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Piracetam (2-oxo-1-pyrrolidine acetamide) is the most well-known nootropic agent. The word nootropic comes from Greek noos (mind) and tropein (towards), and refers to a class of drugs which have common properties including enhancement of learning and memory, enhancement of the resistance of the brain towards chemical and physical injuries, and a general lack of stimulant or sedative properties or other side effects. Piracetam was the first compound discovered to have all of these properties, and became the prototypical nootropic which serves as the reference drug for newer nootropics. Although the definition and requirements are a common topic of debate, a drug is generally considered a nootropic only if it improves memory in the absence of a cognitive deficit [7]. In clinical practice, nootropics are commonly used to treat brain distrubances caused by various chemical and physical agents, for the treatment of dementia and mild cognitive impairment, and as cerebroprotective agents in stroke [3].
Piracetam was first synthesized in 1961 and then submitted to clinical investigations in 1965 [2]. Early uses were in the treatment of motion sickness, vertigo, nystagmus, and childhood epilepsy [32]. From 1968-1971, effects on memory were discovered in spinal cord fixation experiments, research on hypoxia-induced and electroshock-induced amnesia, and passive avoidance experiments in rats [26, 29]. It first reached clinical practice in France in 1971, and by 1972, 700 papers had been published on piracetam [4, 16]. Since that point, piracetam has become licensed in many countries, and is approved in the treatment of alcohol withdrawal, alcoholism, head injury, learning disorders, dyslexia, post-traumatic vertigo and coma, sickle-cell anemia, epilepsy, Raynaud's disease, Parkinson's disease, and others [4].
The discovery of piracetam also lead to the synthesis of a number of structurally related compounds with similar pharmacological profiles [1]. Piracetam is very similar in molecular structure to the amino acid pyroglutamate; they have the same base chemical structure (2-oxo-pyrrolidine), but differ by the side chain [16]. About 1600 pyrrolidones have been synthesized, more than 300 of which have been taken to preclinical studies or further by more than 10 pharmaceutical companies, and about a dozen of which are either licensed or at an advanced stage of clinical development [4]. Licensed nootropics other than piracetam include aniracetam, fasoracetam, levetiracetam, nebracetam, nefiracetam, oxiracetam, and pramiracetam [4]. Many of these compounds have memory enhancing properties similar to those of piracetam.
Mechanism of action
Although much progress has been made in understanding the mechanism of action of piracetam since the early research, a unifying hypothesis has yet to receive widespread acceptance [1]. Piracetam has no specific action at GABA receptor sites, on dopaminergic, serotenergic, adrenergic transmission, or any other known receptor, enzyme, or transporter system, with the exception of weak interaction at L-glutamate binding sites [4, 5]. A multitude of biochemical effects have been observed in many systems after piracetam administration, but these are rarely consistent between experiments. Many different mechanisms have been suggested, but this is only further evidence that an exact mechanism is still not well established in the scientific community [25].
One of the hypothesized mechanisms of action is an increase in neuronal membrane fluidity. Unlike the other proposals, this model would explain the numerous effects observed after piracetam administration. Increased neuronal membrane fluidity has been observed in vivo in animals and in vitro in mouse, rat, and human tissue [23]. In 1995, Peuvot et al. explained how piracetam interacts with neuronal membranes:
"Piracetam molecules, by surrounding the polar heads, modify the shape of the phospholipids complexed with the drug. An interface curvature is induced by the piracetam molecules inserted between the phospholipids, preferentially at the level of the polar headgroups. The phospholipid-piracetam complexes adopt a more conical shape." [28]There is also a large amount of experimental evidence which is in good agreement with the hypothesis that the effects of piracetam are due to increased membrane fluidity. Reduced membrane fluidity is responsible for many functional alterations associated with aging, and increasing membrane fluidity has repeatedly been shown to correct these deficits [13, 23]. Increased membrane fluidity would explain the improvement in membrane-bound functions after piracetam administration, including secondary messenger activity, ATP production and neurotransmission [15]. In aged rodents, it has been observed that piracetam increases muscarinic, NMDA, and AMPA receptor density [3, 14], and a smaller increase in muscarinic receptor density has also been observed in young rats [29]. Experimental evidence indicates that this increase in receptor density is most likely due to an increase in neuronal membrane fluidity [14].
The piracetam-induced increase in neuronal membrane fluidity is also dependent on the functional status of the brain. Although it does increase membrane fluidity in young, healthy animals, the effect is much more pronounced in older animals or animals that are impaired due to physical injury, chemicals, or stress [13, 23, 29]. This is a different case than with other, nonspecific membrane fluidizing agents [23], and may very well be the source of piracetam's low toxicity – it brings membrane fluidity to the optimal level, rather than just causing a nonspecific increase.
Animal research
Extensive animal research has been conducted with piracetam. Piracetam has been found to have nootropic effects in all animals tested, including mice, rats, guinea pigs, rabbits, cats, dogs, marmosets, monkeys, goldfish, and cockroaches [4, 16, 34, 41, 46]. There are a number of experimental models which measure memory ability and cognitive function. Piracetam has improved performance in a variety of models, such as tests of spatial learning, complex motor skills, social learning, object recognition, active avoidance, and passive avoidance [4, 8, 26]. Most studies have focused on long-term memory, but improvements in short-term memory have also been demonstrated [20].
Although most of the research has used animals that are impaired in some way, studies have also been conducted using normal, unimpaired animals, and memory is still improved [13, 21, 27, 31]. In a test of active avoidance performance, piracetam improved memory in both young and old rats, although there was a larger effect in the old rats [14]. In another study in young rats using a three-choice task, rats treated with piracetam had an error rate 29% lower than that of control rats [20]. Another study in mice found that piracetam improved retention of a passive avoidance task when tested 24 hours later [21]. Finally, piracetam improves memory in healthy animals even after circumstances that produce weak learning (in other words, a situation which few animals remember) [22].
In addition to improving memory in healthy animals, piracetam improves memory in animals subjected to a variety of chemical and physical insults which normally cause amnesia. These include electroshock treatment, cerebral injury, hypoxia, hypercapnia (excessive CO2), undernutrition, environmental impoverishment, anticholinergics (such as scopolamine), cycloheximide, sodium nitrite, ethanol, barbiturates, and other amnestic agents [4, 7, 9, 13, 31, 50]. Animal research has also found piracetam to have other beneficial effects in the brain, such as improved cerebral circulation, increased glucose utilization, and decreased buildup of lipofuscin pigment [4, 29, 53].
Human research
As with other animals, piracetam is more effective in humans in situations of impaired cognition [29]. The focus of piracetam research in humans has been in the elderly. Trials have found it to improve cognition in patients with Alzheimer's, Parkinson's, and age-related cognitive impairment [16, 20, 29]. However, there have also been quite a few studies done in unimpaired or mildly impaired humans, and results have been uniformly positive.
In one study, normal volunteers were given 4.8 g of piracetam daily. Each subject learned a series of words to assess verbal learning abilities. There was no significant effect after 7 days of treatment, but after 14 days subjects had a statistically significant increase in verbal learning ability [24]. An early Russian study also found that piracetam improved mental performance in "hypertensive patients exposed to psychoemotional stress at work" [54]. In another study, when healthy subjects were exposed to hypoxia, piracetam caused less errors on a test of concentration, with a more pronounced effect after longer periods of exposure [36].
Studies have also been conducted in elderly individuals without cognitive impairment. In a double-blind cross-over study on 18 aged individuals, four weeks of piracetam administration increased performance on perceptual motor tasks [18]. In a similar vein, a study with 101 elderly motorists found 4.8 g of piracetam for six weeks to cause a significant increase in driving ability compared to placebo [58].
Other uses
In addition to improving learning and memory, piracetam has been used to treat a multitude of conditions. It has been successfully used to treat alcoholism and alcohol withdrawal syndrome in both animals and humans [16]. It both reduces seizure susceptibility and mental impairment during alcohol withdrawal, and also helps prevent alcohol-induced lipofuscin pigment buildup in rats [16, 45, 51]. Piracetam also shows benefit in animal models of both anxiety and depression [2, 57], and has antifatigue and antistress properties similar to those of ginseng in mice [39]. When combined with anti-epileptic drugs in humans, piracetam potentiates their anticonvulsant action while simultaneously eliminating the cognitive deficits induced by them [16]. Piracetam is highly effective at treating cortical myoclonus (severe muscle spasms) and Raynaud's syndrome (severe vasospasm in the hands and/or feet) [5, 16]. In children, piracetam has been used to treat breath holding spells, epilepsy, and dyslexia [16, 42]. In dyslexic children, piracetam improved memory, verbal learning, and speed and accuracy of reading and writing [16]. Piracetam improves the degree and speed of recovery from post-stroke aphasia (speech impairment) [6, 16]; this may indicate that piracetam facilitates the transference of abilities from one brain region to another. Piracetam has also restored various functions such as use of limbs and speech in those suffering from cerebral ischemia, as well as reducing the severity and occurence of symptoms of post-concussional syndrome [16]. In animals, piracetam markedly improves the survival rate after exposure to barbiturates [16]. It also improves the survival rate after severe hypoxia, as well as speeding renormalization of the EEC; piracetam has also been shown to increase high-altitude resistance [16, 29, 48]. Other conditions that piracetam has been successfully used to treat include motion sickness, vertigo, schizophrenia, viral neuroinfections, cerebral palsy, and sudden deafness [10, 16, 29-30, 38, 44].
Piracetam also has been used to treat some conditions of peripheral origin; this could be due to altered membrane kinetics, antihypoxic effects, or an increase in general resistance to stress. Piracetam has an antiarrhythmic effect, and along with vitamin E, improved exercise tolerance in patients with ischemic heart disease [43, 56]. It has also been used to treat sickle cell anemia in many instances [49]. Piracetam accelerates wound healing and reduces infections after thermal burns [19]. Some animal studies indicate that it has anticarcinogenic effects [35, 47]. Finally, piracetam had significant anti-ulcerogenic activity against stress- and asprin-induced gastric ulcers in rats [55]. Note that this is only a sample of the literature, and piracetam has a variety of other demonstrated benefits.
Dosage & safety
Piracetam is one of the safest drugs in existence. The literature reports no significant drug interactions, side effects, or serious idiosyncratic side effects [4]. These include measures of changes in heart rate and blood pressure, effects on other vital signs, tests of renal, hepatic, and hematological functions, and signs of sedation, tranquilization, locomotor stimulation, and psychodysleptic symptomatology [16]. In fact, in some trials, reports of side effects are higher in the placebo group than in the treated group [16]. In animal studies, rats have been given 1 g/kg orally for six months and 8 g/kg IV acutely, rats and mice have been given 10 g/kg orally, and dogs have been given 10 g/kg orally for one year; in all of these instances piracetam has been nontoxic [16, 29].
The oral bioavailability of piracetam is almost 100%, and it has no metabolites [22]. Peak blood concentrations are reached in 30-50 minutes, but the maximal CNS effect is at about 6 hours after administration; similarly, the plasma half-life is 5 hours and the CNS half life is about 8 hours [4, 22]. The drug is completely eliminated 30 hours after administration [29].
The dosage curve for memory improvement from piracetam is bell-shaped [3]. Two human studies have been conducted on the EEG effect of acute dosing of 2.4, 4.8, or 9.6 grams, and the maximal effect was found at 2.4 g in one and 4.8 g in the other [11]. This would indicate that the ideal dose for memory improvement in healthy individuals is 2.4-4.8 g daily (spread out over 3-4 doses), and this is in line with the clinical data. For the treatment of some conditions, such as myoclonus and alcohol withdrawal, much larger doses are used – up to 24-32 g daily in some cases [4, 17, 51]. There is even a report of 60 g daily being used to treat cerebellar ataxia [33].
There are a few nootropic substances with which piracetam is synergistic. Piracetam is potently synergistic with both citicholine and choline [9, 37, 40, 52]. In experiments on mice, piracetam is reported to be synergistic with hydergine in improving learning and memory [12]. One study also found that vitamin B6 increased the antihypoxic effect of piracetam [29].
In conclusion, piracetam is a safe and effective memory enhancing agent. It may also confer other benefits, such as neuroprotection, relief of anxiety and/or depression, reduced stress and fatigue, increased vigilance, improved fine motor skills, and many others. Combining piracetam with other nootropics may have even further benefits.
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