We have previously discussed the properties of the prototypical nootropic drug, piracetam. Piracetam improves learning and memory and provides neuroprotection in a number of experimental models, and also appears to improve learning and memory in healthy humans, all the while being devoid of side effects and toxicity. Although the mechanism of action is not well established, there is evidence for the involvement of the glutamatergic and cholinergic systems. Corticosteroids, direct effects on ion channels, and a direct effect on membrane fluidity may also be involved. In this installment, we will discuss the nootropic drug aniracetam, which is an analogue of piracetam. Part I will discuss the research on the use of aniracetam as a nootropic, while part II will cover aniracetam’s mechanism of action.
Aniracetam (1-(p-anisoyl)-2-pyrrolidinone, Draganon, Memodrin, Sarpul/Sarple, Ampamet, Reset) was first reported as a nootropic in 1979, and this was followed by a large amount of research in both animals and humans . In 1993, aniracetam was first introduced into clinical practice . Research on aniracetam has also contributed greatly to one of the newer developments in nootropics; namely, it has lead to the creation of the ampakines, and in-depth studies into their mechanisms of action. Aniracetam is a licensed drug in both Italy and Switzerland. It was recently withdrawn in Japan after the publication of a negative study . Like piracetam, oxiracetam, and pramiracetam, aniracetam contains the pyrrolidinone nucleus, but unlike these drugs, it does not contain an acetamide group .
The nootropic properties of aniracetam have been the subject of extensive animal research. The research up until 1994 was summarized by Gouliaev and Senning . In tests categorized as “tests of learning,” aniracetam prevented or reduced the negative effects of scopolamine and hypoxia in rats and scopolamine in monkeys. In maze tests, aniracetam prevented or reduced the negative effects of scopolamine and basal forebrain lesions in rats and scopolamine and electroconvulsive shock in mice. In passive avoidance tests, aniracetam prevented or reduced the amnestic effect of bicuculline, scopolamine, clonidine, diethyldithiocarbamate, potassium ethylxanthogenate, electroconvulsive shock, and hypoxia in rats and cycloheximide and hypoxia in mice. In an active avoidance test, aniracetam reversed the amnestic effects of clonidine in rats. An experiment is also described in which aniracetam prevented the lethal effect of hemicholinium-3.
Other animal studies have found aniracetam to block the amnestic effect of 6-hydroxydopamine, ischemia, methamphetamine treatment, apomorphine, low-intensity electromagnetic fields, motion sickness, fetal alcohol syndrome, aging, and alprazolam [5-11]. In addition to the animals mentioned above, memory enhancement has been observed in gerbils and pigeons, but in the second case the improvement was not statistically significant [12-13]. Some of the tests in which aniracetam is effective are the two-lever choice reaction task, the radial maze (which tests working memory and spatial memory), the Y-maze, and object recognition (which tests episodic memory) [14-16]. In a study that compared various doses of piracetam and aniracetam, piracetam was only active in six of the nine tests used while aniracetam was active in all of them. And, aniracetam was approximately ten times as potent .
There have also been a number of studies on healthy adult or young animals, with either positive or equivocal results. Gouliaev and Senning reference studies showing aniracetam to improve learning in healthy monkeys, as well as studies showing it to improve passive avoidance, learning, and maze performance in healthy rats at dosages ranging from 30-50 mg/kg i.p. and 12.5-800 mg/kg orally . Other literature has commented on aniracetam’s ability to improve cognitive function in healthy animals .
Of particular interest is the research of Thompson et al. using patas monkeys . They found that aniracetam did not improve cognition in monkeys on a conventional test of learning, but did cause an improvement when they increased the complexity of the task. This increased the total number of errors, but also amplified the difference in performance between control and aniracetam-treated monkeys. Similarly, another study found better results could be achieved in either old rats or young/adult rats depending on the test used . This indicates that the conventional tests may often not be complex enough for aniracetam to offer a statistically significant improvement in healthy animals, which may be the reason for some of the negative results.
Aside from improving learning and memory, aniracetam has a variety of other cognitive effects in animals. Aniracetam provides a significant benefit in multiple animal models of depression and anxiety, such as the forced swim test, the reduction of submissive behavior model, the social interaction test, the elevated plus-maze, and conditioned fear stress [11, 20-21]. The forced swim test is commonly used to screen for compounds with antidepressant properties, while some of the other tests mentioned are used as indicators of compounds that may be useful for the treatment of social phobia, panic anxiety, and generalized anxiety . One study found aniracetam to be superior to piracetam in a model of depression .
Aniracetam also improves experimentally-induced deficits in attention and vigilance and improves age-related deficits in temporal regulation of behavior . It was found to increase motivation in animals, as evidenced by increased performance on a task to find food despite satiation, without differences in food intake . In stroke-prone spontaneously hypertensive rats (SHRSP), used as a model of multiple cerebral infarction, aniracetam improves REM sleep .
Aniracetam’s main use, as supported by the research, is for the treatment of mild to moderate dementia of vascular origin [12, 24-25]. Three studies have shown it to have positive effects in patients with Alzheimer’s, and it improved the condition of patients with brainstem infarction [18, 26]. Some of the studies in elderly populations are summarized by Mondadori . One six-month study found that aniracetam treatment caused improvement in all 18 parameters measured, while another study of the same duration found that it caused improvement in 17 of 18 tests, while piracetam treatment caused no change on a number of these tests. Some trials have failed to find a benefit from aniracetam treatment .
Aniracetam does not just improve scores on tests of learning and memory. It also affects many other variables. In patients with Alzheimer’s, Parkinson’s, and cerebral infarction, aniracetam reduces anxiety, depression, and the incidence of sleep disorders, and it has also been reported to improve vigilance . It is also very effective in treating post-stroke depression and sleep disorders [22, 29].
There are no studies concerning the use of aniracetam in healthy, unimpaired humans. However, one study did find it reduced the learning deficits induced by hypoxia in healthy humans . Since piracetam can improve learning and memory in healthy humans, and aniracetam is always superior to piracetam when they are compared, it is presumable that it will have a similar effect, but the degree of this effect is unknown.
Dosage and Pharmacokinetics
Compared to piracetam, there are many differences in the pharmacokinetic profile of aniracetam. After rapid absorption in the intestine, about 90% of the drug is readily metabolized . The three primary metabolites are N-anisoyl-GABA (4-p-anisaminobutyric acid), 2-pyrrolidinone, and p-anisic acid. All of these metabolites, along with aniracetam itself, have been implicated in the activity profile of the drug [2, 14, 22, 31]. In humans, about 70% is metabolized to N-anisoyl-GABA, while in rodents the main metabolite appears to be p-anisic acid. Further confusing the picture is the fact that the different metabolites have different elimination kinetics, which can vary based on dose. Additionally, 2-pyrrolidinone and p-anisic acid undergo further metabolization .
The large amount of metabolites in addition to interspecies variation can make studying this drug more difficult. What’s more, the fact that the metabolization occurs primarily on the periphery makes many of the in vitro studies less applicable. However, the multiple metabolites, and their different activity profiles, may be one of the reasons this drug has such diverse benefits.
Another of aniracetam’s interesting properties is that its effects are very short-lived. After oral administration, the onset of activity is rapid and the total duration of activity is short . In rats, peak plasma levels of aniracetam are reached 20-30 minutes after oral administration, and the half-life is 1.7-2.1 hours . In humans, the highest blood levels of the metabolites are reached two hours after administration, and this coincides with the largest changes in the EEG [32-33]. Plasma levels of the metabolites reach baseline within 6 hours, although the half-life and AUC are both significantly increased in the elderly . It has been suggested that one of the reasons aniracetam is not more widely used is because it is so short-acting .
Like piracetam, the dose-response curve for aniracetam is bell-shaped . In rodents, effective doses are usually in the 10-100 mg/kg range, while the dose of piracetam used in most rodent studies falls in the 100-600 mg/kg range . Also like piracetam, a lower dose is required in primates to exert the same effect. The commonly recommended dose for clinical use is 1500 mg daily . A study comparing oral administration of 12.5, 25, and 50 mg/kg to monkeys found that all of the doses improved performance on a match-to-sample task, but the greatest effect was found at 25 mg/kg . In a study in the elderly, 1000 mg exerted greater EEG changes than 250 and 500 mg, as well as 2000 mg of piracetam . The commonly recommended dose for nootropic use is 750-1500 mg, and this information supports that dosage range. Because of the short duration of activity, it would be ideal to take aniracetam multiple times during the day.
Like other nootropics, aniracetam is very safe, although it may be slightly more toxic than piracetam. The LD50 is 4.5 g/kg orally in rats and 5.0 g/kg orally in mice ; for an 80 kg human, this would equate to over 500 times the standard dose of 1.5 g. Animal studies have not found evidence of toxic effects in normal animals, no teratogenic effects have been found, and aniracetam does not influence food intake in rodents [1, 3, 24]. Monkeys do not self-administer aniracetam, and after 31 days of daily dosing, no physical or behavioral withdrawal symptoms are observed upon discontinuation .
No drug interactions are known and there are no reported cases of overdose. It is recommended that those with renal insufficiency lower their dose however . In human trials, side effects are rare, but some have been reported, such as insomnia and anxiety. These side effects disappear if the doses are restricted to earlier in the day , indicating that they are due to aniracetam’s stimulating effect.
One potential problem with aniracetam that has been discussed is excitotoxicity. In an animal model of multiple sclerosis, aniracetam increased the onset and duration of symptoms, and this has been presumed to be due to the effects of aniracetam on AMPA transmission, since AMPA antagonists are therapeutic in this condition. However, the effect of aniracetam in worsening this condition was referred to as “slight” . Aniracetam has not been found to induce seizures. In fact it has slight antiepileptic action , but it is possible that it may interfere with some antiepileptic drugs.
Other literature contradicts the notion that aniracetam could cause or worsen excitotoxicity. For example, Thompson et al.  comment:
Drugs that increase glutamatergic transmission may produce behavioral adverse effects even at pharmacologically active doses; for example, exaggerated increase in sensory motor responses and seizures. In this respect, aniracetam, presumably because it is an allosteric modulator with a relatively low intrinsic activity at AMPA-sensitive glutamate receptors, does not disrupt the physiological oscillation of glutamatergic transmission. It also differs from direct AMPA receptor agonists such as kainate in that it fails to produce changes in the complex behavioral processes or any other gross behavioral abnormalities triggered by a persistent receptor stimulation achieved by administering kainate.
This is in line with the bulk of the experimental data on aniracetam, as well as the research on other positive allosteric AMPA modulators. Multiple studies indicate that aniracetam protects against excitotoxicity [3, 12, 36-37], and it also has other neuroprotective effects, such as reducing free radical formation and improving glucose metabolism [38-39]. During conditions of neuronal injury, aniracetam may facilitate the release of inhibitory neurotransmitters . Other compensatory mechanisms may be involved.
This question has not been fully answered, but the bulk of the evidence indicates that aniracetam is unlikely to contribute to excitotoxicity, and if it does, the effect would be very small. Still, it would be a good idea to avoid taking it if one is being treated for epilepsy. This issue will be discussed further in part II, in which the effects of aniracetam on glutamatergic transmission, and the corresponding changes that occur throughout the brain, will be covered in detail.
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