The potential of non-psychedelic 5-HT2A agents in the treatment of substance use disorders: a narrative review of the clinical literature.
Expert opinion on pharmacotherapy February 1, 2025 Alejandra Pulido-Saavedra, Anna Borelli, Razi Kitaneh et al.
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.