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

Substance use disorders remain a public health challenge; few have FDA-approved treatments, and those that do suffer from high dropout rates. This narrative review examined clinical evidence for non-psychedelic medications that primarily target the 5-HT2A receptor. Results on craving and abstinence were mixed, with some positive effects but no consistent pattern. Comparing these findings with those for psychedelic agents (which are typically 5-HT2A agonists) suggests that mixed results are not unique to non-psychedelics. Because most non-psychedelic agents reviewed are 5-HT2A antagonists, while psychedelic agonists show more uniformly positive outcomes, the authors propose that 5-HT2A receptor agonists are a promising avenue for treating substance use disorders, possibly by addressing a common underlying chronic hypodopaminergic state.

Study at a glance

Abstract

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