Low doses of psilocybin as adjunct pharmacological treatment to virtual reality exposure therapy for social anxiety disorder: A study protocol for a double-blind randomized controlled trial.
Background: Social anxiety disorder is a chronic and disabling condition with limited response to standard therapies. Low-dose psilocybin may enhance the effectiveness of exposure-based treatments by modulating neural circuits associated with fear and avoidance. Virtual reality exposure therapy offers a controlled and individualized platform for intervention. Objective: This phase 2b, double-blind clinical trial (n = 32) investigates feasibility and tolerability of low-dose psilocybin as an adjunct to virtual reality exposure therapy in individuals with social anxiety disorder. Design and Methods: Participants will be randomized to receive either low-dose psilocybin or placebo alongside virtual reality exposure therapy. The primary outcome is the change in social anxiety symptoms, measured by the Liebowitz Social Anxiety Scale (LSAS). The primary endpoint is a Cohen’s d ≥ 0.5 for LSAS reduction in the psilocybin group versus placebo. Secondary outcomes include identification of multimodal biomarkers predictive of treatment response. Neuroimaging (e.g., amygdala reactivity, thalamo-cortical connectivity), psychophysiological (e.g., heart rate variability, galvanic skin response, sleep quality), and behavioral task measures (e.g., Affective Shift Task, Emotional Go/No-Go Task) will be analyzed to stratify participants and predict therapeutic response. Successful biomarker stratification is defined as a significant correlation with LSAS change and classification accuracy >70%. Conclusion: This study will provide proof-of-concept evidence for low-dose psilocybin as an adjunct to virtual reality exposure therapy in social anxiety disorder and evaluate multimodal biomarkers for patient stratification. Positive results will support progression to a larger phase 3 trial and inform precision-based approaches for treatment of social anxiety disorder.