Adjunctive ketamine for affective symptoms, craving, and relapse prevention in opioid use disorder: protocol for a randomised, double-blind, placebo-controlled clinical trial

Abstract Background Opioid use disorder (OUD) is a chronic relapsing condition associated with substantial mortality. Although medications for opioid use disorder (MOUD) can be effective in reducing opioid use and improving treatment outcomes, relapse to drug use remains common, highlighting the need for adjunctive interventions that address relapse-relevant symptoms not fully targeted by MOUD alone. Ketamine has demonstrated promise as a rapid-acting intervention in mood disorders, but its efficacy, safety, and neuro-bio-physiological effects in patients with OUD remain insufficiently characterised. In this context, depressive and other affective symptoms during MOUD or periods of opioid use reduction may represent motivational triggers for relapse and a key therapeutic target of adjunctive ketamine treatment. Methods This manuscript describes the protocol for a randomised, double-blind, placebo-controlled clinical trial evaluating intravenous ketamine as adjunctive therapy in patients with OUD receiving MOUD. Participants will be randomised to receive either six intravenous infusions of ketamine at 0.5 mg/kg or placebo over a two-week period. Clinical outcomes will be assessed at baseline, during the infusion phase, in the acute primary analysis window through the 2-week post-final-infusion assessment, and at follow-up time points up to nine months after the final infusion. Discussion This phase II clinical trial is designed to estimate the effects of adjunctive ketamine on depressive symptoms and other relapse-associated outcomes in patients with OUD receiving MOUD, while assessing safety, tolerability, and mechanistic signals. By incorporating clinical, neurophysiological, autonomic, and blood-based biomarker measures, the study is also positioned to identify candidate mechanisms of action and potential predictors of ketamine response. Findings from this trial are expected to inform the design, sample-size assumptions, and endpoint selection of larger multicentre trials targeting affective symptoms and relapse vulnerability in OUD, with relevance to concomitant multidisciplinary rehabilitation approaches. Clinical trial registration/identifiers The trial ( PROUD study) was prospectively registered in EudraCT under EudraCT number 2022-001997-70 on 17 November 2022. The public EudraCT record is available at https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-001997-70/CY. Following transition to the Clinical Trials Information System (CTIS), the trial was registered under EU CT Number 2025-520843-34-00 on 29 January 2025; the public CTIS record is available at https://euclinicaltrials.eu/ctis-public/view/2025-520843-34-00. A substantial modification was submitted to CTIS on 21 July 2026. Sponsor protocol number: EXCELLENCE/0421/0543v1. Protocol version Version 2.0, 13 July 2026; supersedes Version 1.0, 01 November 2022.