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 health challenge with over 140,000 UK individuals currently in treatment.

Death rates are rising every year and are twenty times higher than the average, with approximately half dying before 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 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 overarching aim is to conduct the first-in-patient phase-IIa (two-staged) proof-of-concept, placebo-randomised, double-blind, controlled trial to investigate the feasibility, safety and efficacy of PT in detoxified patients with OUD.

Primary objectives: To determine the most safe, effective, and tolerable (single, oral) psilocybin dose in work package-1 (WP-1), and then, in the next phase (WP-2) to further test this dose of psilocybin to assess feasibility, safety and clinical outcomes (opioid use/relapse) in a larger group.

Methods Participants with OUD who have completed detox from opioids such as heroin or opioid replacement medication will be recruited through established collaborations with clinical addiction services.

In WP-1 we will test 25/30/35mg psilocybin doses with therapeutic support in a dose escalation phase in up to n=24 OUD participants across 3 sequential groups.

After completion of each dose level, a Safety Review Group will decide on stop versus escalation based on set measures for tolerability and psychedelic experience intensity.

From this, a “final dose” will be selected for use in WP-2 in an additional 28 OUD patients, in a placebo-controlled 1:1 randomisation to either “final dose” or placebo (1mg psilocybin) with equal therapeutic support.

Primary outcomes: Feasibility: 1) rate of recruitment of patients into the study, 2) % patients remaining in the study at 7 days and 1 month, and 3) % providing 1° efficacy outcome at 3 months. Clinical: Time to first return to opioid use in first 3 months. Timelines for delivery We plan to complete WP-1 in 11 months and WP-2 in 15 months.

In total, the timeline for the entire study is 3-years.

Anticipated Impact and Dissemination 1970s research found a 30% one-year abstinence rate after psychedelic therapy in detoxified patients with OUD compared with a 5% response rate in controls.

Proving the feasibility of PT today and exploring its efficacy in OUD should lead to further larger trials which could have major clinical benefit in an area of great unmet need.

We will share this research with clinicians, policymakers pharmaceutical investors and the public through scientific papers, policy documents and the media.