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A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these real-world patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics.