Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety

Depression and anxiety are highly prevalent and burdensome mental health conditions for which many existing treatments are inaccessible or insufficiently effective for a sizable subset of people. Interest has grown in the therapeutic potential of classic serotonergic psychedelics (for example psilocybin, LSD, ayahuasca, 5‑MeO‑DMT), which produce profound alterations in perception, mood and cognition and have shown preliminary efficacy for reducing symptoms of depression and anxiety in both clinical trials and naturalistic contexts. Prior work suggests that the intensity of certain acute subjective effects during a psychedelic session—notably mystical-type phenomena and psychological insight—relates to subsequent reductions in depressive and anxious symptoms, but the psychological mechanisms that might explain these associations remain incompletely specified. Davis and colleagues set out to test whether increases in psychological flexibility could account for the relationship between acute psychedelic effects and self-reported decreases in depression and anxiety. Psychological flexibility is a transdiagnostic construct central to Acceptance and Commitment Therapy (ACT), encompassing processes such as acceptance, cognitive defusion, present-moment contact, values-based action and self-as-context; reductions in psychological flexibility (i.e., inflexibility) are theorised to underlie many forms of psychopathology. The study hypothesised that (H1) greater acute mystical and insight effects would predict larger decreases in depression/anxiety, and in a path model that (H2) acute effects would predict increases in psychological flexibility, (H3) increases in psychological flexibility would predict decreases in depression/anxiety, and (H4) psychological flexibility would mediate the relationship between acute effects and symptom change.

The investigators conducted a large anonymous cross-sectional internet survey targeting adults who reported a moderate-to-strong single-substance psychedelic experience that produced psychological insight. Recruitment occurred between June 2018 and January 2019 via online forums, email announcements and a popular-press article; respondents accessed a Qualtrics survey, provided consent and completed questionnaires. Inclusion criteria required being at least 18 years old, fluent in English, having used only a single psychedelic during the focal experience, and reporting that the experience contributed to psychological insight. Of 14,911 people who clicked the study link, 3,080 consented and completed the survey; after excluding those who reported multi-substance use and respondents who did not indicate a change in depression or anxiety, the analysed sample comprised 985 individuals. Participants reported demographic information and characteristics of the psychedelic session (substance used, subjective dose level, route of administration, and time since the experience). Acute mystical-type phenomena were measured with the 30-item Mystical Experiences Questionnaire (MEQ; items rated 0–5; total mean score used; alpha = .94). Acute psychological insight was measured with the 28-item Psychological Insight Questionnaire (PIQ; 0–5 scale; total mean score used; alpha = .93); the PIQ was under development and its psychometrics would be reported elsewhere. Depression and anxiety before and after the experience were assessed using the Depression, Anxiety, and Stress Scale (DASS-21); the authors combined the DASS depression and anxiety subscales to create a single change score by subtracting post-experience from pre-experience totals (negative values represent symptom decreases). Psychological flexibility was assessed with the Acceptance and Action Questionnaire-II (AAQ‑II); because lower AAQ‑II scores indicate greater flexibility, the team calculated an after-minus-before change score so a positive value indicates an increase in psychological flexibility. Internal consistencies for the pre/post measures were acceptable to good. Data quality checks examined completion time distributions to identify careless responding. Analyses began with descriptive statistics and Pearson/point-biserial correlations among age, sex, MEQ, PIQ, depression/anxiety change, and psychological flexibility change; given the large sample, a correlation coefficient threshold of 0.20 and a significance level of p < .001 were used to denote meaningful and statistically significant associations. Hypothesis testing used multiple linear regression to examine H1 and structural path analysis to test H2–H4, controlling for age and sex. Path models were estimated in MPlus v7.0 using weighted least square mean and variance estimators; other analyses used SPSS v25. Supplementary subgroup analyses split respondents by whether symptom change was intended or spontaneous and examined depression and anxiety subscales separately.

The final sample (N = 985) was predominantly male (72%), white/Caucasian (84%), with mean age 32.2 years (SD = 12.6). Most respondents lived in the United States (65%) and around three-quarters reported that their focal experience had occurred at least one year prior to the survey. The most commonly reported substances were LSD (42%) and psilocybin/mushrooms (38%); 36% reported a moderately-high dose and 21% a high dose. Mean change scores indicated an overall decrease in combined depression/anxiety from before to after the psychedelic experience (M = -6.80, SD = 5.61; range -21 to +9) and an increase in psychological flexibility (mean change M = 2.01, SD = 1.44; range -4.14 to +6). Mean acute-effect scores were MEQ M = 3.81 (SD = 0.89) and PIQ M = 3.38 (SD = 0.91). Bivariate analyses showed that mystical and insight intensities were moderately correlated with each other; insight intensity showed a moderate correlation with decreases in depression/anxiety, and both acute effects correlated with increases in psychological flexibility to varying degrees. Drug type (psilocybin, LSD, other) was not meaningfully correlated with the primary variables. A multiple linear regression testing H1 (mystical and insight predicting depression/anxiety change) yielded a significant overall model (p < .001) that accounted for 10% of variance in symptom change. Both mystical and insight intensities were associated with greater decreases in depression/anxiety, though the model explained a relatively small portion of variance. Path analysis controlling for age and sex supported H2–H4. Greater acute mystical and insight intensities were directly associated with increases in psychological flexibility (Mystical: β = 0.09, p < .01; Insight: β = 0.46, p < .001). In turn, increases in psychological flexibility were strongly associated with decreases in depression/anxiety (β = -0.62, p < .001). Indirect (mediated) effects were observed: psychological flexibility mediated the relation between mystical intensity and symptom change (indirect β = 0.06, SE = 0.02, p < .01) and between insight intensity and symptom change (indirect β = 0.29, SE = 0.02, p < .001). Model fit indices indicated good fit (RMSEA = 0.055, 95% CI 0.01–0.12; CFI = 0.995; WRMR = 0.394). Supplementary subgroup analyses replicated the main findings across groups defined by whether symptom change was intended or spontaneous and when examining depression and anxiety separately, with two exceptions: among participants who intended to change their anxiety, mystical intensity was not significantly associated with decreases in anxiety and was not significantly related to increases in psychological flexibility in that subsample.

Davis and colleagues interpret their findings as consistent with the idea that acute psychedelic experiences—both mystical-type phenomena and psychological insight—are associated with subsequent reductions in depressive and anxious symptoms, and that increases in psychological flexibility provide a plausible mediating pathway. The path coefficients indicated that psychological insight had a substantially larger direct association with increases in psychological flexibility than mystical experiences did, and correspondingly larger indirect effects on symptom change; the authors highlight psychological insight as a particularly robust predictor in their models. These results align with earlier research linking acute psychedelic phenomenology to therapeutic benefit and with preliminary evidence that psychedelics can alter psychological flexibility. The investigators situate their findings within broader mechanistic discussions of psychedelic action, noting that psychological flexibility is one among several proposed mediators (others include changes in brain network dynamics and experiences of awe or ego dissolution). They further suggest clinical implications: if psychological flexibility proves to be a consistent mediator in prospective trials, combining psychedelic administration with contextual behavioural therapies such as Acceptance and Commitment Therapy (ACT), which expressly target psychological flexibility processes, might enhance therapeutic outcomes. The discussion also notes qualitative parallels between acute psychedelic effects and ACT processes (for example, self-as-context, defusion, values clarification and contact with the present moment) and points to prior trial data showing behavioural change following psychedelic-assisted interventions. Several limitations are emphasised. The anonymous internet-based, retrospective survey design introduces potential selection bias and recall bias, and the parent study’s recruitment focus on insight experiences may have accentuated associations involving insight. The sample lacked demographic diversity (predominantly young, white, and male), limiting generalisability. Because the data are cross-sectional and retrospective, causal inferences cannot be drawn. The authors therefore call for prospective, controlled laboratory trials that assess psychological flexibility and the core ACT processes longitudinally to test causality and to determine whether targeting these processes in psychotherapy augments psychedelic treatment effects.

The study concludes that increases in psychological flexibility appear to mediate the association between acute psychedelic effects and self-reported decreases in depression and anxiety. Davis and colleagues recommend future controlled trials that measure psychological flexibility and core ACT processes before and after psychedelic administration to establish causal pathways and to evaluate whether integrating psychedelic dosing with therapies that explicitly target psychological flexibility can enhance durable therapeutic outcomes.