<p>Psychedelic use has been linked to major life changes that may impact health outcomes, yet few studies have systematically examined the prevalence, types, and demographic characteristics that may be associated with such changes. This paper draws subsamples of respondents who endorsed lifetime psychedelic use from two samples of US adults – one nationally representative by age, race/ethnicity, and sex (Study 1; <i>n</i> = 613) and one larger, more sociodemographically diverse but non-representative (Study 2; <i>n</i> = 3,168). Study 1 was used to estimate the prevalence of reported major life changes following psychedelic use and to characterize the types of changes reported; Study 2 was used to extend the findings from Study 1 by exploring demographic characteristics that might be associated with the likelihood of experiencing major life changes following psychedelic use. In Study 1, 18.4% of respondents (<i>n</i> = 113) reported at least one major life change that they attributed to psychedelic use, with common changes involving relationships (6.9%, <i>n</i> = 42); diet and exercise (6.2%, <i>n</i> = 38); quitting alcohol, tobacco, or other substance use (5.5%, <i>n</i> = 34), and religious beliefs (5.5%, <i>n</i> = 34). In Study 2, higher religiosity, younger age, and greater lifetime psychedelic use emerged as factors strongly associated with reporting a major life change following psychedelic use (aORs &gt; 3.0, <i>p</i> &lt; 0.001 for all). These findings suggest that major life changes following psychedelic use occur in approximately 1 in 5 users and may vary by demographic factors. Further research using longitudinal designs is warranted to clarify the persistence, valence, and health impact of such changes and to guide evidence-based approaches to preparation, integration, and support.</p>