Rationale <p>The human psyche's interaction with death fundamentally shapes cognition, emotions, and behavior in both individuals and society. Death-related psychological phenomena have been shown to be influenced by psychedelic interventions. However, the literature lacks a comprehensive assessment of death-related processes in non-clinical settings, the mechanisms underlying long-term changes, and particularly the effects of ayahuasca on these dimensions.</p> Objectives <p>This cross-sectional study investigates death processing, potential mechanisms of change, and their predictors in ayahuasca veterans (N = 54) compared to non-users (N = 53).</p> Methods <p>A battery of questionnaires and behavioral assessments were used to evaluate different aspects of death processing in both ayahuasca veterans and non-users. These assessments measured death fear and anxiety, death-acceptance, death-avoidant behaviors, and the accessibility of death-related thoughts. Mediators tested included personality traits, beliefs about the afterlife, trait mindfulness, and the concept of impermanence.</p> Results <p>The findings demonstrated lower levels of death anxiety, avoidant behavior, and fear of death, as well as greater death acceptance in ayahuasca veterans. Mediation analyses revealed that group differences were not due to demographics, personality, trait mindfulness, ontological beliefs, or impermanence awareness, but rather to impermanence acceptance. Finally, within the ayahuasca group, lifetime ego dissolution experiences predicted the degree of impermanence acceptance.</p> Conclusions <p>These findings reveal significant, multi-dimensional differences in death processing between ayahuasca and non-psychedelic users. Impermanence acceptance emerged as the key mechanism of change. Additionally, the results highlight the role of acute ayahuasca experiences in producing lasting effects. Future interventions may focus on promoting impermanence acceptance as a strategy for managing existential fear.</p>