Lasting increases in trait mindfulness after psilocybin correlate positively with the mystical-type experience in healthy individuals

Psilocybin, a tryptamine alkaloid found in Psilocybe mushrooms, has shown promise as a therapeutic agent across several psychiatric conditions and is known to produce an altered state of consciousness that can include a mystical-type experience. Previous small studies have reported increases in trait mindfulness after psilocybin administration, and other psychedelics and meditation-linked interventions have produced similar short- and medium-term increases in mindfulness-related measures. Given that trait mindfulness correlates with indices of psychological health and that 5-HT2A receptor (5-HT2A R) signalling is central to psilocybin’s effects, the relationships among psilocybin-induced mystical experiences, changes in trait mindfulness, and pre-drug 5-HT2A R binding in the healthy brain remain of interest. Conceicao and colleagues set out to test three related hypotheses in healthy volunteers: (1) that trait mindfulness increases from baseline to 3 months after a medium-to-high dose psilocybin session, (2) that the intensity of the psilocybin-induced mystical-type experience is positively associated with any such increase in trait mindfulness, and (3) that baseline (pre-drug) 5-HT2A R binding in neocortex and selected frontolimbic regions is negatively associated with trait mindfulness. The study therefore combines self-report measures taken before and after psilocybin with pre-drug PET imaging in a subset of participants to explore behavioural and neurochemical correlates of mindfulness-related change.

The study recruited 39 healthy volunteers from a research database; seven of these completed two separate psilocybin interventions at least 12 months apart, yielding 46 intervention datasets for analyses of behavioural change. Exclusion criteria were comprehensive and included current or past psychiatric or neurological disorder, recent psychedelic use (within 6 months), pregnancy, significant medical conditions, and MRI/PET contraindications; screening included a physical exam, ECG, blood tests and a structured psychiatric interview. Psilocybin was administered orally in 3 mg capsules at a weight-adjusted maximum dose of either 0.21 mg/kg (12 sessions) or 0.31 mg/kg (34 sessions). Sessions were conducted in a comfortable clinical setting or partly in PET/MR scanners; psychological support was provided by a trained lead psychologist and a trainee, with standardised preparation and integration sessions for all participants. Trait mindfulness was measured with the Danish version of the 15-item Mindful Attention and Awareness Scale (MAAS) at baseline and at a 3-month follow-up. The Mystical Experience Questionnaire (MEQ, 30-item Danish version) was completed about 6 hours after psilocybin to quantify the acute mystical-type experience; its total score and four subscales (mystical, positive mood, transcendence of time and space, ineffability) were used. In a subset of 32 participants, pre-drug PET scans using the [11C]-Cimbi-36 tracer were acquired to estimate regional 5-HT2A R binding (non-displaceable binding potential, BP_ND) over 120 minutes; high-resolution structural MRI was used for co-registration. Neocortical BP_ND (volume-weighted neocortex average) was the primary PET outcome, and post-hoc analyses examined frontolimbic regions (frontal cortex, left/right amygdala, left/right anterior cingulate cortex). Statistical analysis used linear mixed-effect models (LMMs) to test change in MAAS from baseline to 3 months and to test associations between MEQ total score and change in MAAS, accounting for repeated measures by including participant ID as a random effect. Baseline MAAS was included as a covariate when modelling change because of scale limits and known baseline–change relationships. Psilocybin dose and setting were considered but omitted from final models because their inclusion did not materially affect results. Associations between pre-drug BP_ND and MAAS were tested with linear regression including age and body mass index (BMI) as covariates. Statistical thresholds were p < 0.05 for primary hypotheses; post-hoc tests were corrected for multiple comparisons using Bonferroni correction (four tests for MEQ subscales; five tests for frontolimbic PET regions). Effect sizes (Cohen’s d) and 95% confidence intervals were reported where relevant. Analyses were performed in R (v4.0.5).

Thirty-nine participants provided baseline and 3-month follow-up MAAS data, yielding 46 intervention datasets after accounting for seven participants with two sessions. Thirty-two participants also completed baseline PET imaging. The MAAS showed excellent internal consistency in this sample (Cronbach’s α: baseline = 0.86, follow-up = 0.90). Primary outcome: A significant increase in trait mindfulness was observed from baseline to 3-month follow-up. In the full sample of 46 sessions, the change in average MAAS score reached statistical significance (p = 3.24 × 10^-6). Reporting for an independent replication subset that excluded 10 participants from a prior study (n = 36), the standardised effect size was Cohen’s d = 0.71, with a mean percentage change of 7.5% (95% CI: 4.0; 10.9) and p = 1.0 × 10^-4. In discussion the authors summarise the full-sample increase as approximately 8.1%. Association with mystical-type experience: The overall increase in MAAS was positively associated with the intensity of the mystical-type experience as measured by the MEQ (the abstract reports p = 0.035 for this association). In post-hoc analyses of MEQ subscales, the “mystical” subscale showed a significant positive association with change in MAAS, whereas other subscales did not survive Bonferroni correction (for example, the positive mood subscale had p_unc = 0.019 but p_FWER = 0.076). Pre-drug 5-HT2A R binding: In the PET subsample (n = 32), pre-drug neocortical [11C]-Cimbi-36 BP_ND showed a negative but non-significant association with MAAS (β = -0.55, 95% CI [-1.48; 0.38], adjusted R^2 = 0.0051; p = 0.24). Post-hoc regional analyses revealed a significant negative association between pre-drug BP_ND in the right amygdala and MAAS (β = -0.67, 95% CI [-1.06; -0.28], adjusted R^2 = 0.30; p_unc = 0.0016, p_FWER = 0.008). No other frontolimbic regions showed significant associations after correction for multiple testing (frontal cortex, left amygdala, left and right ACC all non-significant with corrected p-values > 0.05). Adverse events or other clinical safety outcomes are not reported in the extracted text. The authors note that inclusion of dose and setting as covariates did not substantially affect the principal findings.

Conceicao and colleagues interpret their findings as evidence that a single medium-to-high dose psilocybin session can produce a sustained increase in trait mindfulness at least up to 3 months in healthy volunteers. The observed magnitude of change is comparable to that reported after intensive mindfulness-based stress reduction (MBSR) training in previous studies, and the current results replicate and extend the team’s earlier small-sample work. The authors emphasise the novel observation that greater intensity of the psilocybin-induced mystical-type experience—particularly the MEQ "mystical" component—was associated with larger increases in trait mindfulness, suggesting that the acute phenomenology may catalyse a shift in awareness conducive to mindful living. The discussion situates these results among prior findings showing psychedelic-related increases in mindfulness and parallels between mystical experiences and meditative states, including shared themes such as ego-dissolution and altered self-referential processing and possible common neurobiological signatures (for example, reduced default mode network integrity). The authors also consider the PET results: although neocortical 5-HT2A R binding was not significantly related to baseline mindfulness, a post-hoc negative association between right amygdala 5-HT2A R binding and MAAS suggests a potential link between serotonin signalling in limbic circuitry and individual differences in trait mindfulness. They note a plausible interpretation in which lower 5-HT2A R binding might reflect higher available serotonin, a pattern previously observed with serotonergic antidepressant effects, but caution that such mechanistic inferences are preliminary. Key limitations acknowledged by the authors include the open-label design without a blinded control group, the absence of repeated intermediate assessments between the psilocybin session and the 3-month follow-up (so other life events could have influenced MAAS scores), and technical caveats regarding PET measurement in small structures such as the amygdala where time-activity curves can be noisy. The authors recommend replication of the right-amygdala finding and suggest future research on combining psilocybin with mindfulness-based interventions in clinical populations, and exploring whether psilocybin might lower barriers to engagement in mindfulness training. Overall, the authors present the results as supporting the idea that psilocybin—and particularly psilocybin-evoked mystical-type experiences—may have mindfulness-enhancing capacities that could be therapeutically useful, while emphasising the need for further controlled and mechanistic work.

The study reports that trait mindfulness increased in healthy volunteers at least 3 months after a single medium-to-high dose psilocybin intervention, and that the self-reported intensity of the mystical-type experience during the session was positively associated with this lasting increase. Additionally, a post-hoc analysis identified a negative association between pre-drug 5-HT2A R binding in the right amygdala and trait mindfulness. The authors suggest these findings indicate psilocybin and mystical-type experiences may enhance mindfulness and could potentially be combined with mindfulness-based therapies in clinical settings, while calling for replication and controlled studies to confirm and extend these observations.