Targeting Serotonin 5-HT2A Receptors in the Treatment of Aggression: from Antipsychotics to Psychedelics.
Simona Scheggi, Giulia Braccagni, Caterina Branca, Marco Bortolato
Aggression and violent behavior 2026 DOI: 10.1016/j.avb.2026.102139 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Aggression Antipsychotics Psychedelics |
| Key findings | The authors argue that heightened prefrontal 5-HT2A receptor levels are implicated in reactive aggression and antisocial behavior, and that 5-HT2A antagonists such as atypical antipsychotics reliably reduce aggression and irritability across neuropsychiatric disorders. They contend that agonist effects are more complex: classic psychedelics have been linked to reduced aggression and improved emotional regulation, whereas other agonists can heighten irritability or provoke violent behavior depending on dose, environmental context, and pharmacodynamic properties. |
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-HT2A receptor has emerged as a key modulator of aggressive behavior. Convergent neuroimaging, postmortem, and preclinical studies consistently implicate heightened prefrontal 5-HT2A receptor levels in reactive aggression and antisocial behavior. In this review, we examine how 5-HT2A receptor function shapes the pathophysiology of aggression and synthesize the pharmacological evidence that informs its therapeutic relevance. Antagonists at the 5-HT2A receptor, including atypical antipsychotics, reliably reduce aggression and irritability across a range of neuropsychiatric disorders. By contrast, the effects of 5-HT2A 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-HT2A antagonism and agonism can attenuate aggression, whether distinct aggression subtypes rely on different modes of 5-HT2A signaling, what mechanisms drive selective upregulation of prefrontal 5-HT2A receptors, and how genetic or epigenetic factors shape receptor function. Clarifying these issues will be essential for developing more precise and mechanistically grounded 5-HT2A-targeted strategies for pathological aggression.
Comparable studies
Other narrative reviews on serotonin, most cited first.
Citations in the library
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and 40 more in the library