Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

Background: Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aims: Evaluate changes in resting-state functional connectivity (RSFC) at one-week and threemonths after one psilocybin dose in 10 healthy psychedelic-naive volunteers and explore associations between change in RSFC and related measures. Methods: Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state fMRI scans at baseline, one-week and three-months post-administration and [11C]Cimbi-36 PET scans at baseline and one-week. 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 in psychological measures and neocortex serotonin 2A receptor binding. Results: Psilocybin was well tolerated and produced positive changes in well-being. At one-week only, executive control network (ECN) RSFC was significantly decreased (Cohen9s d=-1.73, pFWE=0.010). 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 at one-week predicted increased mindfulness at three-months (r =-0.65 ). Conclusions: These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic afterglow period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at three-months, when personality changes are observed, remain to be identified. Key words: functional magnetic resonance imaging, resting-state connectivity, executive control network, psilocybin, psychedelic, mindfulness