A Phase 2a placebo-controlled, randomised, proof of concept trial to investigate the feasibility, safety, and efficacy of psilocybin therapy in opioid use disorder (OUD).

Research Question Is psilocybin therapy (PT) a safe and effective way of promoting abstinence in individuals detoxed from opioids? Background Opioid Use Disorder (OUD) is a major public health challenge, with over 140,000 people currently in treatment in the UK. Death rates are rising each year and are around twenty times higher than the national average, with approximately half dying before the age of 50. Although the opioid substitution medicines methadone and buprenorphine are effective in reducing deaths and harm, abstinence is a goal for many. As approximately 90% of abstinent OUD individuals relapse within 12 months of completing detox, new treatments are needed urgently. Recent work has demonstrated that PT is effective in promoting abstinence from tobacco and alcohol; therefore a trial in OUD is warranted. Our group has pioneered PT as a treatment for depression and anorexia nervosa. In this grant, we bring together our expertise in both PT and addiction treatment to test this promising new treatment paradigm. Aims and Objectives The overall objective is to conduct a Phase 2a trial to assess the feasibility, tolerability, proof-of-concept efficacy, and brain mechanisms of psilocybin therapy (PT) in a randomised, controlled and parallel groups design. The primary objective is to determine whether PT demonstrates superiority in reducing the return to opioid use, as compared to the control, in people who have recently completed detox from all opioids. Methods Participants who have recently completed detox from opioids such as heroin or opioid substitution therapies will be recruited. Each participant will receive structured psychological support, including preparation, guided dosing sessions and post-session psychological integration. The study will evaluate feasibility measures (such as recruitment and retention rates) and clinical outcomes related to return to opioid use and opioid use over time, as well as measures of health and wellbeing. There will also be pre-dose and post-dose fMRI assessments. Anticipated Impact and Dissemination Earlier research from the 1970s suggested that psychedelic-assisted therapy may improve long-term abstinence outcomes in people recovering from opioid dependence. This study will provide updated clinical data to explore the efficacy of psilocybin therapy. Findings will inform the design of future large-scale trials and may ultimately contribute to new treatment options for a population with unmet need. Results will be disseminated through scientific publications, conferences, and engagement with clinicians, policymakers, and the public.