The Center for Addiction Sciences and Therapeutics and Department of Pharmacology and Toxicology, John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX, USA.
2 papers in the library · 22 citations · publishing 2023-2025
Opioid misuse and overdose deaths are a major public health problem involving prescription opioids and potent fentanyl derivatives. Repeated overdose events indicate opioid use disorder (OUD). Opioids reduce pain by activating µ-opioid receptors (MOR) in the central nervous system, and dysregulation of reward circuitry underlies OUD. Serotonin (5-HT) contributes to opioid pharmacology and OUD. There is renewed interest in psychedelic compounds acting through the 5-HT2A receptor (5-HT2AR) for treating substance use disorders. Emerging data suggest MOR and 5-HT2AR crosstalk at cellular levels and in OUD circuitry, offering opportunities for novel pharmacological intervention. This review discusses the opportunities and challenges of using 5-HT2AR agonists as therapeutics for OUD.
A single dose of the psychedelic compound (-)-DOI, which activates the 5-HT2A serotonin receptor, reduced cocaine intake and motivation for cocaine in male rats. The drug made cocaine less rewarding and made rats more sensitive to price increases, effectively devaluing the drug. Blocking the 5-HT2A receptor with M100907 eliminated these effects, confirming the receptor's role. The findings suggest that 5-HT2A receptor-acting psychedelics may hold promise for reducing cocaine use, warranting further preclinical research into their effects on intake and relapse.