The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors.
Abstract
2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic with high affinity for 5-HT<sub>2</sub> receptors. In 2022 and 2023, the US Drug Enforcement Administration proposed to place DOI, along with a similar compound, 2,5-dimethoxy-4-chloroamphetamine, in Schedule I of the Controlled Substances Act based on their psychoactivity and alleged abuse potential. Here, we describe the history of DOI, its utility in preclinical neuroscience research, and how it has significantly advanced the study of 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors. Finally, we suggest alternative compounds for studying 5-HT<sub>2</sub> receptors, should obtaining DOI for research become restricted. SIGNIFICANCE STATEMENT: 2,5-Dimethoxy-4-iodoamphetamine, the key pharmacological tool for studying 5-HT<sub>2A</sub> receptor function and localization, has been used in more 1200 publications across 5 decades. This review covers its utility, research barriers if the Drug Enforcement Administration schedules it, and alternatives for continued investigation of serotonin receptors.
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