Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied. Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants ( n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support – each participant having an assigned, dedicated therapist available throughout the session. Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing. Clinical Trial Registration: EudraCT ( https://www.clinicaltrialsregister.eu/ ) number: 2018-000978-30.

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Mindfulness-based interventions (MBIs) are effective in reducing chronic stress, but their therapeutic mechanisms are unclear. One possibility is that MBIs act by re-training attention monitoring and acceptance skills that have been impaired by chronic stress exposure. However, little research has investigated the association between chronic stress, monitoring, and acceptance. In this cross-sectional study we hypothesised observing correlations between stress, and (impaired) monitoring and acceptance. Moreover, we exploratively compared the magnitude of the correlations between chronic stress and four acceptance measures. Finally, we explored whether the association between stress and monitoring is moderated by acceptance. Eighty-five adults participated in the study and completed self-reported chronic stress and acceptance questionnaires and a mindful attention behavioural task. The results revealed that chronic stress was associated with reduced acceptance (all ps < 0.01) but not with monitoring. Exploratory analyses revealed no differences in the magnitude of the correlations between stress and each acceptance measure, except for the combined facets of mindfulness acceptance subscales and nonreactivity subscale (p = 0.023). Further analyses revealed a significant negative association between stress and the interaction between acceptance and the target detection component of monitoring (p = 0.044). Surprisingly, these results show that stress is associated with reduced monitoring at higher levels of acceptance. Theory-driven intervention studies are warranted to complement our results.

Intolerance of uncertainty (IU) is associated with difficulty in updating contingencies from threatening to safe during extinction learning. However, it is unknown whether high IU individuals have difficulty (1) generally with updating threat to safe associations when contingencies change or (2) specifically with updating threat to safe associations during extinction learning, where direct threat is omitted. To address this question, we recorded IU, expectancy ratings, and skin conductance in 44 healthy participants during an associative learning paradigm, where threat and safety contingencies were reversed. During acquisition and reversal, we observed larger skin conductance response (SCR) magnitude and expectancy ratings for threat versus safety cues. However, during reversal, higher IU was associated with larger SCR magnitude to new threat versus new safety cues, compared with lower IU. These results were specific to IU-related variance, over shared variance with trait anxiety (State-Trait Anxiety Inventory, Trait Version). Overall, these findings suggest that individuals high in IU are able to reverse threat and safety associations in the presence of direct threat. Such findings help us understand the recently revealed link between IU and threat extinction, where direct threat is absent. Moreover, these findings highlight the potential relevance of IU in clinical intervention and treatment for anxiety disorders.

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