Psychoactive and Neurobiological Effects of Ketamine in Humans: A Scoping Review of Clinical Evidence.

Background/Objectives: Ketamine has attracted interest in psychiatry due to its rapid antidepressant effects, particularly in patients with inadequate response to conventional treatments. This scoping review maps ketamine's neuropharmacology, mechanisms of action, clinical applications, safety, and use in psychiatric disorders. Methods: This scoping review was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. PubMed, Scopus, Web of Science, and Google Scholar were searched for English-language publications addressing ketamine pharmacology, clinical applications, and psychoactive effects. Included sources comprised randomized controlled trials, observational studies, systematic reviews, and relevant mechanistic studies, while non-English publications, editorials, commentaries, and studies without sufficient methodological information were excluded. Data were extracted using a structured data-charting form and synthesized narratively and thematically. Results: A total of 69 studies were included in the final synthesis. Ketamine demonstrated early improvements in depressive symptoms, especially in treatment-resistant depression (TRD), although the durability of benefits varied across studies. Intravenous racemic ketamine was the most extensively investigated administration route, while intranasal esketamine represents the primary approved formulation for TRD. Mechanistically, the drug acts through N-methyl-D-aspartate receptor antagonism and downstream modulation of glutamatergic signaling, synaptic plasticity and neural connectivity. Comparisons with conventional antidepressants and neuromodulatory interventions highlighted ketamine's faster onset of action, although variability remained regarding long-term effects and treatment strategies. Conclusions: Ketamine represents an important rapid-acting treatment for TRD and severe depressive episodes associated with suicidal ideation. However, information regarding long-term efficacy and safety remains limited due to study heterogeneity, short follow-up periods, and variability in dosing protocols. Further research is needed to address gaps related to long-term outcomes, maintenance strategies, and optimal dosing approaches.