Psilocibin: Current Evidence, Safety Signals, and Challenges in Assessing Potential Multi-Organ Effects

Background/Objectives: Psilocibin (PSY), a serotonergic hallucinogen, has attracted increasing scientific interest due to its therapeutic potential, particularly in treatment-resistant depression. In parallel with its growing clinical and research relevance, important questions have emerged regarding its safety profile, including potential effects on the liver, kidneys, cardiovascular system, and immune function. The aim of this narrative review was to systematically collect, critically appraise, and organize the dispersed evidence regarding potential multi-organ safety signals associated with PSY exposure. Methods: A narrative review was conducted including preclinical studies, pharmacological investigations, available clinical data, and published case reports, including reports of mushroom-related intoxications involving PSY-containing species. All available sources addressing potential toxicological outcomes associated with PSY were considered, regardless of exposure context, in order to reflect the current state of evidence. Results: The available evidence base is limited and heterogeneous, consisting primarily of case reports, observational data, and mechanistic preclinical studies. Reported adverse events are rare and frequently confounded by polysubstance use, uncertainty of dose, co-ingestion of other compounds, and lack of exposure standardization. Despite these limitations, biologically plausible mechanisms related to serotonergic receptor activation provide a rationale for further investigation of potential organ-specific effects. However, current controlled clinical data do not provide consistent evidence supporting intrinsic multi-organ toxicity of PSY. Conclusions: Current evidence does not confirm clinically meaningful intrinsic multi-organ toxicity of PSY under controlled conditions. Nevertheless, the available literature suggests the presence of potential safety signals that warrant further systematic evaluation. In the context of growing clinical interest in PSY, this review provides a structured synthesis of current knowledge and highlights critical gaps in understanding its organ-specific safety profile.