Nefiracetam

Overview

Nefiracetam is a non-peptide small molecule in the racetam (pyrrolidinone/2-oxopyrrolidine acetamide) class, investigated as a cognitive enhancer. It was never approved by the FDA, EMA, or Japan's PMDA; Daiichi Seiyaku withdrew its Japanese NDA (Translon) in February 2002 after a repeat Phase III trial in dementia failed to demonstrate efficacy. A US/Canada Phase II trial in poststroke depression (600 mg and 900 mg/day) showed no overall separation from placebo, though a subgroup analysis suggested benefit in the most severely depressed patients at 900 mg. No validated therapeutic dose or approved indication exists; it is sold by research-chemical and laboratory-reagent suppliers for research use only.

Mechanism of Action

No single validated human mechanism exists. In vitro and animal electrophysiology studies attribute effects to modulation of multiple neurotransmitter systems via second-messenger/protein-kinase pathways rather than direct receptor agonism. In rat cortical neurons, nefiracetam potentiates native neuronal α4β2-type nicotinic acetylcholine receptor currents via a G(s)-protein-dependent, PKA/PKC-independent pathway; however, in human α4β2 recombinant receptors (HEK293 cells) it was inhibitory rather than potentiating, indicating an unreconciled species-dependent effect. Rat studies also show dual (potentiating or suppressing) effects on GABA_A receptor-channel currents mediated via cAMP-dependent protein kinase and Gi/Go proteins, enhancement of high-voltage-activated N/L-type calcium channel currents, and modulation of NMDA receptor function via PKC-dependent phosphorylation. Review sources propose an integrative model of normalization of cholinergic, GABAergic, and possibly monoaminergic transmission plus calcium-channel modulation, but this is assembled from separate in vitro/animal experiments, not a confirmed human mechanism.

Research Summary

Human clinical data are limited and largely negative or mixed. Japanese Phase II/III trials in dementia/cognitive sequelae after cerebrovascular disorders showed improvement over placebo in some early trials, but a Ministry of Health-mandated repeat Phase III trial under revised guidelines failed to demonstrate efficacy, and Daiichi Seiyaku withdrew its Japanese NDA (Translon) in February 2002. A US/Canada multicenter randomized double-blind Phase II trial (28 sites, 1999–2001, n=159) tested nefiracetam 600 mg and 900 mg/day vs. placebo for poststroke depression; the drug did not separate from placebo overall (response >70%, remission >40% in both arms) but showed significant benefit in the most-severely-depressed subgroup at 900 mg (Robinson et al., J Neuropsychiatry Clin Neurosci 2008). A related post hoc analysis examined apathy outcomes in the same cohort. Preclinical findings include: rat cortical neurons showed potentiation of native α4β2-type nicotinic acetylcholine receptor currents via a G(s)-protein-dependent pathway; rat dorsal root ganglion neurons showed dual concentration-dependent effects on GABA_A receptor-channel currents mediated via cAMP-dependent protein kinase and Gi/Go proteins; rat neuronal preparations showed enhancement of high-voltage-activated N/L-type Ca²⁺ channel currents and modulation of NMDA receptor function via PKC-dependent phosphorylation; rat passive avoidance models showed reversal of apomorphine-induced amnesia and preservation of hippocampal NCAM-mediated memory consolidation during scopolamine disruption.

Prescribers who offer Nefiracetam

3 prescribers in our directory work with Nefiracetam, each confirmed from their own website. Peptides like Nefiracetam require a prescription from a licensed provider — telehealth options are available.

Reported Side Effects

• No validated human consumer dose or regulator-reviewed safety label exists
• Long-term and general-population safety data are not established
• Species-dependent pharmacology (rat vs. human recombinant nAChR data diverging in direction of effect) means animal findings may not reliably predict human receptor-level effects
• Never approved by FDA, EMA, or Japan's PMDA
• WADA/doping status unconfirmed (not verified against current official WADA Prohibited List)

Compare Nefiracetam with Others

Research References

• Nefiracetam - PubChem Compound Summary for CID 71157.
• Nefiracetam. DM 9384, DZL 221, Translon (Drugs R&D review). 2002. PMID 12099172.
• Nefiracetam. Daiichi Seiyaku (Curr Opin Investig Drugs). 2002. PMID 12090554.
• Double-blind randomized treatment of poststroke depression using nefiracetam. 2008. PMID 18451188.

Frequently asked questions

Has Nefiracetam been independently lab-tested?

Disclosed Labs has collected 2 Certificates of Analysis (COA) for Nefiracetam from 2 independent testing labs. 1 vendor has submitted material for testing. Products average 99.6% tested purity across the corpus. Full testing data is available at https://www.disclosedlabs.com/peptides/nefiracetam/testing.

Which prescribers offer Nefiracetam with a prescription?

3 prescribers in the Disclosed Labs directory work with Nefiracetam, each confirmed from their own website, with telehealth options available. Nefiracetam requires a prescription from a licensed provider. Browse them at https://www.disclosedlabs.com/prescribers?peptide=Nefiracetam.

How does Nefiracetam work?

No single validated human mechanism exists. In vitro and animal electrophysiology studies attribute effects to modulation of multiple neurotransmitter systems via second-messenger/protein-kinase pathways rather than direct receptor agonism. In rat cortical neurons, nefiracetam potentiates native neuronal α4β2-type nicotinic acetylcholine receptor currents via a G(s)-protein-dependent, PKA/PKC-independent pathway; however, in human α4β2 recombinant receptors (HEK293 cells) it was inhibitory rather than potentiating, indicating an unreconciled species-dependent effect. Rat studies also show dual (potentiating or suppressing) effects on GABA_A receptor-channel currents mediated via cAMP-dependent protein kinase and Gi/Go proteins, enhancement of high-voltage-activated N/L-type calcium channel currents, and modulation of NMDA receptor function via PKC-dependent phosphorylation. Review sources propose an integrative model of normalization of cholinergic, GABAergic, and possibly monoaminergic transmission plus calcium-channel modulation, but this is assembled from separate in vitro/animal experiments, not a confirmed human mechanism.

What does the research say about Nefiracetam?

Human clinical data are limited and largely negative or mixed. Japanese Phase II/III trials in dementia/cognitive sequelae after cerebrovascular disorders showed improvement over placebo in some early trials, but a Ministry of Health-mandated repeat Phase III trial under revised guidelines failed to demonstrate efficacy, and Daiichi Seiyaku withdrew its Japanese NDA (Translon) in February 2002. A US/Canada multicenter randomized double-blind Phase II trial (28 sites, 1999–2001, n=159) tested nefiracetam 600 mg and 900 mg/day vs. placebo for poststroke depression; the drug did not separate from placebo overall (response >70%, remission >40% in both arms) but showed significant benefit in the most-severely-depressed subgroup at 900 mg (Robinson et al., J Neuropsychiatry Clin Neurosci 2008). A related post hoc analysis examined apathy outcomes in the same cohort. Preclinical findings include: rat cortical neurons showed potentiation of native α4β2-type nicotinic acetylcholine receptor currents via a G(s)-protein-dependent pathway; rat dorsal root ganglion neurons showed dual concentration-dependent effects on GABA_A receptor-channel currents mediated via cAMP-dependent protein kinase and Gi/Go proteins; rat neuronal preparations showed enhancement of high-voltage-activated N/L-type Ca²⁺ channel currents and modulation of NMDA receptor function via PKC-dependent phosphorylation; rat passive avoidance models showed reversal of apomorphine-induced amnesia and preservation of hippocampal NCAM-mediated memory consolidation during scopolamine disruption.