Nefiracetam
•Last Updated: September 28 2022
Nefiracetam is a nootropic compound of the racetam family with similarities to Aniracetam. It seems to enhance both GABAergic and cholinergic signalling, and long term usage appears to be both neuroprotective and nootropic in research animals (similar trends in human studies).
Nefiracetam is most often used for
Last Updated: September 28 2022
Nefiracetam is a cognitive enhancer (nootropic) of the racetam class, derived initially from the parent molecule piracetam but it shares most structurally similarity to aniracetam. Both nefiracetam and aniracetam are fat soluble racetam drugs for the purpose of memory enhancement or the treatment of cognitive decline.
In regards to acute usage, a single dosage of nefiracetam does not appear to significantly affect memory formation. Nefiracetam appears to be able to increase memory formation when taken daily over a prolonged period of time (7 days or longer), which has been repeatedly shown in animal studies with some limited human evidence suggesting the same. Prolonged supplementation is also associated with a higher rate of neurogenesis, which is not seen acutely.
The mechanisms of nefiracetam seem to be linked back to two pathways. One of these pathways is prolonging the opening of calcium channels (tied into PKA and a Gi/o protein) which enhances signalling of a receptor independent of the synapse, and the other pathway seems to be tied into PKC and CAMKII which then augments signalling through cholinergic receptors (which then releases most excitatory neurotransmitters from the presynaptic level in a manner similar to nicotine).
The former pathway (calcium channels) appears to be critical for long-term potentiation, whereas the latter pathway (PKC/CAMKII) appears to be vital for neuronal signal enhancement.
Some other minor pathways include being a partial agonist at the glycine binding site of the NDMA receptor (may enhance signalling when there are subpar levels of glycine, but attenuates excessive signalling) and increasing affinity of the muscarinic acetylcholine receptors for its ligand, acetylcholine.
Nefiracetam is a cogntive enhancer that appears to promote memory formation, and it does so via enhancing signalling of acetylcholine and glutamate at the synapse and then prolonging the calcium in the activated neuron. It does not appear to work acutely, but requires daily supplementation
In regards to the potential toxicity of nefiracetam, it does appear to be reliably toxic in dogs at doses that are much higher than the recommended supplemental dosage; lower doses seem to be free from toxicity, and these lower doses barely fit into the recommended dosage range.
That being said, there is evidence to suggest that this toxicity is exclusive to canines as it has not been detected in rats nor monkeys. There is insufficient human testing to absolutely confirm that it isn't a concern for humans, but the limited human evidence at this point in time using the recommended nefiracetam dosages do not find any significant complications.
Nefiracetam is highly toxic to dogs, but this does not appear to extend to monkeys nor rodents. While it has not been completely confirmed to be harmful or harmless in humans, the standard supplemental dosages do not appear to be associated with overt toxicity in preliminary studies
Note that Nefiracetam is also known as:
- DM-9384
- N-2 6-dimethylphenyl)-2-(2-oxopyrrolidine-1-yl)-acetamide
Supplementation of nefiracetam appears to be in the 150-450mg range over the course of a day (usually divided into three even doses). Animal studies using acute doses tend to note most benefits in the 3-10mg/kg range, and this correlates to a human dose of 0.48-1.6mg/kg (for a 150lb person, 33-110mg) which is similar to the aforementioned human doses.
Although single doses of nefiracetam do not appear to promote cognition, it is able to affect the brain within 30-60 minutes following oral ingestion. It is not certain whether nefiracetam needs to be taken prior to cognitive training.
1.^Effects of nefiracetam, DM-9384 on amnesia and decrease in cholineacetyltransferase activity induced by cycloheximide.()
2.^Farsa OChromatographic behaviour predicts the ability of potential nootropics to permeate the blood-brain barrierSci Pharm.(2013 Mar)
4.^Kumar R, Reeta KH, Ray SBAntinociceptive effect of intrathecal loperamide: role of mu-opioid receptor and calcium channelsEur J Pharmacol.(2012 Dec 5)
5.^Lu XC, Dave JR, Chen Z, Cao Y, Liao Z, Tortella FCNefiracetam attenuates post-ischemic nonconvulsive seizures in rats and protects neuronal cell death induced by veratridine and glutamateLife Sci.(2013 Jun 13)
6.^ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase.()
7.^Katada T, Bokoch GM, Northup JK, Ui M, Gilman AGThe inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase. Properties and function of the purified proteinJ Biol Chem.(1984 Mar 25)
9.^Nishizaki T, Nomura T, Matuoka T, Kondoh T, Enikolopov G, Sumikawa K, Watabe S, Shiotani T, Yoshii MThe anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptorsBrain Res Mol Brain Res.(2000 Aug 14)
10.^Narahashi T, Moriguchi S, Zhao X, Marszalec W, Yeh JZMechanisms of action of cognitive enhancers on neuroreceptorsBiol Pharm Bull.(2004 Nov)
12.^The impact of postsynaptic calcium on synaptic transmission — its role in long-term potentiation.()
13.^Chorvat RJ, Zaczek R, Brown BSIon channel modulators that enhance acetylcholine release: potential therapies for Alzheimer's diseaseExpert Opin Investig Drugs.(1998 Apr)
14.^Yoshii M, Watabe SEnhancement of neuronal calcium channel currents by the nootropic agent, nefiracetam (DM-9384), in NG108-15 cellsBrain Res.(1994 Apr 11)
16.^Yamada K, Nakayama S, Shiotani T, Hasegawa T, Nabeshima TPossible involvement of the activation of voltage-sensitive calcium channels in the ameliorating effects of nefiracetam on scopolamine-induced impairment of performance in a passive avoidance taskJ Pharmacol Exp Ther.(1994 Sep)
17.^Kim H, Han SH, Quan HY, Jung YJ, An J, Kang P, Park JB, Yoon BJ, Seol GH, Min SSBryostatin-1 promotes long-term potentiation via activation of PKCα and PKCε in the hippocampusNeuroscience.(2012 Dec 13)
18.^Moriguchi S, Shioda N, Maejima H, Zhao X, Marszalec W, Yeh JZ, Fukunaga K, Narahashi TNefiracetam potentiates N-methyl-D-aspartate (NMDA) receptor function via protein kinase C activation and reduces magnesium block of NMDA receptorMol Pharmacol.(2007 Feb)
19.^Moriguchi S, Shioda N, Han F, Narahashi T, Fukunaga KCaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 regionJ Neurochem.(2008 Aug)
20.^Ohmitsu M, Fukunaga K, Yamamoto H, Miyamoto EPhosphorylation of myristoylated alanine-rich protein kinase C substrate by mitogen-activated protein kinase in cultured rat hippocampal neurons following stimulation of glutamate receptorsJ Biol Chem.(1999 Jan 1)
21.^Tingley WG, Ehlers MD, Kameyama K, Doherty C, Ptak JB, Riley CT, Huganir RLCharacterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodiesJ Biol Chem.(1997 Feb 21)
22.^Roche KW, O'Brien RJ, Mammen AL, Bernhardt J, Huganir RLCharacterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunitNeuron.(1996 Jun)
23.^Edwards S, Simmons DL, Galindo DG, Doherty JM, Scott AM, Hughes PD, Wilcox REAntagonistic effects of dopaminergic signaling and ethanol on protein kinase A-mediated phosphorylation of DARPP-32 and the NR1 subunit of the NMDA receptorAlcohol Clin Exp Res.(2002 Feb)
24.^Moriguchi S, Han F, Shioda N, Yamamoto Y, Nakajima T, Nakagawasai O, Tadano T, Yeh JZ, Narahashi T, Fukunaga KNefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized miceJ Neurochem.(2009 Jul)
25.^Yamagata YNew aspects of neurotransmitter release and exocytosis: dynamic and differential regulation of synapsin I phosphorylation by acute neuronal excitation in vivoJ Pharmacol Sci.(2003 Sep)
26.^Moriguchi SPharmacological study on Alzheimer's drugs targeting calcium/calmodulin-dependent protein kinase IIJ Pharmacol Sci.(2011)
27.^Nabeshima T, Tohyama K, Murase K, Ishihara S, Kameyama T, Yamasaki T, Hatanaka S, Kojima H, Sakurai T, Takasu Y, et alEffects of DM-9384, a cyclic derivative of GABA, on amnesia and decreases in GABAA and muscarinic receptors induced by cycloheximideJ Pharmacol Exp Ther.(1991 Apr)
28.^Nabeshima T, Noda Y, Itoh K, Kameyama TRole of cholinergic and GABAergic neuronal systems in cycloheximide-induced amnesia in micePharmacol Biochem Behav.(1988 Oct)
29.^Abe EReversal effect of DM-9384 on scopolamine-induced acetylcholine depletion in certain regions of the mouse brainPsychopharmacology (Berl).(1991)
30.^Pak J, Green J, Heifets B, Pak M, Woodruff-Pak DNefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbitMed Sci Monit.(2002 Apr)
31.^Woodruff-Pak DS, Green JT, Pak JT, Shiotani T, Watabe S, Tanaka MThe long-term effects of nefiracetam on learning in older rabbitsBehav Brain Res.(2002 Oct 17)
32.^Fontán-Lozano A, Troncoso J, Múnera A, Carrión AM, Delgado-García JMCholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioningLearn Mem.(2005 Nov-Dec)
33.^Woodruff-Pak DS, Li YT, Hinchliffe RM, Port RLHippocampus in delay eyeblink classical conditioning: essential for nefiracetam amelioration of learning in older rabbitsBrain Res.(1997 Feb 7)
34.^Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi TStructure of the human M2 muscarinic acetylcholine receptor bound to an antagonistNature.(2012 Jan 25)
35.^Nishizaki T, Matsuoka T, Nomura T, Kondoh T, Watabe S, Shiotani T, Yoshii MPresynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmissionAlzheimer Dis Assoc Disord.(2000)
36.^Nomura T, Nishizaki TNefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam actionBrain Res.(2000 Jul 7)
37.^Moriguchi S, Zhao X, Marszalec W, Yeh JZ, Fukunaga K, Narahashi TNefiracetam and galantamine modulation of excitatory and inhibitory synaptic transmission via stimulation of neuronal nicotinic acetylcholine receptors in rat cortical neuronsNeuroscience.(2009 May 5)
38.^Sakurai T, Kato T, Mori K, Takano E, Watabe S, Nabeshima TNefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis studyNeurosci Lett.(1998 Apr 24)
39.^Kawajiri S, Taniguchi K, Sakurai T, Yamasaki TNefiracetam enhances acetylcholine outflow from the frontal cortex: in vivo microdialysis study in the ratJ Neural Transm Gen Sect.(1994)
40.^Fukatsu T, Miyake-Takagi K, Nagakura A, Omino K, Okuyama N, Ando T, Takagi N, Furuya Y, Takeo SEffects of nefiracetam on spatial memory function and acetylcholine and GABA metabolism in microsphere-embolized ratsEur J Pharmacol.(2002 Oct 18)
41.^Oyaizu M, Narahashi TModulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetamBrain Res.(1999 Mar 20)
42.^Zhao X, Kuryatov A, Lindstrom JM, Yeh JZ, Narahashi TNootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neuronsMol Pharmacol.(2001 Apr)
43.^Nishizaki T, Matsuoka T, Nomura T, Sumikawa K, Shiotani T, Watabe S, Yoshii MNefiracetam modulates acetylcholine receptor currents via two different signal transduction pathwaysMol Pharmacol.(1998 Jan)
44.^Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EXNicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networksJ Neurosci.(2000 Jan 1)
45.^Moriguchi S, Marszalec W, Zhao X, Yeh JZ, Narahashi TPotentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neuronsJ Pharmacol Exp Ther.(2003 Oct)
46.^Chen L, Huang LYProtein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulationNature.(1992 Apr 9)
47.^Nishizaki T, Matsuoka T, Nomura T, Matsuyama S, Watabe S, Shiotani T, Yoshii MA 'long-term-potentiation-like' facilitation of hippocampal synaptic transmission induced by the nootropic nefiracetamBrain Res.(1999 May 1)
48.^Moriguchi S, Zhao X, Marszalec W, Yeh JZ, Narahashi TModulation of N-methyl-D-aspartate receptors by donepezil in rat cortical neuronsJ Pharmacol Exp Ther.(2005 Oct)
49.^Choi DW, Rothman SMThe role of glutamate neurotoxicity in hypoxic-ischemic neuronal deathAnnu Rev Neurosci.(1990)
50.^Aihara H, Li X, Fujiwara S, Matsumura T, Okumura S, Tozaki H, Kanno T, Ohta K, Nagai K, Nishizaki TThe protective action of nefiracetam against electrophysiological and metabolic damage in the hippocampus after deprivation of glucose and oxygenBrain Res.(2001 Dec 13)
51.^Watabe S, Yamaguchi H, Ashida SDM-9384, a new cognition-enhancing agent, increases the turnover of components of the GABAergic system in the rat cerebral cortexEur J Pharmacol.(1993 Jul 20)
52.^Nabeshima T, Noda Y, Tohyama K, Itoh J, Kameyama TEffects of DM-9384 in a model of amnesia based on animals with GABAergic neuronal dysfunctionsEur J Pharmacol.(1990 Mar 20)
53.^Huang CS, Ma JY, Marszalec W, Narahashi TEffects of the nootropic drug nefiracetam on the GABAA receptor-channel complex in dorsal root ganglion neuronsNeuropharmacology.(1996)
54.^Nakamoto Y, Watabe S, Shiotani T, Yoshii MPeripheral-type benzodiazepine receptors in association with epileptic seizures in EL miceBrain Res.(1996 Apr 22)
55.^Ducis I, Norenberg LO, Norenberg MDThe benzodiazepine receptor in cultured astrocytes from genetically epilepsy-prone ratsBrain Res.(1990 Oct 29)
56.^Bénavidès J, Guilloux F, Allam DE, Uzan A, Mizoule J, Renault C, Dubroeucq MC, Guérémy C, Le Fur GOpposite effects of an agonist, RO5-4864, and an antagonist, PK 11195, of the peripheral type benzodiazepine binding sites on audiogenic seizures in DBA/2J miceLife Sci.(1984 Jun 25)
57.^Shiotani T, Nakamoto Y, Watabe S, Yoshii M, Nabeshima TAnticonvulsant actions of nefiracetam on epileptic EL mice and their relation to peripheral-type benzodiazepine receptorsBrain Res.(2000 Mar 24)
58.^Nakamoto Y, Shiotani T, Watabe S, Nabeshima T, Yoshii MNootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL miceAnn N Y Acad Sci.(2004 Oct)
59.^Luthman J, Lindqvist E, Dell'Anna E, Kojima H, Shiotani T, Tachizawa H, Olson LEffects of DM-9384, a pyrrolidone derivative, on ischemia-induced changes in the central monoamine systemsPharmacol Biochem Behav.(1992 Jan)
60.^Luthman J, Lindqvist E, Kojima H, Shiotani T, Tanaka M, Tachizawa H, Olson LEffects of nefiracetam (DM-9384), a pyrrolidone derivative, on brain monoamine systemsArch Int Pharmacodyn Ther.(1994 Sep-Oct)
61.^Cassaday HJ, Hodges H, Gray JAThe effects of ritanserin, RU 24969 and 8-OH-DPAT on latent inhibition in the ratJ Psychopharmacol.(1993 Jan)
62.^Nakamura K, Kurasawa MSerotonergic mechanisms involved in the attentional and vigilance task performance of rats and the palliative action of aniracetamNaunyn Schmiedebergs Arch Pharmacol.(2000 May)
63.^Brandão ML, Lopez-Garcia JA, Graeff FG, Roberts MHElectrophysiological evidence for excitatory 5-HT2 and depressant 5-HT1A receptors on neurones of the rat midbrain tectumBrain Res.(1991 Aug 16)
64.^Murphy KJ, Foley AG, O'connell AW, Regan CMChronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearingNeuropsychopharmacology.(2006 Jan)
65.^Young D, Lawlor PA, Leone P, Dragunow M, During MJEnvironmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotectiveNat Med.(1999 Apr)
66.^Odumeru O, Murphy KJ, O'Connell AW, Regan CM, Shiotani TInfluence of nefiracetam on NGF-induced neuritogenesis and neural cell adhesion molecule polysialic acid expression: in vivo and in vitro comparisonsBehav Brain Res.(1997 Feb)
67.^Sakurai T, Ojima H, Yamasaki T, Kojima H, Akashi AEffects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (DM-9384) on learning and memory in ratsJpn J Pharmacol.(1989 May)
68.^Nabeshima T, Nakayama S, Ichihara K, Yamada K, Shiotani T, Hasegawa TEffects of nefiracetam on drug-induced impairment of latent learning in mice in a water finding taskEur J Pharmacol.(1994 Apr 1)
70.^Nabeshima T, Tohyama K, Kameyama TEffects of DM-9384, a pyrrolidone derivative, on alcohol- and chlordiazepoxide-induced amnesia in micePharmacol Biochem Behav.(1990 Jun)
71.^Doyle E, O'Boyle KM, Shiotani T, Regan CMNefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: delayed emergence of the memory retention effectsNeurochem Res.(1996 Jun)
72.^Improvement by nefiracetam of β-amyloid-(1-42)-induced learning and memory impairments in rats.()
73.^Hiramatsu M, Koide T, Ishihara S, Shiotani T, Kameyama T, Nabeshima TInvolvement of the cholinergic system in the effects of nefiracetam (DM-9384) on carbon monoxide (CO)-induced acute and delayed amnesiaEur J Pharmacol.(1992 Jun 5)
74.^Doyle E, Regan CM, Shiotani TNefiracetam (DM-9384) preserves hippocampal neural cell adhesion molecule-mediated memory consolidation processes during scopolamine disruption of passive avoidance training in the ratJ Neurochem.(1993 Jul)
75.^Woodruff-Pak DS, Hinchliffe RMMecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetamPsychopharmacology (Berl).(1997 May)
76.^Kitano Y, Komiyama C, Makino M, Takasuna K, Satoh H, Aoki T, Kinoshita M, Takazawa A, Yamauchi T, Sakurada SAnticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in ratsBrain Res.(2005 Sep 28)
77.^Kitano Y, Komiyama C, Makino M, Takasuna K, Takazawa A, Sakurada SAnticonvulsant properties of the novel nootropic agent nefiracetam in seizure models of mice and ratsEpilepsia.(2005 Jun)
78.^Kitano Y, Komiyama C, Makino M, Kasai Y, Takasuna K, Kinoshita M, Yamazaki O, Takazawa A, Yamauchi T, Sakurada SEffects of Nefiracetam, a novel pyrrolidone-type nootropic agent, on the amygdala-kindled seizures in ratsEpilepsia.(2005 Oct)
79.^Han F, Nakano T, Yamamoto Y, Shioda N, Lu YM, Fukunaga KImprovement of depressive behaviors by nefiracetam is associated with activation of CaM kinases in olfactory bulbectomized miceBrain Res.(2009 Apr 10)
80.^Robinson RG, Jorge RE, Clarence-Smith K, Starkstein SDouble-blind treatment of apathy in patients with poststroke depression using nefiracetamJ Neuropsychiatry Clin Neurosci.(2009 Spring)
81.^Robinson RG, Jorge RE, Clarence-Smith KDouble-blind randomized treatment of poststroke depression using nefiracetamJ Neuropsychiatry Clin Neurosci.(2008 Spring)
82.^Starkstein SE, Petracca G, Chemerinski E, Kremer JSyndromic validity of apathy in Alzheimer's diseaseAm J Psychiatry.(2001 Jun)
83.^Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RGReliability, validity, and clinical correlates of apathy in Parkinson's diseaseJ Neuropsychiatry Clin Neurosci.(1992 Spring)
85.^Fonnum F, Myhrer T, Paulsen RE, Wangen K, Oksengård ARRole of glutamate and glutamate receptors in memory function and Alzheimer's diseaseAnn N Y Acad Sci.(1995 May 10)
86.^Giacobini ECholinesterase inhibitor therapy stabilizes symptoms of Alzheimer diseaseAlzheimer Dis Assoc Disord.(2000)
88.^Shimomura K, Shimada M, Hagiwara M, Harada S, Kato M, Furuhama KTesticular toxicity induced in dogs by nefiracetam, a neutrotransmission enhancerReprod Toxicol.(2004 May)
89.^Sugawara T, Kato M, Furuhama K, Inage F, Suzuki N, Takayama SSingle dose toxicity study of the new cognition-enhancing agent nefiracetam in mice, rats and dogsArzneimittelforschung.(1994 Feb)
90.^Sugawara T, Kato M, Suzuki N, Akahane K, Takayama SThirteen-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogsArzneimittelforschung.(1994 Feb)
91.^Hooks WN, Burford P, Begg S, Gopinath C, Inage F, Kato M, Takayama SFifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogsArzneimittelforschung.(1994 Feb)
92.^Kashida Y, Yoshida M, Ishii Y, Nomura M, Kato MExamination of lesions in the urinary bladder and kidney of dogs induced by nefiracetam, a new nootropic agentToxicol Pathol.(1996 Sep-Oct)
93.^Tsuchiya Y, Tominaga Y, Matsubayashi K, Jindo T, Furuhama K, Suzuki KTInvestigation on urinary proteins and renal mRNA expression in canine renal papillary necrosis induced by nefiracetamArch Toxicol.(2005 Sep)
94.^Tsuchiya Y, Yabe K, Takada S, Ishii Y, Jindo T, Furuhama K, Suzuki KTEarly pathophysiological features in canine renal papillary necrosis induced by nefiracetamToxicol Pathol.(2005)