Piracetam (2-oxo-1-pyrrolidine-acetamide) is the parent compound of the racetams
class of nootropic drugs
that is a cyclic derivative of gamma-aminobutyric acid. It has extensive applications but is predominantly known for its cognitive enhancing effects.
[top]Introduction to Piracetam
Piracetam is the parent compound of the racetams class of nootropic supplements (“smart drugs”) and is the first ever nootropic drug
. It controls excessive excitation in neurons and enhances glucose and oxygen metabolism in hypoxic brain tissue. Piracetam is virtually free of toxic effects; however some might suggest this to be a lack of specific pharmacological activity. It has many applications including indication for vertigo, dyslexia, cortical myoclonus, sickle cell anemia, as well as in age-related disorders. It is also used by individuals simply seeking its reported efficacies in improving learning capacity and enhanced memory functioning, among other reported benefits.
Piracetam is usually dosed depending on body weight. The average dosing is approximately 4.75 grams consumed in two to three servings a day. When taken in small doses as part of a slow regime, the full effects of piracetam may not be realized until up to one week after starting administration. Some typical examples of piracetam regimes include:
- Roughly 50 mg per kg of body weight, spread evenly throughout the day (2 to 4 moderate doses)
- 800 mg single doses, available as a pill
- 2,500 mg or 3,200 mg single doses in powder form
For therapeutic dosing, it varies based on its intended use. For cognitive disorders and vertigo, it ranges from 2.4 grams to 4.8 grams daily; for dyslexia, 3.2 grams daily; for cortical myoclonus, 7.2 grams to 24.0 grams daily; for prophylaxis of vaso-occlusive crises in sickle cell anemia, 160 mg/kg daily; and for remission of vaso-occlusive crises, 300 mg/kg day in four divided doses. Piracetam is typically taken orally in doses of 800mg for cognitive benefits. Dementia and Alzheimer's sufferers typically take 4-8 times the dose of 800mg on a daily basis.
[top]Ways of Administration
Piracetam can be consumed in powder form or as a pill. It is quickly absorbed in the system and reaches its “peak effects” (depending on one's size, weight, and dosage) after only 1.5 hours since original consumption. Most of it is excreted via urination.
[top]Effects of Piracetam
Conflicting reports remain about piracetam. Otherwise healthy individuals seeking cognitive benefits generally agree that piracetam lives up to its reputation of promoting mental and cognitive acuity. Fighting the aging process, reducing long term repercussions of alcoholism, and notable relief from depression and anxiety related to cognitive functions, have all been reported. However, there is not enough sufficient empirical evidence to validate these claims.
[top]Side Effects of Piracetam
Piracetam holds limited side effects
in both prevalence and intensity. The most common reported are:
- Mild nausea or stomach ache
- Increased sweating
These side effects can be mitigated. For example, taking a form of choline
can help with the uptake and absorption of piracetam. When piracetam is taken at high doses, there are usually no sedative, stimulant, locomotor or autonomic side effects experienced.
[top]Combinations with Piracetam
Since piracetam is not metabolized by the liver nor bound to plasma albumin, drug-drug interaction occurrences are low. However, it does enhance the anticonvulsants effects of carbamazepine. Piracetam should not be taken with warfarin. Warfarin is a coumarin anticoagulant and is highly protein bound and is metabolized by a number of CYP450 enzymes. Piracetam may increase the effects of warfarin, although evidence is limited. Piracetam is well-tolerated in low doses (up to 10 g daily) and does not interact with antibiotics, anticonvulsants, analgesics
, antihypertensives or hormone replacement therapy (HRT). Both alcohol
and amphetamines are counter-indicated for use with Piracetam, due to decreased blood flow to the brain.
Piracetam is contraindicated for the following:
- Patients with renal impairment, and hepatic impairment (piracetam is largely excreted by the kidneys)
- Patients with cerebral hemorrhage and persons hypersensitive to piracetam
- Patients with underlying disorders of hemostasis, major surgery, or severe haemorrhage
- Sudden cessation of treatment should be avoided because myoclonic or generalized serious in some myoclonic patients is possible
- Women who are breastfeeding (piracetam is excreted in human breast milk)
[top]Different Uses for Piracetam
Many people across the world take piracetam to retain knowledge and improve memory. It has many other therapeutic purposes besides treating CNS disorders; examples include epilepsy and seizure disorders, neurodegenerative diseases, and stroke and ischemia related conditions. In its entirety, piracetam has indications for use in the following:
- Learning capabilities
- Memory processes
- Membrane fluidity
- Brain injury
- Short-term memory loss
- Alcohol and withdrawal syndrome
- Obsessive compulsive disorders
- Cortical myoclonus
- Acute Ischemic stroke
- Circulatory disorders
- Heart disease
- Sickle cell anemia
- Age-related cognitive disorders such as Alzheimer
- Stress, anxiety, and depression
- Social Anxiety Disorder
Piracetam repeatedly shows efficacy in treating age-related mental impairments. Specifically, patients with cerebral ischaemia-induced short-term memory or cognitive deterioration after heart bypass surgery have benefited the most from piracetam, confirming piracetam’s neuroprotective effects. In other studies, piracetam considerably mitigated depression. As an add-on therapy with drugs such as risperidone to treat autism, autistic children showed improved behavior compared to risperidone treatment alone.
Piracetam has shown potential in the treatment of patients with tardive dyskinesia (TD). In a 4-week trial, 67% of TD patients taking piracetam as an add-on therapy responded positively; motor impairment significantly improved as, but improved symptoms worsened after discontinuation of piracetam therapy.
Piracetam may play a role in successfully treating stroke/cerebral ischaemia. Ischaemic stroke is the third leading cause of death in developed countries, and the first leading cause of long-term disability in survivors. The efficacy and safety of piracetam in acute stroke patients is not yet proven though.(Piracetam for acute ischaemic stroke). However, neuroimaging tests confirm pirecetam’s ability to help stroke patients with aphasia to recover their verbal skills, but it’s effects are limited in other areas, such as reasoning abilities.
Piracetam shows potential in the treatment of some aspects of traumatic brain injuries. Piracetam improved color discrimination in patients aged 19-24 years who suffered from traumatic brain injuries. The authors of this particular study viewed piracetam’s efficacy as resulting from it acting as a GABA-mimetic drug, where GABA is present in the retina.
Several double-blind studies have investigated the efficacy of piracetam in the treatment of dyslexia. Those with dyslexia have difficulty in interpreting written language despite adequate intelligence and normal vision. Dyslexic persons also have problems related to writing and spelling. Although not conclusive, piracetam may help to improve reading speed and accuracy. Improvement of dyslexia with piracetam is minor and may take months to manifest, but it works well in combination with education programs.
The usefulness of piracetam for patients with Alzheimer's disease, vascular dementia or unspecified dementia is still controversial. Studies have produced mixed results, particularly in small trials, but results from larger trials have been more encouraging.
Piracetam shows some clinical benefit in the treatment of vertigo. It is believed this is a result of its effects on neurotransmission and microcirculation. Vertigo is a type of dizziness that specifically refers to the illusion of movement of the self or the environment that is typically rotatory in nature. Piracetam also has potential to treat sickle cell anemia. Sickle cell anemia is a genetic condition resulting from abnormal or sickled hemoglobin.
[top]Potentiation of Psychostimulants
There is a lack of valid experimental studies about the phenomenon of drug users using the nootropic drug piracetam to enhance the stimulating effects of methamphetamine
). When taken in combination, there is a belief among the user community that more desirable effects occur while limiting hangover. In a study conducted in March 2012 by the Central European Institute of Technology by K. Slais et al., results showed that when piracetam was combined with either methamphetamine or MDMA, stimulatory effects were significantly enhanced.
As such, the trend of using piracetam to intensify the effects of psychostimulants may have more validity than previously thought. Although no conclusive answer as to the mechanisms that produce this interaction among piracetam and either methamphetamine or MDMA, the most promising theory is that it is rooted in the mechanisms that facilitate a turnover of monoaminergic neurotransmitters (dopamine
, noradrenalin, serotonin
), which is shared by most psychostimulant drugs.
There is only one prior study in the available literature, and it focuses on the changes methamphetamine has on locomotor activity and shuttle-box avoidance acquisition in mice (co-administration of 100mg/kg of piracetam and administration of 2 mg/kg of methamphetamine). The authors concluded that nootropic drugs may interact with the effects of methamphetamine on processes involved in learning and memory.
It is important to note that the amount of piracetam may play a significant role in its effects on psychostimulants, as in the first study on this subject showed no significant influence on dopaminergic brain system, whereas at 300 mg/kg of piracetam, there was an influence on the dopaminergic system.
Piracetam has no toxic or addictive properties (neither mental or physical). Repeated use of piracetam does not produce tolerance to its effects.
Piracetam taken alone has no addictive properties, even when taken in high doses; however, if a similarly high dose of piracetam is taken with either methamphetamine or MDMA, it enhances stimulatory effects. This topic needs more research and a second consideration as to the abuse potential of nootropic drugs such as piracetam. It is clear that piracetam enhances the desirable effects of psychostimulants, so it could pose a threat to abstaining individuals as the drug increases the risk of developing dependence on methamphetamine and MDMA.
[top]Pharmacology of Piracetam
Piracetam (pyrrolidone acetamine) and its derivatives (with which some have unknown therapeutic value) share a five-carbon oxopyrrolidone ring, known as racetams that belong to the class of nootropic compounds. Piracetam-like compounds for cognitive enhancers include oxiracetam
and phenylpiracetam. Piracetam-like compounds for antiepileptic drugs include levetiracetam, brivaracetam, and seletracetam, and piracetam-like compounds with unknown clinical value as of 2010 include nefiracetam
, nebracetam, rolipram, fasoracetam (NS-105), coluracetam (MKC-231), rolziracetam, and dimiracetam. Levetiracetam is the only approved drug besides piracetam out of pirecetam’s derivatives used for cognition and memory as it very safe with little side effects. Levetiracetam is a second-generation homologue of piracetam. It has become a popular drug in recent studies based on its potential to have more efficacy than piracetam for cognitive and memory process.
[top]Possible Mechanism of Action: the Membrane Hypothesis
Some literature indicates that the underlying action of piracetam is in restoring cell membrane fluidity. Cell membranes are fluid structures that consist of a bilayer of lipid molecules combined with protein molecules. Membrane fluidity is important for processes such as membrane transport, enzyme activity, chemical secretion, and receptor binding and stimulation. Piracetam’s interaction with cell membranes appeared in a study where piracetam partially prevented alcohol-related changes in a synthetic phosphatylcholine monolayer. Its interaction with cell membranes also has subsequent support, including a recent in vitro study on neuronal membranes.
Piracetam can also influence membrane fluidity, notably when normal fluidity compromises, which happens in the aging process. This may partially explain the beneficial effects of piracetam when treating Alzheimer disease. Piracetam affects more than just brain membranes; in a study reported by Müller and colleagues, piracetam significantly improved fluidity of platelet membranes in samples from elderly. Membrane fluidity affects many membrane activities (such as membrane transport, chemical secretion, and receptor binding and stimulation).
Neuronal Effects: Piracetam’s affect other neurotransmitter
systems as well, including the serotoninergic, noradrenergic, and glutamatergic systems. Its wide raging effects on neurotransmitter system are not a result from agonism or antagonism. Rather, it increases the number of postsynaptic receptors and restores their ability to function. The membrane hypothesis proposes then, that membrane fluidity affects neurotransmitter function because fluidity affects embedded membrane proteins. Neurotransmitters bind to these proteins, influencing cell signaling. If piracetam can affect fluidity, than it can also affect neurotransmitter action and cell signaling.
As already noted, piracetam has clinical benefits in treating cognitive disorders. Cholinergic and glutamatergic systems might have a relation to cognitive decline (given increasing support for this). This could explain piracetam’s abilities in cognitive disorders, since it affects these neurotransmitter systems. In a study where piracetam was used as treatment in the glutamatergic system, density of the NMDA receptor in the forebrain increased by roughly 20%. It may also be able to restore NMDA receptor function as the same study found that piracetam normalized the age-related elevated affinity of L-glutamate for the NMDA receptor.
Neuroprotective effects: Preclinical studies have shown that piracetam appears to offer neuroprotective benefits in several circumstances. This is consistent with the suggestion that interactions between piracetam and membrane lipids may decrease the risk of membrane fusion. Piracetam has been shown to reduce the incidence of animal death following barbiturate overdose, and to protect against morphological changes related to long-term alcohol use.
Neuroplastic effects: Involves a process largely involved in memory and learning. This process involves alternation of neural circuitry through the modification and development of synaptic and neural connections, and limits the damage caused by ischeamia and degenerative lesions.
Neuroplasticity is also relevant to alcohol and its damaging effects, as neuronal loss is associated with alcohol consumption and alcohol withdrawal. Piracetam’s effects on neuroplasticity effects include reducing neuronal loss caused by alcohol use and alcohol withdrawal. For instance, in two studies involving alcohol-treated rats, the number of synapses in the hippocampus increased by approximately 20% following piracetam therapy. This suggests that piracetam promotes neuroplasticity when neural circuits are recoverable.
Effects on microcirculation: Piracetam has important clinical uses for vascular indications, specifically for sickle cell anemia. Piracetam treatment enhances cerebral blood flow and also microcirculation at a peripheral level. Enhancing cerebral blood flow for individuals with acute cerebral ischemia is important for treatment. Piracetam’s effects on microcirculation are likely due to the combination of its effects on blood vessels, blood coagulation, and erythrocytes.
[top]Pharmacokinetics of Piracetam
Oral formulations of piracetam have a bioavailability of close to 100%. Following an oral dose of 3.2 grams, peak concentration is around 84 igmL. Piracetam is rapidly absorbed and it takes roughly 30 minutes to reach peak plasma concentrations. Food does not impact the extent of absorption of piracetam, but it does decrease the maximal plasma concentration of it by 17% and prolongs peak plasma by 1 and ½ hours. The drug is excreted in the urine and remains unchanged, where no metabolites of piracetam have been discovered. Piracetam crosses blood–brain and placental barriers and is found in all tissues, except adipose tissue. The uptake into the brain is less rapid than into the circulation, and, at nearly 8 h, half-life
in cerebrospinal fluid is longer than in plasma (about 5 h).
[top]Chemistry of Piracetam
|Systematic(IUPAC) name:||2-oxo-1-pyrrolidineacetamide |
|Synonyms:||2-(2-Oxopyrrolidin-1-yl)acetamide2-(2-Oxopyrrolidino)acetamide2-Oxo-1-pyrrolidineacetamide, 2-pyrrolidinoneacetamide, 2-pyrrolidoneacetamide, 2-ketopyrrolidine-1-ylacetamide, 1-acetamido-2-pyrrolidinone, UCB-6215, Avigilen, Axonyl, Cerebroforte, Encetrop, Gabacet, Geram, Piracetrop, Sinapsan|
|Molar mass:||142.16 g/mol|
|CAS Registry Number:||7491-74-9|
|Boiling Point:||no data|
|Flash Point:||no data|
|Solubility:||Soluble to 100 mL in water|
|Notes:||crystallized from isopropanol|
Piracetam-like compounds include oxiracetam, aniracetam, pramiracetam and phenylpiracetam. Oxiracetam and aniracetam are no longer in clinical use. Pramiracetam has shown to improve cognitive deficits caused by traumatic brain injuries. Phenylpiracetam is more potent than piracetam and is used for a larger range of indication.
The rest of the racetam family are not water soluble, but fat soluble. As such, these compounds are not able to cross the blood brain barrier as they cannot be properly absorbed. Oxiracetam is water-soluble and one of the more potent compounds. Aniracetam is a fat soluble racetam and consistently demonstrates stronger effects than piracetam. Pramiracetam is produced and available in many forms, where it ranges from between ten to thirty times that of piracetam’s strength.
There are six relevant medications on the market worldwide:
- Piracetam and levetiracetam were developed by UCB Pharma, Belgium;
- Oxiracetam by ISF, Italy;
- Aniracetam by Roche Pharmaceuticals, Switzerland;
- Pramiracetam by Warner-Lambert, USA; and
- Phenylpiracetam by the Medical-Biological Institute of the Russian Academy of Sciences.
Piracetam is sold under a wide variety of brand names worldwide, some requiring prescription while others are available freely.
- Nootropyl - United States
- Nootropil, Lucetam, Oikamid, Geratam, Biotropil - Europe, Brazil
- Neurobasal - Colombia
- Breinox - Ecuador, Venezuela
- Dinagen - Mexico
- Noostan - Argentina
[top]Legal Status of Piracetam
Piracetam is not sold under the auspices of the FDA as it does not fall under their purview as a health aid. It is fully legal to use, possess, and import piracetam on a 'personal use' basis. Overseas distributors have reported that they have very little trouble shipping to the U.S., and over the past few years piracetam has become available from a number of U.S. companies. What follows is a large excerpt taken from a text on the FDA web site http://www.fda.gov/
circa 2003, covering various elements of legality like 'serious conditions' and 'personal use'.
"For many years FDA has permitted individuals to bring into the country small "personal-use" quantities of drugs sold abroad but not approved in the U.S. -- provided that the drugs do not pose unreasonable or significant safety risks, that their use will not be commercialized, and that they are for a serious condition for which there is no satisfactory treatment available in this country. The policy was designed to allow people to import through their personal baggage small quantities of medicines they may have been treated with while traveling abroad, and to allow individuals with serious conditions the ability to import through the mail personal-use quantities of unapproved drugs that they feel might be helpful in treating their conditions."
"Personal-use quantities are generally considered to be amounts for a patient's treatment for three months or less. Imports involving larger quantities may not be permitted as they lend themselves to commercialization."
"In recent years this policy has gained greater attention because of the plight of people with AIDS who have sought to import unapproved therapies from abroad. These include importations brought into the country though personal baggage carried back from a trip to another country or through mail shipments."
"Persons with additional questions about importation of drugs for personal use should consult with the local FDA district office or the Imports Operations Branch in Rockville, MD at (301) 443-6553."
In the UK, the import of piracetam is not prohibited and personal consumption is allowed without penalty. It appears that there is no limitation on the sale of piracetam in the EU, though some countries require a prescription for purchase.
Canada does not regulate the drug for purchase. However it is still illegal to produce and sell within the Commonwealth with the intent of human consumption. In Mexico, the drug is legally available only with a prescription.
[top]History of Piracetam
Piracetam was synthesized in 1964 in Belgium by Dr. Giurgea, a psychochemist. It is the first “nootropic” drug and is considered the pioneer “smart drug”. The term ‘nootrope’ (from the Greek words “noos” for mind, “tropein” for towards) was coined after piracetam demonstrated positive effects on cognitive functions. Piracetam was originally marketed in 1971 by UCB Pharma.
[top]More Piracetam Sections
Despite the many reported benefits of piracetam (and piracetam-like compounds) and its many applications of use, research is inadequate; many trials are inconclusive, their mechanisms of action are largely elusive, and potential biases in the design and interpretation of trials are hard to separate. Piracetam and its compounds display promising results for many indications, most notably for cognitive and memory functions. With a large segment of the population aging, the current trend will be to obtain research that will provide a better clinical understanding of these drugs, and to be able to test them for new indications, particularly CNS disorders. Their potential neuroprotective and neuroregenerative effects are the least explored, so with well controlled studies and more modern techniques, the potential efficacy of piracetam and piracetam-like compounds is even further reaching.
[top]The Latest Piracetam Threads
- ^ a b c http://www.drugs-forum.com/forum/local_links.php?action=jump&catid=103&id=12294
- ^ a b c http://www.drugs-forum.com/forum/local_links.php?action=jump&catid=103&id=8510
- ^ a b c d e f g h i j k l m n http://www.drugs-forum.com/forum/local_links.php?action=jump&catid=69&id=11393
- ^ http://www.jle.com/en/revues/medecine/epd/e-docs/00/01/AE/26/article.phtml
- ^ a b c d e f http://www.drugs-forum.com/forum/local_links.php?action=jump&catid=103&id=12315
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