nefiracetam
A selected post-stroke analysis found a larger apathy-score improvement with nefiracetam at 900 mg/day than with placebo. The parent 159-person depression trial was negative, a later 13-person apathy trial did not replicate the result, and Daiichi withdrew its Japanese application after a revised trial showed insufficient efficacy.
Small-molecule investigational racetam
- The 900 mg/day apathy signal came from 70 selected four-week completers inside a negative 159-person depression trial.
- A prospective apathy trial screened 2,514 stroke admissions, randomized 13 people, and found no between-group benefit.
- A completed 50-person NIH Alzheimer trial has no posted results, and the cited sources include no results paper.
- High-dose animal studies identified kidney and testis as target organs; chronic healthy-user safety is not established.
What is nefiracetam?
Nefiracetam, development code DM-9384, is an oral pyrrolidone compound developed by Daiichi. Human efficacy studies generally used 450 to 900 mg/day.
Healthy volunteers contributed short pharmacokinetic studies, while clinical programs enrolled stroke, dementia or depression populations. Animal and cell routes do not define a consumer regimen.
PubChem: nefiracetam chemical identity
Government chemical identity database
National Library of Medicine. PubChem CID 71157.
C14H18N2O2; molecular weight 246.30 g/mol.
- Participants / model
- Chemical record
- Follow-up
- Living database
- Study design
- Curated structure record
Formula and molecular weight establish the recorded structure, not the contents of a retail product or an effective dose.
Read the original sourceNefiracetam pharmacokinetics in healthy volunteers
Primary human pharmacokinetic study
Fujimaki Y, Sudo K, Hakusui H, Tachizawa H, Murasaki M. Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers. The Journal of pharmacy and pharmacology. 1992. DOI 10.1111/j.2042-7158.1992.tb05513.x.
After oral dosing in healthy Japanese men, peak concentrations occurred within two hours and half-lives were 3 to 5 hours. No clinically significant accumulation was observed during the seven-day repeated-dose study.
- Participants / model
- Healthy Japanese male volunteers
- Follow-up
- Single exposures and seven days of repeated dosing
- Study design
- Single- and multiple-dose pharmacokinetic study
This is exposure characterization, not proof of cognitive benefit or long-term safety.
Read the original sourceNefiracetam. Daiichi Seiyaku.
Indexed development-program profile
Crespi F. Current Opinion in Investigational Drugs. 2002. PMID 12090554.
Daiichi withdrew the Japanese application after a revised phase 3 trial supplied insufficient efficacy; completed Chinese trials were also noted without results.
- Participants / model
- Japanese and Chinese clinical development programs
- Follow-up
- Program history through February 2002
- Study design
- Development-status report
The report does not provide the protocol, denominators, endpoint table, or Chinese results.
Read the original sourceWhy did one apathy analysis look positive?
A secondary analysis found a 7.5-point apathy-score change with 900 mg/day versus 2.0 with placebo in 70 selected post-stroke patients (p=0.038 across groups).
The analysis excluded every participant with less than four weeks of follow-up. Only 3/22 early dropouts had apathy versus 70/137 retained patients, so the analyzed group differed sharply from those excluded.
Four of 22 people at 900 mg met the paper’s 75% remission threshold versus none of 22 on placebo. The 600 mg group did not separate, depression change was similar across groups, and apathy improvement did not track cognitive improvement.
Double-blind treatment of apathy in patients with poststroke depression using nefiracetam.
Primary human study
Robinson RG et al. The Journal of neuropsychiatry and clinical neurosciences. 2009. PMID 19622685. DOI 10.1176/jnp.2009.21.2.144.
The higher-dose group showed a greater change in apathy scores in the analyzed subgroup.
- Participants / model
- 70 patients with apathy among 137 stroke patients with major depression
- Follow-up
- At least 4 weeks
- Study design
- Randomized placebo-controlled analysis using participants with at least four weeks and last observation carried forward
The parent trial randomized 159 patients. This secondary analysis used 70 participants with apathy from a modified set of 137 who received at least four weeks of treatment. Excluding early withdrawals can bias the estimate.
Read the original sourceDouble-blind randomized treatment of poststroke depression using nefiracetam.
Primary human study
Robinson RG, Jorge RE, Clarence-Smith K. Double-blind randomized treatment of poststroke depression using nefiracetam. The Journal of neuropsychiatry and clinical neurosciences. 2008. DOI 10.1176/jnp.2008.20.2.178
The overall depression analysis did not show a significant time-by-treatment interaction.
- Participants / model
- 159 enrolled patients with major depression after stroke
- Study design
- Double-blind randomized nefiracetam-versus-placebo study
A severe-depression subgroup favored nefiracetam after the overall analysis was negative and without multiplicity adjustment.
Read the original sourceDid the later trial confirm the apathy effect?
No clear benefit appeared. After 2,514 stroke admissions were screened, only 13 people with post-stroke apathy entered the 12-week randomized trial.
Apathy scores fell across the study, but the week-12 treatment comparison was nonsignificant. A later evidence table gives a 1.2-point difference with a 95% CI from −14.8 to 17.2, too wide to settle benefit or harm.
A Randomized, Placebo-Controlled, Double-Blind Efficacy Study of Nefiracetam to Treat Poststroke Apathy.
Primary human study
Starkstein SE et al. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2016. PMID 26915605. DOI 10.1016/j.jstrokecerebrovasdis.2016.01.032.
Nefiracetam did not significantly outperform placebo on apathy at 12 weeks.
- Participants / model
- 13 randomized participants with post-stroke apathy, after 2,514 screened
- Follow-up
- 12 weeks
- Study design
- Two-center randomized double-blind placebo trial
Severe recruitment limitations produced a very small trial; absence of significance is not proof of equivalence.
Read the original sourceDid the 159-person depression trial work?
No. Neither 600 nor 900 mg/day separated from placebo on depression across 12 weeks (time-by-treatment p=0.56).
Response rates were 71.8%, 76.5% and 71.4%; remission rates 43.6%, 41.2% and 40.5% for 600 mg, 900 mg and placebo. A severe-subgroup signal followed the overall null and lacked multiplicity adjustment. Cognitive performance also did not improve.
Double-blind randomized treatment of poststroke depression using nefiracetam.
Primary human study
Robinson RG, Jorge RE, Clarence-Smith K. Double-blind randomized treatment of poststroke depression using nefiracetam. The Journal of neuropsychiatry and clinical neurosciences. 2008. DOI 10.1176/jnp.2008.20.2.178
The overall depression analysis did not show a significant time-by-treatment interaction.
- Participants / model
- 159 enrolled patients with major depression after stroke
- Study design
- Double-blind randomized nefiracetam-versus-placebo study
A severe-depression subgroup favored nefiracetam after the overall analysis was negative and without multiplicity adjustment.
Read the original sourceWhat did the older Japanese program show?
Historical Japanese summaries describe favorable global and psychiatric ratings in cerebrovascular disease, but the cited records do not report complete results from several underlying studies or the later pivotal retrial.
A summarized 259-person placebo comparison reported moderate-or-greater global improvement of 32.3% versus 10.1%. Open 50- and 65-person series reported 42 to 46% global improvement, and an idebenone comparison had baseline imbalance.
A 2002 development record says Daiichi withdrew the application after the revised phase 3 trial supplied insufficient efficacy. The missing pivotal table prevents exact reconstruction. The program did not confirm the earlier findings.
Technology review summarizing the Japanese nefiracetam cerebrovascular program.
Secondary evidence synthesis
Pitt FA, Chilcott J, Golightly P, Sykes J, Whittingham M. A Review of the Use of Donepezil in the Treatment of Alzheimer's Disease. Trent Institute for Health Services Research. Guidance Note for Purchasers 97/09. 1997.
The review summarizes favorable global and psychiatric ratings in Japanese controlled and open studies, but it does not report complete results from the underlying studies or the pivotal retrial.
- Participants / model
- Japanese patients with cerebrovascular disorders in several historical studies
- Follow-up
- Mostly eight-week to 12-month studies
- Study design
- Technology assessment summarizing primary program reports
The review does not report trial-specific endpoint hierarchy, missing-data handling, or every study duration.
Read the original sourceNefiracetam. Daiichi Seiyaku.
Indexed development-program profile
Crespi F. Current Opinion in Investigational Drugs. 2002. PMID 12090554.
Daiichi withdrew the Japanese application after a revised phase 3 trial supplied insufficient efficacy; completed Chinese trials were also noted without results.
- Participants / model
- Japanese and Chinese clinical development programs
- Follow-up
- Program history through February 2002
- Study design
- Development-status report
The report does not provide the protocol, denominators, endpoint table, or Chinese results.
Read the original sourceWhich completed trials still have no usable results?
The completed 50-person NIH Alzheimer phase 2 has no posted results, and the cited sources include no results publication. A Chinese program was reported complete by 2000 without a cited dataset.
NCT00001933 planned 20 weeks of double-blind placebo-controlled treatment with cognitive and safety measures. Its uncited narrative about a prior response does not replace results from the completed trial.
Nefiracetam in the Treatment of Alzheimer's Disease
Primary trial registry
US National Institutes of Health. ClinicalTrials.gov NCT00001933.
A completed 50-person, 20-week double-blind placebo-controlled phase 2 Alzheimer trial has no posted results, and the cited sources include no results paper.
- Participants / model
- 50 adults with probable mild-to-moderate Alzheimer disease
- Follow-up
- 20 weeks with a possible extension
- Study design
- Randomized double-blind placebo-controlled phase 2 study
The registry narrative repeats an uncited prior response claim; without its source or results it is not efficacy evidence.
Read the original sourceNefiracetam. Daiichi Seiyaku.
Indexed development-program profile
Crespi F. Current Opinion in Investigational Drugs. 2002. PMID 12090554.
Daiichi withdrew the Japanese application after a revised phase 3 trial supplied insufficient efficacy; completed Chinese trials were also noted without results.
- Participants / model
- Japanese and Chinese clinical development programs
- Follow-up
- Program history through February 2002
- Study design
- Development-status report
The report does not provide the protocol, denominators, endpoint table, or Chinese results.
Read the original sourceWhat do the amyloid and 2025 neuron studies show?
Nefiracetam improved memory after amyloid-beta infusion in rats and rescued axon growth in a specific mutant mouse-neuron culture. Neither experiment tested healthy human cognition.
The amyloid study began with experimentally induced impairment. The 2025 study used 10 micromolar drug for 24 hours in embryonic or young Cyfip1+/- neurons and measured axonal growth, not adult behavior or clinical recovery.
Improvement by nefiracetam of beta-amyloid-(1-42)-induced learning and memory impairments in rats.
Preclinical primary study
Yamada K et al. British Journal of Pharmacology. 1999. PMID 10051141.
Oral nefiracetam improved several memory tasks after intracerebroventricular amyloid-beta infusion and changed hippocampal cholinergic/dopamine measures.
- Participants / model
- Rats with experimentally induced amyloid-beta impairment
- Follow-up
- Acute or repeated animal treatment
- Study design
- Controlled disease-model behavioral and biochemical experiments
This is induced animal impairment, not human Alzheimer efficacy or healthy-memory enhancement.
Read the original sourceCYFIP1 governs the development of cortical axons by modulating calcium availability.
Preclinical primary study
Ricci C et al. Nature Communications. 2025. PMID 41315480.
Ten-micromolar nefiracetam for 24 hours rescued delayed axonal growth in cultured Cyfip1+/- mouse neurons.
- Participants / model
- Embryonic/young mouse cortical neurons with Cyfip1 haploinsufficiency
- Follow-up
- 24-hour in-vitro treatment
- Study design
- Cellular neurodevelopment experiment
No adult animal received the drug and no cognition, clinical symptom or human outcome was measured.
Read the original sourceHow long did nefiracetam remain in human serum?
In healthy Japanese men, peak serum concentration occurred within two hours and reported parent half-life was about three to five hours.
Food delayed absorption. A seven-day 200 mg three-times-daily study found no clinically significant accumulation. Less than 10% of a 300 mg dose appeared unchanged in 24-hour urine. These measurements do not establish memory, motivation or mood benefit.
Nefiracetam pharmacokinetics in healthy volunteers
Primary human pharmacokinetic study
Fujimaki Y, Sudo K, Hakusui H, Tachizawa H, Murasaki M. Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers. The Journal of pharmacy and pharmacology. 1992. DOI 10.1111/j.2042-7158.1992.tb05513.x.
After oral dosing in healthy Japanese men, peak concentrations occurred within two hours and half-lives were 3 to 5 hours. No clinically significant accumulation was observed during the seven-day repeated-dose study.
- Participants / model
- Healthy Japanese male volunteers
- Follow-up
- Single exposures and seven days of repeated dosing
- Study design
- Single- and multiple-dose pharmacokinetic study
This is exposure characterization, not proof of cognitive benefit or long-term safety.
Read the original sourceWhat do human and animal data say about long-term risk?
Short human trials cannot settle uncommon or chronic harm. Repeated high-dose animal studies found kidney and reproductive target-organ toxicity.
High-dose beagle studies found renal papillary injury and reduced spermatogenesis. Comparative work suggests the papillary lesion depends on dog renal metabolism, but high-dose rat studies also impaired sperm, testes and fertility.
Animal doses do not define a human threshold. They matter because prolonged healthy-user exposure and human renal or reproductive monitoring have not been adequately studied.
Double-blind randomized treatment of poststroke depression using nefiracetam.
Primary human study
Robinson RG, Jorge RE, Clarence-Smith K. Double-blind randomized treatment of poststroke depression using nefiracetam. The Journal of neuropsychiatry and clinical neurosciences. 2008. DOI 10.1176/jnp.2008.20.2.178
The overall depression analysis did not show a significant time-by-treatment interaction.
- Participants / model
- 159 enrolled patients with major depression after stroke
- Study design
- Double-blind randomized nefiracetam-versus-placebo study
A severe-depression subgroup favored nefiracetam after the overall analysis was negative and without multiplicity adjustment.
Read the original sourceFifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in rats.
Preclinical primary toxicity study
Hooks WN et al. Arzneimittelforschung. 1994. PMID 8018094.
Repeated high-dose exposure produced dose-related renal pathology; investigators called 10 mg/kg/day the non-toxic level in that rat study.
- Participants / model
- Rats
- Follow-up
- 52 weeks
- Study design
- 52-week oral toxicity study
Animal no-effect levels cannot be converted by body weight into a human regimen.
Read the original sourceFifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogs.
Preclinical primary toxicity study
Hooks WN et al. Arzneimittelforschung. 1994. PMID 8018095.
High repeated doses caused renal papillary/collecting-duct injury and reduced spermatogenesis in beagles.
- Participants / model
- Beagle dogs
- Follow-up
- 52 weeks
- Study design
- 52-week oral toxicity study
Comparative work suggests the renal papillary lesion is dog-specific; reproductive findings also occurred in rats at high exposure.
Read the original sourceMale reproductive toxicity study of nefiracetam in rats.
Preclinical primary toxicity study
Harada S et al. Journal of Toxicological Sciences. 1995. PMID 8667455.
Very high repeated doses impaired sperm and testicular measures and reduced fertility in male rats.
- Participants / model
- Male rats
- Follow-up
- Four to nine weeks
- Study design
- Repeated-dose reproductive toxicity study
The exposure is not a human threshold, but it prevents dismissing all reproductive toxicity as dog-specific.
Read the original sourceStudies and sources
Double-blind treatment of apathy in patients with poststroke depression using nefiracetam.
Primary human study
Robinson RG et al. The Journal of neuropsychiatry and clinical neurosciences. 2009. PMID 19622685. DOI 10.1176/jnp.2009.21.2.144.
The higher-dose group showed a greater change in apathy scores in the analyzed subgroup.
- Participants / model
- 70 patients with apathy among 137 stroke patients with major depression
- Follow-up
- At least 4 weeks
- Study design
- Randomized placebo-controlled analysis using participants with at least four weeks and last observation carried forward
The parent trial randomized 159 patients. This secondary analysis used 70 participants with apathy from a modified set of 137 who received at least four weeks of treatment. Excluding early withdrawals can bias the estimate.
Read the original sourceA Randomized, Placebo-Controlled, Double-Blind Efficacy Study of Nefiracetam to Treat Poststroke Apathy.
Primary human study
Starkstein SE et al. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2016. PMID 26915605. DOI 10.1016/j.jstrokecerebrovasdis.2016.01.032.
Nefiracetam did not significantly outperform placebo on apathy at 12 weeks.
- Participants / model
- 13 randomized participants with post-stroke apathy, after 2,514 screened
- Follow-up
- 12 weeks
- Study design
- Two-center randomized double-blind placebo trial
Severe recruitment limitations produced a very small trial; absence of significance is not proof of equivalence.
Read the original sourceNefiracetam pharmacokinetics in healthy volunteers
Primary human pharmacokinetic study
Fujimaki Y, Sudo K, Hakusui H, Tachizawa H, Murasaki M. Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers. The Journal of pharmacy and pharmacology. 1992. DOI 10.1111/j.2042-7158.1992.tb05513.x.
After oral dosing in healthy Japanese men, peak concentrations occurred within two hours and half-lives were 3 to 5 hours. No clinically significant accumulation was observed during the seven-day repeated-dose study.
- Participants / model
- Healthy Japanese male volunteers
- Follow-up
- Single exposures and seven days of repeated dosing
- Study design
- Single- and multiple-dose pharmacokinetic study
This is exposure characterization, not proof of cognitive benefit or long-term safety.
Read the original sourcePubChem: nefiracetam chemical identity
Government chemical identity database
National Library of Medicine. PubChem CID 71157.
C14H18N2O2; molecular weight 246.30 g/mol.
- Participants / model
- Chemical record
- Follow-up
- Living database
- Study design
- Curated structure record
Formula and molecular weight establish the recorded structure, not the contents of a retail product or an effective dose.
Read the original sourceDouble-blind randomized treatment of poststroke depression using nefiracetam.
Primary human study
Robinson RG, Jorge RE, Clarence-Smith K. Double-blind randomized treatment of poststroke depression using nefiracetam. The Journal of neuropsychiatry and clinical neurosciences. 2008. DOI 10.1176/jnp.2008.20.2.178
The overall depression analysis did not show a significant time-by-treatment interaction.
- Participants / model
- 159 enrolled patients with major depression after stroke
- Study design
- Double-blind randomized nefiracetam-versus-placebo study
A severe-depression subgroup favored nefiracetam after the overall analysis was negative and without multiplicity adjustment.
Read the original sourceNefiracetam. Daiichi Seiyaku.
Indexed development-program profile
Crespi F. Current Opinion in Investigational Drugs. 2002. PMID 12090554.
Daiichi withdrew the Japanese application after a revised phase 3 trial supplied insufficient efficacy; completed Chinese trials were also noted without results.
- Participants / model
- Japanese and Chinese clinical development programs
- Follow-up
- Program history through February 2002
- Study design
- Development-status report
The report does not provide the protocol, denominators, endpoint table, or Chinese results.
Read the original sourceNefiracetam in the Treatment of Alzheimer's Disease
Primary trial registry
US National Institutes of Health. ClinicalTrials.gov NCT00001933.
A completed 50-person, 20-week double-blind placebo-controlled phase 2 Alzheimer trial has no posted results, and the cited sources include no results paper.
- Participants / model
- 50 adults with probable mild-to-moderate Alzheimer disease
- Follow-up
- 20 weeks with a possible extension
- Study design
- Randomized double-blind placebo-controlled phase 2 study
The registry narrative repeats an uncited prior response claim; without its source or results it is not efficacy evidence.
Read the original sourceTechnology review summarizing the Japanese nefiracetam cerebrovascular program.
Secondary evidence synthesis
Pitt FA, Chilcott J, Golightly P, Sykes J, Whittingham M. A Review of the Use of Donepezil in the Treatment of Alzheimer's Disease. Trent Institute for Health Services Research. Guidance Note for Purchasers 97/09. 1997.
The review summarizes favorable global and psychiatric ratings in Japanese controlled and open studies, but it does not report complete results from the underlying studies or the pivotal retrial.
- Participants / model
- Japanese patients with cerebrovascular disorders in several historical studies
- Follow-up
- Mostly eight-week to 12-month studies
- Study design
- Technology assessment summarizing primary program reports
The review does not report trial-specific endpoint hierarchy, missing-data handling, or every study duration.
Read the original sourceImprovement by nefiracetam of beta-amyloid-(1-42)-induced learning and memory impairments in rats.
Preclinical primary study
Yamada K et al. British Journal of Pharmacology. 1999. PMID 10051141.
Oral nefiracetam improved several memory tasks after intracerebroventricular amyloid-beta infusion and changed hippocampal cholinergic/dopamine measures.
- Participants / model
- Rats with experimentally induced amyloid-beta impairment
- Follow-up
- Acute or repeated animal treatment
- Study design
- Controlled disease-model behavioral and biochemical experiments
This is induced animal impairment, not human Alzheimer efficacy or healthy-memory enhancement.
Read the original sourceCYFIP1 governs the development of cortical axons by modulating calcium availability.
Preclinical primary study
Ricci C et al. Nature Communications. 2025. PMID 41315480.
Ten-micromolar nefiracetam for 24 hours rescued delayed axonal growth in cultured Cyfip1+/- mouse neurons.
- Participants / model
- Embryonic/young mouse cortical neurons with Cyfip1 haploinsufficiency
- Follow-up
- 24-hour in-vitro treatment
- Study design
- Cellular neurodevelopment experiment
No adult animal received the drug and no cognition, clinical symptom or human outcome was measured.
Read the original sourceFifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in rats.
Preclinical primary toxicity study
Hooks WN et al. Arzneimittelforschung. 1994. PMID 8018094.
Repeated high-dose exposure produced dose-related renal pathology; investigators called 10 mg/kg/day the non-toxic level in that rat study.
- Participants / model
- Rats
- Follow-up
- 52 weeks
- Study design
- 52-week oral toxicity study
Animal no-effect levels cannot be converted by body weight into a human regimen.
Read the original sourceFifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogs.
Preclinical primary toxicity study
Hooks WN et al. Arzneimittelforschung. 1994. PMID 8018095.
High repeated doses caused renal papillary/collecting-duct injury and reduced spermatogenesis in beagles.
- Participants / model
- Beagle dogs
- Follow-up
- 52 weeks
- Study design
- 52-week oral toxicity study
Comparative work suggests the renal papillary lesion is dog-specific; reproductive findings also occurred in rats at high exposure.
Read the original sourceMale reproductive toxicity study of nefiracetam in rats.
Preclinical primary toxicity study
Harada S et al. Journal of Toxicological Sciences. 1995. PMID 8667455.
Very high repeated doses impaired sperm and testicular measures and reduced fertility in male rats.
- Participants / model
- Male rats
- Follow-up
- Four to nine weeks
- Study design
- Repeated-dose reproductive toxicity study
The exposure is not a human threshold, but it prevents dismissing all reproductive toxicity as dog-specific.
Read the original sourceWhy is nefiracetam in D tier?
D reflects a selected secondary apathy signal, a negative parent depression trial, a null tiny replication, a failed Japanese pivotal retrial and major missing completed datasets. No controlled healthy-cognition, anxiety, sleep or longevity benefit has been shown.