Results. Trends indicated that patients with alcohol dependence and patients with comorbid depression and alcohol dependence had attenuated increases in negative symptoms compared to healthy individuals due to hydromorphone administration as measured by the ARCI negative composite scale; results that were not significant. Patients with depression, alcohol dependence, and comorbid depression and alcohol dependence experienced attenuated decreases in positive symptoms compared to healthy individuals as measured by the ARCI positive composite scale; results that were also not significant.Objective. To use hydromorphone as a mu-opioid receptor agonist probe of the brain reward system in major depressive disorder and alcohol dependence. A dysfunctional brain reward system may be associated with anhedonic symptoms in these disorders.Design. Randomized, double-blind, placebo-controlled, crossover study comparing controls (n=10) to patients with major depressive disorder (n=4), with alcohol dependence (n=9), and with comorbid major depressive disorder and alcohol dependence (n=8). Physiological, subjective, and psychomotor effects of hydromorphone were measured.Conclusion. Further work needed, however, the results may suggest a hypofunctional opioid system in alcohol dependence and comorbid major depressive disorder and alcohol dependent patients.