In a commentary published in April in the journal Alcoholism: Clinical and Experimental Research, Raye Litten, Ph.D., and other NIAAA scientists describe the evolution of our understanding of the heterogeneity of alcohol use disorder (AUD), and outline new treatment and research regimes that follow from the recognition that alcohol problems are manifested along a continuum of severity, ranging from the occasional binge drinker to the chronic relapsing heavy drinker.

“Each patient develops an AUD based on his or her unique neurobiological makeup and lifetime experiences—a complex interaction of underlying genetic and environmental mechanisms,” write Dr. Litten and his colleagues. “This heterogeneity can be understood as a number of subphenotypes, each having its own unique profile of drinking pattern, motivation for drinking, alcohol-related consequences, and neurobiological underpinnings.”

“Not surprisingly,” they note, “a wide variety of clinically acceptable treatment outcomes are possible with AUD, including not only abstinence, but also low-risk drinking, and even some less-conservative forms of moderate drinking.”

A menu of effective treatment options is available today, including three FDA-approved medications to treat alcohol dependence—disulfiram, oral and injectable naltrexone, and acamprosate. A variety of behavioral therapies have also been shown to be effective. However, the authors note that due to the complex heterogeneity of AUD, no single treatment will work for every person with AUD. However, ongoing research progress in both the neurobiology and pharmacogenetics of AUD holds the promise of identifying biologically based AUD subtypes and the selection of treatments to target those subtypes.

“Neurobiological researchers have identified more than 30 molecular targets that appear to alter people’s craving or drinking behaviors,” they write, “and emerging knowledge of the neurobiology and neurocircuitry of AUD provides a framework for organizing targets.”

Dr. Litten and his colleagues say that current evidence allows alcohol addiction, in general, to be broken down into a three-stage cycle: binge–intoxication, withdrawal–negative affect, and preoccupation–anticipation.

“These three stages interact with and build on one another, becoming more intense, and ultimately leading to the pathological state known as addiction. Within this concept, AUD can be conceptualized as a disorder that involves elements of both impulsivity and compulsivity. As an individual moves from impulsivity to compulsivity, a shift occurs from positive rein-forcement to negative reinforcement driving the motivated behavior.”

To promote systematic research discovery efforts based on current knowledge, the NIAAA scientists propose a new framework, called Alcohol Addiction Research Domain Criteria, modeled after a program in use at the National Institute of Mental Health (NIMH). Such a system, they say, enables researchers to “drill down” to the core mechanisms underlying dysfunction, and link behavior and mood to their brain function, neural circuitry, neurotransmitters, and genes.

“The development of an alcohol addiction domain criteria-based framework to conceptualize research on AUD that probes the sources of the disorder could serve to organize and advance our understanding of alcohol addiction,” the authors conclude. “Identifying the major domains underlying AUD and how the profile of vulnerability to each domain varies among individuals, and over time, not only will be vital to understand the heterogeneity of the disorder, but will also enable us to tailor treatment effectively to the individual. This will substantially advance the field of personalized medicine, and foster the translation of findings from basic research into practical, clinical applications.”


Litten, R.Z.; Ryan, M.L.; Falk, D.E.; Reilly, M.; Fertig, J.B.; and Koob, G.F. Heterogeneity of alcohol use disorder: Understanding mechanisms to advance personalized treatment. Alcoholism: Clinical and Experimental Research 39(4):579–584, 2015. PMID: 25833016



Reprinted from the NIAAA Spectrum, Volume 7, Issue 3, September 2015.