Neuroendocrinology meets addiction: Emerging pharmacotherapies on the horizon

Alcohol and other substance use disorders (ASUDs) are prevalent and major contributors to global morbidity and mortality. Their impact extends beyond the individual, imposing significant burdens on families, communities, healthcare systems, and society at large. Treatments include psychosocial, behavioral, and pharmacological interventions. However, available pharmacological treatments remain limited, primarily targeting alcohol, tobacco, and opioid use disorders, with a lack of approved pharmacotherapies for other substance use disorders. This gap highlights a critical need to develop novel treatment options. Emerging evidence suggests that bidirectional brain-periphery communications play important roles in the pathophysiology and progression of ASUDs. Gut-brain hormones that are involved in the regulation of feeding and metabolism have been shown to influence reinforcing properties of food, alcohol, and other addictive substances. Additionally, stress-related pathways, especially the hypothalamic-pituitary-adrenal axis, play a significant role in regulating behaviors that are related to ASUDs. Accordingly, feeding- and stress-related neuroendocrine pathways represent novel pharmacotherapeutic targets for ASUDs. This narrative review discusses preclinical and clinical evidence for emerging pharmacotherapies that target ASUD-related neuroendocrine systems. Special emphasis is placed on recent work with glucagon-like peptide-1, ghrelin, fibroblast growth factor-21, amylin, glucocorticoids, and mineralocorticoids.