Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial

Objective: Depression varies along a difficulty-to-treat spectrum. Patients whose illness fails to respond to at least five treatments may be considered to have severely treatment- resistant depression (TRD). The objective of this study was to document the safety and efficacy of psilocybin in patients with severe TRD. Methods: This was a 12-week, open-label trial conducted at Sheppard Pratt Hospital. Participants were 18-65 years of age, in a major depressive episode with documented insufficient benefit from at least five treatments during the current episode. Asingle dose of synthetic psilocybin (25 mg) was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing through at least 3 weeks post-dosing. Therapists met with patients for three sessions during pretreatment, during the 8-hour dosing day, and for three integration sessions posttreatment. The primary outcome measure was change in Montgomery-& Aring;sberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures including MADRS scores up to 12 weeks posttreatment, and subject-rated scales capturing depression and level of function were completed at baseline and all subsequent visits. Results: Twelve participants (six male, six female; mean age=40.6 years [SD=9.6]) with severe TRD were followed over the study period. Depressive symptoms were significantly decreased at week 3 (MADRS least-squares mean change=-15.8, 95% CI=-25.4 to -6.3) and Week 12 (MADRS least-squares mean change=-17.2, 95% CI=-25.2 to -9.1). In exploratory analyses, the Oceanic Boundlessness (OB) dimension of the psychedelic experience correlated with post-dosing antidepressant responses. Patients with comorbid PTSD (N=5) showed significantly less antidepressant effect of psilocybin. Conclusions: This open-label study suggests efficacy and safety of psilocybin in severe TRD and supports further study of psychedelics in this population, including consideration of PTSD interaction effects.