A study in Biological Psychiatry identifies divergent neural pathways that could guide effective, sex-specific prevention and intervention strategies

April 13, 2026 – New research shows that the threat-response in the brain’s amygdala (which processes emotions) is linked to different patterns of drinking by sex. In young males, heightened amygdala reactivity was linked to increased depressive symptoms, which in turn predicted heavier alcohol consumption. In young females, no such pathway existed. Instead, greater amygdala reactivity was associated with lower levels of problematic drinking. The findings from the study in Biological Psychiatry, published by Elsevier, address a critical gap in our understanding of the underlying neurological mechanisms that lead to harmful drinking patterns in males and females, which is increasingly important for designing effective prevention and intervention programs.

Problematic alcohol use is most prevalent during young adulthood, a period characterized by increased frequency of drinking and elevated rates of binge consumption. While alcohol use often declines with increasing age (“maturing out”), early and frequent alcohol use in adolescence is associated with an increased risk of developing Alcohol Use Disorder later in life.

Previous findings on sex differences in depression-related drinking have been inconsistent. “Some studies found depressive symptoms more predictive of alcohol problems in women, others in men, and nobody really had a good explanation as to why,” explains lead author Annika Rosenthal, PhD, Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, and Department of Psychology, MSB Medical School Berlin. “We thought that looking at the underlying neuroscience, specifically at how the brain processes negative emotions, might help clarify things. The amygdala was an obvious candidate given its established role in both mood disorders and alcohol use.”

Previous research has linked amygdala reactivity to both depression and alcohol use separately, but biological sex was rarely examined as a formal moderator. This study addresses that gap.

Researchers analyzed data from 958 19-year-olds in the IMAGEN study, a large European multisite research project that tracks adolescent brain development. Participants underwent functional MRI (fMRI) while viewing video clips of faces displaying threatening expressions. Amygdala activation in response to these stimuli was then measured. The investigators tested whether this neural measure predicted hazardous drinking, with depressive symptoms as a mediator and biological sex as a moderator.

The study found that male participants reported higher levels of problematic drinking, while female participants reported more depressive symptoms. The research team was surprised to find that despite higher depression scores, females did not show the neural pathway linking brain responses to drinking that was found in males. Specifically, the path from amygdala activation to depressive symptoms was significant in males but not in females.

“Additionally, we observed a highly significant negative association specifically in females: greater neural threat sensitivity was linked to lower alcohol risk scores. This suggests a ‘threat-avoidance’ profile in young females, where a more reactive amygdala may actually act as a protective factor against hazardous drinking. While the overall statistical difference between biological sexes for this specific direct link was just above the traditional threshold, the effect within the female group was striking,“ notes Dr. Rosenthal.

Importantly, the sex difference emerged in the link between amygdala reactivity and depressive symptoms, rather than in how depressive symptoms related to drinking.

John Krystal, MD, Editor of Biological Psychiatry, concludes, “We can now point to a specific neural mechanism in the relationship between amygdala activation and heavy drinking: the amygdala's response to social threat appears to feed into depressive symptoms much more strongly in young males than in young females. This adds to growing insights into differences in the drivers of pathological drinking in men and women, which can help to develop more targeted prevention and intervention.”

Based on these findings, the study’s authors suggest that while targeting depressive symptoms is important for everyone, the neural origins of those symptoms may differ by biological sex. These findings highlight the importance of considering sex-specific mechanisms, while warranting further research to better understand their implications.