The opioid crisis has driven a search for new treatments for opioid use disorder (OUD). A systematic review of 40 preclinical animal studies found that the psychedelic compounds 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, and ketamine generally reduced opioid self-administration, eased withdrawal symptoms, and altered conditioned place preference. However, seven studies showed no improvement over controls. Most research has focused on iboga derivatives, which appear effective but carry higher cardiovascular risk than other psychedelics. The review calls for more translational and clinical studies that test a broader range of psychedelic agents and explore mechanisms, safety, dosing, and treatment frequency.
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.