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])
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 insufficient evidence of piracetam as a treatment for 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][unreliable source?] 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.
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]
According to a 2005 review, piracetam has been observed to have the following side effects: hyperkinesia, weight gain, anxiety, somnolence, depression, and weakness.[4]
Piracetam reduces platelet aggregation as well as fibrinogen concentration, and thus is contraindicated to patients with cerebral hemorrhage.[4][3]
Toxicity
The LD50 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 increases the action of the neurotransmitteracetylcholine via muscariniccholinergic (ACh) receptors[citation needed], which are implicated in memory processes.[24] Furthermore, piracetam may have an effect on NMDAglutamate 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 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 U.S. companies for decades.[6] 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[36] for adults 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 the 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.
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.
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.
^ abFlicker L, Grimley Evans G (2001). "Piracetam for dementia or cognitive impairment". The Cochrane Database of Systematic Reviews (2): CD001011. doi:10.1002/14651858.CD001011. PMID11405971.
^Farooq MU, Min J, Goshgarian C, Gorelick PB (September 2017). "Pharmacotherapy for Vascular Cognitive Impairment". CNS Drugs (Review). 31 (9): 759–776. doi:10.1007/s40263-017-0459-3. PMID28786085. S2CID23271739. 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.
^Zhang J, Wei R, Chen Z, Luo B (July 2016). "Piracetam for Aphasia in Post-stroke Patients: A Systematic Review and Meta-analysis of Randomized Controlled Trials". CNS Drugs. 30 (7): 575–587. doi:10.1007/s40263-016-0348-1. PMID27236454. S2CID22955205.
^Yeo SH, Lim ZI, Mao J, Yau WP (October 2017). "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. doi:10.1007/s40261-017-0558-4. PMID28756557. S2CID6520934.
^Chouinard G, Annable L, Ross-Chouinard A, Olivier M, Fontaine F (1983). "Piracetam in elderly psychiatric patients with mild diffuse cerebral impairment". Psychopharmacology. 81 (2): 100–106. doi:10.1007/BF00429000. PMID6415738. S2CID32702769.
^Hakkarainen H, Hakamies L (1978). "Piracetam in the treatment of post-concussional syndrome. A double-blind study". European Neurology. 17 (1): 50–55. doi:10.1159/000114922. PMID342247.
^ abWinnicka K, Tomasiak M, Bielawska A (2005). "Piracetam--an old drug with novel properties?". Acta Poloniae Pharmaceutica. 62 (5): 405–409. PMID16459490.
^ abGrau M, Montero JL, Balasch J (1987). "Effect of Piracetam on electrocorticogram and local cerebral glucose utilization in the rat". General Pharmacology. 18 (2): 205–211. doi:10.1016/0306-3623(87)90252-7. PMID3569848.
^Nickolson VJ, Wolthuis OL (October 1976). "Effect of the acquisition-enhancing drug piracetam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine". Biochemical Pharmacology. 25 (20): 2241–2244. doi:10.1016/0006-2952(76)90004-6. PMID985556.
^Tacconi MT, Wurtman RJ (1986). "Piracetam: physiological disposition and mechanism of action". Advances in Neurology. 43: 675–685. PMID3946121.
^Yeh HH, Yang YH, Ko JY, Chen SH (July 2006). "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. doi:10.1016/j.chroma.2005.11.071. PMID16343512.
^Bravo-Martínez J, Arenas I, Vivas O, Rebolledo-Antúnez S, Vázquez-García M, Larrazolo A, García DE (October 2012). "A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons". Experimental Biology and Medicine. 237 (10): 1209–1218. doi:10.1258/ebm.2012.012128. PMID23045722. S2CID25909697.
