Piracetam - the
by James South MA
was developed in the mid-1960's by UCB
pharmaceutical company of Belgium. It was originally used to treat motion
(1) Between 1968 and 1972, however, there was an explosion of Piracetam
research which uncovered its ability to facilitate learning, prevent
amnesia induced by hypoxia and electroshock, and accelerate electroencephalograph
return to normal
in hypoxic animals. (1) By 1972 700 papers were published on
Yet already by 1972 Piracetam's pharmacologic uniqueness led C.E. Giurgea,
UCB's principal Piracetam researcher and research coordinator, to formulate an
entirely new category of drugs to describe Piracetam: the nootropic drug. (2)
to Giurgea, nootropic drugs should have the following characteristics:
should enhance learning and memory.
2) They should enhance the resistance of
learned behaviors/memories to conditions which tend to disrupt them (e.g.
electroconvulsive shock, hypoxia).
3) They should protect the brain against
various physical or chemical injuries (e.g. barbiturates, scopalamine).
should ''increase the efficacy of the tonic cortical/subcortical control
6) They should lack the usual pharmacology of other
psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side
effects and extremely low toxicity.
As research into Piracetam and other
nootropics (e.g. pyritinol,
centrophenoxine, oxiracetam, idebenone) progressed
over the past 30 years, section 5) of Giurgea's original definition has been
gradually dropped by most researchers. (3)
Nonetheless, the nootropic drugs
represent a unique class of drugs, with their broad cognition enhancing, brain
protecting and low toxicity/ side effect profiles. It is an interesting comment
on the AMA/FDA stranglehold on American medicine that as of January 2001, not a
single nootropic drug has ever been given FDA approval for use in the U.S.
has been used experimentally or clinically to treat a wide range of diseases and
conditions, primarily in Europe. (Although much of the research on Piracetam has
been published in English, a large amount of Piracetam research has been
published in German, French, Italian, and Russian.)
brain formula Raise your IQ
has been used successfully to treat alcoholisrn/ alcohol withdrawal syndrome in
animals and man.
(4,5,19) Piracetam has brought improvement, or slowed
deterioration, in "senile involution" dementia and Alzheimer’s
(6,7) Piracetam has improved recovery from aphasia (speech impairment)
Piracetam has restored various functions (use of limbs,
speech, EEC, slate of consciousness) in people suffering from acute and chronic
cerebral ischemia (decreased brain blood flow).
(9,10) Piracetam has improved
alertness, co-operation, socialization, and IQ in elderly psychiatric patients
suffering from "mild diffuse cerebral impairment."
has increased reading comprehension and accuracy in dyslexic children.
Piracetam increased memory and verbal learning in dyslexic children, as well as
speed and accuracy of reading, writing and spelling.
potentiated the anticonvulsant action of various anti-epileptic drugs in both
animals and man, while also eliminating cognitive deficits induced by
anti-epileptic drugs in humans.
has improved mental performance in "aging, nondeteriorated
individuals" suffering only from "middle-aged forgetfulness."
Elderly outpatients suffering
from "age-associated memory impairment" given Piracetam showed
significant improvement in memory consolidation and recall. (8)
Piracetam reversed typical EEC slowing associated with
"normal" and pathological human aging, increasing alpha and beta
(fast) electroencephalograph activity and reducing delta and theta (slow) electroencephalograph
simultaneously increasing vigilance, attention and memory.
reduced the severity and occurrence of major symptoms of "post-concussional
syndrome," such as headache, vertigo, fatigue and decreased alertness (18),
while it also improved the state of consciousness in deeply comatose
hospitalized patients following head injuries. (19) Piracetam has successfully
treated motion sickness and vertigo. (1) Piracetam "is one of the best
available drugs for treating myoclonus [severe muscle spasms] of cortical
origin." (20) Piracetam has successfully treated Raynaud's syndrome (severe
vasospasm in hands and/or feet), with "a rapid and marked improvement.
The efficacy of Piracetam has been maintained in several patients already
followed for 2-3 years." (21)
Piracetam has been used to inhibit sickle cell anemia, both clinically and
Piracetam has improved Parkinson's disease, and may
synergize with standard L-dopa treatment. (1) A key part of Piracetam's
specialness is its amazing lack of toxicity. Piracetam has been studied in a
wide range of animals: goldfish, mice, rats, guinea pigs, rabbits, cats, clogs,
marmosets, monkeys, and humans. (1,19)
In acute toxicity studies that attempted
to determine Piracetam's "LD50" (the lethal dose which kills 50% of
test animals), Piracetam failed to achieve an LD50 when given to rats
intravenously at 8gm/kg bodyweight. (1)
Similarly, oral LD50 studies in mice, rats, and dogs given 10gm Piracetam/kg
bodyweight also produced no LD50! (1) This would he mathematically equivalent to
giving a 70 kg (154 pound) person 700gm (1.54 pounds) of Piracetam! As Tacconi and Wurtman note, ''Piracetam apparently is
virtually non-toxic. Rats treated chronically with 100 to 1,000 mg/kg orally for
6 months and dogs treated with as much as 10g/kg orally for 1 year did not show
any toxic effect. No teratogenic
(birth deformity) effects were found, nor was behavioral tolerance noted."
(22) Thus, Piracetam must be considered one of the toxicologically safest drugs
the earliest days of Piracetam research, the ability of Piracetam to partly or
completely prevent or reverse the toxic action of a broad array of chemicals and
conditions has been repeatedly demonstrated. Paula-Barbosa and colleagues
discovered that long-term (12 month) alcohol-feeding to rats significantly
increased formation of lipofuscin (an age-related waste pigment) in brain cells.
Giving high dose Piracetam to the alcohol-fed rats reduced their
lipofuscin levels significantly below both the control and alcohol/no Piracetam rats' levels.
Piracetam antagonized the normally lethal neuromuscular
blockade (which halts breathing) induced by mice by intravenous hemicholinium-3
(HC-3) (23), and Piracetam also blocked the lethal neuromuscular blockade
induced in cats by d-tubocurarine. (1)
Piracetam reversed learning and memory
deficits in mice caused by the anti-cholinergic substance, HC-3.
were given oxydipentonilim, a short-acting curare-like agent which halts
breathing, at a dose sufficient to kill 90% of one group and 100% of another
group of placebo-treated controls, the two groups of Piracetam-treated mice had
a 90% and 100% survival rate.
synthesis of new protein in brain cells is required for memory formation.
Piracetam has ameliorated the amnesia induced by rodents by cycloheximide,
a protein synthesis inhibitor.
is a toxic chemical that induces edema, membrane damage, and increased sodium
/decreased potassium in brain cells. (Hexachlorophene was used in shampoos,
soaps and other personal care products until about a decade ago.)
Rats were fed hexachlorophene orally for 3 weeks, then given Piracetam or
one of 5 other drugs by injection for 6 days. Hexachlorophene seriously
disrupted the rats' ability to navigate a horizontal ladder without frequently
falling off the rungs. Piracetam reduced the fall rate 75% compared to
saline-injected controls on the first day of treatment. None of the other drugs
came close to that improvement.
increases the survival rate of rats subjected to severe hypoxia. (1,25) When
mice, rats and rabbits have been put under diverse experimental hypoxic (low
oxygen) conditions, Piracetam has acted to attenuate or reverse the
hypoxia-induced amnesia and learning difficulties, while speeding up
post-hypoxic recovery time and reducing time to renormalize the EEC}. (1,2,25)
When a single 2400mg dose of Piracetam was given to humans tested under 10.5%
oxygen (equivalent to 5300m./17,000 ft. altitude), eye movement reflexes were enhanced,
while breathing rate and choice reaction time were reduced by Piracetam. (26)
convulsive shock (electro convulsive shock) is a powerful disruptor of learning
and memory. When a group of rats
were taught to avoid a dark cubicle within their cage there was 100% retention
of the learned behavior 24 hours later.
a maximal electro convulsive shock right after learning caused the
learning-retention rate to drop lo 20% 24 hours later in the control group,
while Piracetam-treated electro convulsive shock rats still had a 100% retention
of the avoidance behavior 24 hours later. (2) Other experiments with mice and
rats show Piracetam's ability to attenuate or reverse electro convulsive
shock-induced amnesia. (19.27)
given the fast acting barbiturate secobarbital, combined with Piracetam injected
1 hour before the secobarbital, 10 of 10 rabbits survived, with only minimal
abnormalities in their electroencephalograph records. The electroencephalograph
records the electrical activity of
large groups of corticol neurons, and also reflects cerebral oxygen/glucose
metabolism and blood flow. (25)
3 of 10 rabbits given) secobarbital with saline injection survived, and most of that
groups' electroencephalograph records showed rapid onset of electrical silence, followed quickly
by death. When secobarbital was given to rabbits combined with oral Piracetam, 8
survived, with only 3 of 9 saline-fed controls surviving.
The electroencephalograph records of both groups were similar to those of the rabbits given
i.v. Piracetam and saline.
the 1980s neuroscientists had discovered that brain cholinergic neural networks,
especially in the cortex and hippocampus, are intimately involved in memory and
learning. Normal and pathological
brain aging, as well as Alzheimer's-type dementia were also discovered lo
involve degeneration of both the structure and function of cholinergic nerves,
with consequent impairment of memory and learning ability.
this same period a growing body of evidence began to show that Piracetam works
in part through a multimodal cholinergic activity. Studies with both aged rats
and humans which combined Piracetam with either choline or lecithin (phosphatidyl
choline), found radically enhanced learning abilities in rats, and produced
significant improvement in memory in Alzheimer’s patients.
giving choline or lecithin alone (they are precursors for the neurotransmitter
acetylcholine) in these studies provided little or no benefit, while Piracetam alone provided only modest benefit.
research has also shown that Piracetam increases high-affinity choline uptake, a
process that occurs in cholinergic nerve endings which facilitates acetylcholine
formation. (23,29) "High-affinity choline uptake rate has been shown to be
directly coupled to the impulse flow through the cholinergic nerve endings and
it is a good indicator of acetylcholine utilization nootropic drugs (including Piracetam) activate brain cholinergic neurons"
(29) HC-3 induces both
amnesia and death through blocking high-affinity
in the brain an din peripheral nerves that control breathing.
Since Piracetam blocks HC-3 asphyxiation death and amnesia, this is
further evidence of Piracetam's pro-high-affinity
choline uptake actions. (23,29)
is a drug that blockades acetylcholine receptors and disrupts energy metabolism
in cholinergic nerves. When rats
were given Scopalamine, it prevented the learning of a passive avoidance task,
and reduced glucose utilization in key cholinergic brain areas. When rats given
Scopalamine were pretreated with 100/kg Piracetam, their learning performance
became almost identical to rats not given Scopalamine.
(36) The Piracetam treatment also reduced the Scopalamine depression of glucose-energy metabolism
in the rats' hippocampus and anterior cingulate cortex, key areas of nerve
damage and glucose metabolism reduction in Alzheimer’s disease.(36)
researchers added to the picture of Piracetam's cholinergic effects in 1988 and
1991. Treatment for 2 weeks with
high dose oral Piracetam in aged mice elevated the density of frontal cortex
acetylcholine receptors 30-40%, restoring the levels to those of healthy young
mice. A similar decline in cortex
acetylcholine receptors occurs in "normal" aging in humans.
same group of researchers then discovered that there is a serious decline in the
functional activity of acetylcholine receptors in aged mice; with many receptors
becoming "desensitized" and inactive. Oral treatment with high dose Piracetam also partially
restored the activity of acetylcholine cortex nerves, as measured by the release
of their "second messenger," inositol-1-phosphate.
acid (glutamate) is the chief excitatory neurotransmitter in the mammalian
brain. Piracetam has little affinity for glutamate (glutamate) receptors, yet it
does have various effects on glutamate neurotransmission.
One subtype of glutamate receptor is the AMPA receptor.
Micromolar amounts [levels which are achieved through oral Piracetam intake] of
Piracetam enhance the efficacy of AMPA-induced calcium influx [which
"excites" nerve cells to fire] in cerebeller [brain] cells.
Piracetam also increases the maximal density of [AMPA glutamate
receptors] in synaptic membranes from rat cortex due to the recruitment of a
subset of AMPA receptors which do not normally contribute to synaptic
Further support for involvement of the glutamate system
in Piracetam's action is provided by a Chinese study which showed that the
memory improving properties of Piracetam can be inhibited by ketamine, an NMDA
(another major subtype of glutamate receptor) channel blocker. (1) Furthermore,
high dose injected Piracetam decreases mouse brain glutamate content and the
glutamate/GABA ratio, indicating an increase in excitatory nerve activity (1)
micrornolar levels, Piracetam potentiates potassium-induced release of glutamate
from rat hippocampal nerves.
that acetylcholine and glutamate are two of the most central
"activating" neurotransmitters and the facilatory effects of
acetylcholine/glutamate neural systems on alertness, focus, attention, memory and
learning. Piracetam’s effects on acetylcholine/glutamate neurotransmission
must he presumed to play a major role in its demonstrated ability to improve
mental performance and memory. Although
Piracetam is generally reported to have minimal or no side effects, it is
interesting to note that Piracetam’s occasionally reported side effects of
anxiety, insomnia, agitation, irritability and tremor
(18) are identical to the
symptoms of excess acetylcholine/glutamate neuroactivity.
spite of the many and diverse neurological/psychological effects Piracetam has
shown in human, animal and cell studies, Piracetam is generally NOT considered
to he a significant agonist (direct activator) or inhibitor of the synaptic
action of most neurotransmitters. Thus,
major nootropic researchers Pepeu and Spignoli report that "the
pyrrolidinone derivatives [Piracetam and other racetams] show little or no
affinity for central nervous system receptors for dopamine, glutamate; serotonin,
GABA or benzodiazepine." (23)
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 [electrical activity] within specific neuronal
and colleagues note that "there exist papers giving data of bioelectric
activity as affected by Piracetam, and suggesting that it acts as a non-specific
activator of the excitability. [i.e.
brain electrical activity] thus optimizing the functional state of the
and Senning similarly state "we think that the racetams exert their effect
on some species [of molecule] present in the cell membrane of all excitable
cells, i.e. the ion carriers or ion channels and that they somehow accomplish an
increase in the excitatory (electrical) 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 [neurotransmitter-like] 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 toward stimulation." (1)
Piracetam is NOT 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 antidepressants,
amphetamines, Ritalin®, benzodiazepines (Valium), etc.
key finding on Piracetam in various studies is its ability to enhance brain
energy, especially under deficit conditions. Energy (ATP) is critical to the
brain's very survival; it typically uses 15-20% of the body's total ATP
production, while weighing only 2-3% or so of bodyweight.
Brain cells must produce all their own ATP from glucose (sugar) and
oxygen - they cannot "borrow" ATP from other cells. Branconnier has
observed that "evidence from studies of cerebral blood flow, oxygen uptake
and glucose utilization have shown that brain carbohydrate metabolism is
impaired in a variety of dementias and that the degree of reduction in brain
carbohydrate metabolism is correlated with the severity of the dementia."
(39) In a 1987 study, Grau and co-workers gave saline or Piracetam
i.v. to rats
who were also fed i.v. radioactive deoxygilicose to help measure brain
metabolism. Compared to saline controls, Piracetam rats had a 22% increase in
whole brain glucose metabolism, while the increase in 12 different brain regions
ranged from L6 to 28%.
(25) This increase in brain energy metabolism occurred
under normal oxygen conditions.
1976 Nickolson and Wolthuis discovered that Piracetam increased the activity of
adenylate kinase in rat brain. Adenylate kinase is a key energy metabolism
enzyme that converts ADP into ATP and AMP and vice versa. It comes into
play especially when low brain oxygen begins to reduce mitochondrial ATP
production. As existing ATP is used
up, ADP is formed. Under the
influence of adenylate kinase, 2ADP becomes ATP plus AMP. Thus Piracetam-activated adenylate kinase can slow down the drop in ATP in
oxygen-compromised brains. This helps explain Piracetam’s ability to prevent
abnormalities in animals subjected to hypoxia or barbiturates.
When oxygen levels return toward normal, adenylate kinase can convert AMP
into ADP, which can then be used in the reactivated mitochondria to make more
ATP. This accounts for the ability
of Piracetam to speed up recovery from hypoxia seen in animal studies.
their 1987 study with rats, Piercey and colleagues found that Piracetam could
restore scopalamine depressed energy metabolism modestly in many brain areas,
and significantly in the hippocampus and anterior cingulate cortex. (36)
has also been shown to increase synthesis and turnover of cytochrome b5, a key
component of the electron transport chain, wherein most ATP energy is produced
Piracetam also increases permeability of mitochondrial
membranes for certain intermediaries of the Krebs cycle, a further plus for
brain ATP production.
his 1989 paper on cerebral ischemia in humans, Herrschaft notes that the Herman
Federal Health Office has conducted controlled studies that indicate a
"'significant positive" effect of Piracetam (4.8 - 6gm/day) to
increase cerebral blood flow, cerebral oxygen usage metabolic rate and cerebral
glucose metabolic rate in chronic impaired human brain function - i.e.
multi-infarct dementia, senile dementia of the Alzheimer type, and
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
has shown that most people favor one hemisphere over the other, with the
dominant hemisphere being more electrically active and the non-dominant
hemisphere relatively more electrically silent, when a person is being tested or
asked to solve problems or respond to information.
The two cortical hemispheres are linked by a bundle of nerve fibers: 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.
a neurological perspective, the cerebral basis for a well-functioning mind would
he the effective, complementary, simultaneous integrated function of both
cortical hemispheres, with neither hemisphere being automatically or permanently
dominant. This in turn would
require the corpus callosum and cerebral commisure to optimize information flow
between the two hemispheres. Research has shown Piracetam to facilitate such
inter-cerebral information transfer-indeed, it's part of the definition of a
and Moyersoons reported in 1972 that Piracetam 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.
and Bures, in a complex series of experiments involving monocular (one-eye)
learning in rats, demonstrated that "Piracetarn
enhances transcommisural encoding mechanisms and some forms of inter-hemispheric
and co-workers used a technique called "dichotic listening" to verily
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 to the right ear than
the left ear. This occurs because
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 from the right cortex. Dimond's research with healthy young volunteers showed that Piracetam
significantly improved left ear word recall, indicating Piracetam increased interhemispheric transfer.
and Aihara tested the effect of aniracetam, a Piracetam analog, 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. The researchers
reported that "the present results indicate that Piracetam...increased the
amplitude of the negative wave, thereby facilitating inter-hemispheric transfer.
Thus, it is considered that the functional increase in interhemispheric
neuro-transmission by nootropic drugs may be related to the improvement of the
cognitive function [that nootropics such as Piracetam and aniracetam
notable absence of biochemical, physiological, neurological or psychological
side effects, even with high dose and/or long-term Piracetam use, is routinely
attested to in the Piracetam literature. Thus
in their 1977 review Giurgea and Salama point out: "Piracetam is devoid of
usual 'routine' pharmacologic activities [negative side effects] even in high
doses. In normal subjects no side
effects or 'doping' effects were ever observed.
Nor did Piracetam induce any sedation, tranquilization, locomotor
stimulation or psychodysleptic symptomatology." (19)
Wilshen and colleagues, in their study on 225 dyslexic children, note
that "Piracetam was well tolerated, with no serious adverse clinical or
laboratory effects reported." (12) In this particular study (as in many
others), the incidence of (mild) side effects was higher in the placebo group
than in the Piracetam group! In his
1972 8 week study on 196 patients with "senile involution" dementia,
Stegink reported that "No adverse side effects of Piracetam [2.4gm/day]
were reported." (6) In their
study of 30 patients treated for one year with 8gm Piracetam/day, Croisile and
colleagues observed that "Few side effects occurred during the course of
the study - one case of constipation in the Piracetam group.... Piracetam had no
effect on vital signs, and routine tests of renal, hepatic, and hematological
functions remained normal. No significant changes in weight, heart rate, or
blood pressure occurred...." (7)
as noted in the section on glutamate, because Piracetam is a cholinergic/glutamatergic
activator, there is the potential for symptoms related to cholinergic/glutamatergic
excess to occur, especially in those unusually sensitive to Piracetam.
Such symptoms - anxiety, insomnia, irritability, headache, agitation,
nervousness, and tremor - are occasionally reported in some people taking Piracetam.
Reducing dosage, or taking magnesium supplements
(300-500mg/day), which reduce neural activity, will frequently alleviate such
"overstimulation" effects. Persons
consuming large amounts of MSG (monosodium glutamate) and/or aspartame in their
diet should be cautious in using Piracetam, as should those who are highly
sensitive to MSG-laden food (the "Chinese restaurant syndrome").
Caffeine also potentiates Piracetam's effects, as do other nootropics
idebenone, vinpocetine, and centrophenoxine, and it may be
necessary to use Piracetam in a lower dosage range if also using any of these
drugs regularly. Those wishing to augment Piracetam's cholinergic effects may
wish to combine it with cyprodenate or centrophenoxine, which are much more
powerful acetylcholine enhancers than choline or lecithin.
complex vitamins, NADH, lipoic acid, Co
Q10, or idebenone, and magnesium will
enhance Piracetam's brain energy effects. In
the clinical literature on Piracetam, dosages have ranged from 2.4 gm/day (6,11)
up to 8gm/day (7,21), continued for years
Piracetam has a relatively short half-life in the blood, although there
is some short-term bioaccumulation in the brain. (1,22) Piracetam is therefore
usually taken 3-4 times daily. 1.6
gm, 3 times daily, or 1.2 gm 3-4 times daily is a fairly typical Piracetam dosage, although some people report noticeable improvement in memory and
cognition from just 1.2 gm twice daily.