Reactivations after 5-methoxy-N,N-dimethyltryptamine use in naturalistic settings: An initial exploratory analysis of the phenomenon’s predictors and its emotional valence

Interest in short-acting psychedelics has grown because prolonged acute drug effects (as with psilocybin or LSD) create logistical and resource barriers for therapeutic delivery. The tryptamine 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) produces a much shorter altered state (around 20–60 minutes) yet can reliably induce intense mystical-type experiences, and preclinical and survey data suggest potential benefits for anxiety, depression and wellbeing. However, epidemiological reports and online anecdotes indicate that use of 5-MeO-DMT is frequently followed by transient re-experiencing phenomena—termed "reactivations"—that resemble historically described psychedelic "flashbacks" and the DSM-5 construct Hallucinogen Persisting Perceptual Disorder (HPPD). These phenomena vary in content and emotional tone and remain poorly characterised in relation to 5-MeO-DMT.

Aday and colleagues analysed secondary data from an online survey of English-speaking individuals who had used synthetic 5-MeO-DMT at least once. Recruitment occurred April–August 2017 via two parallel subsamples: a "structured group" subsample (n = 344) recruited from a US email list for people who used 5-MeO-DMT in ceremonial, laboratory-like group contexts, and a "general population" subsample recruited via online forums and websites (initially n = 216). After excluding respondents with missing data the analytic sample comprised 513 participants (structured n = 344; general population n = 169). No identifying information was collected and the study was exempted from IRB review by Bowling Green State University. Primary outcomes were lifetime report of a spontaneous reactivation (yes/no) and, for those who reported a reactivation, its self-reported emotional valence (negative vs neutral/positive). Predictors included demographics (age, sex, age at first dose, education), prep behaviours (how far in advance participants planned; use of harm-reduction/benefit-enhancement strategies), patterns of use (lifetime doses, dosing frequency, re-dosing, time since last use), subjective measures of acute experience (MEQ30 total score, meaningfulness, perceived impact on wellbeing), propensity for non-drug non-dual experiences, and global wellbeing (SWLS). Some categorical items were recoded numerically for regression analyses (for example, planning time coded as 0, 3, 7, 30 days). Statistical analysis proceeded in five stages: descriptive statistics, chi-square and t-tests comparing subsamples, bivariate logistic regressions of each predictor on each outcome, tests for interactions between predictors and study subsample, and multivariable logistic regression including all 18 predictors simultaneously. Effect sizes used Cohen's d and Cramér's V. Analyses were exploratory and no corrections for multiple comparisons were applied. All analyses were performed in Stata 15.

Sample characteristics indicated a mean age of 43 years and about two thirds male; approximately 65% held a bachelor's degree or higher. Context of use differed between subsamples and was associated with different prevalence rates of reactivation. In the structured group subsample 73% of participants reported a reactivation event, compared with 27% in the general population subsample. Reported emotional valence of reactivations was predominantly positive or neutral: within the structured group 86% reported positive, 10% neutral and 4% negative valence; within the general population 73% reported positive, 20% neutral and 7% negative valence. Bivariate logistic regressions identified several predictors of reporting any reactivation: female sex, older age at first 5‑MeO‑DMT dose, higher educational attainment, and membership of the structured group subsample were associated with increased odds of reporting a reactivation. Interaction tests suggested that the associations of age at first dose and time since last use with reactivation were stronger in the structured group than in the general population. In the multivariable model (all 18 predictors included simultaneously), females were about twice as likely to report reactivations (odds ratio [OR] = 1.82, 95% CI: 1.11–2.99, p = 0.016). Other independent predictors of higher likelihood of reactivation included having used 5‑MeO‑DMT in the structured group (OR = 2.28, CI: 1.19–4.39, p = 0.013), longer planned-ahead time before a session (OR = 1.02 per unit increase, CI: 1.00–1.04, p = 0.006), and greater meaningfulness attributed to the first 5‑MeO‑DMT experience (OR = 1.27, CI: 1.04–1.55, p = 0.015). Conversely, longer time since last 5‑MeO‑DMT use was associated with reduced odds of reporting a reactivation (OR = 0.94, CI: 0.90–0.98, p = 0.007). Regarding emotional valence of reported reactivations, bivariate analyses showed that longer time since last use was associated with decreased odds of a neutral/positive valence, whereas higher MEQ30 mystical-experience scores, greater personal wellbeing, and a history of non‑drug-induced non‑dual experiences were associated with increased odds of neutral/positive valence. Interaction tests found that the relation between current wellbeing and positive/neutral valence was stronger in the structured group. In the multivariable model, older age at first dose (OR = 0.88, CI: 0.79–0.99, p = 0.041) and longer time since last use (OR = 0.71, CI: 0.56–0.94, p = 0.008) decreased the likelihood of reporting neutral/positive valence. Factors that increased that likelihood included being in the structured subsample (OR = 16.14, CI: 1.34–194.32, p = 0.028), higher personal wellbeing (OR = 2.86, CI: 1.49–5.48, p = 0.002), and having had a non‑dual experience without substances (OR = 9.32, CI: 1.20–72.10, p = 0.032). The extracted text also contains a statement that "Study group was not associated with emotional valence of reactivation events," which appears inconsistent with the multivariable result reported above; the extraction does not clarify this discrepancy. Additional findings included moderation effects by subsample for some predictors (age at first dose and time since last use for reactivation; wellbeing for valence). The authors report that lifetime number of doses and dosing frequency were not associated with increased odds of reactivation.

Aday and colleagues interpret their findings as indicating that reactivation phenomena after synthetic 5‑MeO‑DMT use are relatively common in this dataset and are most often perceived as neutral or positive rather than adversarial. The large difference in reported reactivation prevalence between contexts—73% in the structured ceremonial group versus 27% in general population users—led the authors to emphasise the influence of context of use. Female sex and structured-group use showed the strongest independent associations with reporting any reactivation. The investigators note that previous literature on LSD-related flashbacks did not report such a sex difference, but those prior samples were often heavily male, which might have obscured sex effects; they recommend focused study of the phenomenon among females. The authors position reactivations observed here as more akin to HPPD Type 1—transient, intermittent, and typically benign—rather than the persistent, distressing HPPD Type 2. They suggest several possible mechanisms and correlates: higher mystical-experience scores, greater meaningfulness and higher wellbeing were associated with neutral/positive valence, and a prior tendency for non‑drug non‑dual experiences predicted positive/neutral reactivations. Neurophysiological hypotheses are advanced cautiously: acute 5‑MeO‑DMT produces alpha suppression followed by an alpha rebound, and common precipitants of reactivations (falling asleep, meditation, relaxation) are associated with shifts in alpha power; such oscillatory dynamics could conceivably trigger memory-like re-experiencing of the transition between drug state and baseline consciousness. The authors note sex differences in alpha dynamics as a potential explanatory avenue and call for high-density EEG studies to probe these mechanisms. Several important limitations are acknowledged. The cross-sectional, retrospective design precludes causal inference and is vulnerable to recall bias. No dose information was available and the inhalation route used by most participants delivers non-standardised doses, limiting comparisons to other routes such as intramuscular injection. Selection bias is a concern: respondents with negative reactivations may have been less likely to participate, and participants drawn from a ceremonial setting may have greater expectancy and orientation toward positive outcomes. Purity testing occurred in the structured group but not necessarily among general population users, which could confound differences in reactivation rates. The authors also note the presence of anecdotal reports—particularly concerning toad-derived 5‑MeO‑DMT and high-dose unregulated exposures—that describe longer-lasting, distressing reactivations, underscoring heterogeneity in experiences depending on source and dose. In terms of implications, the researchers suggest that reactivations following synthetic 5‑MeO‑DMT often need not be construed as adverse events and might even contribute to therapeutic benefits, but they emphasise the need to identify characteristics that predict negative reactivations so such outcomes can be prevented. Practical recommendations include collecting systematic reactivation data in prospective clinical trials, exploring EEG correlates, and considering route and dosing strategies that may mitigate risk. The authors conclude that the occurrence of reactivations should not automatically deter clinical research on synthetic 5‑MeO‑DMT, while urging further study to better characterise precipitating factors, duration, frequency and the phenomenology of reactivation episodes.