Oxiracetam

Oxiracetam (4-hydroxy-2-oxo-1-pyrrolidineacetamide) is a synthetic racetam: piracetam with a hydroxyl group on its pyrrolidinone ring. It has been studied since the 1980s in rodent memory models (Mondadori et al., 1986) and dementia trials (Maina et al., 1989). It is used clinically as a racemate; in a rat hypoperfusion model, its (S)-enantiomer, not the (R)-enantiomer, carried the activity (Li et al., 2017).

PubChem CID 4626 matches the CAS number, formula and weight and is the source of the aliases and structure. The listed CAS number is the racemate's; confirm on the certificate whether a lot is the racemate or one enantiomer.

Published work on oxiracetam falls into five areas. Each summary states the model used. The mechanism and memory data come only from cell cultures, rodent tissue and live rodents.

Glutamate and acetylcholine signaling in rodent tissue

In cultured cerebellar granule cells, micromolar oxiracetam raised AMPA-stimulated calcium influx (efficacy, not potency) without changing kainate or NMDA responses, and it increased AMPA binding sites in rat cortical membranes (Copani et al., 1992). In rat hippocampal slices, 0.01 to 1 µM raised evoked release of D-aspartate, a glutamate tracer, and to a lesser degree acetylcholine, while 10 to 100 µM did not; isolated nerve terminals showed no effect (Raiteri et al., 1992).

In rats, 50 and 100 mg/kg given before scopolamine lessened the passive avoidance deficit and the fall in cortical and hippocampal acetylcholine, while lower and higher amounts were inactive; the authors said a direct link to memory needed confirmation (Spignoli and Pepeu, 1987). Models: neuron cultures, rat brain tissue and rats.

Learning and memory in rodents

Oxiracetam and piracetam both reduced electroshock-induced amnesia in mice, but only oxiracetam raised step-down retention. In aged rats (24 to 27 months), oxiracetam at 30 and 100 mg/kg raised active avoidance acquisition, while piracetam at 100 mg/kg did not (Mondadori et al., 1986). In learning-impaired DBA/2 mice, 9 days at 50 mg/kg raised Morris water maze learning and contextual fear conditioning, and the water maze gain tracked a rise in membrane-bound hippocampal protein kinase C; C57BL/6 mice showed neither change (Fordyce et al., 1995). Models: mice and rats.

Ischemia and hypoperfusion models

In rats with chronic cerebral hypoperfusion, a model of vascular cognitive impairment, oxiracetam lessened cognitive deficits and losses in neural plasticity, white matter and synaptic ultrastructure (Yao et al., 2016). In the same model, (S)-oxiracetam, but not (R)-oxiracetam, reduced learning and memory deficits, neuron damage and white matter lesions and raised cerebral blood flow (Li et al., 2017).

After middle cerebral artery occlusion in rats, intravenous (S)-oxiracetam, tested at 0.12 to 0.48 g/kg for 3 days, reduced infarct size, edema and blood-brain barrier leakage and raised the tight junction proteins occludin and claudin-5 (Huang et al., 2017). In that model, an α7 nicotinic receptor antagonist and a PI3K inhibitor each blocked its effects on spatial learning (Fan et al., 2021). Model: rats.

Dementia trials

In a multicenter, double-blind trial led from Turin, 289 analyzed adults with primary degenerative, multi-infarct or mixed dementia received oxiracetam or placebo twice daily for 12 weeks. All three main rating scales favored oxiracetam (p<0.01), and minor unwanted effects were reported by 31 people on oxiracetam and 27 on placebo (Maina et al., 1989).

A placebo-controlled study at Emory University in 24 people with probable Alzheimer's disease found no gain on a broad neuropsychological battery, and its authors called oxiracetam ineffective there (Green et al., 1992). A 2024 network meta-analysis of 194 vascular dementia trials, partly from Chinese databases, ranked oxiracetam outside the top five drugs for MMSE and daily living scores and among the five with the lowest adverse reaction rates (Dang et al., 2024). Models: human trials and a meta-analysis.

Recent trials in South Korea and China

A multicenter, double-blind trial commissioned by South Korea's Ministry of Food and Drug Safety randomized 500 adults at high risk of post-stroke cognitive impairment to oxiracetam or placebo for 36 weeks. The co-primary endpoints, MMSE (p=0.49) and Clinical Dementia Rating-Sum of Boxes (p=0.38), did not differ (Lim et al., 2026). In China, a phase 1 study in healthy volunteers found no conversion of (S)-oxiracetam to the (R)-form and a half-life near 6 hours (Zhang et al., 2024).

The phase 3 LOCATE trial at 51 hospitals randomized 590 adults with mild-to-moderate traumatic brain injury to L-oxiracetam, described as the major active enantiomer, racemic oxiracetam or placebo. At 90 days the LOTCA cognitive score had risen more with L-oxiracetam than with placebo (difference 8.97 points, p<0.001) or the racemate (4.54 points); serious adverse events did not differ, and a drug company paid for trial medication (Liu et al., 2025).

A 2026 meta-analysis of 33 Chinese brain injury trials found higher short-term MMSE scores with oxiracetam but rated the evidence low or very low certainty (Wang et al., 2026). Models: human trials and a meta-analysis.