Fasoracetam (NS-105)

Identity, and which solid the published studies used

Fasoracetam carries four development codes and still resolves to one record in each of the three databases that hold it. PubChem lists it as CID 198695, CAS 110958-19-5, formula C10H16N2O2, molecular weight 196.25, InChIKey GOWRRBABHQUJMX-MRVPVSSYSA-N, IUPAC name (5R)-5-(piperidine-1-carbonyl)pyrrolidin-2-one. The FDA Global Substance Registration System holds the same CAS and formula under UNII 42O8UF5CJB, with molecular weight 196.2466, stereochemistry recorded as ABSOLUTE, INN code 7708, and NS-105, AEVI-001, LAM-105 anhydrous and NFC-1 anhydrous all sitting on that one record. ChEMBL2106179 arrives at the same weight and the same InChIKey independently. Formula, weight and InChIKey agree across all three.

Qualifiers on those registry names matter. The FDA record spells two of the codes LAM-105 ANHYDROUS and NFC-1 ANHYDROUS because a second substance record exists: fasoracetam monohydrate, UNII 55BRM1BEZN, CAS 2055646-53-0, formula C10H16N2O2 and one water, molecular weight 214.26, PubChem CID 10198262. That record carries a Japanese Accepted Name, fasoracetam hydrate, and a KEGG drug entry, D09830. The monohydrate is the material named by the Japanese papers, by Elia 2018 and on NCT05290493; the other records cited here do not state a solid form. Both Mukai 1999 communications name the test article (+)-5-oxo-D-prolinepiperidinamide monohydrate and then print CAS 110958-19-5, which is the anhydrous number. The other Japanese abstracts of that period name the monohydrate without printing any registry number.

Harmsen and colleagues analysed the solid forms in 2017 and found two hydrated and one non-hydrated crystalline form by single-crystal X-ray analysis, with hydrate form I the most stable under ambient conditions at a melting point of 57 degrees Celsius. That paper closes on a practical consequence: a melting point that low, combined with possible water loss, was described as a problem for formulating the hydrate and for its storage conditions. Its title calls the compound a potential anti-Alzheimer pharmaceutical and its opening sentence says the research chemical counters the effects of Alzheimer's disease, with no citation attached to either statement.

What the Japanese pharmacology measured

Oka and colleagues reported bidirectional modulation of cyclic AMP in rat brain in 1997. In cerebrocortical membranes, NS-105 at ten to the minus eight through ten to the minus six molar inhibited forskolin-stimulated cAMP formation, and in pertussis-toxin-pretreated membranes the same compound enhanced it, an enhancement abolished by cholera toxin. Both directions were mimicked by a metabotropic glutamate receptor agonist and by an adrenergic alpha-2 agonist, and blocked by a metabotropic antagonist but not by yohimbine. The same paper reports that across ten to the minus nine to ten to the minus three molar the compound had no influence on various neurotransmitter receptor bindings, including alpha-2 receptors.

Subclass assignment came from two further papers. In cultured mouse cerebrocortical neurons the compound inhibited cAMP formation in a pertussis-toxin-sensitive manner and enhanced it after pertussis toxin, while it did not itself increase phosphoinositide hydrolysis and attenuated the increase produced by a metabotropic agonist. Hirouchi and colleagues then used selective antagonists and antisense oligodeoxynucleotides: the inhibitory action was blocked by group II and group III antagonists but not by a group I antagonist, and disappeared after antisense treatment against mGlu2, mGlu3, mGlu4 and mGlu7, while the facilitatory action was abolished by the group I antagonist alone.

Shimidzu and colleagues took the compound into two rat behavioural models in 1997. Oral administration at 1 to 100 mg/kg decreased immobility time in forced swimming, an effect the paper compares with desipramine, and repeated administration reversed escape failure in a shuttle-box after inescapable footshock. Binding work in the same paper reported an increase in the number of GABA-B receptors in rat cerebral cortex after repeated administration, with no change in beta-adrenoceptor or 5-HT2 binding properties. The compound did not inhibit monoamine uptake in vitro and did not change monoamine concentrations in brain tissue or extracellular fluid.

Ogasawara and colleagues ran the memory battery in 1999. Rats were rendered amnestic by scopolamine, electrolytic lesion of the nucleus basalis magnocellularis, AF64A, baclofen, cerebral ischaemia and electroconvulsive shock, then tested on passive avoidance or radial arm maze. NS-105 was reported active across those models; of four comparator drugs, only aniracetam improved the scopolamine disruption and none reversed the baclofen disruption. At 10 mg/kg the paper records increased acetylcholine release from cerebral cortex and enhanced high-affinity choline uptake in cortex and hippocampus, with no change in choline acetyltransferase activity.

Pharmacokinetics in four species, then in people

Mukai and colleagues published the animal disposition work in two 1999 communications. After intravenous carbon-14-labelled NS-105, plasma concentrations fell monoexponentially with elimination half-lives of 0.67 hours in rats, 2.1 hours in dogs and 1.3 hours in monkeys. Systemic availability after oral administration was 97 per cent in rats, 90 per cent in dogs and 79 per cent in monkeys, with first-pass metabolism described as very limited. Roughly 90 per cent of the dose was excreted unchanged in urine in rats and monkeys and 60 per cent in dogs; serum protein binding was under 3.3 per cent in every species tested, humans included.

The second communication covered distribution in rats. Radioactivity peaked in most tissues 0.5 hours after a single oral dose, highest in kidney and stomach and lowest in white fat, and fell below or near the detection limit by 24 hours. In pregnant rats the maximum fetal concentration was 66 per cent of the maternal plasma value, and in lactating rats milk concentrations were similar to plasma. Repeated oral dosing produced tissue concentrations about twice the single-dose values by the seventh administration and no further accumulation thereafter; 10 mg/kg did not affect hepatic drug-metabolising enzyme activities.

Human data begin with a fourteen-subject parallel-group comparison. Kumagai and colleagues gave a single 100 mg tablet after breakfast to seven healthy men aged 68 to 79 and seven aged 20 to 32. Maximum plasma concentration was 3.06 against 2.13 micrograms per millilitre in the elderly and young groups, area under the curve 24.6 against 14.4 microgram-hours per millilitre, and total clearance 0.076 against 0.121 litres per kilogram per hour. Renal clearance correlated with creatinine clearance across subjects. The abstract reports a tendency towards a longer elimination half-life in the older group and publishes no half-life value.

Elia and colleagues profiled single doses from 50 to 800 mg in adolescents with ADHD, six subjects per dose group. Maximum plasma concentration rose from 1.19 to 20.52 micrograms per millilitre across that range and area under the curve to infinity from 6.87 to 136.46 hour-micrograms per millilitre. Terminal half-life was reported as 4.44, 6.99, 4.48, 4.11 and 4.06 hours at 50, 100, 200, 400 and 800 mg. These are the only half-life figures for people located under any of the compound's names, and each rests on six subjects.

One uncontrolled trial, and how its design is described

The 2018 Nature Communications paper is the only journal publication of a clinical trial of this compound. Its abstract calls the study open-label, single-blind and placebo-controlled. What the paper describes is a single-dose pharmacokinetic run, then a fixed single-blind placebo week, then four weeks in which the dose was raised on symptom response up to the study's ceiling, in thirty adolescents aged 12 to 17 selected for copy number variants in metabotropic glutamate receptor network genes. Efficacy was assessed by two-sided paired t-tests comparing each subject's week-five score against that same subject's placebo week.

The registry record and the paper describe different designs. The ClinicalTrials.gov record, NCT02286817, lists allocation not applicable, a single-group intervention model, masking none, and one arm labelled single arm of 30 subjects. Neither description contains a parallel placebo group; what the paper calls the placebo control is a one-week lead-in serving as each participant's own baseline. Mutation tier was blinded to the investigators, which is a different blind from treatment allocation. No results have been posted to that registry record, eleven years after the study began.

Reported outcomes were within-subject improvements. Mean CGI-I fell from 3.79 at the placebo week to 2.33 at week five and mean CGI-S from 4.86 to 3.93, with parental Vanderbilt falling from 28.7 to 19.7 and parental BRIEF from 68.4 to 62.1. Stratified by tier, seventeen subjects carried tier-one variants, seven tier-two and six tier-three, and the tier-three group reached significance on neither CGI-I nor CGI-S. Headache was recorded in 19 of 30 subjects and fatigue in 11. Abstract and table disagree on two figures: the abstract gives CGI-S as 4.83 falling to 3.86, and prints the CGI-I p-value as under 0.001 where the table gives 1.2 times ten to the minus nine and the body text 1.2 times ten to the minus five.

One sentence in that paper's introduction has travelled further than any of its results. It states that the compound had previously undergone extensive phase 1 to phase 3 clinical trials in humans for vascular dementia, and attaches reference 14. Reference 14 is Ogasawara 1999, the rat memory study described above. No human vascular dementia trial appears anywhere in the paper's reference list, and none is indexed in PubMed under any of the compound's names.

Four randomised trials, and where their results live

The first randomised trial enrolled 101 adolescents aged 12 to 17 with ADHD and disruptive variants in metabotropic glutamate receptor network genes, over six weeks, masked to participants and investigators. Its posted results give a modified intent-to-treat population of 46 on drug and 50 on placebo, and a least-squares mean change in ADHD-RS-5 total score of minus 14.2 with standard error 1.82 against minus 12.1 with standard error 1.75. The co-primary CGI-I responder count was 26 of 46 against 16 of 50. No statistical analysis and no p-value was posted for either co-primary outcome.

Two further trials ran the same six-week masked protocol in children and adolescents aged 6 to 17, split by biomarker status. In the 69-subject part enrolling subjects with copy number variants in the specified genes, change in ADHD-RS-5 total score was minus 9.17 with standard error 2.235 on drug against minus 11.34 with standard error 2.122 on placebo, in 33 and 34 analysed subjects. In the 109-subject part enrolling subjects without those variants it was minus 11.04 against minus 10.38, in 52 and 54 analysed subjects. Placebo produced the larger change in the biomarker-selected group.

A fourth trial tested the compound in 22q11 deletion syndrome. Thirty-seven children and adolescents aged 6 to 17 were randomised to a two-period crossover, six weeks per period with a one-week washout, quadruple-masked, at 200 mg twice daily. Safety was the primary outcome and no serious treatment-emergent adverse event occurred in either period. Every efficacy comparison was secondary and each was posted with its p-value: CGI-I 3.34 against 3.69, p equals 0.0672; CGI-S p equals 0.2045; Pediatric Anxiety Rating Scale p equals 0.2931; ADHD-RS-5 inattention p equals 0.7799; hyperactivity p equals 0.7974; Social Responsiveness Scale p equals 0.8286.

None of those four trials has been published. A PubMed search on their registry identifiers returns two papers, both methodology papers from the same clinical group - one a copy-number-variant study, one an electronic-health-record phenotyping algorithm - which list the identifiers in a registration footnote and report no trial outcome. A 2019 systematic review that searched ClinicalTrials.gov for novel ADHD compounds identified the programme among 28 registered randomised trials and had no published outcome to review. Secondary reviews have not absorbed the registry record either: a 2019 review calls the compound successfully used in a clinical trial, a 2022 review says the mutation-carrying subjects had better therapeutic response, and a 2023 overview states that a clinical trial demonstrated efficacy in reducing ADHD symptoms. All three cite the 2018 uncontrolled study and none cites a randomised one.

Regulatory position and status in sport

No approval was located in any jurisdiction. The openFDA drug application and labelling endpoints return no match for fasoracetam under a generic-name query or a full-text query, while the same endpoint returns a record for an approved control compound queried alongside it. A Japanese Accepted Name exists for the monohydrate and KEGG carries it as drug entry D09830 under the group racetam derivative, nootropic, with no therapeutic category and no approval date on the record. A 2022 survey of ADHD pharmacotherapy lists it among drugs with suspended clinical development.

Anti-doping status is unresolved. Pokrywka and colleagues tabulate fasoracetam in 2025 in a table headed substances with unclear status, including presumed to meet WADA criteria, and give 4-phenylpiracetam under section S6 as its structural comparator; aniracetam, coluracetam, nefiracetam, noopept, oxiracetam and pramiracetam carry the same comparator in the same table. Napoletano and colleagues had listed the compound in 2020 among 21 image and performance enhancing drugs identified from psychonaut fora, and wrote in that same paragraph that no studies are available on coluracetam, fasoracetam and phenylpiracetam.

What is not known

No efficacy result for this compound has been established under a parallel-group comparison against placebo that carries a posted statistical analysis. Four randomised placebo-controlled trials have run, three in ADHD and one in 22q11 deletion syndrome, and all four posted results to ClinicalTrials.gov without a journal publication; the three ADHD trials posted point estimates and standard errors with no statistical analysis and no p-value attached to any primary outcome, so the reader is left to judge separation from the posted numbers alone, and in NCT02777931 the two co-primaries point in different directions. Nothing is established about the compound in adults, in whom the only study located is a single-dose pharmacokinetic comparison in fourteen men; no adult efficacy trial of any design was located. No published human pharmacokinetic study reports metabolite identification in people, and the metabolite work is entirely animal. No toxicology study of any kind was located under fasoracetam, NS-105 or prolinepiperidinamide: a PubMed search pairing those names with toxicity, toxicology, carcinogenicity or genotoxicity returns zero records, so there is no chronic toxicology, no reproductive toxicology beyond the rat distribution measurement showing fetal transfer at 66 per cent of maternal plasma and milk concentrations similar to plasma, and no safety pharmacology in the public record. Longest exposure in any published or posted study is six weeks. Nothing addresses discontinuation, dependence or tolerance, and the GABA-B receptor up-regulation reported after repeated dosing has been measured in rat cortex only, never in a person. The compound is not approved for human use in any jurisdiction located: the openFDA drug application and labelling endpoints return no match, and the Japanese Accepted Name held by the monohydrate is a naming decision, with no marketing authorisation located.

Questions