This page describes pharmacological agents that may have legal restrictions, side effects, and drug interactions in your jurisdiction. Information is for educational research only — consult a clinician before considering any compound.
Nefiracetam
Daiichi Seiyaku's "anti-apathy" racetam (DM-9384) — piracetam analog with a 2,6-dimethylphenyl group that gives it unique GABA_A agonism…
Aliases (7)
Overview
What is Nefiracetam?
Nefiracetam is a pyrrolidinone-class racetam nootropic developed in Japan by Daiichi Pharmaceutical, structurally related to piracetam but with greater lipophilicity and potency. It was investigated for post-stroke cognitive impairment, Alzheimer's, and post-stroke depression.
Key Benefits
Reported to enhance memory, learning, and cognitive recovery after ischemic injury, with additional anxiolytic and antidepressant effects in trial settings. Subjective effects include improved focus, motivation, and emotional resilience; clinical development was halted due to toxicity findings in beagles.
Mechanism of Action
Potentiates nicotinic acetylcholine receptors (especially α4β2), enhances NMDA receptor calcium currents via PKC, and modulates GABA-A receptor function. Increases hippocampal acetylcholine release and protein kinase C activation, supporting long-term potentiation.
Pharmacokinetics
▸Brand options6 known
StatusAustralia S4 (prescription only); Unscheduled in US/EU; never approved anywhere — Daiichi withdrew Japanese NDA Feb 2002. Research-chem-only globally.
Research Indications
The racetam scaffold + the 2,6-dimethylphenyl twist
Nefiracetam (DM-9384) is *N*-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide — a piracetam derivative where the simple amide of pi…
Five mechanistic prongs (each documented in vitro / in vivo)
1. GABA_A receptor — the unique racetam. Nefiracetam binds GABA_A with IC50 ≈ 8.5 nM and inhibits ~80% of muscimol binding (Yamamoto et a…
GABAergic + cholinergic + monoaminergic — the cytoprotective triad
Reviews summarize nefiracetam's cytoprotective actions as enhancement of GABAergic, cholinergic, and monoaminergic neuronal systems. In a…
Plain English
Nefiracetam is the racetam that does five things at once: it nudges your GABA_A receptors toward calm (the anxiolytic flavor users descri…
Why the apathy/depression indication
Apathy after stroke is hypothesized to involve disrupted prefrontal-subcortical / mesocortical circuits affecting motivation. Nefiracetam…
Peptide Interactions
Mechanistically complementary — pramiracetam dominates choline uptake / cholinergic memory side, nefiracetam adds GABA_A + motivation. Some community users r…
AMPA-mediated mood + nefiracetam GABA_A modulation = anxiolytic stack. Sociability / mood + anti-apathy. Theoretical complement.
Both have GABA-flavored anxiolytic profile but different receptors (GABA_A vs GABA_B). Stack rationale weak; might be redundant.
Acetylcholine substrate support — required for any racetam stack. Already in the canonical stack.
Cerebrolysin provides exogenous neurotrophic peptides; nefiracetam upregulates endogenous BDNF via CREB. Theoretically complementary, particularly post-strok…
Bromantane = dopaminergic anti-asthenia; nefiracetam = GABAergic anti-apathy. Both target motivation by orthogonal pathways. Theoretical synergy for "low-mot…
No documented interaction. Orthogonal mechanism (orexin/histamine vs racetam multi-target). Modafinil daytime + nefiracetam BID-TID with last dose mid-aftern…
Theoretical GABA_A receptor competition — nefiracetam is a GABA_A agonist with significant binding affinity; chronic BZD use complicates the receptor state. …
Nefiracetam 5-OH metabolism is CYP3A4-dominant. Strong inhibitors raise nefiracetam exposure; titrate down or avoid combination.
Diminishing returns + cumulative choline depletion → headache cascade. Pick one primary racetam.
Theoretical compounding of any (very low) renal risk. Probably negligible in humans but conservative.
Quality Indicators
Pharmacy-dispensed, intact packaging
Prescription tablets in original sealed packaging from a licensed pharmacy.
Generic vs branded
Generics are usually fine but bioavailability can vary slightly; track if you switch.
Unbranded blister or counterfeit risk
Counterfeit pharmaceuticals are a known issue; verify pharmacy and lot if buying internationally.
What to Expect
- Acutesingle-dose effects: minimal to none for most users. Unlike phenylpiracetam (felt within 1-2 hours) or modafinil, nefiracetam is a "build-up" molecule.
- Week 2-4The "nefiracetam phenotype" emerges — calm focus, reduced mental friction, motivation lift, less apathy/inertia. Verbal fluency reportedly improved. Mild an…
Side Effects & Safety 6
Side Effects
- 1Headache — most common; dose-dependent; substantially mitigated by choline co-administration (CDP-choline / alpha-GPC). The canonical stack's Cognizin already covers this.
- 2Mild GI — nausea, dyspepsia. More likely on empty stomach. Take with food.
- 3Nervousness / anxiety paradox — some users report stimulation rather than calm at higher doses (despite GABA_A agonism). Resolves with dose reduction.
- 4Insomnia — uncommon at standard doses, more likely with late-day dosing
- 5Mild fatigue — paradoxical, especially at >600 mg/day
- 6Mild mood blunting — rare, dose-dependent, reversible
When to Stop
- No documented cardiovascular signal in human trials
- No hepatotoxicity signal in humans — see "Controversies" section below; this is the spot the "rat hepatotoxicity" rumor lives, and it appears to be misattribution
- No suicidality signal in pooled trial data
- No human renal toxicity signal — despite the dog renal papillary necrosis finding, humans do not produce the M-18 metabolite responsible for the dog finding, and human urinary metabolite profiles match monkeys (the non-affected species)
- First 2 weeks: GI tolerance window. Headache window — should resolve with choline.
- Week 4-8: Subjective-effect detection window. If no effect at 450-600 mg/day, the molecule probably isn't doing anything for you.
- Indefinite for chronic use: No human safety data beyond ~12 weeks of continuous dosing. Treat any longer-term use as off-label / self-experimental.
- Beagle dog 13-week and 52-week oral toxicity studies:
- 20 mg/kg/day = no-observed-effect level (NOEL)
- 60 mg/kg/day → hypospermatogenesis + splenic hemosiderin
- 90-180 mg/kg/day → renal papillary necrosis, decreased food intake, urinary protein/volume changes, testicular toxicity (seminiferous atrophy with multinucleated giant cells)
- Mechanism: Dog-specific M-18 metabolite penetrates renal papilla, inhibits prostaglandin synthesis, and accumulates due to dog-specific metabolism. M-18 is not formed in humans.
- Rat: No renal papillary necrosis. Testicular toxicity appears only at much higher doses than dogs. No documented hepatotoxicity in standard rat tox studies.
- Monkey: Human-like metabolism; no renal papillary necrosis; clean tox profile.
References
Nefiracetam — Wikipedia
chemistry, mechanism summary, regulatory status (Australia S4), GABA_A IC50, cytoprotective triad
View StudyNefiracetam. Daiichi Seiyaku — PubMed (Drugs in R&D)
Daiichi pipeline review covering NDA history, Japanese Phase 3 retrial outcome, Feb 2002 withdrawal
View StudyRobinson et al. 2008 — Double-blind randomized treatment of poststroke depression using nefiracetam (J Neuropsychiatry Clin Neurosci)
Phase 2 multicenter US/Canada, n=159; primary HDRS endpoint missed; top-quintile subgroup showed 900 mg effect
View StudyRobinson et al. 2009 — Double-blind treatment of apathy in patients with poststroke depression using nefiracetam (J Neuropsychiatry Clin Neurosci)
Apathy substudy of 2008 cohort, n=70 with apathy; 900 mg arm significantly improved Apathy Scale vs 600 mg or placebo
View StudyRobinson 2009 paper — psychiatryonline.org full citation
primary publication record
View StudyStarkstein et al. 2016 — Randomized placebo-controlled double-blind efficacy study of nefiracetam to treat poststroke apathy (J Stroke Cerebrovasc Dis)
Perth Australia 2-center trial; n=13 randomized of 2,514 screened; 12 weeks 900 mg/day; no significant between-group difference (P > 0.14); underpowered null
View StudyCellular mechanism of action of cognitive enhancers: effects of nefiracetam on neuronal Ca²⁺ channels — Yoshii et al. (PubMed 10850736)
L-type and N-type Ca²⁺ channel facilitation in NG108-15 cells; PKA-mediated
View StudyNefiracetam Modulates Acetylcholine Receptor Currents via Two Different Signal Transduction Pathways (Mol Pharmacol)
13147-1/abstract) — dissociation of PKC (nAChR) vs PKA (Ca²⁺ channel) signaling
View StudyNefiracetam facilitates hippocampal synaptic transmission via presynaptic α4β2 nAChR — Watanabe (ScienceDirect)
PKC-mediated nicotinic ACh receptor potentiation, presynaptic glutamate release, hippocampal LTP-like effect
View StudyNefiracetam Potentiates NMDA Receptor Function via PKC and Reduces Mg²⁺ Block — Moriguchi et al. (ResearchGate)
NMDA arm of mechanism
View StudyDM-9384 increases turnover of GABAergic system in rat cerebral cortex (PubMed via Sciencedirect)
original GABA turnover + GAD activity finding
View StudyEffects of nefiracetam on BDNF and synapsin I in microsphere-embolized rats — Tanabe et al. 2005
CREB-mediated BDNF/synapsin restoration in rat cerebral ischemia model
View StudyPersistent Effects of Delayed Nefiracetam on Water Maze in Rats with Sustained Cerebral Ischemia (Sciencedirect)
adenylyl cyclase / cAMP / PKA pathway protection in cerebral ischemia model
View StudyInfluence of nefiracetam on NGF-induced neuritogenesis and NCAM polysialic acid expression — Belluardo et al. 1997
aged rat hippocampal NCAM-PSA polysialylation, 9 mg/kg/day i.p. × 40 days
View StudyAntiepileptic effect of nefiracetam on kainic acid-induced limbic seizure in rats
antiepileptic signal at >100 mg/kg with sedation; never advanced to humans
View StudySingle- and multiple-dose pharmacokinetics of nefiracetam in healthy volunteers — Fujimaki 1992
human PK: Tmax ~2 h, t1/2 3-5 h
View StudyPharmacokinetics of nefiracetam and three metabolites in humans — stereoselective hydroxylation (Xenobiotica 1993)
human metabolite profile; 17.8% urinary excretion of pyrrolidine-ring scission product
View StudyNefiracetam metabolism by human liver microsomes — CYP3A4 and CYP1A2 in 5-OH formation
CYP3A4 dominant for 5-OH metabolite; minor CYP1A2 + CYP2C19 contribution
View Study52-week oral toxicity study of nefiracetam in dogs (PubMed 8018095)
beagle dog chronic tox: 10 mg/kg NOEL; 90 mg/kg renal + testicular target organs
View Study13-week oral toxicity study of nefiracetam in dogs (PubMed 8018093)
subchronic dog tox; 20 mg/kg NOEL; renal papillary necrosis at 180 mg/kg
View StudyComprehensive evaluation of canine renal papillary necrosis induced by nefiracetam
dog-specific M-18 metabolite mechanism; renal-papillary prostaglandin inhibition
View StudyInvestigation on urinary proteins and renal mRNA in canine nefiracetam papillary necrosis (Arch Toxicol 2005)
300 mg/kg/day × 11 weeks beagle dog mechanistic detail
View StudyTesticular toxicity induced in dogs by nefiracetam (PubMed 15082078)
seminiferous atrophy + multinucleated giant cells at 180-300 mg/kg/day in dogs
View StudyInvestigation of testicular toxicity of nefiracetam in rats (ResearchGate)
rat testicular tox at very high doses (less sensitive than dog)
View StudySynapse PatSnap drug profile — Nefiracetam
pipeline status aggregator: discontinued; Neuren Pharmaceuticals listed; no 2020-2026 activity
View StudyNootropics Expert — nefiracetam
community-facing dosing + subjective-effect aggregation
View StudyWholistic Research — nefiracetam guide
community dosing protocols + side-effect summary
View StudyThe Pharmaletter — Daiichi aims to regain Translon approval
historical Translon brand context
View StudyImproving Nefiracetam Dissolution and Solubility Using Cocrystallization (Pharmaceutics 2020)
formulation chemistry; relevant for absorption variability
View StudyHow was your experience with this compound?
Anonymous · one vote per session · results below at 5+ votes.
See something off?
Most of this wiki is AI-generated. Suggest a correction, dosing update, or new evidence — we review every submission.