The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors.
Lindsay P Cameron, Alaina M Jaster, Raul A Ramos, Elijah Z Ullman
Molecular pharmacology January 1, 2026 DOI: 10.1016/j.molpha.2025.100093 via PubMed
Summary
AI-generated from the abstract2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic that binds tightly to 5-HT2 receptors, especially 5-HT2A and 5-HT2C. The US Drug Enforcement Administration proposed placing DOI and a similar compound in Schedule I of the Controlled Substances Act, citing their psychoactivity and potential for abuse. This review describes DOI's history, its essential role as a pharmacological tool in over 1,200 publications across five decades, and how it advanced the study of serotonin receptors. It also suggests alternative compounds for studying 5-HT2 receptors if DOI becomes restricted for research.
Study at a glance
| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Amphetamines Psychedelic Receptor pharmacology Research methods Serotonin receptors |
| Citations | 3 |
| Key finding | DOI has been a key pharmacological tool for studying 5-HT2A and 5-HT2C receptors in over 1,200 publications, but its potential scheduling may restrict future research, prompting the need for alternative compounds. |
Abstract
2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic with high affinity for 5-HT2 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-HT2A and 5-HT2C receptors. Finally, we suggest alternative compounds for studying 5-HT2 receptors, should obtaining DOI for research become restricted. SIGNIFICANCE STATEMENT: 2,5-Dimethoxy-4-iodoamphetamine, the key pharmacological tool for studying 5-HT2A 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.