Ketamine Trial Aims to Blunt Depression, Craving and Relapse in Opioid Use Disorder

Opioid use disorder remains one of the most lethal chronic conditions in modern medicine, and even the best available treatments leave a dangerous gap. Medications for opioid use disorder, such as buprenorphine and methadone, reduce opioid use and improve survival, yet relapse to drug use remains stubbornly common. Now a team of researchers in Cyprus has launched a rigorously designed phase II clinical trial to test whether intravenous ketamine, delivered alongside standard medication, can target the depressive symptoms, craving and emotional dysregulation that so often precede a return to opioid use. The protocol, published in BMC Psychiatry, describes a randomised, double-blind, placebo-controlled study known as the PROUD study, prospectively registered in the European clinical trials system.

The trial’s central hypothesis is deceptively simple but clinically consequential: the depressive and other affective symptoms that emerge during medication-assisted treatment or periods of reduced opioid use may act as motivational triggers for relapse. If ketamine can rapidly lift those symptoms, it might close a therapeutic window that current medications leave open. Ketamine has already demonstrated striking promise as a rapid-acting intervention in mood disorders, but its efficacy, safety and neuro-bio-physiological effects in people with opioid use disorder remain insufficiently characterised. This study is designed to fill that evidence gap with clinical, mechanistic and safety data.

The design is a classic test of adjunctive therapy. Participants with opioid use disorder who are already receiving medications for opioid use disorder will be randomised to receive either six intravenous infusions of ketamine at 0.5 milligrams per kilogram of body weight or a placebo over a two-week period. Clinical outcomes will be assessed at baseline, throughout the infusion phase, in an acute primary analysis window extending through two weeks after the final infusion, and at follow-up time points stretching to nine months after the last infusion. That long tail of follow-up is unusual for ketamine studies and reflects the trial’s explicit focus on relapse prevention rather than short-term symptom relief alone.

A notable feature of the protocol is its disciplined endpoint hierarchy. In a substantial protocol modification submitted in July 2026, the investigators replaced a previously registered broad, composite primary objective with a single primary clinical endpoint: change in total score on the Montgomery-Åsberg Depression Rating Scale over the acute primary analysis window. Everything else, including longer-term depression follow-up, craving, withdrawal symptoms, treatment retention, lapse and relapse-related outcomes, safety, electroencephalography, heart rate variability and peripheral biomarkers, is retained as secondary or exploratory. The revision was adopted to avoid a composite primary endpoint mixing heterogeneous domains and to align the protocol with SPIRIT and ICH E9 principles for coherent analysis.

The measurement battery is unusually comprehensive for a psychiatry trial of this size. Depression will be tracked with the Montgomery-Åsberg scale and the Patient Health Questionnaire-9, anxiety with the Generalised Anxiety Disorder-7 and the state version of the State-Trait Anxiety Inventory, and overall psychological distress with the Depression Anxiety Stress Scales-21. Craving will be measured with the Brief Substance Craving Scale, while withdrawal is monitored through both the Subjective and Objective Opiate Withdrawal Scales. Emotion regulation, alexithymia, anhedonia and positive and negative affect are captured with dedicated instruments, including the Difficulties in Emotion Regulation Scale-18, the Toronto Alexithymia Scale-20, the Snaith-Hamilton Pleasure Scale, the Temporal Experience of Pleasure Scale and the Positive and Negative Affect Schedule. A primary care screen for post-traumatic stress disorder rounds out the affective picture.

Beyond the clinical scales, the study is built to probe mechanism. Electroencephalography will track changes in brain oscillatory activity, heart rate variability will index autonomic nervous system function, and blood-based biomarkers, including brain-derived neurotrophic factor and stress-axis hormones such as adrenocorticotropic hormone and corticotropin-releasing factor, will be sampled to map the hypothalamic-pituitary-adrenal axis response. Dissociative effects during infusions will be quantified with the six-item Clinician-Administered Dissociative States Scale, and recovery from each session will be verified with the Modified Aldrete Score. By weaving together clinical, neurophysiological, autonomic and molecular measures, the investigators aim to identify candidate mechanisms of action and potential predictors of ketamine response, information that could eventually allow clinicians to select which patients are most likely to benefit.

Safety receives equally careful attention. Adverse events will be graded with the Common Terminology Criteria for Adverse Events, tracked through an adverse event checklist, and monitored with electrocardiograms. The protocol specifies halting rules, blinding-integrity assessment and procedures for handling concomitant medications, all clarified in the revised version 2.0 dated 13 July 2026. The trial was approved by the Cyprus National Bioethics Committee on 28 April 2022, received regulatory authorisation in EudraCT on 17 November 2022 before the first participant was enrolled, and was subsequently assigned EU CT Number 2025-520843-34-00 following the transition to the Clinical Trials Information System. It is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, with written informed consent from all participants.

The trial’s status is a study in methodological transparency. Recruitment began on 2 April 2024, after prospective registration. At the time of manuscript submission, fourteen participants had been enrolled and randomised, and all fourteen had received at least one ketamine or placebo infusion. Thirteen had completed the full six-infusion treatment phase and entered the post-treatment follow-up phase. No serious adverse events had occurred to date. Crucially, the investigators report only aggregate blinded status data; no treatment-arm-specific outcome data have been examined or disclosed while the study remains blinded, and investigators, treating clinicians, outcome assessors, laboratory personnel and data analysts all remain unaware of allocation.

The study is anchored at the University of Cyprus, with the Department of Psychology and the Center for Applied Neuroscience at its core, and involves the GEFYRA Substitute Substance Unit in Nicosia, the State Health Services Organization of Cyprus, the Athalassa Psychiatric Hospital Pharmacy, European University Cyprus, Umeå University in Sweden and a clinical laboratory in Larnaca. Funding comes from the Research and Innovation Foundation of Cyprus under grant numbers EXCELLENCE/0421/0543 and EXCELLENCE/0524/0357, with the funder having no role in study design, data collection, analysis, interpretation or publication decisions. The sponsor is the University of Cyprus, which carries responsibility for trial oversight, safety reporting and insurance arrangements in line with Regulation (EU) No 536/2014.

What makes this protocol newsworthy is its positioning within the broader ketamine story. Ketamine’s rapid antidepressant action, mediated through glutamatergic pathways and studied intensively in treatment-resistant depression, has never been rigorously tested as an adjunct in opioid use disorder at this level of mechanistic depth. If the PROUD study demonstrates meaningful reductions in depressive symptoms and downstream effects on craving and relapse, it would inform the design, sample-size assumptions and endpoint selection of larger multicentre trials targeting affective symptoms and relapse vulnerability in opioid use disorder, with relevance to concomitant multidisciplinary rehabilitation approaches. If it does not, the rich biomarker dataset should still clarify why, sharpening the field’s understanding of who responds and why. Either way, the trial’s transparent registration, disciplined endpoint hierarchy and nine-month follow-up set a methodological benchmark for adjunctive interventions in addiction medicine, a field where relapse, not abstinence at discharge, is the outcome that ultimately determines whether treatment saves lives.

Subject of Research: A randomised, double-blind, placebo-controlled phase II trial protocol testing adjunctive intravenous ketamine for affective symptoms, craving and relapse prevention in opioid use disorder

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

Article References: Koumas, M., Apostolakis, M., Bella, E., Michael, A., Onisiforou, A., Georgiou, P., Papacharalambous, C., Kyprianides, P., Stylianou, M., Paraskevopoulos, E., Panayiotou, G., Fotopoulos, D., Chatzittofis, A., & Zanos, P. (2026). Adjunctive ketamine for affective symptoms, craving, and relapse prevention in opioid use disorder: protocol for a randomised, double-blind, placebo-controlled clinical trial. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08628-3

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08628-3

Keywords: ketamine, opioid use disorder, clinical trial, depression, relapse prevention, MOUD, psychiatry, biomarkers, EEG, craving, Adjunctive, affective