Functional Unblinding Evaluation of Central raters in a Large Psychedelic Clinical Trial

Background: This study evaluated if central raters (CRs) in psychedelic clinical research trials experience functional unblinding to treatment allocation while assessing key endpoints due to spontaneous participant responses.
Design: Data were collected during a phase 2b (NCT05407064) multicenter, randomized, double-blind, placebo-controlled, dose-finding study of MM120 (lysergide D-tartrate) in adults (18 to 74 years) diagnosed with generalized anxiety disorder (GAD). For each study visit, CRs were assigned to rate the Hamilton Anxiety Rating Scale (HAM-A) and Montgomery-Asberg Depression Rating Scale (MADRS) for participants based on availability. CRs were blinded to all study information; including the study visit, subject information (rated via telephone), and treatment type. Following conclusion of rating both assessments, CRs completed ‘rater blinding questionnaires’, 5-point Likert scale: 1. I am certain the subject received the active drug; 2. I believe that the subject received the active drug; 3. I am unable to discern whether the subject received the active drug or placebo; 4. I believe the subject received placebo; 5. I am certain the subject received placebo.
Results: The study collected over 1500 unique assessments of subjective CR blinding from 198 participants from screening out to 12 weeks post-administration. Data supported CRs remaining blinded, with >80% indicating they were largely unable to discern drug versus placebo.
Conclusion: This is the first large psychedelic randomized controlled trial to collect data on CR unblinding. Results support the use of CRs as a viable method to reduce functional unblinding, as the majority of the CRs were unable to discern drug versus placebo.