643. A mechanism-informed clinical trial of psilocybin-assisted therapy for opioid use disorder: rationale and neurobiological framework

Abstract Background Opioid Use Disorder (OUD) is associated with substantial morbidity and mortality, with relapse remaining common despite the availability of opioid agonist and antagonist pharmacotherapies. Scotland continues to experience a disproportionate burden of drug-related deaths relative to other parts of the United Kingdom and Europe, reflecting the ongoing clinical and public health challenges associated with opioid dependence. While current pharmacological strategies are effective in reducing withdrawal and craving, they have limited impact on broader neurobiological alterations linked to chronic opioid exposure, including reward dysregulation, anhedonia, and impairments in social functioning. These features are increasingly recognised as key contributors to relapse vulnerability, highlighting the need for novel, mechanism-informed treatment approaches. PsilOpioid is a phase II, proof-of-concept clinical trial designed to investigate psilocybin-assisted therapy as a novel pharmacological intervention for OUD, grounded in contemporary models of addiction neurobiology. Aims & Objectives The primary aim of the PsilOpioid trial is to assess the feasibility and preliminary clinical impact of psilocybin-assisted therapy in Opioid Use Disorder, with time to return to opioid use as the primary outcome. Secondary objectives include evaluating changes in physical and mental wellbeing, quality of life, and broader psychosocial functioning. In addition, the study aims to characterise neurobiological mechanisms associated with treatment response using hypothesis-driven functional neuroimaging, with the goal of identifying candidate biomarkers of treatment engagement and relapse vulnerability.

Method: PsilOpioid is a phase II, proof-of-concept clinical trial integrating a single-dose psilocybin intervention with structured psychological support. Psilocybin is a serotonergic compound with high affinity for the 5-HT2A receptor and is hypothesised to transiently modulate neural plasticity and large-scale brain network organisation relevant to addiction pathology. The trial incorporates predefined clinical endpoints alongside task-based functional magnetic resonance imaging (fMRI) paradigms designed to probe neural responses to natural reward stimuli, with a particular focus on social reward processing and fronto-striatal and salience-related networks implicated in relapse vulnerability.

Results: The presentation will focus on the conceptual and methodological framework of the PsilOpioid trial, including predefined clinical outcomes and hypothesis-driven neuroimaging analyses. Emphasis will be placed on how these measures are used to probe treatment engagement, relapse vulnerability, and underlying neurobiological mechanisms. Discussion & Conclusions PsilOpioid presents a pharmacologically grounded, mechanism-informed framework for investigating psilocybin-assisted therapy in Opioid Use Disorder. By prioritising clinically meaningful outcomes alongside exploratory neurobiological measures, the trial aims to address limitations of existing pharmacotherapies that primarily target withdrawal and craving. This integrated approach may inform future addiction treatment development by shifting focus toward circuit-level mechanisms underlying relapse vulnerability, with particular relevance for clinical settings experiencing a high burden of opioid-related harm, such as those seen in Scotland. More broadly, the study contributes to ongoing efforts to develop mechanism-driven pharmacological interventions for treatment-refractory substance use disorders.