Abstract

Background: Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms, self‐reported well‐being and personality following a single dose. There is little research into the long‐term effects of psilocybin on brain connectivity after the short‐term psychoactive effects have subsided. Resting-state functional connectivity ﴾RSFC﴿ is a quantification of blood oxygen level dependent functional magnetic resonance imaging ﴾fMRI﴿ data that estimates correlation strength between brain regions while participants are instructed to allow their mind to wander freely. Resting‐state network connectivity strength has also been associated with personality. Recent studies have examined effects on RSFC during the psychedelic experience, but lasting effects on RSFC remains an open question as only one such study has been reported to date. Aim: Evaluate change in RSFC at one‐week and three‐months after a single psilocybin dose in 10 healthy, psychedelic‐naïve volunteers and explore associations between change in RSFC and related measures including changes in personality, mindfulness andneocortex 5‐HT2A binding using the agonist positron emission tomography ﴾PET﴿ ligand [11C]Cimbi‐36.

Methods: Participants received 0.2‐0.3 mg/kg psilocybin in a controlled setting. Participants completed resting‐state fMRI scans on a day before psilocybin administration, one‐week and three‐months post‐administration; [11C]Cimbi‐36 PET scans pre‐administration and one‐week post‐administration. We examined changes in within‐network, between‐network and region‐to‐region RSFC. We explored associations between changes in RSFC and psilocybin‐induced phenomenology as well as changes inpsychological measures and neocortex 5‐HT2A receptor binding. Paired t‐tests were used to compare changes in within‐ and between‐network connectivity and related estimates. These were corrected for multiple comparisons using the Bonferroni‐Holmmethod, we determined Cohen’s d values for each post‐hoc effect evaluated. A linear latent variable model was used to compare change in RSFC with subjective persistent positive effects of psilocybin, assessed three‐months post‐administration.

Results: Psilocybin was well tolerated and produced positive changes in well‐being. At one‐week only, executive control network ﴾ECN﴿ RSFC was significantly decreased ﴾Cohen’s d=‐1.73, pFWE=0.010﴿. At one month, ECN RSFC remained reduced, albeit asmaller effect ﴾Cohen’s d = ‐0.4﴿ and not statistically significant ﴾punc = 0.23﴿. We observed no other significant changes in RSFC at one‐week or three‐months, nor changes in region‐to‐region RSFC. Exploratory analyses indicated that decreased ECN RSFC atone‐week was associated with increased mindfulness at three‐months ﴾Pearson’s r =‐0.65﴿ and greater increases in subjective persistent positive effects of psilocybin at three‐months ﴾standardised regression coefficient = ‐0.49﴿.

Conclusions: These findings in a small, healthy cohort indicate that psilocybin affects ECN function within the so‐called psychedelic “afterglow” period. Our findings implicate a role of ECN connectivity in psilocybin‐induced, long‐lasting increases in mindfulness and subjective well‐being. Although we show associations between psilocybin and ECN function and between ECN function and lasting psilocybin effects, it is notable that outstanding changes in neuroimaging measures at three‐months, when personality andclinical changes are observed, remain to be identified. Future research should consider similar analyses in patient populations.