The potential of non-psychedelic 5-HT2A agents in the treatment of substance use disorders: a narrative review of the clinical literature.

Introduction: Substance use disorders (SUDs) are a public health issue, with only some having FDA-approved indicated treatments and these having high attrition. Consequently, there has been interest in novel interventions (e.g. psychedelics that target 5-HT2A receptors) with some promising results. In this narrative review, we aim to focus on the role of the 5-HT2A receptors on the effectiveness of the treatment of SUDs.

Areas covered: We evaluated the clinical evidence of the treatment of SUDs with non-psychedelic medications with a primary affinity for the 5-HT2A receptor.

Expert opinion: The reviewed literature showed some positive effects on craving and abstinence but, overall, results were mixed. Comparison of this work with work on psychedelic agents suggests that mixed results are not unique to non-psychedelic agents. Both psychedelic and non-psychedelic drugs with 5-HT2A affinity are not exclusively selective for 5-HT2A receptors. The observation that most agents reviewed are 5-HT2A receptor antagonists instead of agonists and that psychedelics (typically 5-HT2A receptor agonists) may have more homogenous positive results gives more support to 5-HT2A receptor agonists as a promising group for treating SUDs. Mechanisms may target a common denominator across SUDs (e.g. chronic hypodopaminergic states).