Discussion
TRD, depression, TEAE, anxiety
DRUG WITHDRAWAL
In participants with TRD, a single administration of psilocybin 25 mg with psychological support adjunctive to an SSRI demonstrated a generally favorable safety profile and therapeutic efficacy across a range of clinician and self-rated measures. Contrary to speculation in prior literature [Most TEAEs were mild, short-lived, and resolved on the day of onset without medical intervention, occurring in just over half of participants. A TEAE of blood pressure increase occurred in three participants. Effects of psilocybin on heart rate and blood pressure have been reported in the literature before [There were meaningful improvements in depression severity from Baseline to Week 3, indicating that ongoing SSRI treatment did not inhibit the therapeutic potential of psilocybin. Improvements were evident across measures of depression assessed by an independent clinician (MADRS), investigator (CGI-S), and self-report (QIDS-SR-16) and persisted from Day 2 to the end of the study. Changes were apparent in every item of the MADRS with substantial improvement in the symptoms thought to be core to depression. Consistent with these findings, exploratory measures of quality of life, wellbeing, affect, and anxiety indicated improvements from Baseline across all timepoints.Although the difference in study design limits formal comparison, these efficacy findings are similar to those from the largest phase IIb randomized controlled study of psilocybin in TRD (COMP 001) in which antidepressant withdrawal was required prior to psilocybin administration [A single study has previously examined the psychedelic effect of psilocybin co-administered with an SSRI, using controlled, randomized, cross-over design in healthy volunteers [The acute subjective effects resulting from psilocybin and linked to its agonist activity at 5-HT2A/C receptors are suggested to be critical to therapeutic response [The freedom to administer psilocybin as a treatment adjunctive to an ongoing SSRI has important implications for clinical practice. Allowing continuation of antidepressant drugs would increase treatment accessibility for those who prefer to stay on their current medication and reduce the potential negative impact of antidepressant drug withdrawal or tapering. The present study was limited by its small size, open-label design and absence of a comparator, the lack of a demographically diverse sample, and the exclusion of participants with high suicide risk or current hospitalization. It is possible that the open-label design influenced participant bias and expectations towards the study treatment, and definitive comparisons with studies that included a withdrawal from SSRIs is not necessarily valid. The findings will need to be confirmed in a larger, double-blind, comparator-controlled study.This study found that a single, open-label administration of psilocybin 25 mg led to an acceptable experience for participants with TRD when administrated adjunct to an SSRI and supports further development of psilocybin with psychological support for people with TRD. This study demonstrated the feasibility of simultaneous psilocybin administration to multiple participants as previously reported [