Alcohol misuse continues to be a public health problem and identifying effective medications for the treatment of alcohol use disorders remains a high priority for NIAAA. One promising, yet relatively unexplored avenue for medication development for alcohol use are therapeutics that target stress-reactivity. Several lines of evidence suggest that stress is a primary mediator of alcohol use and relapse. Preclinical research demonstrates that noradrenergic pathways are involved in stress-induced consumption and reinstatement to alcohol, as well as alcohol-related reinforcement and withdrawal, and that their manipulation may be of potential therapeutic benefit for alcohol use. In a study evaluating guanfacine, an alpha2a noradrenergic agonist, for smoking cessation we demonstrated that 3mg/day guanfacine was well tolerated, attenuated the effects of stress on smoking, reduced smoking-related reinforcement, improved cognition, and significantly reduced smoking during a brief treatment phase. In a subsample of drinkers from our smoking study, guanfacine robustly reduced the quantity and frequency of alcohol consumption, reduced the frequency of binge consumption, and improved cognition. Medication effects on drinking were evident during the 3-week titration phase, and were independent of medication effects on smoking behavior. Our results suggest that guanfacine should be further evaluated as a potential treatment for alcohol use disorders. For this revised R01 application, we plan to build upon our promising pilot data and conduct the first Phase II human laboratory study evaluating the effect of guanfacine on alcohol consumption. Non-treatment seeking adults with alcohol use disorders will be randomized to guanfacine (3mg/day, 1.5mg/day, or placebo, n=50 per cell, n=150 total), titrated to steady state levels over a 3-week period, and will then complete two laboratory sessions consisting of a well validated method for inducing a stress or neutral/relaxing state (order counterbalanced), followed by a 2-hour alcohol self-administration paradigm known to be sensitive to medication effects. We hypothesize that guanfacine (1.5, or 3.0mg/day) compared to placebo (0 mg/day) will decrease the number of drinks consumed during the self-administration period, and that this effect will be more pronounced following stress. We also expect that guanfacine will be safe and well tolerated during the titration period and in combination with alcohol, and that adverse events will be dose-dependent. Results will provide important information concerning dose selection for future Phase II clinical trial investigations, evidence that targeting the noradrenergic system to reduce stress reactivity is a viable medication development strategy for alcohol use disorders, and elucidate potential mechanisms for these effects.

Public Health Relevance

Currently, 8% of the US population meets criteria for alcohol use disorders, with a total cost to the US economy estimated at $234 billion per year. Identifying effective medications for the treatment of alcohol use disorders remains a high priority research area for NIAAA. This research will contribute to public health by conducting the first human laboratory study to evaluate whether guanfacine, an alpha2a adrenergic agonist, demonstrates efficacy for alcohol consumption.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Biomedical Research Review Subcommittee (AA)
Program Officer
Fertig, Joanne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Roberts, Walter; Moore, Kelly E; Peltier, MacKenzie R et al. (2018) Electronic Cigarette Use and Risk of Harmful Alcohol Consumption in the U.S. Population. Alcohol Clin Exp Res 42:2385-2393
Roberts, Walter; McKee, Sherry A (2018) Effects of varenicline on cognitive performance in heavy drinkers: Dose-response effects and associations with drinking outcomes. Exp Clin Psychopharmacol 26:49-57
Roberts, Walter; Shi, Julia M; Tetrault, Jeanette M et al. (2018) Effects of Varenicline Alone and in Combination With Low-dose Naltrexone on Alcohol-primed Smoking in Heavy-drinking Tobacco Users: A Preliminary Laboratory Study. J Addict Med 12:227-233
Roberts, Walter; Harrison, Emily L R; McKee, Sherry A (2017) Effects of varenicline on alcohol cue reactivity in heavy drinkers. Psychopharmacology (Berl) 234:2737-2745
Verplaetse, Terril L; McKee, Sherry A (2017) An overview of alcohol and tobacco/nicotine interactions in the human laboratory. Am J Drug Alcohol Abuse 43:186-196
Verplaetse, Terril L; Smith, Philip H; Smith, Kathryn M Z et al. (2017) Guanfacine alters the effect of stress and smoking on heart rate variability in regular daily smokers. Psychopharmacology (Berl) 234:805-813
Verplaetse, Terril L; Pittman, Brian P; Shi, Julia M et al. (2016) Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders. J Addict Med 10:166-73