Piracetam – the original nootropic
by James South MA
Piracetam (technically known as 2-oxo-pyrrolidone) was developed in the mid-1960’s by UCB pharmaceutical company of Belgium. It was originally used to treat motion sickness. (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 Piracetam. (1) 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)
According to Giurgea, nootropic drugs should have the following characteristics:
1) they 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).
5) They should ”increase the efficacy of the tonic cortical/subcortical control mechanisms.”
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. (3)
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.
Piracetam 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.)
Piracetam 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 disease. (6,7) Piracetam has improved recovery from aphasia (speech impairment) after stroke. (8) 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.” (11)
Piracetam has increased reading comprehension and accuracy in dyslexic children. (8,12) Piracetam increased memory and verbal learning in dyslexic children, as well as speed and accuracy of reading, writing and spelling. (13,14) Piracetam 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. (15,16) Piracetam has improved mental performance in “aging, nondeteriorated individuals” suffering only from “middle-aged forgetfulness.” (17) 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 activity, while simultaneously increasing vigilance, attention and memory. (17A)
Piracetam 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 experimentally. (11) 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 ever developed.
From 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. (4) 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. (23) When mice 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. (19)
Rapid 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. (1)
Hexachlorophene 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. (24)
Piracetam 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)
Electro 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.
Giving 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)
When 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)
Only 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 of 9 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. (28)
By 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. (29)
During 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. (30-35)
Yet 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.
Animal 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 choline uptake 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)
Scopalamine 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)
German 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. (37) The 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. (38)
Glutamic 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 transmission.” (1) 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)
At micrornolar levels, Piracetam potentiates potassium-induced release of glutamate from rat hippocampal nerves. (1)
Given 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.
In 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 pathways.” (23)
Grau 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 brain.” (25)
Gouliaev 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)
Thus 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.
A 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.
In 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. (40)
In 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)
Piracetam 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 in mitochondria. (22) Piracetam also increases permeability of mitochondrial membranes for certain intermediaries of the Krebs cycle, a further plus for brain ATP production. (25) In 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 pseudo-dementia. (9)
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 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.
From 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 “nootropic drug.”
Giurgea 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. (41) Buresova 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 transfer.” (42)
Dimond 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. (43)
Okuyama 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 promote].” (44)
The 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)
Yet 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. (11,18) 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 such as deprenyl, 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.
B 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 (7,21). 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.
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