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Aniracetam: A Comprehensive Yet Easy Reading Review
Dr. Michael P. Ludwig
1-[(4-methoxybenzoyl)]-2-pyrrolidinone
Aniracetam
Disclaimer: Nothing presented in this article is to be construed as constituting
**** medical advice or pharmaceutical consultation. This article is intended purely ****
as general knowledge and entertainment
ABSTRACT
As the purpose of this review article is to provide a general background and hopefully generate interest
in aniracetam and other nootropics, many topics will be touched upon. Positive allosteric AMPA
receptor modulation and long-term potentiation will be discussed as possible mechanisms of memory
enhancement. The hippocampus being a major memory center will be touched upon. Studies, both
human and animal, delving into aniracetam's effects on visual enhancement, anxiolysis, anti-depression
in the elderly, increased tolerance to alcohol and lastly aniracetam's effects on sleep deprevation will be
covered and analyzed. A description of physical properties of the compound and its dosing will be
covered before finishing with this author's conclusion regarding aniracetam.
INTRODUCTION
When presented with the opportunity to possibly increase one's memory and general cognition, reduce
anxiety without the common side effect of sedation, enhance one's vision, and reduce the symptoms of
depression all from one supplement with a proven safety record, would one make the decision to take
such a supplement? The purpose of this article is to provide the reader with enough information to
make that decision. The focus of this article is on the supplement aniracetam, although there will also
be some basic background information concerning the racetam class of drugs, as well as some
background and definition on the word “nootropic”itself.
When one thinks of racetams, well those who do think of racetams, they usually think first of
piracetam. This is expected, as it is the prototypical racetam; it is the drug that defined the class. Since
piracetam was first synthesized in 1964 by Dr. Corneliu Giurgea⁽²⁷⁾, the class has since grown to
include more than 25 unique compounds. Only one, levetiracetam, is approved by the FDA for human
use in the United States⁽²⁾, however several other members of the class have been approved in Europe
and Russia for human use for many years. Over those years they have built a reputation of safety and
efficacy in the individuals for which they are approved. One such drug, that is available by prescription
overseas, but is sold as a supplement in the United States, is aniracetam.
Aniracetam is commonly quoted around the internet as being first synthesized in the 1970's shortly
after piracetam, however the earliest issued patent for the synthesis of the compound dates to July 14th
1982, however it claims priority to an earlier patent application dating to February 10th 1978⁽²⁾. The
compound was invented by Emilio Kyburz and Werner Aschwanden, and owned via assignment by
Hoffmann-La Roche. This first patent for aniracetam was a European patent, however the Patent
Cooperation Treaty would have extended its protection to the United States. The first aniracetam patent
filed in the United States was issued on January 18th 1983⁽³⁾. It was also invented by Emilio Kyburz
and Werner Aschwanden, and owned via assignment by Hoffmann-La Roche. Since then, 183 various
utility patents have been issued for aniracetam⁽²⁴⁾.
In Europe and Russia, aniracetam is usually sold under the brand name Ampamet™, but may also be
sold under the brand names Draganon™, Sarpul™, and Memodrin™⁽²³⁾. In the United States,
aniracetam is not currently sold under any official brand names as it is not FDA approved. It is usually
sold as a supplement marked simply as generic aniracetam. Some nootropic vendors will assign a
pseudo brand name to their aniracetam such as “Neuro Wave” though this is not an official brand name.
Why would one want to take aniracetam? That is a good question. Aniracetam exhibits a multitude of
positive, efficacious effects, with little to no adverse reactions or side effects. These attributes are what
classifies aniracetam as a nootropic drug. Miriam-Webster dictionary defines nootropic as a substance
that enhances cognition and enhances memory and facilitates learning⁽¹⁵⁾. However, Dr Corneliu
Giurgea, who originally defined the word nootropic, stated that among a few other requirements the
drugs must exhibit few side effects and low toxicity⁽⁷⁾. Giurgea's definition is still the generally
accepted definition of the word nootropic as his added requirements are what separate nootropics from
general cognitive enhancers. Aniracetam fits all the requirements of Giurgea's definition and is thus a
true nootropic.
MECHANISM OF ACTION
Before getting into the actual effects of aniracetam, it will be beneficial to first provide an
understanding of what the drug actually does in the brain that ultimately results in its various effects.
This is referred to as the drug's mechanism of action, commonly abbreviated to MOA. Aniracetam does
not exert its effects on its own. When taken orally, aniracetam is rapidly broken down through the
process of first pass metabolism. Roughly 10% of the aniracetam dose survives this process; the rest is
metabolized into various metabolites. Of these metabolites, 2-pyyrolidinone and N-anisoyl-GABA are
two active metabolites that will be focused on here. Aniracetam and its active metabolites have a
multitude of effects on various receptors in the brain which will be briefly touched upon, however due
to the scope of this article, positive modulation of AMPA receptors will be the the primary focus. This
MOA will be focused upon, because it is an interesting, relatively well understood mechanism that
many drugs exhibit to a certain degree; among the drugs exhibiting this MOA are aniracetam itself and
the active metabolite 2-pyyrolidinone⁽²⁹⁾. Getting into positive modulation of AMPA receptors, the
brain heavily utilizes two main chemicals to result in either inhibition or excitation in various, and
selective sites. The main inhibitory chemical is GABA while the main excitatory chemical is glutamate.
Glutamate acts on three subsets of ionotropic receptors: NMDA, Kainate, and AMPA. Aniracetam and
2-pyyrolidinone act on the AMPA glutamate receptor, but do not directly activate it. This is where the
term “positive modulation” comes in. When glutamate binds to an AMPA receptor in the presence of
aniracetam or 2-pyyrolidinone, the AMPA receptor remains sensitized for a longer period than had
glutamate bound to the receptor alone without the presence of aniracetam or 2-pyyrolidinone. This
MOA allows for a controlled increase in the excitation caused by glutamate⁽⁹⁾. Drugs that bind directly
to glutamate receptors and activate them all on their own are referred to as “direct agonists.” Glutamate
agonists, especially ones that bind to NMDA receptors, can result in a toxic condition known as
excitotoxicity⁽¹⁴⁾. This is generally not seen with positive AMPA receptor modulators due to the more
controlled increase in glutamanergic excitation as well as a special function of one of the AMPA
receptor's subunits, GluR2, which intrinsically protects against exitotoxity. The other well known active
metabolite of aniracetam, N-anisoyl-GABA, exerts its effect on the metabotropic glutamate receptor 2,
mGluR2, which is usually found presynaptically⁽³⁰⁾. Being presynaptic means it tends to act in a
negative feedback role. It realizes when there is enough glutamate floating around and say "Hey guys
that's enough." This results in a decrease of glutamanergic activity. This helps prevent exitotoxicity and
may be where the anxiolytic effects of aniracetam arise from. N-anisoyl-GABA also indirectly
increases levels of dopamine and serotonin in the prefrontal cortex. It seems to do this via interaction
with nicotinic acetylcholine, nACh, receptors. When N-anisoly-GABA acts on nACh receptors in the
Ventral Tegmental Area, a specific brain area heavily associated with dopamine, dopamine levels in the
prefrontal cortex increase. When N-anisoyl-GABA acts on nACh receptors in the Dorsal Raphe
Nucleus, a specific brain area associated with serotonin, serotonin levels in the prefrontal cortex
increase⁽³¹⁾. Even with all the mechanisms discussed above, there are still more that are beyond the
scope of this article, and there are probably other mechanisms not yet discovered. Though this author
focused on positive AMPA modulation, the effects of aniracetam are likely a result of many combined
mechanisms with no single, clear MOA.
MEMORY ENHANCEMENT
Like most popular racetams, aniracetam is usually recognized for its memory enhancing effects.
Elderly patients experiencing dementia have been shown to respond better to treatment with aniracetam
than to treatment with acetylcholinesterase inhibitors which are currently the gold standard for
treatment of dementia and Alzheimer’s disease⁽⁴⁾. Studies have shown aniracetam to increase working
memory and spacial awareness in mice exhibiting preexisting cognitive deficit either through the
administering of drugs known to cause cognitive decline, or through selective, biotechnological
breeding⁽⁵⁾. There is no doubt that aniracetam exhibits positive memory enhancing effects in both
animal models and human models with preexisting cognitive deficit. The question now is, does it
produce the same effects on healthy subjects? If aniracetam has the ability to bring cognitively
impaired subjects either back to or close to baseline, then one might logically infer that an average, non
cognitively impaired subject could possibly be brought above baseline, and thus experience a cognitive
enhancing nootropic experience.
To this day, no trials have been able to show conclusively whether aniracetam has the ability to increase
memory and spacial awareness in subjects not experiencing preexisting cognitive deficit. This may
sound disappointing, but it is not necessarily the case. Despite the lack of clinical research data
supporting the use of aniracetam as a memory enhancer in healthy individuals, there are countless
anecdotal reports across nootropic forums of individuals taking aniracetam as a supplement and self
reporting noticeable increases in working memory and recall. A common theme among these anecdotal
reports is the ability to recall memories long since forgotten. While a good portion of this could be
attributed to the placebo effect, this author believes that aniracetam does produce increased memory
recall in healthy individuals. The trials that failed to show efficacy in healthy individuals all looked at
working memory, not recall. Between the anecdotal reports and the drug's established safety record,
aniracetam can still be considered a viable nootropic.
So how exactly does aniracetam's positive modulation of AMPA receptors effect memory? To
understand this, we first have to understand the concept of long-term potentiation. When neurons talk
to one another, they do so with different intensities. Some are able to whisper and get their point across
while other have to yell and still might not be heard. The process of two neurons gaining the ability to
communicate more efficiently, so that they can whisper as opposed to yell happens through the process
of long-term potentiation. Over time, long-term potentiation leads to the strengthening of neuronal
circuits which is believed to be the mechanism of memory creation. Long-term potentiation happens in
various parts of the brain, but the part of the brain that is usually focused upon in terms of memories is
the hippocampus⁽⁴⁾⁽¹³⁾⁽⁸⁾ . Long-term potentiation itself is thought to be influenced mostly by glutamate
acting on NMDA receptors, so what does this have to do with aniracetam whose effects are on AMPA
receptors and not NMDA receptors? Long-term potentiation of NMDA receptors is thought to causes a
downstream potentiation or strengthening of AMPA receptors. When aniracetam positively modulates
AMPA receptors in the hippocampus, and possibly other parts of the brain its effect seem to mimic that
of long-term potentiation, and thus enhancement of memory⁽⁸⁾. See Figure (A) below for a better
understanding of the hippocampus and were it exists in respect to the rest the brain.
Figure (A) The Exposed Brain. (see citation in the lower right corner of illustration)
The hippocampus, highlighted in purple, normally sits under the temporal lobe of the cerebral cortex.
For the sake of clarity, the left temporal lobe has be left out of this illustration, so as to provide easy
viewing of the hippocampus. The hippocampus is composed of two individual hippocampi, one located
in each hemisphere of the brain. Fairly small and vaguely resembling the shape of a seahorse, the
hippocampus is thought to play an important role in memory consolidation. Aniracetam's enhancement
of long-term potentiation in the hippocampus may play a major role in its memory enhancing effects.
VISUAL ENHANCEMENT
Aniracetam possesses many positive effects other than memory enhancement. Many users report a
brightening of colors which some describe as intense. There are many drugs that can cause brightening
of colors, however they are also usually accompanied by psychedelic effects. Aniracetam has the ability
to drastically increase color brightness and saturation without any psychedelic effects. Studies show
that aniracetam's positive modulation of retinal AMPA receptors is the likely cause of the effect⁽¹⁶⁾.
Retinal AMPA receptors seem to play a part in a phenomenon know as Retinal Spreading Depression.
The purpose of Retinal Spreading Depression is thought to control the circadian rhythm through either
release or suppression of melatonin⁽¹º⁾. Two studies conflicted over whether aniracetam's positive
modulation of the retinal AMPA receptor lead to a Retinal Spreading Depression⁽¹⁰⁾⁽¹⁶⁾. Either way,
aniracetam's positive modulatory effect on retinal AMPA receptors does lead to an increase in
brightness, saturation, and intensity of color. Having the world appear brighter and thus more
interesting could be a possible treatment modality, either as mono-therapy, or add-on therapy for
patients experiencing depression and/or anhedonia. This writer personally experienced, after taking
aniracetam, the ability to look up at the sky and for the first time appreciate how beautiful the clouds
are. This was no placebo effect, as this writer was not aware of aniracetam's effects on retinal AMPA
receptors at the time.
ANTI-ANXIETY EFFECTS
Another possible benefit of aniracetam is anxiolysis, or the quelling of anxiety. It has been known since
the early 1990's that aniracetam provides anxiolysis in patients suffering from cerebrovascular
disorders such as post-stroke⁽²²⁾. It wasn't until 2001 that a study proved that aniracetam was
efficacious in relieving anxiety in healthy mice⁽¹⁹⁾. The study utilized various antagonists, chemicals
that block aniracetam's effects at specific receptors, to determine the MOA of aniracetam's anxiolytic
properties. Unlike aniracetam's effects on memory and sight, the study determined that the anxiolytic
properties were not due to positive AMPA modulation. The study introduced three antagonists:
haloperidol which acts to block aniracetam's effects on dopamine D2 receptors, mecamylamine which
acts to block aniracetam's effects on nicotinic acetylcholine receptors, and ketanserin which acts to
block aniracetam's effects on serotonin 5-HT2a receptors. All three antagonists blocked the anxiolytic
effect of aniracetam. Mecamylamine and ketanserin blocked the anxiolytic effect strongly, though not
completely. Haloperidol blocked the anxiolytic effects completely. These results suggest that the MOA
of aniracetam's anxiolytic effect is mediated via its interaction with dopamine, acetylcholine, and
serotonin, with interaction with dopamine being the main mechanism, though the total anxiolytic effect
is most likely a result of a synergistic effect on all three systems. To this day there are no clinical
studies proving anxiolytic effects in humans, though many people who have taken aniracetam have
reported experiencing a non-drowsy anxiolysis.
ANTIDEPRESSANT EFFECTS
Users have anecdotally reported antidepressant effects after taking aniracetam. The antidepressant
effect of aniracetam has been clinically proven in an animal model⁽²⁰⁾. A study in 2001 has shown
statistically significant antidepressant effects in aged rats, though the study failed to show
antidepressant effects in young rats. The authors attributed the antidepressant effects in aged rats to
aniracetam's enhancement of cholinergic and dopaminergic nerurotransmission. The authors also
suggested that the antidepressant effect was not due to aniracetam alone, but also to two of its active
metabolites, N-anisoyl-GABA and 2-pyrrolidinone. The results of the study suggest that aniracetam
could be a viable treatment option for treating depression in the elderly.
EFFECTS ON SLEEP DEPRIVATION
There are times when one may be forced to function on little or no sleep. Those that have experienced
sleep deprivation can attest , that the longer they go without sleep, the more their cognitive abilities
suffer. There are most likely a number of neurotransmitter and neuromodulator systems taking part in
this effect, but for now, to keep things on topic, let us examine the effects of glutamate and AMPA
receptors on sleep deprivation. It Is believed, during periods of sleep deprivation, AMPA receptors
become less sensitive to glutamate⁽⁶⁾. A study that put rats through 96 hour periods of sleep
deprivation, had them complete complex tests and then ultimately removed their brains to perform a
more intimate experiment, noticed a significant decrease of glutamate binding to AMPA receptors. This
was noticed in a few parts of the brain, but most noticeably in the hippocampus. Rats in the group that
had been pre-treated with 100mg/kg of aniracetam did not receive the cognitive disabilities experienced
by rats in the in the groups that received 50mg/kg or 25mg/kg or aniracetam, nor did they experience
the cognitive disabilities seen in rats in the control group as well as rats in the group that received the
negative allosteric AMPA modulator GYKI 52466⁽⁶⁾. The results of this study indicate that decreased
binding of glutamate to AMPA receptors in the hippocampus is a possible mechanism for the cognitive
decline experienced after sleep deprivation. It is interesting to point out though that the dose of
aniracetam necessary to prevent sleep deprivation induced cognitive decline in incredibly high.
Considering the average person weighs roughly in the range of 70-80kg, one would be looking at an
aniracetam dose in the range of 7000mg-8000mg which is way above the recommended daily dose.
One would have to keep in mind, though, that due to differences in the way that rats and humans
metabolize drugs, the doses wouldn't actually be that high, but they would definitely be higher than
normal recommended doses. Let us just say it would be a dose this author would not feel comfortable
recommending. Despite aniracetam's safety record, there are times when one must pull in the reins and
error on the side of precaution.
ANIRACETAM'S EFFECTS ON ALCOHOL TOLERANCE
May users of aniracetam have, for a long time, noted a self reported increase in alcohol tolerance while
taking aniracetam. Basically, they could drink much more before achieving intoxication. At this point,
one might take this as nothing more than some anecdotal reports used as an excuse to drink more, but
in 2009 a study was done that determined that pretreatment with aniracetam at either 10mg/kg,
15mg/kg, or 22.5mg/kg resulted in rats developing a rapid tolerance to ethanol⁽²⁶⁾. It is currently
unknown why this happens, but one can suggest perhaps tolerance to ethanol is, at least partially, a
learned process. If learning involves long-term potentiation, then one can draw the logical conclusion
that aniracetam may may increase the rate and sensitivity at which long-term potentiation creates the
neuronal circuits responsible for the learned process of ethanol tolerance. As a precaution, this writer
highly recommends not taking a large dose of aniracetam for the purpose of going out to drink. One
may not feel as drunk, but they still may be causing neuronal damage, as well as possible liver damage,
and most likely setting themselves up for a bad hangover.
PHYSICAL PROPERTIES AND DOSING
Aniracetam differs from piracetam not only in its subjective effects, but also in its physical properties.
While piracetam is water soluble, aniracetam is fat soluble⁽¹²⁾. Taking aniracetam along with a source
of fat may help its absorption. If the reader also takes fish oil capsules, they may want to take them
together. A larger implication of aniracetam's fat solubility, or lipophilicity, is that it is able to
conveniently cross the blood brain barrier allowing more of the drug to reach the brain. This is a
possible reason for aniracetam's increased potency compared to piracetam. The average dose of
aniracetam as a supplement is 750mg twice daily⁽¹⁾; for comparison, the average dose of piracetam is
800mg three times daily or 1200mg twice daily⁽²⁾, though many individuals take doses much higher.
The manufacture of Ampamet™ recommends that patients with kidney failure (creatinine clearance
<10 mL/min) cut the daily dose in half⁽¹⁾. This author tends to be more conservative and would
recommend patients with kidney failure not take aniracetam. The half-life of aniracetam, the time it
takes the body to get rid of half the dose, is 35 minutes⁽¹²⁾. Normally with a half-life this short, dosing
more than twice daily is required, though aniracetam seems to have active metabolites, 2-pyrrolidinone,
p-anisic acid and N-anisoyl-GABA, that provide continued effects after the parent drug has already
been eliminated⁽¹²⁾.
POSSIBLE SIDE EFFECTS
Giurgea's original definition of the word “nootropic” specified that the drug must exhibit few side
effects and low toxicity. Aniracetam fits Giurgea's definition as it does exhibit few side effects. Some
users anecdotally report a mild headache that goes away with choline supplementation. For subjects
who do experience headache, 500mg of choline a day seems to be sufficient for prevention. The
choline can either be sourced through supplementation or diet; eating a few eggs every morning is a
good way to get a head start on staying on top of one's daily choline requirement. Some users report
agitation, anxiety, restlessness, and insomnia⁽¹⁾. Taking one 1500mg dose in the morning as opposed to
two 750mg doses throughout the day may help prevent this⁽¹⁾. Though no studies have ever shown
aniracetam to be teratogenic, it is still advised to avoid use during pregnancy and breast feeding⁽¹⁾.
NON-RESPONDERS
There exists a minority of aniracetam users who report no beneficial effects. These users are typically
referred to as non-responders. When one attempts to come up with a possible reason why some
individuals respond positively while others do not, they may be left baffled. With so many possible
variables, it seems the simplest answer is that “everybody is different.” It is true that everybody is
different, but to satisfy the curiosity as to what exactly results in whether an individual is a responder or
a non-responder involves looking a little deeper. While there are most likely a variety of differences in
play, there have been two studies that point to two specific differences that may determine whether an
individual is a responder or a non-responder. In 1992, a study revealed that elevated levels of the
steroid cortisol blocked the memory enhancing effects of aniracetam⁽¹⁸⁾. This is an important
consideration. There are many reasons why a person may have an elevated cortisol level. High levels of
stress, chronic inflammation, Cushing's syndrome, certain medications, are all among the many reasons
a person may experience elevated cortisol level and thus be more likely to be a non-responder. In 1990,
another study revealed that low levels of the steroid aldosterone blocked the memory enhancing effects
of aniracetam⁽¹⁷⁾. Certain drugs that act on the kidneys such as ACE inhibitors which are used to lower
blood pressure, NSAIDS which are used to relieve pain and swelling, and diuretics which are usually
used to control blood pressure, all have the ability to lower aldosterone levels. Patients with Addison's
disease have markedly low levels of aldosterone. One can see that between the many ways that either
cortisol can be elevated and aldosterone can be lowered, there exists a possible explanation as to why
certain individuals are non-responders.
CONCLUSION
This author feels that aniracetam is a safe and effective supplement that offers many benefits. The
reader has to take the information presented, process it, possibly conduct some of their own additional
research, and ultimately come to a decision on whether they think aniracetam is right for them.
Aniracetam is just one of many available nootropics. This author would advise the reader to view as
many articles as possible, decide what is right for them, and consult their physician as well as their
pharmacist to make sure there are no drug interactions. Aniracetam, nor any other nootropic will make
a person “Limitless” but they just might find their quality of life increased even if only subtly.
Author Available for Correspondence
Dr. Ludwig would be happy to answer any question one may have.
Please, do not hesitate to contact Dr. Ludwig. He can be reached at [email protected]
Thank you for reading.
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