Psychedelics are now being shown by medical and scientific practices to be helpful as a mental health therapy across many common diagnostic categories, including depression, PTSD, and more. Importantly, animal research could help to answer unknown interactions between psychedelics and various administration contexts, but this has not yet been done. We injected mice with psilocybin and placed them in either a positive context or a negative, fearful context and used genetically encoded fluorescent markers to label neurons activated during the treatment. We then used behavioral tasks to assess anxiety behavior in the weeks following treatment. We found that the context in which the psilocybin was administered did influence brain activation in the hippocampus, a brain region implicated in anxiety. We also found that context affected long-term anxiety behaviors in one of our behavioral tasks, such that administration in a positive context led to reduced anxiety metrics while administration in the negative context did not. These preliminary results indicate that contextual factors may drive the long-term effects of psychedelics and may be important for therapeutic outcomes. In this study, we established a model that can be used to investigate context-dependent effects of psychedelic use to minimize potential for danger and to maximize positive outcomes following psychedelic-assisted therapy