first scientific studies on PIR in the late 1960's over
1000 scientific papers on PIR, OXR, PRM and ANR have been published,
with about two thirds of them on PIR.
Nootropics - Lack of toxicity
The action of the PIR-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 PIR and its "cousins" is amazingly low- almost non-existent.
In acute toxicity studies, intravenous doses
of PIR 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, and no teratogenic (birth defect causing) effects
were found, either (Tacconi and Wurtman 1986).
The PIR-nootropics are among the toxicologically
safest drugs ever developed.
The four main commercially available "racetam"
nootropics all share a pyrrolidine nucleus, while PIR, OXR and
PRM also share an acetamide group (see figure one). The racetams
(especially PIR and OXR) are also closely related in structure
to the amino acid Pyroglutamic Acid (PGA). PGA has been shown
in some studies to have weak nootropic activity (Gouliaev and
Senning 1994). PGA is naturally present in many human foods, as
well as the mammalian brain.
Nootropics - Their structure
The concept and definition of a "nootropic
drug" was first proposed in 1972 by C.E. Giurgea, the principal
PIR researcher and research co-ordinator for UCB, the Belgian
company that launched PIR. "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 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) [absence of the usual negative pharmacologic effects of psychotropic
drugs]." (Giurgea and Salama 1977).
Giurgea derived the term "nootropic"
from the Greek words "noos" (=mind) and "tropein"
(=to turn toward).
Nootropics - Method of action
Schaffler and Klausnitzer (1988) have given
an excellent brief overview of some of the chief effects of the
PIR-nootropics. "From animal biochemistry it is known that
[PIR-nootropics] enhance the brain metabolism by stimulation of
oxidative catabolism, increase of ATP-turnover and cAMP levels,
enhancement of phospholipid metabolism and protein biosynthesis.
[PIR-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 synaptic transmission.
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 [PIR-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= Alzheimer's
type; Multi Infarct [stroke] Dementia), ischaemic [poor brain
blood flow] insults, hypoxia, anoxia and toxicologically or dietary
based deficiencies." (Footnotes in the original text omitted
Nootropics - Animal experiments
From the beginning of PIR research, the ability
of the PIR-nootropics to partly or completely prevent or reverse
the toxic action of a broad array of chemicals and conditions
has been repeatedly demonstrated.
ANR reverses the memory impairment in rats induced
by Clonidine. PIR, OXR, PRM and ANR all antagonise the normally
lethal neuromuscular blockade induced by Hemicholinium-3 (HC3)
PIR, OXR and ANR have all attenuated or reversed
the Scopalamine (anticholinergic agent)- induced amnesia in rats
and mice under a broad range of experimental conditions.
OXR has reversed the typical "spaced out"
electroencephalogram (EEG) of healthy humans given Valium, restoring
a normal vigilance EEG while maintaining Valium's anti-anxiety
PIR and ANR have ameliorated the amnesia produced
by the protein synthesis inhibitor Cycloheximide. PIR, OXR, PRM
and ANR all attenuate or reverse the amnesia in mice and rats
induced by electroconvulsive shock treatment (ECS) in both passive
and active learning conditions.
When mice were given Oxydipentonium, a short
acting curare-like agent that induces asphyxia, at a dose sufficient
to kill 90-100% of the placebo treated controls, the two groups
of PIR treated mice had a 90 and 100% survival rate.
When humans, rats, mice and rabbits have been
put under diverse hypoxic experimental conditions, PIR, OXR and
ANR 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 EEG
(Gouliaev and Senning 1994, Giurgea and Salama 1977).
Moyersoons and Giurgea reported a classic series
of experiments on the protective power of PIR against barbiturate
poisoning in 1974. Rabbits connected to EEG machines were given
either PIR or saline injections before intravenous (i.v.) administration
of the fast acting barbiturates- Secobarbital (SEC).
When PIR was given i.v. one hour before SEC,
10/10 rabbits survived, versus 3/10 survivors given saline. EEG
records showed only minimal abnormalities in the PIR rabbits,
while the saline rabbits showed massive EEG silence, rapidly followed
by death. When given only one-half hour before SEC, 7/11 PIR rabbits
survived, versus 3/11 control rabbits.
EEG records of the PIR rabbits showed somewhat
more abnormalities than those given one hour PIR pre-treatment,
but still far more normal appearing than the saline control rabbits'
PIR was also given orally one hour before SEC.
8/9 PIR rabbits survived, while only 3/9 controls survived. The
EEG records of both groups were similar to those of the rabbits
given PIR and saline i.v. one hour before SEC.
The experiments then treated PIR against a slower
acting barbiturate-Allobarbital (ALB), giving the PIR i.v. two
minutes after the ALB infusion, 11/13 PIR rabbits survived, while
only 2/13 saline control rabbits survived. EEG records of the
PIR rabbits again showed electrical silences to be almost absent,
and if present, to be shorter and appear later than in the control
In the ALB experiment, one of the two surviving
control rabbits actually presented a more normal EEG after ALB
than did one of the 11 PIR survivors. Yet an EEG 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 PIR rabbit, however, was well awake, behaved
normally, moved around and its EEG was normal.
Thus, whether given i.v. or orally, and before
or after general lethal (to controls) barbiturate infusion, PIR
served to protect both life and brain structure and function,
as evidenced by EEG records and post recovery behavior.
The rabbit experiments just described are hardly
unusual. The PIR-nootropics routinely show an ability to stabilise
or normalise the EEG's of humans and animals under a broad range
of experimental and medical conditions. The EEG records the electro-chemical
activity of large groups of cortical neurons, and thus provides
a "macro" picture of brain activity.
Aging, dementia, hypoxia and benzodiazepines
all promote a similar shift in EEG frequency patterns. 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
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. OXR or saline in
a double blind crossover experiment.
OXR strongly decreased the excessive delta activity
while simultaneously strongly increasing alpha activity, and also
induced a modest increase in beta activity. Thus OXR restored
the EEG to a pattern indicating in-creased 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
OXR or placebo for three months. The double blind study used OXR
in doses of 800, 1600 and 2400mg daily. Quantitative EEG data
indicated that in patients with dementia, OXR had a mode of action
similar to other vigilance enhancing compounds.
The majority of patients who had abnormal slow
EEG 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 OXR (2400mg 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 OXR treatment.
Their report noted; "The attenuation of the slow activity
and the elevation of the alpha and/or slow wave beta activity
after [OXR- other studies have shown similar results with PIR
and ANR] 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 drugs."
Nootropics - And the healthy
PIR-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
Subjects received either 4.8 grams a day PIR
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 PIR 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 already 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 PIR for five
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 information. After four
weeks of 4.8 grams per day PIR, PIR subjects were switched to
placebo for four weeks, while the original placebo group then
received PIR for four weeks.
Results of a series of paper and pencil tests,
as well as computerised tests to measure perceptual motor reactions,
showed a clear benefit of PIR over placebo. 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 computerised tests PIR 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 PIR, with P<.10.
Wilsher and co-workers (1979) related their
results with 4.8 grams per day PIR in a double blind, crossover
trial to study the benefits of PIR 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 memorise nonsense
syllables while using PIR as com-pared to placebo.
Their improvement from baseline was a 19.5%
decrease in the number of trials needed to learn the nonsense
syllables while using PIR, versus a 10.9% decrease from baseline
while using placebo, P<.05. PIR-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 "hemispheric super-connection."
Nootropics - Towards the mind
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 non-dominant cortex relatively more electrically
silent (when the person is being tested or asked to solve problems,
or respond to information).
A bundle of nerve "cables"; the corpus
callosum and the anterior commisure link the two cortical hemispheres.
In theory these two structures should unite the function of the
two hemispheres; in practice they act more like a wall separating
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
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 both cortical
hemispheres, with neither hemisphere being automatically dominant
This in turn would require the corpus callosum
and anterior commisure to optimise information flow between the
two hemispheres. Research has shown the PIR-nootropics to facilitate
such intercerebral information transfer- indeed, it's part of
the definition of a "nootropic drug."
Giurgea and Moyersoons reported in 1970 that
PIR increased by 25 to 100% the transcallosal evoked responses
elicited in cats by stimulation of one hemisphere and recorded
from a symmetrical region of the other 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 of interhemispheric transfer..."
Dimond (1976, 1979) used a technique called
"dichotic listening" to verify the ability of PIR 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
to the 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 PIR significantly improved left ear word recall, indicating
PIR increased inter-hemispheric information transfer.
Okuyama and Aihara (1988) tested the effect
of ANR 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.
ANR at two different i.v. doses (10 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
Nootropics - And neurotransmitters
In spite of the many and diverse neurological
and psychological benefits they have shown in human, animal and
cell studies, the PIR-nootropics are generally considered NOT
to be major agonists or inhibitors of the synaptic action of most
Thus, major nootropic researchers Pepeu and
Spignoli (1990) state; "the pyrrolidinone derivatives [PIR-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 [PIR-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 neuronal sensitivity
Thus the PIR-nootropics would NOT be prone to
the (often-serious) side effects of drugs which directly amplify
or inhibit neurotransmitter action e.g. MAO inhibitors, Prozac-style
"selective serotonin reuptake inhibitors," tricyclic
anti-depressants, amphetamines, benzodiazepines, etc.
Nootropics - Side effects and contraindications
The notable absence of biochemical, physiological,
neurological or psychological side effects, even with high dose
and/ or long term PIR-nootropic use, is routinely attested to
in the vast literature on them.
Thus in their 1977 review Giurgea and Salama
point out: "Piracetam, while active in previously described
situations, is devoid of usual 'routine' pharmacologic activities
even in high doses... In normal subjects.. no side effects or
'doping' effects were ever observed. Nor did Piracetam induce
any sedation, tranquillisation, locomotor stimulation or psychodysleptic
Itil and co-workers reported in 1983 that "This
investigation has confirmed that [PRM] is a safe and well tolerated
compound that can be given in dosages up to 1500mg 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 [PRM] 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 [OXR] 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 treatments [OXR and placebo]."
Moglia and co-workers (1986) concluded from
a study of 43 organic brain syndrome patients "side effects
during [OXR] treatment were headache (3 cases), constipation (1
case), sleep disturbances (1 case). Side effects during placebo
treatment were headache (2 cases) and constipation (1 case). The
side effects spontaneously disappeared and required neither any
medication or treatment interruption.
No significant [adverse] change in neurological
and laboratory examinations, ECG and EEG could be detected at
the end of treatment, both in the [OXR] and in the placebo groups."
When side effects are occasionally reported
in the clinical literature on PIR-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 PIR-nootropics when these symptoms are pre-existing
in the patients. Thus Itil (1986) notes, "...[PIR] showed
more improvement than [OXR] in factors of paranoid delusion and
Maina (1989) noted that "[OXR] 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 PRM 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 PRM to improve existing sleep disturbances.
One potentially limiting factor in obtaining
clinical benefit from PIR-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 PIR-nootropics in animals. High doses of either corticosterone
or aldosterone abolish the memory enhancing benefits of PIR-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 studies.
Nootropics - Synergy
Since PIR-nootropics act (in part) through subtly
amplifying neuronal electrical excitability, they will tend to
increase the activity of other drugs that modify neural activity
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
A key normal regulator of neuronal sensitivity
is the essential mineral, Magnesium (Mg). 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 Mg intake (Wester 1987).
Thus, the occasional over stimulation seen with
PIR-nootropics may simply evidence an undetected synaptic Mg deficiency,
and Mg supplementation may provide a natural remedy to minimize
such over stimulation.
PIR-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 PIR and OXR to synergise 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 by the anti-epileptic drug, have been found in multiple
studies (Chaudhry 1992).
PIR combined with Pentoxifylline (a caffeine
analogue cerebral blood flow enhancer) increased both "psycho-intellectual
performance" (i.e. measures of cerebral blood flow), significantly
more than placebo or either drug alone (Parnetti 1985).
Human and animal studies have shown increased
benefit from combining PIR with Choline, the raw material for
neuronal production of both the neurotransmitter Acetylcholine,
as well as Phosphatidylcholine, a fluidising component of cell
membranes (Ferris 1982).
When PIR was combined with Hydergine in experiments
with mice testing both brain survival time and learning/ memory
deficits induced by hypoxia, it was noted that "The effect
of the combination was clearly greater than the sum of the effects
of the individual agents and indicates that synergism had occurred"
A 1994 report looked at the synergy between
PIR and intensive speech therapy given to post-stroke aphasic
patients; "In general, changes under [PIR] were 160% of the
changes observed in patients receiving placebo, while getting
the same intensive speech therapy" (Deberdt 1994).
Those wishing to get the maximum benefit from
PIR-nootropics may wish to include in their regimen nutrients
known to enhance brain structure/ function in various ways.
The B-complex vitamins (including NADH), Lipoic
Acid, CoQ10 (Idebenone-ed.), Magnesium and Manganese are all essential
to brain ATP energy production through the glycolytic and citric
acid cycles and the electron transport side chain.
DMAE (Cyprodenate or Lucidril-ed.) is an excellent
Choline precursor that passes the blood brain barrier better than
Choline or Lecithin.
Acetyl-L-Carnitine (ALC) enhances the activity
of the enzyme Choline Acetyl Transferase (CAT) that combines Acetyl
groups with Choline to produce Acetylcholine. ALC also renews
the structure and energy generating power of aging neuronal mitochondria.
Phosphatidylserine is a natural neuronal membrane
component and stabilizer.
Anti-oxidants, such as vitamins C and E, as
well as Pycnogenol or grape seed extract, may protect polyunsaturated
fat-rich neuronal and mitochondrial membranes from the damage
caused by the inevitable re-lease of large numbers of free radicals,
generated through brain mitochondrial energy production.
Nootropics - Their differences
Individual differences of action between PIR,
OXR, PRM and ANR are often subtle, and in many studies they show
similar modes of action. One intriguing benefit I have seen reported
only for PRM, is its ability to increase goal directed and purposive
behavior (Branconnier 1983). After trying PRM in my regimen several
years ago, I did notice an increase in my tendency to quickly
take care of routine household, auto and personal maintenance
chores I habitually tended to ignore avoid or postpone.
I have taken PIR for eight years, PRM and ANR
for the past two years and OXR for about 9 months. During the
past year, my lifelong severe writer's block has gradually disappeared,
and my writing output of the past year has exceeded that of the
Some studies on dementia comparing PIR and OXR
(the two most nearly identical racetams), have suggested that
OXR may be more effective in restoring the cognitive deficits
of dementia (decreased memory, concentration and alertness). While
PIR may be more effective at normalising the emotional problems
of dementia such as agitation, tension-anxiety, hostility, insomnia
Quantitatively, PIR is the least potent racetam,
with clinical doses typically being 2400mg to 4800mg per day,
occasionally even 6000mg to 10,000mg per day.
OXR is usually given 800mg to 2400mg per day.
ANR doses are typically 750mg to 1500mg per
day, while PRM has shown benefit even at 150mg to 300mg per day,
although 600mg to 1500mg per day is more typical.
PIR and OXR are highly water soluble (96-98%),
while ANR and PRM are more fat-soluble. Their lipophilicity may
allow for less frequent dosing (once or twice daily) with ANR
and PRM, compared to 3 to 4 doses a day with PIR and OXR.
The Japanese, who have contributed much research
on it, favor ANR. It is widely used there as an agent to rapidly
promote clarity of thought.
Nootropics - Uses and conclusion
During the past 30 years, the PIR-nootropics
have been used to treat an amazingly broad range of human ailments
and conditions, either alone or with other drugs, with moderate
to major benefit.
PIR-nootropics have been used to treat various
forms of dementia and "organic brain syndrome." They
have been used successfully to treat dyslexia, epilepsy and age-associated
PIR-nootropics have successfully treated post-concussional
syndrome, vertigo, alcohol withdrawal, cerebrovascular insufficiency
They have shown benefit in normalising blood
flow parameters; decreased platelet aggregation, increased red
blood cell (RBC) deformability, decreased adherence of damaged
and sickle cell RBC's to endothelium (blood cell lining) and increased
Prostacyclin (PGI2) production and activity.
Yet the most exciting potential benefits of
the racetams have yet to be seriously explored in clinical studies.
The racetams are cerebral homeostatic normalizers,
neuroprotectants, cerebral metabolic enhancers and brain integrative
agents. They enhance brain energy, especially under deficit conditions-
e.g. hypoxia, chemical toxicity or impaired cerebral microcirculation.
They preserve, protect and enhance synaptic
membrane and receptor structure and plasticity. They enhance brain
integration- horizontally, by increased coupling of the cerebral
hemispheres; and vertically by enhancing cerebral connection with
and tonic control of the limbic system, through nootropics effects
on the hippocampus- a major link between cerebrum and limbic system.
This vertical integration increase may help
to integrate reason (cerebrum) and emotion (limbic system- sometimes
called the "horse brain"). The increased tonic cortico-subcortical
control and regulation may also prevent our limbic passions and
desires from "running away with us," as in crimes of
In middle aged and older individuals who do
not yet suffer any specific neural malady or major mental impairment,
nootropics may not only slow down or postpone entropic brain aging,
but they may even reverse some mild neural/ mental decline.
Thus a person at 50 might be smarter, have better
memory, quicker reflexes and greater vigilance and alertness than
when they were 40.
The racetams may literally be safe and effective
pharmacologic tools to enhance, protect and optimize truly normal,
fully human neuro-psychological structures and function, well
into old age.
Nootropics - References
1. P. Berga et al (1986) "Synergistic interactions
between Piracetam and [Hydergine] in some animal models of cerebral
hypoxia and ischaemia" Arzneim Forsch/ Drug Res 36, 1314-20.
2. R.J. Branconnier et al (1983) "The therapeutic efficacy
of Pramiracetam in Alzheimer's disease- preliminary observations"
Psychopharmacol Bull 19, 726-30.
3. O. Buresova, J. Bures "Piracetam induced facilitation
of interhemispheric transfer of visual information in rats"
Psychopharmacologia (Berlinr) 46, 93-102.
4. H.R. Chaudhry et al (1992) "Clinical use of Piracetam
in epileptic patients" Curr Ther Res 52, 355-60.
5. W. Deberdt (1994) "Interaction between psychological and
pharmacological treatment in cognitive impairment" Life Sci
6. S.J. Dimond (1976) "Drugs to improve learning in man"
in the neuro-psychology of learning disorders, R. Knight, D. Bakker,
eds., 367-79. Univ. Park Baltimore.
7. S.J. Dimond, E. Brouwers (1976) "Increase in the power
of human memory in normal man through the use of drugs" Psychopharmacol
8. S.J. Dimond et al (1979) "Some effects of Piracetam..
on chronic schizophrenia" Psychopharmacol 64, 341-48.
9. S.H. Ferris et al (1982) "Combination Choline/ Piracetam
treatment of senile dementia" Psychopharm Bull 18, 94-98.
10. S. Giaquinto (1986) "EEG changes induced by Oxiracetam
on Diazepam-Medicated volunteers" Clin. Neuropharmacol 9,
11. C. Giurgea, F. Moyersoons (1970) "Differential pharmacological
reactivity of three types of cortical evoked potentials"
Arch Int. Pharmacodyn Ther. 188, 401-04.
12. C. Giurgea, M. Salama (1977) "Nootropic drugs" Prog.
13. A. Gouliaev, A. Senning (1994) "Piracetam and other structurally
related nootropics" Brian Res. Rev. 19, 180-222.
14. T. Itil et al (1983) "Pramiracetam, a new nootropic,
a controlled quantitative pharmaco-EEG study" Psychopharm.
Bull. 19, 708-16.
15. T. Itil et al (1986) "CNS pharmacology and clinical therapeutic
effects of Oxiracetam" Clin. Neuropharmacol. 9, S70-S72.
16. G. Maina et al (1989) "Oxiracetam in the treatment of
primary degenerative and multi infarct dementia" Neuropsychobiol.
17. P. Mindu et al (1976) "Piracetam induced improvement
of mental performance" Acta Psychiat. Scanda.
18. A. Moglia et al (1986) "Activity of Oxiracetam in patients
with organic brain syndrome" Clin. Neuropharmac 9, S73-S78.
19. C. Mondadori et al (1992) "Elevated corticosteroid levels
block the memory improving effects of nootropics" Psychopharmac.
20. F. Moyersoons, C. Giurgea (1974) "Protective effect of
Piracetam in experimental barbiturate intoxication: EEG and behavioural
studies" Arch. Int. Pharmacodyn Ther 210, 38-48.
21. S. Okuyama, H. Aihara (1988) "Action of nootropic drugs
on transcallosal responses of rats" Neuropharmac. 27, 67-72.
22. L. Parnetti et al (1985) "Haemorheological pattern in
initial mental deterioration; Results of a long term study using
Piracetam and Pentoxi-fylline" Arch Gerontol. Geriatr 4,
23. G. Pepeu, G. Spignoli (1990) "Neurochemical actions of
nootropic drugs" in Advances in Neurology V51; Alzheimer's
disease, R. Wurtman ed. 247-52, Raven Press.
24. B. Saletu et al (1985) "..Oxiracetam in the organic brain
syndrome of late life" Neuropsychobiol 13, 44-52.
25. K. Schaffler, W. Klausnitzer (1988) "..Antihypoxidotic
effects of Piracetam using psychophsiological measures in healthy
volunteers" Arzneim Forsch. Drug Res. 38, 288-91.
26. M. Tacconi, R. Wurtman (1986) "Piracetam, physiological
disposition and mechanisms of action" in Advances in Neurology
V43; Myoclonus, S. Fahn, ed. 675-685, Raven Press.
27. P. Wester (1987) "Magnesium" Am. J. Clin. Nutr.
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to Anti-Aging Medicine Index