This is a series devoted to exploring the use of cognition enhancing drugs and nutrients. Discussion will range from the scientific to the philosophical and everywhere in between. This first article serves as a brief introduction to the original nootropic, piracetam. Further articles will discuss other nootropic substances, while also exploring many of the issues brought up in this article in greater depth. Part I covers the history, uses, and “practical” information concerning piracetam, while part II will discuss piracetam’s mechanism of action.
Piracetam (also referred to as UCB-6215, 2-oxo-pyrrolidone, or 2-oxo-1-pyrrolidine acetamide; pronounced pur-AHS-uh-tam) was first synthesized in 1964 and submitted to clinical investigations in 1965 . It was first reported to inhibit central nystagmus in the rabbit, and this was followed by investigations on its use in the treatment of motion sickness, vertigo, and epilepsy in children [1-3]. Between 1968 and 1972, piracetam research skyrocketed following spinal cord fixation experiments [3-4]. During this period, it was discovered that piracetam protected against amnesia caused by both hypoxia and electroshock, enhanced acquisition of passive avoidance in rats, and normalized the EEG in animals subjected to hypoxia. By 1972, 700 papers had been published concerning piracetam [3-4]. In 1971, the year that piracetam first reached clinical practice (in France), C.E. Guirgea coined the term “nootropic” after Greek noos (mind) and tropos (turn towards) to describe the activity of piracetam and related compounds [4-6]. According to Guirgea, a nootropic should meet certain criteria. It must:
1) Enhance learning and memory
2) Enhance resistance of learned behavior to disruptive conditions
3) Protect the brain from physical and/or chemical injuries
4) “Increase the efficacy of the tonic cortical/subcortical control mechanisms”
5) Lack sedative, stimulant, and other such properties and has very few side effects and low toxicity .
However, since this initial definition was made, the term “nootropic” has in many instances become much more broad. Some sources refer to nootropics as only substances that improve memory in the absence of a cognitive deficit , any drug that is useful in the treatment of dementia , drugs that overcome natural or induced cognitive impairments , or a cognition enhancing drug that “lead[s] to a physiological activation of adaption,” in opposition to psychostimulants and analeptics . In many cases, the term seems to be used to describe only piracetam and chemically related compounds.
After the discovery of piracetam, over 1600 structurally related molecules (all containing the pyrrolidine structure) were synthesized, over 300 of which have been studied pre-clinically [6, 11]. About a dozen of these substances have been licensed or are in advanced stages of clinical development in various areas of the world (primarily Asia). This list includes aniracetam, fasoracetam, levetiracetam, nebracetam, nefiracetam, oxiracetam, and pramiracetam . Rolziracetam is also of interest. All of these compounds possess nootropic activity and none exhibit CNS toxicity .
Piracetam’s effects on learning and memory have been studied using a multitude of experimental paradigms. Cognitive enhancement from piracetam has been demonstrated in rats, mice, guinea pigs, rabbits, cats, marmosets, dogs, goldfish, and cockroaches [4, 6, 12-14]. Piracetam has inhibited the amnesic effects induced by anticholinergics (such as scopolamine), cycloheximide, hexachlorophene, barbiturates, baclofen, diazepam, alcohol, cerebral injuries, hypercapnia (excessive CO2), hypoxia, electroshock, ischemia, malnourishment, environmental impoverishment, and aging [4, 6, 8-9, 15-17]. Animal models in which piracetam has been beneficial include passive avoidance, active and conditional avoidance, object recognition, matching-to-sample, choice reaction, delayed comparison tasks, delayed alternation tasks, match-to-position tasks, social learning, win-stay water-escape tasks, the Y maze, the eight-arm radial maze, the Morris water maze, the elevated plus-maze, and tests of complex motor function (note that many of these overlap) [6-7, 11, 18-21]. Collectively, these results imply facilitation of both acquisition and retention along with both long term memory (LTM) and short term memory (STM), to name but a few. Piracetam also has effects in animal models of depression, anxiety, stress, and exploratory behavior, but we will discuss this in more depth in later articles.
While a large amount of the research on piracetam is carried out in aged or otherwise impaired animals, there has still been a considerable amount of study on healthy, normal ones. Indeed, many of these models (such as scopolamine-induced amnesia) may have little application for healthy humans, as they are primarily aimed towards screening for anti-dementia drugs. Piracetam does improve memory in normal animals, although this effect tends to be much less pronounced [8, 15, 17, 22-24]. Whether or not this carries over into healthy humans will be discussed in further detail below.
Although all of the research discussed above has been positive, there is some research indicating a piracetam-induced impairment of memory, specifically piracetam impaired reversal learning and extinction in a three-choice test . In this paradigm, rats first undergo a training phase in which they are taught to pick the correct of three boxes for a reward. Piracetam facilitates the speed at which this ability is acquired and decreases the number of errors. However, in the reversal-learning test, a different one of the three boxes is rewarded, and the speed at which the animal learns to go to that new box rather than the previous one is measured. Piracetam inhibits this process of “relearning.” During extinction, none of the boxes is rewarded. In this test, piracetam slows the rate at which animals realize that the previously rewarded box is now a waste of their time.
Although extinction is differentiated from forgetting (as amnesic agents impair, rather than facilitate extinction), piracetam’s effect may not indicate an impairment of learning in this case. Rather, the test results may indicate that piracetam is strengthening consolidation of the original memory. However, affirming this hypothesis would be very difficult. If we are to take the effects on reversal learning at face value, it would appear that piracetam may impair acquisition of a new skill if that new skill is in opposition to a previously learned skill. As mentioned above, this could only be due to increased consolidation of the original memory, rather than an impairment of acquisition, as multiple tests have demonstrated that piracetam facilitates the speed and strength of acquisition. This leads one to speculate whether any cognitive enhancer could cause improvement on the reversal learning and extinction tests. It is also noteworthy that an earlier study found piracetam to facilitate acquisition but not interfere with extinction . For further discussion on this topic, see Christoffersen et al. .
Piracetam is an approved drug in many parts of the world, for conditions including alcohol withdrawal, alcoholism, head injuries, learning disorders, vertigo, dyslexia, post-traumatic vertigo and coma, sickle-cell anemia, epilepsy, Raynaud’s disease, and Parkinson’s disease . Recent research has focused on the use of piracetam in cortical myoclonus (severe muscle spasms) . It is also commonly used to treat brain disturbances and intellectual disorders caused by tranquilizers, neuroleptics, depressants, barbiturates, electroconvulsive therapy, and agents that impair brain circulation; mild cognitive impairment (MCI); Alzheimer’s disease; intrauterine hypoxia in prematurely born infants; ischemic stroke; and aphasia [5-6, 20, 27]. A multitude of other possible benefits have also been identified, such as treatment of schizophrenia, depression, congestive heart failure, myocardial infarction, arrhythmia, hypertension, fetal alcohol syndrome, sudden deafness, neuropathic pain, viral neuroinfections, breath holding spells, burn wounds, hypoxia associated with altitude and hazardous jobs, motion sickness, bronchitis, gastric ulcers, cancer, and cerebral palsy [3, 5, 28-39]. There are also data on stress, anxiety, and depression, but like the animal research this will be discussed in a later article.
As is the case with most nootropics, the data on memory improvement in healthy humans are limited. In 1976, a double-blind study was conducted to determine if piracetam could improve verbal learning in normal volunteers. It was found that piracetam did not significantly improve verbal learning at the one-week point, but did so at the two-week point . Some studies have also been conducted in normal individuals subjected to hypoxia (oxygen deprivation). In a double-blind study with crossover design, piracetam’s effect on the concentration of 12 subjects under hypoxic conditions was determined. Piracetam did not affect the speed of the concentration test, but significantly lowered the number of errors, having a more pronounced effect during longer periods of oxygen deprivation . Other studies have found that piracetam protects against the detrimental effects of high altitudes . Some research has also been done on aging individuals without significant cognitive impairment. In a single-blind study, piracetam was associated with improvement on a number of clinical scales . In a study on driving capacity of elderly motorists, piracetam improved scores on a driving test from 77.08% to 84.16% compared to 79.86% to 80.07% with placebo (the tests were spaced six weeks apart) . Finally, piracetam has reportedly improved memory function in hypertensive patients “exposed to psychoemotional stress at work” .
When it comes to MCI and other age-related mental illnesses, there is a much greater research base. Instead of looking at individual studies, we can draw conclusions from meta-analyses and reviews. A meta-analysis conducted last year following the Cochrane Collaboration methodology found that the existing evidence suggests that piracetam has a favorable effect in many types of age-related cognitive impairments . Other reviews agree with these findings, especially in the cases of mild to moderate dementia [2-3]. Present data indicates that piracetam is as effective as cholinesterase inhibitors in the treatment of dementia [2, 45].
All in all, it appears that the effect on humans is similar to the effect on animals, with modest memory improvements seen in healthy individuals and more pronounced improvements in individuals in which memory is compromised in a variety of ways, including chemical, physical, and mental stress.
Dosage and Pharmacokinetics
Side effects resulting from piracetam are very rare (equivalent to placebo values), and serious side effects are unheard of, even at doses of 24 grams daily [6, 46]. There is one exception, which is that piracetam may worsen the symptoms of Huntington’s disease [47-48]. There are also no known significant drug interactions . Acutely, doses of 8 g/kg IV in rats and 10 g/kg orally in rats, dogs, and mice have been tested without achieving an LD50 [3-4], and rats have been treated with 1 g/kg orally for six months and dogs with 10 g/kg for one year without any signs of toxicity, teratogenicity, or behavioral tolerance . All of this makes piracetam “one of the toxicologically safest drugs ever developed” .
Piracetam is highly water soluble and stable and has no known metabolites . It is excreted primarily, but not solely, by the kidneys [6, 49]. It has an oral bioavailability of almost 100%, and maximum levels in the bloodstream are reached in 30-50 minutes, with a plasma half-life of about 4-5 hours . In contrast, CNS levels reach the maximum amount in 4-5 hours and the CNS half-life is 7.7 hours [3, 22-23]. Piracetam does not appear to accumulate in the brain [50-51], although the literature is contradictory on this point . However, chronic use seems to be more effective than acute use at enhancing memory [22, 52]. The possible reasons for this will be discussed in more detail in part II of this series.
It is important to know that the dose-response curve for piracetam, at least in the case of memory enhancement, follows an inverted U or bell shape, so higher doses are not necessarily better [5, 23, 27, 53]. In contrast, the effectiveness in treating certain ailments, such as cortical myoclonus, cerebellar ataxia, and alcohol organic mental disorder gets progressively higher with increasing dosages, with up to 60 g daily being reported [54-56]. This makes it unwise to believe that the dosages that are effective for treatment of certain conditions cross over to those for memory enhancement in healthy individuals. In rats, 300 mg/kg seems to be the most commonly used dose, in rabbits, 50-300 mg/kg is the effective range , and in chicks, 100 mg/kg displays nootropic activity whereas 300 mg/kg does not , indicating an interspecies variation in the effective dose.
The most effective dosage for healthy humans appears to be in the range of 2.4-4.8 g (equating to roughly 30-60 mg/kg in an 80 kg individual). In a study measuring Global Dimensional Complexity from an acute dose in healthy individuals, the maximal effect was seen at 2.4 g, with 9.6 g showing minimal effects and 4.8 g in between the two . However, another EEG study found the most significant effect at 4.8 g as compared to 2.4 and 9.6 g . It is worthy of note that the first study mentioned used young subjects, while the second one used older individuals. The dosage used successfully on healthy individuals was 4.8 g [40-41], but this was not compared with a different amount.
There are also a number of substances thought to enhance the activity of piracetam. The most well known is choline. The combination of piracetam and choline is reported to be synergistic when used to treat dementia ; a study in mice indicates that 50 mg/kg piracetam along with 50 mg/kg choline IP was superior to up to 1000 mg/kg of piracetam alone or up to 200 mg/kg of choline alone . Another study in rats found 100 mg/kg of both piracetam and choline to be superior to 200 mg/kg of either substance on its own . Finally, researchers found that when normally ineffective doses of piracetam and citicholine (a nootropic form of choline) were combined, retention was enhanced at both the 24-hour and the 7-day point . Other substances that piracetam has been reported to synergize with include vitamin B6 (for hypoxia), phosphatidylserine (for Alzheimer’s treatment), and hydergine [3-4, 61]. James South, MA, also hypothesizes that other B vitamins, NADH, lipoic acid, coenzyme Q10 or idebenone, and magnesium may all enhance the activity of piracetam .
Piracetam has also been studied in conjunction with stimulants such as caffeine, amphetamine, and methamphetamine. In electroshock-induced amnesia, caffeine can differentially synergize with piracetam to produce increased memory enhancement or disrupt acquisition depending on the experimental conditions, whereas no interaction was noted between piracetam and amphetamine . However, piracetam and methamphetamine had a synergistic effect in the same active avoidance paradigm . Piracetam has also been noted to decrease the amnesic effect of diazepam without interfering with the anxiolytic activity .
In conclusion, piracetam has shown to be beneficial in a variety of ways without any toxicity. The optimal dosage is 2.4-4.8 g daily, but it would be best to stay on the lower end if one is taking synergistic supplements. It is possible that use of stimulants such as caffeine will interfere with the activity of piracetam. Part II will discuss the enigmatic mechanism of action of this memory-enhancing drug.
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