Decoding the serotonin–alcohol crosstalk: the role of central serotonergic dysregulation in alcohol use disorder
Pharmacological Reports June 22, 2026 Peer reviewed DOI: 10.1007/s43440-026-00860-8 via OpenAlex
Summary
Alterations in serotonin (5-HT) function are linked to alcohol use disorder (AUD) and depression, with reduced 5-HT activity increasing the risk of developing AUD, particularly Cloninger’s type II. Evidence from animal studies shows that Tph2-deficient mice consume more ethanol and exhibit behaviors similar to this type of alcohol dependence. The review emphasizes the need for better classification of AUD subtypes and the potential of serotonergic psychedelic-assisted therapies targeting 5-HT 2A receptors in treatment.
Study at a glance
| Design | review |
|---|---|
| Key finding | Reduced serotonin activity increases the risk of developing alcohol use disorder, especially Cloninger’s type II, characterized by early onset and antisocial behaviors. |
Abstract
Serotonin (5-hydroxytryptamine; 5-HT) is a key neuromodulator involved in the regulation of mood, appetite, aggression, and impulse control. Dysregulation of central 5-HT function has been implicated in alcohol use disorder (AUD) and comorbid depression. This review summarizes clinical and preclinical evidence on the role of 5-HT in AUD development, heterogeneity, and treatment response. Alterations in 5-HT function may be shaped by stress and genetic variation in serotonergic genes, including TPH2 and SLC6A4 , contributing to individual vulnerability to AUD. Reduced 5-HT activity increases the risk of developing AUD, particularly Cloninger’s type II, characterized by early onset, violent, and antisocial behaviors. Consistently, Tph2 -deficient mice, which lack central 5-HT, exhibit increased ethanol consumption and behavioral features resembling Cloninger’s type II alcohol dependence. Similarly, alcohol-preferring rat lines show reduced 5-HT levels, decreased serotonergic projections to the cortex, and reduced prefrontal 5-HT 2A receptor binding, implicating raphe-prefrontal serotonergic projections as a critical pathway modulating vulnerability to AUD. Given the heterogeneity of AUD, the efficacy of selective 5-HT reuptake inhibitors (SSRIs) remains limited, with beneficial effects observed only in less severe, later-onset forms. Recently, serotonergic psychedelic-assisted therapies have attracted considerable interest as potential AUD treatments; mechanistically, their effects may be linked to activation of 5-HT 2A receptors in the prefrontal cortex – a brain region known to be dysfunctional in AUD. The reviewed literature highlights the need for improved stratification of AUD subtypes and validation of 5-HT-related biomarkers to guide personalized therapeutic approaches.