Structural Neurotoxic and Neuroprotective Effects of Ketamine and Esketamine in Preclinical and Human Studies: A Systematic Review

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. Note to the Editor and Reviewers: We will update our search history (literature search) and evidence during the revision process.