Targeting Serotonin 5-HT<sub>2A</sub> Receptors in the Treatment of Aggression: from Antipsychotics to Psychedelics.

Abstract

Aggression, anger, and irritability emerge from dysregulated interactions between prefrontal and limbic circuits, with serotonin (5-HT) exerting a central regulatory influence. Among serotonergic targets, the 5-HT_2A receptor has emerged as a key modulator of aggressive behavior. Convergent neuroimaging, postmortem, and preclinical studies consistently implicate heightened prefrontal 5-HT_2A receptor levels in reactive aggression and antisocial behavior. In this review, we examine how 5-HT_2A receptor function shapes the pathophysiology of aggression and synthesize the pharmacological evidence that informs its therapeutic relevance. Antagonists at the 5-HT_2A receptor, including atypical antipsychotics, reliably reduce aggression and irritability across a range of neuropsychiatric disorders. By contrast, the effects of 5-HT_2A agonists are more complex. Classic psychedelics have been linked to reduced aggression and improved emotional regulation in several epidemiological and experimental studies, whereas other agonists can heighten irritability or provoke violent behaviors depending on dose, environmental context, and pharmacodynamic properties. These divergent outcomes likely reflect the receptor's intricate molecular architecture, which supports multiple intracellular pathways, ligand-specific signaling biases, heteromeric interactions, and region- and cell-type-specific expression patterns. In the final section, we outline the key unresolved questions that emerge from this literature, including how both 5-HT_2A antagonism and agonism can attenuate aggression, whether distinct aggression subtypes rely on different modes of 5-HT_2A signaling, what mechanisms drive selective upregulation of prefrontal 5-HT_2A receptors, and how genetic or epigenetic factors shape receptor function. Clarifying these issues will be essential for developing more precise and mechanistically grounded 5-HT_2A-targeted strategies for pathological aggression.

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