NIDA Awards UC San Diego $12.6M for Polysubstance Addiction Research

Researchers at the University of California San Diego have received a five-year, $12.6 million award from the National Institute on Drug Abuse to establish the Polysubstance Addiction Research Center, a multidisciplinary effort to map the biology of addiction across substances instead of one drug at a time. The center will study cocaine, oxycodone, alcohol and the combination of cocaine and oxycodone under a single coordinated research strategy.

The award funds work across psychiatry, medicine, obstetrics and gynecology and reproductive sciences, computational biology and bioinformatics, and the Veterans Affairs San Diego Healthcare System — disciplines that rarely share data or animal models.

Why single-drug research misses the problem

Most addiction science still isolates one substance. Olivier George, a professor of psychiatry at UC San Diego School of Medicine who will direct the new center, said that structure does not match how people actually use drugs.

"Addiction research has traditionally been divided into separate areas — alcohol research on one side and drug research on the other," George said. "But that division doesn't reflect how addiction occurs in the real world. People often use more than one substance, so we need to understand what these substances have in common, as well as what makes them different."

Federal surveys have documented that pattern for years: a large share of people who die of an overdose have more than one substance in their system, and polysubstance use involving stimulants alongside opioids has become a defining feature of the recent overdose wave. George said combining psychostimulant, opioid and alcohol research in one center allows investigators to "look across these boundaries and identify biological mechanisms that may be shared across substances."

Four disciplines, one atlas

The center's organizing tool is what its researchers call the One-Individual Multiscale Atlas, a framework meant to integrate information ranging from individual genes and cells up to brain circuits, peripheral organs and behavior in the same subjects. Findings will then be compared against human genetic, brain imaging and other biological datasets to test whether a change at one biological level tracks with a change at another.

Three projects anchor the effort. A brain connectomics project will examine how addiction alters the organization and communication of brain networks. A brain transcriptomics project will track changes in gene activity within specific types of brain cells. A gut-vagus multiomics project will investigate how the gut and the vagus nerve, which connects the brain to organs throughout the body, may influence addiction-related behavior.

Abraham Palmer, a professor and vice chair of basic research in the department of psychiatry, said the center is applying newer techniques to an old observation. "We've known for decades that genetic differences among individuals contribute to risk for addiction," Palmer said. "PARC is using cutting-edge techniques to understand how these individual differences shape addiction risk at the molecular, cellular and brain circuit levels."

From markers to mechanisms

The center's first aim is to identify biological markers associated with vulnerability to addiction-related behaviors, using machine-learning methods to integrate the different data streams. That is the easier half of the problem.

The second aim attempts something harder: testing whether a biological target actually changes behavior. Researchers plan to use medications and other interventions against candidate pathways involved in cellular stress, immune signaling and gut-brain communication, rather than stopping at statistical association.

"We want to go one step further than simply finding a biological difference associated with addiction," George said. "We want to test whether changing that biological process changes addiction-related behavior. That could help us identify targets that are more likely to translate into new treatments."

That translation step is where most addiction biology has stalled. Decades of research have identified differences between the brains of people with and without opioid use disorder, but only a handful of medications — buprenorphine, methadone and naltrexone — are approved for the disorder, and none treats stimulant addiction.

A biobank as shared infrastructure

The third aim is infrastructural. PARC will expand an addiction biobank that already holds more than 40,000 specimens collected from studies of addiction-related behaviors involving cocaine, oxycodone and alcohol. That collection has supported 75 external research projects, according to the university. The center will also provide standardized behavioral models, computational tools and shared datasets, with data routed through National Institutes of Health repositories so outside researchers can reproduce and build on its results.

The new award formalizes six years of collaboration among UC San Diego addiction researchers who have worked across more than a dozen laboratories and produced hundreds of publications. Barbara Jung, associate vice chancellor and dean of the School of Medicine, called the grant a recognition of George's work bringing disciplines together.

The stated goal is a national resource for addiction science — one that treats alcohol, stimulants and opioids as variations on a shared biological problem rather than three separate research fields.