ArticleResearch square2026
Structural Neurotoxic and Neuroprotective Effects of Ketamine and Esketamine in Preclinical and Human Studies: A Systematic Review.
Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors.
Funding
Abstract
Ketamine and esketamine are increasingly used as rapid-acting antidepressants, yet concerns remain regarding potential structural neurotoxicity, particularly with chronic or high-dose exposure. Despite expanding clinical use, no comprehensive systematic review has integrated neurotoxicity evidence across preclinical and human studies while formally evaluating methodological quality. Following PRISMA 2020 guidelines, we searched PubMed/Medline, Embase, PsycINFO, and Cochrane Library from inception through September 18, 2025. Eligible studies included experimental and observational designs reporting structural, molecular, or cellular neurotoxic outcomes following ketamine or esketamine exposure. Risk of bias and methodological quality were assessed. Seventy-six studies met inclusion criteria, comprising 55 animal and 21 human investigations. In preclinical models, repeated or high-dose ketamine exposure consistently produced structural neurotoxicity, including neuronal apoptosis, dendritic spine atrophy, white matter compromise, and cortical thinning, with heightened vulnerability during developmental periods. In contrast, infrequent or lower-dose therapeutic regimens (≤ 0.5 mg/kg) demonstrated minimal neurodegenerative changes, and, in stress-exposed models, paradoxically exhibited neuroprotective effects including synaptic restoration and anti-inflammatory activity. In human studies, chronic recreational ketamine use showed widespread cortical thinning and gray matter volume reductions. Conversely, therapeutic ketamine administration at controlled subanesthetic doses produced minimal structural changes. Methodological quality was medium or high among human studies, whereas preclinical studies frequently lacked clear reporting of randomization and blinding procedures. Ketamine's neurotoxic effects are strongly context-dependent, with risk primarily influenced by dose, cumulative exposure, developmental timing, and underlying pathophysiological state. The available evidence supports a threshold distinction between neurotoxic effects observed with chronic high-dose exposure and the relative structural safety of therapeutic dosing regimens.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.