515. Influence of the context of administration on 5-MeO-DMT-promoted antidepressant-like effects and neuroplasticity

Abstract Background Psychedelics such as psilocybin have demonstrated rapid and sustained antidepressant effects in humans, particularly when administered in carefully designed therapeutic environments (Borkel et al., 2024; Carhart-Harris et al., 2021). DMT and 5-MeO-DMT, distinguished by their brief duration of psychedelic effects, have also shown encouraging preliminary outcomes in depressive disorders (Falchi-Carvalho et al., 2025; Reckweg et al., 2023). Despite these promising results, the role of extra-pharmacological factors, especially the context of administration, in shaping behavioral effects and the underlying neurobiological mechanisms remain poorly understood. Aims & Objectives This study aimed to determine whether the antidepressant-like effects of 5-MeO-DMT depend on the context of administration and whether these effects are associated with changes in brain plasticity, with a particular focus on perineuronal nets (PNNs) surrounding parvalbumin (PV) interneurons.

Method: Healthy and depressed male C57BL/6J mice exposed to corticosterone (CORT) via subcutaneous pellet implantation for 11 days received a single intraperitoneal injection of 5-MeO-DMT (0.5, 5, or 10 mg/kg). Behavioral assessments were conducted 24 hours after administration using validated tests of anxiety-like (Open Field, Elevated Plus Maze) and depression-like behaviors (Splash Test, Tail Suspension Test). An integrated behavioral z-score was calculated to capture overall emotional outcomes. The context of administration was experimentally designed and validated beforehand. A positive setting consisted of enriched and pleasant environmental conditions, whereas a negative setting gathered aversive contextual cues. Following behavioral testing, brains were collected for immunohistochemical analyses of PNN density around PV interneurons in the hippocampal CA1 region.

Results: In healthy mice, 5-MeO-DMT induced a significant antidepressant-like effect 24 hours after its single administration, observable at the lowest dose of 0.5 mg/kg. In CORT-exposed mice, antidepressant-like effects were also observed 24 hours after its administration at the dose of 0.5 mg/kg when injected in a neutral or a positive setting. In contrast, these effects were blunted in a negative setting, which instead promoted anxiogenic-like responses. Remarkably, comparison between positive and negative settings revealed a significant degradation of PNNs surrounding hippocampal PV interneurons 24 hours after 5-MeO-DMT administration, specifically in the positive setting. Moreover, the extent of PNN degradation significantly correlated with improvements in depression-related behavioral z-scores. Discussion & Conclusions These findings support the idea that 5-MeO-DMT produces antidepressant-like effects in both healthy mice and depressed even at a low dose (i.e. 0.5 mg/kg). Importantly, these effects are strongly influenced by the context of administration and are associated with a remodeling of PNNs on PV interneurons. From these data, we raised the possibility that 5-MeO-DMT might transiently enhance neural plasticity, allowing environmental context to guide mice behavior toward either antidepressant or anxiogenic trajectories. This work highlights the critical importance of carefully defining and standardizing administration settings in the development of psychedelic-based interventions notably for major depression.