Pregnenolone Treatment for Alcohol Use Disorder and Major Depressive Disorder

Alcohol Use Disorder (AUD) commonly co-occurs with Major Depressive Disorder (MDD), resulting in substantial morbidity and limited treatment success. Pregnenolone is an endogenous neurosteroid that has demonstrated potential therapeutic effects on alcohol use, craving, mood symptoms, and neural pathways implicated in addiction and depression. This randomized, double-blind, placebo-controlled trial will enroll approximately 100 adults aged 21 to 55 years with DSM-5 diagnoses of AUD and MDD. Participants will be randomized to receive pregnenolone 500 mg/day (250 mg twice daily) or matched placebo for 12 weeks. The primary objective is to determine whether pregnenolone reduces alcohol consumption compared with placebo. Secondary clinical objectives include evaluating effects on alcohol craving, depressive symptom severity, and anxiety symptoms. Mechanistic objectives include examining the effects of pregnenolone on resting-state functional connectivity between the amygdala and prefrontal cortex and on brain responses to alcohol-related cues using functional magnetic resonance imaging (fMRI). Clinical assessments will be conducted throughout the treatment period, and MRI scans will be obtained at baseline and Week 12. Relationships between neuroimaging measures and clinical outcomes will also be evaluated. Findings from this study may support the development of a novel treatment approach for individuals with co-occurring AUD and MDD.