Piracetam

Last updated: Jan 19, 2012



Other names^[12]
2-(2-Oxo-pyrrolidin-1-yl)-acetamide, 2-(2-Oxopyrrolidino)acetamide, 5-21-06-00360 (Beilstein Handbook Reference), Avigilen, Axonyl, BRN 1526393, CI-871, Cerebroforte, Ciclofalina, Encetrop, Euvifor, Gabacet, Genogris, KT-801, N-Carbamoylmethyl-2-pyrrolidinone, Naofukang, Nootron, Nootrop, Nootropil, Nootropyl, Normabrain, Norzetam, Piracetamas, Piracetamum, Piracétam, Pirasetaami, Pirasetam, Pirroxil, Pyracetam, Pyramem, Pyrrolidone Acetamide, UCB-6215.

Background
While the compound has existed since the mid 1960s as a treatment for motion sickness, the 1971 discovery of piracetam’s neuroprotective effects in mouse models effectively kickstarted the nootropic movement. Piracetam falls into a class of similarly-structured nootropics, racetams. All can pass through the blood-brain barrier to a certain degree. While members of this class are structurally similar, the small differences are enough to yield a range of different chemical properties.^[3]

Mode of action
Though piracetam has held the longest market awareness of nootropics, its mode of action is still unclear. A few hypotheses:

1. restoration of membrane fluidity of compromised neuronal cells – higher membrane fluidity ultimately allows signaling molecules to more easily cross the lipid bilayer membrane, which is an integral step in cell signalling (more relevant to our interests, neurotransmission)^[9][13]; piracetam, in concert with calcium ions (an ion important to cell signalling), appears to effect physical changes in membranes.^[10]
   
   
   (Figure 1 from [6])
2. steroid-sensitive protein synthesis-modulation, where protein-synthesis is a part of memory-storage/consolidation; adrenolectomized rats didn’t demonstrate the memory-enhancing effects when given several racetams at different dosage levels, but they could still learn; steroids may play a part in transporting the nootropics through the membrane. Also, when steroid receptor activity (adrenal function) is suppressed by drugs, the different racetams also don’t ‘work’. Amnestic effects seem to be dependent on the adrenal medulla.^[7]
3. interaction with glutamate neurotransmission – potentially binding with glutamate receptors; possibly recruitment of AMPA receptors normally not part of the synaptic transmission^[13]
4. interaction with acetylcholine neurotransmission – increase in cortical muscarinic receptor density (aged rats)^[3]

Benefits
Preclinical studies (mainly rat models) have shown piracetam to 1) enhance subject performance in a standard, passive-avoidance test (learning and memory), 2) protect against shock/hypoxia-induced amnesia (neuroprotection), and 3) reduce alcohol and alcohol-withdrawal related neuronal loss, when neural circuitry is recoverable (neuroplasticity).^[13]

The drug has applications in treating cognitive disorders, vertigo, cortical myoclonus (involuntary, spontaneous muscle movements), dyslexia, and sickle cell anemia.^[13]

The magnitude of piracetam’s cognitive-enhancement varies depending on the individual. Studies have shown more noticeable effects/improvements in aged vs. young animals.^[5]

Dosing
Piracetam taken orally has nearly 100% plasma bioavailability, meaning virtually all of it makes it to the bloodstream unchanged. It is rapidly absorbed by the body, and reaches peak plasma concentration within 30 minutes when taken by fasting subjects. Prescription dosages for cognitive disorders and vertigo are typically around 2.4-4.8 g daily, p.o. (per os, “by mouth”). Cortical myoclonus treatments are around 7.2-24.0 g daily, p.o.^[13] For a 2 g p.o. dose to humans, the CNS half-life is 7.7 hours, and the plasma half-life is 5 hours. Without re-administration, piracetam leaves the body entirely in 30 hours.^[2]

In a study looking at dosage-related efficacy, researchers administered subjects affected by age-associated memory impairment (AAMI) with 3 different levels of dosing: placebo, 2.4 g/day, and 4.8 g/day (55+ years old; placebo wash-out period of 10 days; 3 parallel groups of 45 participants completed). The researchers found that 1) therapy was most effective in those with the worst baseline performance, and 2) of the three dosing levels, 4.8 g/day was the most effective.^[5]

Toxicity
Regarding toxicity, in preclinical trials, there were no irreversible toxic effects in mice, rats, or dogs in single oral doses up to ~4.5 g/lb. Controlled human clinical trials have shown high dosage tolerability, with a typical, no side effect dose in the range of 2.4-4.8 g/day p.o., with “no side effects” being interpreted as a drop-out rate comparable with the control/placebo group. Doses up to 8.0 g/day given to subjects suffering from Alzheimer’s also yielded drop-out rates comparable to the placebo group.^[6] While reproductive studies have shown no risk to fetuses in animal studies, no comparable trials have been conducted for pregnant or lactating women.^[13]

Until recently, piracetam’s recreational applications fell under the category of nutritional supplements; thus, there used to be fairly lax FDA regulation. After further scrutiny, the FDA served warning letters to piracetam manufacturers and distributors in the US notifying them of piracetam’s exclusion from the dietary supplement definition.

Other information
On piracetam’s synergy with choline^[1]
A study was conducted in 1981 to explore the potential synergy in administering choline (a precursor molecule for neurotransmitter acetylcholine) jointly with piracetam for memory-enhancement in rats, using a rat species whose memory noticeably deteriorated with age. The memory loss that increases with age in this species is similar to mice, old world monkeys, new world monkeys, and humans, hence, the researchers’ choice of using this model system. Researchers took a sample of aged (20+ months) rats, and separated them into 4 treatment arms:

1. control (tap water);
2. piracetam (200 mg/kg per day);
3. choline (200 mg/kg per day);
4. piracetam/choline combination (100 mg/kg of each per day).

Fluid treatments were administered chronically for 1 week via drinking water, where the control was tap water.

The well-established passive-avoidance task consists of a two-chamber testing apparatus, with the two chambers separated by an initially shut guillotine door (figure below); one chamber is lit, and the other is not. The test subject is introduced into the light chamber, and allowed to explore for 3 seconds for orientation. The guillotine door is opened. After the rat enters the unlit chamber, the door is shut, and an electric shock is delivered to the dark chamber floor grids for 3 seconds. The rat is then removed from the apparatus and returned to its cage for 24 hours.

(Excerpt from Figure 12.8 in [11])

24 hours later, the rat is returned to the testing apparatus. By measuring the period of hesitance (‘retention latency’) that preceded the rat’s entry into the dark chamber after the guillotine door is opened, the researchers were able to indirectly quantify the efficacy of piracetam, choline, and piracetam + choline treatments on memory. The piracetam + choline combo group results far outshines the results of the other group, where a longer retention latency is interpreted as enhanced learning retention.

(Figure 1 and its captions, from [1])

In the same paper, but an extension of the initial study, the authors explored retention latency of the five treatment arms in a new population of test specimen:

1. single, acute injections of 100 mg/kg of each choline and piracetam before training and testing;
2. a 1 week dosing regimen of 100 mg/kg of each choline and piracetam, as well as a saline control injection before training and testing;
3. a 1 week dosing regimen of 100 mg/kg of each choline and piracetam, as well as single, acute injections of 100 mg/kg of each choline and piracetam before training and testing;
4. a 1 week dosing regimen of 200 mg/kg of choline, as well as single, acute injections of 200 mg/kg of choline before training and testing;
5. a 1 week dosing regimen of 200 mg/kg of piracetam, as well as single, acute injections of 200 mg/kg of piracetam before training and testing.

Groups 4 and 5 were created to see if doubling the dosage of either compound could effect retention latency increases comparable to the initial choline + piracetam combo treatment. The results of the above 5 groups were added to the data pulled from the initial 4 groups, and compiled into the figure below. The new, interesting take-away from this extension study is that chronic treatments (of choline + piracetam) produced longer retention latency times than acute (one-time, pre-training and testing injection) treatments.



(Figure 2 and its captions, from [1]. Note, per the paper, – only 1 choline-treated subject survived, so that specific data is statistically unusable)

On piracetam’s synergy (or lack thereof) with lecithin in treating Alzheimer’s Disease^[4]
-summarize the 1985 Growdon study re: lack of significant improvements when piracetam was coupled with lecithin in treating AD (need to re-read notes and paper and re-confirm)

On the efficacy of piracetam when administered after learning^[8]
-summarize the study about administering drugs AFTER the learning event (“How long does memory consolidation take?”) – if I remember correctly, piracetam (and several others) were still effective up to 8 hrs after the learning event (need to re-read notes and paper to re-confirm)

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http://www.pureacetam.com

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References:

1. ^ Bartus RT, Dean III RL, Sherman KA, Friedman E, Beer B. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiology of Aging [Internet]. 1981 Mar 30 [cited 2012 Jan 11];2(2):105-111. Available from: ScienceDirect.
2. ^ Gobert JG. Genèse d’un medicament: le piracetam, métabolisation et recherche biochimìque. J. Pharm. Belg [Unavailable]. 1972 [cited 2012 Jan 10];27:281-304. Note: Couldn’t get my hands on an actual copy, but it appears that a number of papers reference this paper, solely for the information regarding plasma concentration, bioavailability, CNS half life, complete elimination from the body.
3. ^ Gouliaev AH, Senning A. Piracetam and other structrually related nootropics (full-length review). Brain Research Reviews [Internet]. 1993 Aug 17 [cited 2012 Jan 10];19:180-222. Available from: ScienceDirect.
4. ^ Growdon J, Corkin S, Huff FJ, Rosen JT. Piracetam combined with lecithin in the treatment of Alzheimer’s disease. Neurobiology of Aging [Internet]. 1985 Aug 8 [cited 2012 Jan 11];7(4):269-276. Available from: ScienceDirect.
5. ^ Israel L, Melac M, Milinkevitch D, Dubos G. Drug therapy and memory training programs: a double-blind randomized trial of general practice patients with age-associated memory impairment. International Psychogeriatrics [Internet]. 1994 [cited 2012 Jan 11];6:155-170. Available from: Cambridge Journals. Note: Couldn’t get my hands on an actual copy due to paywall. Cited information was pulled from the abstract
6. ^ McDaniel MA, Maier SF, Einstein GO. “Brain-specific” nutrients: a memory cure? Nutrition [Internet]. 2003 Nov 13 [cited 2012 Jan 11];19(11-12):957-975. Available from: ScienceDirect.
7. ^ Mondadori C, Ducret T, Petschke F. Blockade of the nootropic action of piracetam-like nootropics by adrenalectomy: an effect of dosage? Behavioural Brain Research [Internet]. 1989 Jan 3 [cited 2012 Jan 10];34:155-158. Available from: PubMed.
8. ^ Mondadori C, Hengerer B, Ducret T, Borkowski J. Delayed emergence of effects of memory-enhancing drugs: Implications for the dynamics of long-term memory. Psychology [Internet]. 1994 Mar 15 [cited 2012 Jan 10];91:2041-2045. Available from: PubMed.
9. ^ Müller WE, Koch S, Scheuer K, Rostock A, Bartsch R. Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain. Biochemical Pharmacology [Internet]. 1997 Jan 24 [cited 2012 Jan 10];53(2):135-140. Available from: PubMed.
10. ^ Peuvot J, Schanck A, Deleers M, Brasseurs R. Piracetam-induced changes to membrane physical properties: A combined approach by 31P nuclear magnetic resonance and conformational analysis. Biochemical Pharmacology [Internet]. 1995 May 17 [cited 2012 Jan 10];8:1129-1134. Available from: PubMed.
11. ^ Rodriguiz RM, Wetsel WC. Assessments of cognitive deficits in mutant mice. In: Levin ED, Buccafuso JJ, editors. Animal models of cognitive impairment. Boca Raton (FL): CRC Press; 2006. Ch 12. Available from: NCBI Bookshelf.
12. ^ Structure Details [for Piracetam]. PerkinElmer Inc. / ChemBioFinder.Com Gateway version 3.0; [cited 2012 Jan 19]. Available from: ChemBioFinder.Com.
13. ^ Winblad B. Piracetam: A review of pharmacological properties and clinical uses. CNS Drug Review [Internet]. 2005 [cited 2012 Jan 10];11(2):169-182. Available from: PubMed.