Rapid and sustained antidepressant-like effects of hallucinogenic and non-hallucinogenic serotonergic compounds in a chronic social defeat model

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a substantial proportion of patients failing to respond to conventional antidepressant therapies. Classic serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), have demonstrated rapid and sustained antidepressant effects, primarily via 5-HT₂A receptor-mediated mechanisms. However, their clinical application remains limited by hallucinogenic properties, prompting the development of novel compounds that retain therapeutic efficacy without inducing perceptual disturbances. In this study, we employed the chronic social defeat (CSD) model, a well-validated preclinical model of stress-induced depression, to compare the antidepressant-like effects of hallucinogenic and non-hallucinogenic serotonergic compounds.

Male C57BL/6J mice (n = 100) were subjected to a 10-day CSD paradigm involving repeated exposure to an aggressive male CD1 mice, inducing social stress. Following the CSD procedure, social preference (SP) testing was conducted to quantify social avoidance behaviour and classify animals into stress-susceptible (SUS) and stress-resilient (RES) phenotypes. Based on SP performance, animals were allocated to treatment groups receiving a single administration of vehicle, psilocybin (10 mg/kg, intraperitoneal), LSD (0.1 mg/kg, subcutaneous), or the non-hallucinogenic LSD analogue 2-bromo-LSD (0.3 or 1 mg/kg, intraperitoneal). Behavioural assessment was repeated using SP testing at 24 hours and 7 days post-treatment to evaluate both rapid and sustained effects. Statistical analyses were performed using Kruskal–Wallis tests for phenotype classification and mixed-effects models, followed by appropriate post hoc comparisons.

Exposure to CSD resulted in distinct behavioural phenotypes, with approximately 47% of mice classified as SUS and 53% as RES. SUS animals displayed a robust and significant reduction in social preference compared to RES and non-stressed control animals (p < 0.001), confirming the induction of a depression-like phenotype. This behavioural deficit remained stable over the 7-day observation period in untreated animals. In SUS mice, psilocybin (10 mg/kg) produced significant antidepressant-like effects, as reflected by increased social preference scores at both 24 hours and 7 days following a single administration (p < 0.05). LSD (0.1 mg/kg) elicited a delayed but sustained effect, with significant improvement observed at 7 days (p < 0.05), but not at the 24-hour time point. In contrast, 2-bromo-LSD at both tested doses (0.3 and 1 mg/kg) induced rapid antidepressant-like effects evident at 24 hours (p < 0.01), which persisted for at least 7 days. No significant behavioural changes were observed in RES mice across any treatment condition, indicating phenotype-specific drug responsiveness.

These findings demonstrate that both hallucinogenic and non-hallucinogenic serotonergic compounds can produce robust and sustained antidepressant-like effects following a single administration in stress-susceptible animals. Notably, the rapid onset and persistence of behavioural effects observed with 2-bromo-LSD highlight its potential as a promising therapeutic candidate with reduced hallucinogenic liability. Overall, this study provides evidence that antidepressant efficacy can be dissociated from hallucinogenic activity, supporting the development of safer, next-generation psychedelic-inspired treatments for MDD.

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