Chemistry:Piracetam

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Short description: Chemical compound
Piracetam
Piracetam.svg
Piracetam ball-and-stick.png
Clinical data
Trade namesBreinox, Dinagen, Lucetam, Nootropil, Nootropyl, Oikamid, Piracetam and many others
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth, parenteral, or vaporized
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: Unscheduled
  • UK: POM (Prescription only)
  • US: Unapproved "New Drug" (as defined by 21 U.S. Code § 321(p)(1)). Use in dietary supplements, food, or medicine is unlawful; otherwise uncontrolled. [1])
Pharmacokinetic data
Bioavailability~100%
Onset of actionSwiftly following administration. Food delays time to peak concentration by 1.5 h approximately to 2–3 h since dosing.[2]
Elimination half-life4–5 h
ExcretionUrinary
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6H10N2O2
Molar mass142.158 g·mol−1
3D model (JSmol)
Melting point152 °C (306 °F)
  (verify)

Piracetam is a drug that has efficacy in cognitive disorders, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia; sources differ on its usefulness for dementia.[3][4][5] Piracetam is sold as a medication in many European countries. Sale of piracetam is not illegal in the United States, although it is not regulated nor approved by the FDA, so it is legally sold for research use only.[6]

Piracetam is in the racetams group, with chemical name 2-oxo-1-pyrrolidine acetamide. It is a cyclic derivative of the neurotransmitter GABA[4] and shares the same 2-oxo-pyrrolidone base structure with pyroglutamic acid. Related drugs include the anticonvulsants levetiracetam and brivaracetam, and the putative nootropics aniracetam and phenylpiracetam.

Efficacy

Dementia

A 2001 Cochrane review concluded that there was not enough evidence to support piracetam for dementia or cognitive problems.[5] A 2005 review found some evidence of benefit in older subjects with cognitive impairment.[4] In 2008, a working group of the British Academy of Medical Sciences noted that many of the trials of piracetam for dementia were flawed.[7]

There is no good evidence that piracetam is of benefit in treating vascular dementia.[8]

Depression and anxiety

Some sources suggest that piracetam's overall effect on lowering depression and anxiety is higher than on improving memory.[9] However, depression is reported to be an occasional adverse effect of piracetam.[10]

Attention Deficit Hyperactivity Disorder (ADHD)

Several clinical trials have looked at piracetam's efficacy as a treatment for ADHD. Many of these have found that the drug fails to deliver the same therapeutic effects as current standard treatments for the disorder.[11] However, more than one study has found piracetam to be highly synergistic with standard ADHD therapies, accelerating and potentiating their therapeutic effects. One 2008 clinical trial found that the combination of piracetam and atomoxetine was more effective than atomoxetine alone.[12]

While piracetam may be an effective adjuvant therapy for ADHD (when used with specific medications), there is no evidence that it is effective when used in isolation.

Other

Piracetam may facilitate the deformability of erythrocytes in capillary which is useful for cardiovascular disease.[4][3]

Peripheral vascular effects of piracetam have suggested its use potential for vertigo, dyslexia, Raynaud's phenomenon and sickle cell anemia.[4][3] There is no evidence to support piracetam's use in sickle cell crisis prevention[13] or for fetal distress during childbirth.[14] There is no evidence for benefit of piracetam with acute ischemic stroke,[15] though there is debate as to its utility during stroke rehabilitation.[16][17]

Anti-vasospasm

Piracetam has been found to diminish erythrocyte adhesion to vascular wall endothelium, making any vasospasm in the capillary less severe. This contributes to its efficacy in promoting microcirculation, including to the brain and kidneys.[4][3]

Side effects

Symptoms of general excitability, including anxiety, insomnia, irritability, headache, agitation, nervousness, tremor, and hyperkinesia, are occasionally reported.[10][18][19] Other reported side effects include somnolence, weight gain, clinical depression, weakness, increased libido, and hypersexuality.[10]

According to a 2005 review, piracetam has been observed to have the following side effects: hyperkinesia, weight gain, nervousness, somnolence, depression and asthenia.[4]

Piracetam reduces platelet aggregation as well as fibrinogen concentration, and thus is contraindicated to patients with cerebral hemorrhage.[4][3]

Toxicity

The -1">50 for oral consumption in humans has not been determined.[20] The LD50 is 5.6 g/kg for rats and 20 g/kg for mice, indicating extremely low acute toxicity.[21] For comparison, in rats the LD50 of vitamin C is 12 g/kg and the LD50 of table salt is 3 g/kg.

Mechanisms of action

Piracetam's mechanism of action, as with racetams in general, is not fully understood. The drug influences neuronal and vascular functions and influences cognitive function without acting as a sedative or stimulant.[4] Piracetam is a positive allosteric modulator of the AMPA receptor, although this action is very weak and its clinical effects may not necessarily be mediated by this action.[22] It is hypothesized to act on ion channels or ion carriers, thus leading to increased neuron excitability.[20] GABA brain metabolism and GABA receptors are not affected by piracetam[23]

Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors[citation needed], which are implicated in memory processes.[24] Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes. Piracetam is thought to increase cell membrane permeability.[24][25] Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+).[20] It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains.[26][27] Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5,[28] which is a part of the electron transport mechanism in mitochondria. But in the brain, it also increases the permeability of some intermediates of the Krebs cycle through the mitochondrial outer membrane.[26]

Piracetam inhibits N-type calcium channels. The concentration of piracetam achieved in central nervous system after a typical dose of 1200 mg (about 100 μM)[29] is much higher than the concentration necessary to inhibit N-type calcium channels (IC50 of piracetam in rat neurons was 3 μM).[30]

History

Piracetam was first made some time between the 1950s and 1964 by Corneliu E. Giurgea.[31] There are reports of it being used for epilepsy in the 1950s.[32]

Society and culture

In 2009 piracetam was reportedly popular as a cognitive enhancement drug among students.[33]

Legal status

Piracetam is an uncontrolled substance in the United States meaning it is legal to possess without a license or prescription.[34] Use of piracetam in food, supplements, medical devices, insecticides, infant formula, cosmetics, animal feed, animal drugs, tobacco products, and drugs is unlawful and constitutes an act of misbranding.

Regulatory status

In the United States, piracetam is not approved by the Food and Drug Administration.[1] Piracetam is not permitted in compounded drugs or dietary supplements in the United States .[35] Like most research chemicals, it has been available over-the-counter, self-regulated, and third-party lab tested by many US companies for decades.[6] Yet, nonetheless it is still for the purposes of U.S. law a "New Drug" as defined by 21 U.S. Code § 321(p)(1).

In the United Kingdom, piracetam is approved as a prescription drug Prescription Only Medicine (POM) number is PL 20636/2524[36] for adult with myoclonus of cortical origin, irrespective of cause, and should be used in combination with other anti-myoclonic therapies.[37]

In Japan piracetam is approved as a prescription drug.[38]

In Czech Republic piracetam is available without prescription.[39] [40]

Piracetam has no DIN in Canada, and thus cannot be sold but can be imported for personal use in Canada.[41]

In Hungary, piracetam was a prescription-only medication, but as of 2020, no prescription is required and piracetam is available as an over-the-counter drug under the name Memoril Mite, and is available in 600 mg pills.

See also

  • AMPA receptor positive allosteric modulator
  • Aniracetam
  • Brivaracetam—an analogue of piracetam with the same additional side chain as levetiracetam and a three–carbon chain. It exhibits greater antiepileptic properties than levetiracetam in animal models, but with a somewhat smaller, although still high, therapeutic range.
  • Hydergine
  • Levetiracetam—an analogue of piracetam bearing an additional CH3–CH2– sidechain and bearing antiepileptic pharmacological properties through a poorly understood mechanism probably related to its affinity for the vesicle protein SV2A.
  • Oxiracetam
  • Phenylpiracetam—a phenylated analog of the drug piracetam which was developed in 1983 in Russia where it is available as a prescription drug.
  • Pramiracetam

References

  1. ↑ 1.0 1.1 "Piracetam". DrugBank database. https://www.drugbank.ca/drugs/DB09210. 
  2. ↑ Leaflet of Piracetam.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Nootropil Tablets 1200 mg". 2017-02-15. https://www.medicines.org.uk/emc/medicine/27470. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "Piracetam: a review of pharmacological properties and clinical uses". CNS Drug Reviews 11 (2): 169–182. 2005. doi:10.1111/j.1527-3458.2005.tb00268.x. PMID 16007238. 
  5. ↑ 5.0 5.1 "Piracetam for dementia or cognitive impairment". The Cochrane Database of Systematic Reviews (2): CD001011. 2001. doi:10.1002/14651858.CD001011. PMID 11405971. 
  6. ↑ 6.0 6.1 "Presence of Piracetam in Cognitive Enhancement Dietary Supplements". JAMA Internal Medicine 180 (3): 458–459. March 2020. doi:10.1001/jamainternmed.2019.5507. PMID 31764936. 
  7. ↑ Brain science, addiction and drugs (Report). Academy of Medical Sciences. May 2008. p. 145. ISBN 978-1-903401-18-7. http://www.acmedsci.ac.uk/download.php?file=/images/publication/Report.pdf. 
  8. ↑ "Pharmacotherapy for Vascular Cognitive Impairment". CNS Drugs 31 (9): 759–776. September 2017. doi:10.1007/s40263-017-0459-3. PMID 28786085. "Other medications have been considered or tried for the treatment of VCI or VaD. These include [...] piracetam. There is no convincing evidence about the efficacy of these medications in the treatment of VCI.". 
  9. ↑ "Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders". Drugs 70 (3): 287–312. February 2010. doi:10.2165/11319230-000000000-00000. PMID 20166767. 
  10. ↑ 10.0 10.1 10.2 Nootropil®. Arzneimittel-Kompendium der Schweiz. 2013-09-12. Retrieved 2013-10-27.
  11. ↑ "Is Piracetam Good for ADHD? - Epimodels" (in en-US). 2023-05-11. https://www.epimodels.org/nootropics/piracetam-good-for-adhd/. 
  12. ↑ "[Atomoxetine and piracetam in the treatment of attention deficit hyperactivity disorder in children"]. Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova 108 (7): 43–47. 2008. PMID 18833117. https://pubmed.ncbi.nlm.nih.gov/18833117/. 
  13. ↑ "Piracetam for reducing the incidence of painful sickle cell disease crises". The Cochrane Database of Systematic Reviews 2 (4): CD006111. February 2016. doi:10.1002/14651858.CD006111.pub3. PMID 26869149. 
  14. ↑ "Piracetam for fetal distress in labour". The Cochrane Database of Systematic Reviews 2012 (6): CD001064. June 2012. doi:10.1002/14651858.CD001064.pub2. PMID 22696322. 
  15. ↑ "Piracetam for acute ischaemic stroke". The Cochrane Database of Systematic Reviews 2012 (9): CD000419. September 2012. doi:10.1002/14651858.CD000419.pub3. PMID 22972044. 
  16. ↑ "Piracetam for Aphasia in Post-stroke Patients: A Systematic Review and Meta-analysis of Randomized Controlled Trials". CNS Drugs 30 (7): 575–587. July 2016. doi:10.1007/s40263-016-0348-1. PMID 27236454. 
  17. ↑ "Effects of Central Nervous System Drugs on Recovery After Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Clinical Drug Investigation 37 (10): 901–928. October 2017. doi:10.1007/s40261-017-0558-4. PMID 28756557. 
  18. ↑ "Piracetam in elderly psychiatric patients with mild diffuse cerebral impairment". Psychopharmacology 81 (2): 100–106. 1983. doi:10.1007/BF00429000. PMID 6415738. 
  19. ↑ "Piracetam in the treatment of post-concussional syndrome. A double-blind study". European Neurology 17 (1): 50–55. 1978. doi:10.1159/000114922. PMID 342247. 
  20. ↑ 20.0 20.1 20.2 "Piracetam and other structurally related nootropics". Brain Research. Brain Research Reviews 19 (2): 180–222. May 1994. doi:10.1016/0165-0173(94)90011-6. PMID 8061686. 
  21. ↑ "Piracetam Material Safety Sheet". Spectrum. https://www.spectrumchemical.com/MSDS/P3941.PDF. 
  22. ↑ "Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors". Journal of Medicinal Chemistry 53 (5): 2197–2203. March 2010. doi:10.1021/jm901905j. PMID 20163115. 
  23. ↑ "The nootropic concept and its prospective implications". Drug Development Research 2 (5): 441–446. January 1982. doi:10.1002/ddr.430020505. ISSN 1098-2299. 
  24. ↑ 24.0 24.1 "Piracetam--an old drug with novel properties?". Acta Poloniae Pharmaceutica 62 (5): 405–409. 2005. PMID 16459490. 
  25. ↑ "Piracetam: novelty in a unique mode of action". Pharmacopsychiatry 32 (Suppl 1): 2–9. March 1999. doi:10.1055/s-2007-979230. PMID 10338102. 
  26. ↑ 26.0 26.1 "Effect of Piracetam on electrocorticogram and local cerebral glucose utilization in the rat". General Pharmacology 18 (2): 205–211. 1987. doi:10.1016/0306-3623(87)90252-7. PMID 3569848. 
  27. ↑ "Effect of the acquisition-enhancing drug piracetam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine". Biochemical Pharmacology 25 (20): 2241–2244. October 1976. doi:10.1016/0006-2952(76)90004-6. PMID 985556. 
  28. ↑ "Piracetam: physiological disposition and mechanism of action". Advances in Neurology 43: 675–685. 1986. PMID 3946121. 
  29. ↑ "Rapid determination of piracetam in human plasma and cerebrospinal fluid by micellar electrokinetic chromatography with sample direct injection". Journal of Chromatography A 1120 (1–2): 27–34. July 2006. doi:10.1016/j.chroma.2005.11.071. PMID 16343512. 
  30. ↑ "A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons". Experimental Biology and Medicine 237 (10): 1209–1218. October 2012. doi:10.1258/ebm.2012.012128. PMID 23045722. 
  31. ↑ (in en) Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. 2013. p. 276. ISBN 9781118354469. https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA276. 
  32. ↑ (in en) The End of Epilepsy?: A History of the Modern Era of Epilepsy Research 1860-2010. Oxford University Press. 2016. p. 69. ISBN 9780198725909. https://books.google.com/books?id=upjSDAAAQBAJ&pg=PA68. 
  33. ↑ "Call for testing on 'smart drugs'". Fairfax Media. 1 October 2009. http://www.watoday.com.au/national/call-for-testing-on-smart-drugs-20091002-gf8t.html. 
  34. ↑ "Erowid Piracetam Vault: Legal Status". https://erowid.org/smarts/piracetam/piracetam_law.shtml. 
  35. ↑ "FDA proposes ban on curcumin and other naturopathic favorites in compounded drugs". Science-Based Medicine. 26 September 2019. https://sciencebasedmedicine.org/fda-proposes-ban-on-curcumin-and-other-naturopathic-favorites-in-compounded-drugs/. 
  36. ↑ "Parallel import (PI) licences granted in June 2015". UK Government. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/445573/Monthly_PLPI_listing_June_2015.pdf. 
  37. ↑ "Nootropil Tablets 800 mg". https://www.medicines.org.uk/emc/medicine/27469. 
  38. ↑ "UCB's piracetam approved in Japan". The Pharma Letter. 1999-11-25. https://www.thepharmaletter.com/article/ucb-s-piracetam-approved-in-japan. 
  39. ↑ "Fulltext". https://www.sukl.cz/modules/search/index.php?plugin=3&query=piracetam. 
  40. ↑ https://www.sukl.cz/uploads/Prehledy_a_databaze/SCAU081231i.txt?highlightWords=piracetam
  41. ↑ "Guidance Document on the Import Requirements for Health Products under the Food and Drugs Act and its Regulations (GUI-0084)". Health Canada / Health Products and Food Branch Inspectorate. 1 June 2010. https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/importation-exportation/guidance-document-import-requirements-health-products-under-food-drugs-act-regulations-0084.html#a6. 

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