The core of the argument rests on a technical point that distinguishes addiction from most of psychiatry. Conditions such as schizophrenia or major depression involve subjective experiences, including hallucinations, delusions or pervasive low mood, that cannot be meaningfully reproduced in laboratory animals. Substance use disorders are different. The essential behavioral features of addiction, from escalating drug intake to compulsive seeking despite negative consequences, can be modeled with remarkable fidelity in rodents. This makes the disorder a kind of Rosetta stone for psychiatric neuroscience, allowing researchers to interrogate the same behaviors in mice, in rats and in human patients, and to test mechanistic hypotheses across species with a precision that few other brain diseases permit.

Central to this modeling effort are operant drug self-administration paradigms, the workhorse techniques of preclinical addiction research. In these setups, an animal learns to perform an action, typically pressing a lever or poking a nose into a port, to receive a dose of a drug such as cocaine, heroin or a cannabinoid agonist. Over decades, researchers have refined these procedures so that they now capture the core diagnostic criteria laid out in the DSM-5, the standard manual used by clinicians to diagnose psychiatric illness. Animals can be tested for persistence of seeking behavior, for the motivation driving escalating effort to obtain drugs, for compulsive intake that continues even when the drug is paired with punishment, and for relapse-like reinstatement of seeking after prolonged abstinence. Each of these measures maps onto a criterion that a psychiatrist would recognize in a patient, giving the models genuine face validity.

These paradigms have already paid substantial scientific dividends. By combining self-administration with genetic, pharmacological and neurobiological tools, researchers have identified neural circuits and molecular targets that underlie the addictive process for a range of substances, including opioids, cocaine and cannabis, and have even extended the framework to non-drug compulsions such as food addiction. Work on the opioid receptor system, long championed by Kieffer and her collaborators, exemplifies how preclinical genetics can illuminate the molecular machinery of reward and dependence. The commentary emphasizes that this accumulated mechanistic knowledge represents a genuine asset, a detailed map of the brain’s addiction circuitry that, in principle, should be brimming with candidate therapeutic targets.

Yet the translation from that map to medicine has been disappointing, and the authors are candid about the scale of the shortfall. For several substance use disorders, no approved medications exist at all. Stimulant use disorder, involving cocaine and methamphetamine, stands as a particularly glaring example, with decades of preclinical promise failing to yield a single regulatory-approved pharmacotherapy. Even where medications do exist, such as methadone and buprenorphine for opioid use disorder or naltrexone for alcohol dependence, they help only a subset of patients, and relapse rates remain high across the board. The pipeline from target discovery to approved drug, which in other therapeutic areas has produced steady if incremental progress, has repeatedly stalled for addiction.

The commentary identifies a specific technical culprit behind these failures: poor predictive validity in preclinical models. A model may faithfully reproduce the outward signs of addiction, but if a compound that reduces drug seeking in a rat fails to reduce craving or relapse in a human, the model has not predicted the clinical outcome. Part of the problem, the authors suggest, lies in how candidate compounds are selected for clinical trials. When the choice of which molecule to advance rests on behavioral endpoints in animals that only loosely correspond to the human condition, the odds of clinical success are stacked against the field from the start. Improving the alignment between what is measured in the animal and what matters in the patient is therefore framed as the single most important methodological priority.

One of the most promising tools for achieving that alignment is rodent functional magnetic resonance imaging, an emerging technique that the commentary highlights as a potential game changer. Human neuroimaging studies have generated a rich literature on how addiction alters brain activity, from disrupted prefrontal control systems to hypersensitive reward circuits, but those findings have been difficult to connect to mechanistic work in animals because the two research traditions measured different things. Rodent fMRI changes that calculus. By scanning the brains of rats and mice during task performance, researchers can now look for activity signatures that match those observed in human patients, creating a common biomarker language across species. A neural signal that appears in addicted humans and can be reproduced, manipulated and mechanistically dissected in rodents becomes far more credible as a target for drug development than a behavioral endpoint alone.

The authors argue that such cross-species biomarkers could also open the door to personalized medicine in addiction treatment. If robust imaging or molecular markers can be identified that predict which patients will respond to a given intervention, clinicians could move beyond the current trial-and-error approach and match treatments to individuals. This vision depends, however, on a genuinely bidirectional flow of information. Clinical observations, including patterns of treatment response, relapse triggers and heterogeneity among patients, must inform the design of preclinical experiments, just as laboratory findings must be validated in patient populations. Translational research in this framing is not a one-way pipeline from animal to human but a continuous loop in which each side sharpens the hypotheses of the other.

Achieving that loop, the commentary contends, will require more than good intentions from individual laboratories. The authors call for institutional and policy-level support for translational addiction research, including funding structures that reward cross-disciplinary collaboration between preclinical neuroscientists and clinical psychiatrists, and training that equips researchers to work fluently on both sides of the divide. The commentary itself is a product of such collaboration, bringing together a hospital psychiatry department, an Inserm neuroscience unit in Strasbourg and a neuropharmacology laboratory in Barcelona, with support from the National Institutes of Health and the European Commission’s painFACT project. The authors suggest that this kind of integrated structure, rather than isolated excellence in either preclinical or clinical research, is what the field needs to accelerate innovation.

The stakes of getting this right are difficult to overstate. Substance use disorders impose an enormous burden of disease, disability and death worldwide, and the opioid crisis has only sharpened the urgency of developing new treatments. The commentary’s message is ultimately one of cautious optimism grounded in methodological realism. The tools to understand addiction at a mechanistic level already exist and have been refined over decades; animal models now mirror the diagnostic core of the human disorder; and new technologies such as rodent fMRI promise to knit the preclinical and clinical pictures together. What has been missing, the authors argue, is the systematic, bidirectional translation that converts this knowledge into biomarkers, validated targets and, finally, medications that work for patients. Closing that gap, they conclude, is not merely desirable but essential if the next generation of people affected by substance use disorders is to receive better care than the last.

Subject of Research: Translational research approaches for understanding and treating substance use disorders

Article Title: The need for translational research to advance the understanding of substance use disorders

Article References: Lalanne, L., Darcq, E., Kieffer, B. L., Durpoix, A., & Maldonado, R. (2026). The need for translational research to advance the understanding of substance use disorders. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08909-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08909-1

Keywords: translational research, substance use disorders, addiction, preclinical models, operant self-administration, DSM-5, rodent fMRI, biomarkers, drug development, personalized medicine, neuroscience, psychiatry