A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding

Psilocybin, the active compound in ‘‘magic mushrooms’’, is a serotonergic psychedelic whose active metabolite psilocin stimulates cortical serotonin 2A receptors (5-HT2AR) and produces a transient altered state of consciousness. Previous clinical and experimental studies have reported that a single dose of psilocybin can yield persistent improvements in mood, reductions in depressive and anxiety symptoms, and long-term increases in the personality trait Openness. Reports and small studies have also suggested that mindfulness-related capacities may increase after psychedelic use, but the durability of such changes and their neurobiological substrates remain unclear. Preclinical work and cross-sectional PET data further suggest that 5-HT2AR agonists can induce receptor internalisation or down-regulation, making changes in cerebral 5-HT2AR levels a plausible molecular mechanism for long-term psychological effects. Korsbak Madsen and colleagues set out to evaluate, in healthy psychedelic-naïve volunteers, whether a single oral dose of psilocybin alters cerebral 5-HT2AR binding and whether any early receptor changes predict longer-term changes in personality and mindfulness. To do so, the investigators obtained [11C]Cimbi-36 PET scans before and one week after psilocybin, and assessed personality and trait mindfulness at baseline and at three months, testing the a priori hypothesis that the trait Openness would increase and exploring associations between receptor-level changes and later psychological outcomes. This approach aims to link molecular neuroimaging with persistent psychological effects following a single psychedelic exposure.

Design and participants: The study used a within-subject design in ten healthy, psychedelic-naïve volunteers (mean age 28.4 years, four females) recruited for a psilocybin brain scanning study. Screening included medical examination, ECG, blood tests and a structured psychiatric interview. The extracted text lists extensive exclusion criteria, including present or past primary psychiatric disorders (in participants or first-degree relatives), neurological disease, relevant medication or substance use, pregnancy or breastfeeding, MRI contraindications, low body weight (<50 kg), and low plasma ferritin (<12 μg/L). Intervention and timing: Each participant completed baseline questionnaires and [11C]Cimbi-36 PET and MRI. On a separate day they received a single oral psilocybin dose (0.2 mg/kg, n=4; 0.3 mg/kg, n=6) in a supported session with two staff members present; a standardised music playlist was played. Rescan PET and MRI were performed one week after psilocybin (mean 7.1 days, range 6–8). Questionnaires for personality (NEO PI-R) and mindfulness (Mindful Attention Awareness Scale, MAAS) were re-administered at three months (mean 97.8 days, range 79–120). Acute subjective effects were assessed on the session day using the 11-dimension Altered States of Consciousness (11D-ASC), the Mystical Experiences Questionnaire (MEQ30) and the Ego-Dissolution Inventory (EDI). PET acquisition and outcome measures: [11C]Cimbi-36 PET data were acquired for 120 minutes on a high-resolution research tomograph after bolus injection; arterial blood sampling was not performed. MRI was acquired for anatomical coregistration and processing. Regional time–activity curves were extracted for 42 regions; neocortex was the pre-specified region of interest and cerebellum served as reference region. Kinetic modelling used the simplified reference tissue model (SRTM). The primary PET outcome was non-displaceable binding potential (BP_ND), which reflects the ratio at equilibrium of specifically bound to non-displaceable radioligand and is proportional to the number of 5-HT2ARs available for binding (assuming stable endogenous serotonin levels). Statistics and hypotheses: The main test for change in neocortical BP_ND employed paired t-tests. The a priori hypothesis that Openness would increase at three months was tested with a one-tailed paired t-test; two-tailed paired t-tests were used for the other four NEO PI-R traits and for MAAS. Post hoc exploratory paired t-tests examined 14 bilateral cortical regions and vertex-level BP_ND maps. Associations between change in BP_ND and psychological measures were examined with post hoc linear regression. The primary thresholds were p<0.05 uncorrected for neocortex BP_ND and Openness; familywise error for other tests was controlled with Bonferroni–Holm correction (p_FWER<0.05). Hedge’s g effect sizes are reported; analyses were performed in R (version 3.3.1).

Acute subjective effects: Psilocybin produced pronounced acute effects on consciousness. Mean global ASC score was 600.9 (SD 147.6), MEQ30 total score averaged 3.9 (SD 0.8), and EDI mean was 58.2 (SD 30.0). Eight of ten participants met the study’s criterion for a ‘‘complete mystical experience’’ (≥60% on all four MEQ30 factors). PET outcomes: At the group level there was no evidence of a change in neocortical [11C]Cimbi-36 BP_ND between baseline and one-week rescan (paired t-test p uncorrected = 0.8; mean change 0.007, 95% CI -0.04 to 0.06). Post hoc regional and vertex-level analyses did not produce a consistent direction-specific change across individuals in cortical BP_ND. Long-term psychological outcomes: Personality Openness increased from baseline to three-month follow-up (one-tailed paired t-test p uncorrected = 0.04; mean change reported as 4.2 with a 95% CI in the extracted text given as [0.4; ∞ ], noting the upper bound is not clearly reported in the extraction). Mindfulness (MAAS) increased significantly at three months (p_FWER = 0.023; mean change 0.6, 95% CI 0.3 to 1.0). Responses to the Persistent Effects Questionnaire (PEQ) showed more self-rated positive than negative changes attributable to the psilocybin session. Associations between PET and psychological change: In a post hoc exploratory linear regression, change in neocortical [11C]Cimbi-36 BP_ND at one week correlated negatively with change in MAAS at three months (β = -5.0, 95% CI -9.0 to -0.9; R2 = 0.50; p_FWER = 0.046), indicating that individuals with larger decreases in BP_ND tended to show greater increases in mindfulness. The extracted text also reports a reanalysis including eight additional participants from a prior psilocybin PET study (two having received low doses, 0.05 and 0.07 mg/kg); this larger aggregated sample confirmed an increase in mindfulness (mean change 0.5, 95% CI 0.2 to 0.7; Hedge’s g = 0.78).

Korsbak Madsen and colleagues interpret their findings as evidence that a single oral dose of psilocybin is followed by persistent increases in trait mindfulness and Openness in healthy, psychedelic-naïve individuals. The increase in MAAS at three months replicates and extends prior reports that psychedelics can enhance mindfulness-related capacities, here occurring in the absence of formal mindfulness training. PEQ responses indicated predominantly positive persisting changes in mood, spirituality and outlook, consistent with earlier human studies of single-dose psilocybin. At the molecular level, the investigators did not find a consistent group-level change in neocortical [11C]Cimbi-36 BP_ND one week after psilocybin. The authors discuss two mechanistic interpretations: first, that agonist-induced internalisation or down-regulation of 5-HT2ARs could reduce membrane-bound receptor availability and thus BP_ND; second, that changes in endogenous serotonin could produce the opposite effect on BP_ND due to competition with the radioligand. They note that these opposing processes could cancel at the group level, producing a net null finding. The team also argue that rapid receptor recycling seen in vitro, and prior data on psilocin affinity across post-drug time points, argue against large sustained reductions in membrane-bound receptors one week after dosing. Importantly, a negative correlation between one-week change in BP_ND and three-month change in mindfulness suggests inter-individual variability in 5-HT2AR regulation may help explain differential long-term psychological outcomes. The authors propose that variable 5-HT/5-HT2AR regulation in response to psilocybin warrants further investigation and suggest future PET studies could use markers such as the 5-HT4R radioligand [11C]SB207145 to probe endogenous serotonergic tone. The investigators acknowledge several limitations. The small sample (n=10) was powered to detect a relatively large (15%) BP_ND change and would have limited power for subtler effects. The lack of a placebo control means non-pharmacological contributors to psychological change cannot be excluded. Timing differences between PET rescan (one week) and psychological reassessment (three months) leave open the possibility that receptor levels changed in the intervening period. The authors also note that arterial input functions were not collected and that some numerical details in their tables are not fully presented in the extracted text. Despite these caveats, they highlight strengths including within-subject design, recruitment of psychedelic-naïve participants, and use of [11C]Cimbi-36 — an agonist radioligand that preferentially labels the same receptor pool targeted by psilocin. In conclusion, the study replicates prior findings of increased Openness after psilocybin and reports a statistically significant increase in trait mindfulness measured three months post-dose. Although no consistent neocortical 5-HT2AR binding change was observed at the group level one week after dosing, the negative association between individual changes in BP_ND and later increases in mindfulness suggests a potential receptor-related mechanism that merits further, larger and controlled investigation.