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

The research team, led by Francine R. Vega and colleagues at the McWilliams School of Biomedical Informatics at the University of Texas Health Science Center at Houston, conducted a cross-sectional, anonymous online survey of physicians, nurse practitioners, and physician assistants who were authorized to prescribe opioids or medications for opioid use disorder and were actively providing pediatric care. Using snowball sampling, the investigators recruited participants across the United States and measured five domains: awareness of relevant laws, clinical knowledge, prescribing confidence, concerns about parental consent, and beliefs about medications for opioid use disorder, often abbreviated as MOUD.

The headline finding is a striking paradox. Prescribers who had never given buprenorphine to an adolescent actually claimed higher awareness of the laws governing under-18 prescribing, with 94.2 percent reporting awareness compared with 86.7 percent of those who had prescribed. Yet the non-prescribers were simultaneously more uncertain about what those laws actually meant in practice. For example, 32.3 percent of non-prescribers were unsure whether their state restricts buprenorphine prescribing to minors, compared with 26.5 percent of prescribers, a difference that was statistically significant. In other words, knowing that rules exist is not the same as knowing what they allow.

To quantify these relationships, the researchers compared responses between the two groups using chi-square tests with Monte Carlo estimation, a computational technique that produces reliable significance values when survey data do not fit standard statistical assumptions. They then built a multivariable logistic regression model, adjusting for clinician type, practice setting, years in practice, and other characteristics, and reported the results as odds ratios with 95 percent confidence intervals. This approach allowed the team to isolate which factors independently predicted whether a clinician had ever prescribed buprenorphine for adolescent opioid use disorder.

The adjusted results were revealing. Greater legal clarity roughly two and a half times the odds of having prescribed buprenorphine to an adolescent (OR 2.58, 95 percent CI 1.13 to 5.98). Male gender was also associated with higher odds (OR 1.64, 95 percent CI 1.16 to 2.33), as was reporting parental consent as a barrier, a counterintuitive finding that the authors suggest may reflect engagement: clinicians who have wrestled with consent requirements in real cases are more likely to have prescribed despite them. Meanwhile, working in an office-based group practice (OR 0.52) and certain career stages, including fewer than five years in practice (OR 0.53) and 16 to 20 years in practice (OR 0.55), were associated with lower odds compared with solo practice and the five-to-ten-year reference group.

Notably, the type of clinician mattered less than the environment in which that clinician worked. The study found that prescribing history was more strongly associated with legal clarity, practice characteristics, and beliefs about MOUD than with whether the respondent was a physician, nurse practitioner, or physician assistant. That distinction carries real policy weight. If the barrier were professional training alone, the solution would be more education for one cadre of providers. Because the barrier appears to be regulatory ambiguity and practice-level norms, the solution lies in clearer guidance and institutional support that reaches every prescribing profession.

The clinical stakes are considerable. Opioid-related morbidity and mortality among adolescents continue to rise, driven largely by illicit fentanyl contaminating counterfeit pills. Buprenorphine, a partial opioid agonist that suppresses withdrawal and cravings, has strong evidence of effectiveness and is endorsed by professional societies, including the American Academy of Pediatrics, for adolescents with opioid use disorder. Yet pediatric settings remain among the least likely places for a young person to start this medication, which means many adolescents cycle through emergency departments or drop out of care entirely without ever being offered a treatment that could save their lives.

Parental consent is a uniquely pediatric complication. Unlike adult addiction medicine, where treatment can begin with the patient’s own consent, adolescent care is governed by a patchwork of state laws on minor consent, confidentiality, and mandatory parental notification. Some states permit minors to consent to substance use treatment on their own; others require parental involvement; many leave the boundaries vague. A clinician who cannot quickly determine what their state allows may default to inaction, especially in busy primary care or emergency settings where there is no time for legal research. The survey’s finding that perceived consent barriers correlate with prescribing history suggests these concerns are woven into daily decision-making rather than being abstract worries.

The authors frame their conclusions carefully, acknowledging that the sample was a non-probability sample recruited through snowball sampling, which means the respondents may not represent all US pediatric prescribers and the results describe associations rather than causes. Still, the pattern they identified points to concrete, modifiable targets. Clarifying state-level rules, issuing practical guidance on consent and confidentiality for minor patients, and addressing normative beliefs about medications for opioid use disorder within group practices could all lower the threshold for a first prescription. Because the study received no external funding and was approved by the University of Texas Health Science Center institutional review board, with informed consent obtained from all participants, it offers an unusually transparent window into a workforce decision that has been difficult to measure.

The broader lesson extends beyond buprenorphine. When the law is ambiguous, clinicians behave conservatively, and that conservatism falls hardest on the patients with the least power to advocate for themselves, including minors with a stigmatized, life-threatening condition. This survey of 600 American pediatric prescribers shows that the gap between evidence and practice is not primarily a knowledge gap. It is a clarity gap, and closing it may be one of the fastest available ways to get evidence-based treatment to adolescents who are dying for lack of it.

Subject of Research: Legal and practice barriers to buprenorphine prescribing for adolescents with opioid use disorder among US pediatric prescribers

Article Title: Legal and other barriers to buprenorphine prescribing for adolescents with opioid use disorder: a provider survey

Article References: Vega, F. R., Champagne-Langabeer, T., Cohen, A. S., Vijendra, R., Langabeer, J. R., Yatsco, A., & Bakos-Block, C. (2026). Legal and other barriers to buprenorphine prescribing for adolescents with opioid use disorder: a provider survey. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07582-z

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07582-z

Keywords: buprenorphine, opioid use disorder, adolescents, pediatric prescribers, medications for opioid use disorder, legal barriers, parental consent, prescribing practices, provider survey, BMC Pediatrics, MOUD, opioid crisis

The research, led by Karen L. Roper of the University of Kentucky College of Medicine’s Department of Family and Community Medicine, addresses a well-documented gap in the treatment landscape. Medications for opioid use disorder, commonly abbreviated as MOUD, are demonstrably effective at reducing illicit opioid use, overdose mortality, and relapse, yet the majority of people with opioid use disorder in the United States receive no pharmacological treatment at all. Buprenorphine, a partial opioid agonist that suppresses cravings and withdrawal without producing the full euphoric effect of full agonists, can be prescribed in office-based settings, making primary care an ideal delivery channel. Despite this, many primary care practitioners, or PCPs, cite a thicket of barriers: worry about staff and patient reactions, limited appointment time, reimbursement uncertainty, and a lack of confidence in managing a condition long stigmatized as outside the generalist’s lane.

What distinguishes this intervention is its deliberate grounding in the science of behavior change. Rather than producing generic continuing education content, the team scripted videos specifically tailored to the primary care environment, and especially to the realities of rural practice. The central video was delivered by a rural-setting PCP who described her extensive firsthand experience treating patients with buprenorphine, directly confronting the negative perceptions and practical barriers that clinicians most often raise. Supplementary videos were designed around two distinct motivational pathways: one emphasizing external motivation, such as clinic-level and societal benefits of expanding MOUD access, and the other emphasizing internal motivation, including the personal and professional rewards of treating addiction.

Methodologically, the study took the form of cross-sectional surveys administered through a continuing education platform alongside the videos. Participation was open to family and internal medicine professionals in Kentucky, including physicians, doctors of osteopathy, advanced practice registered nurses, and physician assistants. The survey instrument captured demographic information and career satisfaction, and used a Post/Retrospective-Pre format to assess change in the perceived importance of 19 distinct barriers to MOUD practice, along with confidence in four relevant practice areas. The retrospective-pre design asks respondents to rate their views before the intervention in hindsight after completing it, a technique that can capture shifts that participants might not have recognized in real time. The primary outcome was the learner’s stated intention to explore MOUD, while secondary measures rated the educational content for gains in clinical knowledge and skills and for usefulness of information.

The results, though drawn from a modest sample of 37 professional learners, were statistically meaningful. After viewing the videos, participants rated several prominent barriers as significantly less important, including concern about negative attitudes and perceptions across the practice, spanning staff, other practitioners, and patients; limited appointment time; and reimbursement of clinical visits. Fisher’s non-parametric tests yielded p-values at or below 0.05 for these reductions, suggesting the changes were unlikely to be due to chance alone. Perhaps most strikingly, the intervention appeared to touch something deeper than logistics: participants reported a strengthened sense that offering MOUD fits with one’s calling as a physician, an internal-motivation construct that the supplementary videos were explicitly designed to activate.

Behavioral intentions shifted as well. Viewers reported an increased likelihood to screen patients for opioid use disorder, a critical first step in the treatment cascade, since undiagnosed opioid use disorder cannot be treated. The study also uncovered an intriguing correlate: practitioners who scored higher on career satisfaction were more likely to consider board certification as an Addiction Medicine Specialist. This finding hints that clinician well-being and workforce development in addiction medicine may be intertwined, and that educational interventions could be tailored to leverage the professional fulfillment that many physicians derive from treating a condition they once avoided.

Open-ended feedback collected in the survey added qualitative texture to the quantitative findings, probing viewers’ reactions to specific aspects of the video content and its general impact. While the published abstract does not detail individual responses, the inclusion of these questions reflects a deliberate effort to understand not just whether the videos worked, but why, information that will be essential for scaling the approach beyond a single state. The educational content itself was rated positively for gains in clinical knowledge and skills and for the usefulness of the information presented, suggesting the format succeeded as continuing education even before its attitudinal effects are considered.

The significance of this work lies less in any single statistic than in its proof of concept. Expanding buprenorphine access has been a federal policy priority for years, with regulatory reforms eliminating the former X-waiver requirement and encouraging mainstreaming of addiction treatment into general medicine. Yet policy change alone has not moved the needle far enough, because the remaining barriers are psychological and cultural as much as regulatory. By demonstrating that brief, peer-delivered, behaviorally targeted video education can reduce the perceived salience of those barriers, the Kentucky team offers a low-cost, scalable template. A rural physician speaking to her peers in their own professional language may accomplish what guidelines and mandates have not.

The study’s limitations invite caution. With 37 participants drawn from a single state through a continuing education platform, the sample is small and self-selected; clinicians motivated enough to watch addiction-focused education may already be predisposed toward MOUD. The cross-sectional design cannot establish long-term durability of attitude change, and stated intention to explore MOUD does not guarantee that viewers will ultimately obtain the training and workflow supports needed to prescribe. Still, the authors conclude that education conceived for and specifically responsive to the primary care environment, and especially to the challenges of rural practice, can help overcome perceived barriers and promote consideration of MOUD service in primary care settings. In a crisis that claims tens of thousands of American lives annually, converting even a fraction of the nation’s primary care clinicians into buprenorphine prescribers could translate directly into saved lives, and this study suggests the conversion may begin with nothing more complicated than a colleague telling her story on camera.

Subject of Research: Impact of targeted educational videos on primary care practitioners' attitudes and intentions toward providing buprenorphine for opioid use disorder

Article Title: Changing minds on MOUD: impact of messages to motivate expanded access to buprenorphine in primary care settings

Article References: Roper, K. L., Zook, M., Heier, K., McQuerry, K., Marks, S., & Knudsen, H. K. (2026). Changing minds on MOUD: impact of messages to motivate expanded access to buprenorphine in primary care settings. Addiction Science & Clinical Practice. https://doi.org/10.1186/s13722-026-00719-6

Image Credits: AI Generated

DOI: 10.1186/s13722-026-00719-6

Keywords: buprenorphine, opioid use disorder, primary care, MOUD, rural health, continuing education, behavior change, addiction medicine, clinician attitudes, Kentucky, cross-sectional survey, career satisfaction