Background: Previous research suggests a therapeutic potential of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). However, online anecdotal reports have described a phenomenon following cessation of the acute effects of 5-MeO-DMT use which has been termed reactivation (i.e., re-experiencing [“flashback”]). To date, no research has investigated whether different routes of administration may confer different reactivation rates, effects and experiences. Aims: We aimed to assess whether intramuscular injection (IM) and vaporization of 5-MeO-DMT conferred different reactivation rates, changes in satisfaction with life as well as ratings of the experience with ego dissolution and the mystical. Methods: Using internet-based advertisements, 27 respondents (Mage = 32. Somatic Experiencing (SE) = 1.43; males = 18; North America = 19) completed an online-based survey. Results: Of the 14 participants in the IM group, 3 (21%) reported reactivations; in contrast, of the 13 participants in the vaporization group, 9 (69%) reported reactivations. Redosing (more than 1 dose) occurred more frequently in the vaporization group (N = 8) (1–6 times with 3–35 mg of 5-MeO-DMT), relative to the IM group (N = 2) (1–5 times with 5–10 mg of 5-MeO-DMT). All participants in the IM group experienced release of physical tension, compared to 8 participants in the vaporization group. Participants in the IM group reported longer time of onset of acute effects (between 1 and 3 [N = 6] and 4–6 min [N = 6]), relative to the vaporization group where the majority (N = 11) reported a rapid onset of 1–50 s. Conclusion: Findings suggest that compared to vaporization, the IM route of administering 5-MeO-DMT is associated with lower and less doses, lower frequencies of reporting reactivation, a higher frequency of physical tension release, and longer onset of acute effects