Legal in many countries, psychedelic ceremonies and retreats offer a structured and supportive environment for an ever increasing group of individuals seeking healing, insight, or personal growth through the use of psychedelics. Yet, little is known about the psychological, social and environmental factors which determine acute and long-term responses to guided psychedelic use outside clinical environments. In order to examine the influence of contextual factors on the acute psychedelic experience and its psychological outcomes, the present study prospectively collected data from individuals who planned to take a psychedelic substance in a guided setting. Traits, variables pertaining to set, setting, and the acute psychedelic experience were assessed at five time points before and after a guided psychedelic experience or retreat. Principle component, correlation, and regression techniques were employed to analyse the data. At the time of analysis, sample sizes for the five time points were: N1 = 133; N2 = 96; N3 = 85; N4 = 68; N5 = 49. The main outcome, psychological well-being, was elevated two and four weeks after the experience when compared to baseline. This increase in well-being was more pronounced for individuals who had stronger ‘emotional breakthrough’ experiences during the session. A positive mindset immediately before the experience and the perceived impact of ‘supportive individuals’ were positively associated with emotional breakthrough. In contrast, ‘distractions’ and the intention to ‘escape emotions’ were unfavourable to the occurrence of emotional breakthroughs. These results demonstrate the importance of sufficient preparation and emotional support in guided psychedelic experiences, as well as the capacity of environmental elements to shape responses. This first quantitative examination of psycho-social and environmental factors in guided psychedelic settings is a significant step towards evidence-based guidelines for psychological harm-reduction and benefit-maximisation.