Walk into any addiction treatment clinic and you will rarely meet a patient who uses exactly one substance. Alcohol with cigarettes. Opioids with stimulants. Cannabis alongside almost anything. Polysubstance use, using more than one drug, together or in sequence, is the rule in real life, not the exception (Crummy et al., 2020).
Yet for decades, addiction research has been organized substance by substance: alcohol labs, cocaine labs, opioid labs, each with its own animal models, funding streams, and literatures. That structure produced enormous progress, but it leaves a blind spot exactly where patients live.
The scientific question: shared versus specific mechanisms
Different drugs enter the brain through different doors. Opioids act on opioid receptors, cocaine blocks dopamine reuptake, alcohol acts broadly on multiple receptor systems. But addiction to all of them converges on strikingly similar behavior: escalating use, mounting motivation, use despite consequences, and relapse after abstinence.
That convergence raises the question our center was built to answer:
Which biological mechanisms of addiction are shared across substances, and which are specific to each drug?
The answer matters practically. A mechanism shared across alcohol, opioid, and cocaine addiction is a candidate target for treatments that could help the majority of patients, including the many who use several substances. A drug-specific mechanism explains why some medications help alcohol use disorder but do nothing for stimulants.
How PARC studies substances side by side
The Polysubstance Addiction Research Center takes a simple but demanding approach: study alcohol, opioid, and cocaine addiction in the same genetically diverse rat population, with the same behavioral pipeline, the same measurements, and the same analysis methods: so results are directly comparable across substances.
Every animal is phenotyped for addiction-like behaviors (escalation of intake, motivation, continued use despite negative consequences) and characterized at multiple biological scales: gene expression across brain cell types, brain-wide network connectivity, and gut–vagus–brain signaling. Because all data layers come from the same individuals, we can build a One-Individual Multiscale Atlas that lets convergent and divergent mechanisms be identified rather than assumed.
What we know so far
Cross-substance work is young, but several findings already point to shared biology:
- The three-stage addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/craving, describes the progression of addiction across drug classes, with each stage mapping onto distinct brain systems (Koob & Volkow, 2010).
- Recruitment of stress systems in the extended amygdala drives the negative emotional state of withdrawal for alcohol, opioids, and nicotine alike, the engine of “using to feel normal” (Koob & Le Moal, 1997; de Guglielmo et al., 2016).
- Genetic studies in outbred rats are beginning to reveal loci that influence addiction-like behavior for specific substances, setting up the comparison of genetic architecture across drugs (Lara et al., 2026).
Why it matters for treatment
If polysubstance use is the clinical norm, treatments developed and tested one substance at a time will keep missing the patients most in need. Mapping the shared core of addiction, and the substance-specific branches, is how the field gets to medications and interventions that work for the real, mixed-use population.
References
- Crummy EA, O’Neal TJ, Baskin BM, Ferguson SM (2020). One is not enough: understanding and modeling polysubstance use. Frontiers in Neuroscience 14:569. PMID 32612502
- Koob GF, Volkow ND (2010). Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238. PMID 19710631
- Koob GF, Le Moal M (1997). Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58. PMID 9311926
- de Guglielmo G et al. (2016). Recruitment of a neuronal ensemble in the central nucleus of the amygdala is required for alcohol dependence. Journal of Neuroscience 36:9446–9453. PMID 27605618
- Lara MK, Carrette LLG et al. (2026). Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats. Nature Communications. PMID 42277005