2,5-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.
Research on Schedule I substances in the United States is heavily restricted by the Controlled Substances Act, creating what is termed Research Harm—the restriction or deterrence of legitimate scientific inquiry due to governmental regulatory controls and criminal prohibitions. Barriers include lengthy DEA registration timelines, inconsistent guidance, and policy confusion, limiting access to substances with therapeutic potential like psilocybin, MDMA, cannabis, and DOI. The 2025 HALT Fentanyl Act introduces procedural improvements such as expedited registration and shared institutional access but leaves key regulatory issues unresolved. Recommended reforms include revising medical utility interpretations, conducting periodic evidence reviews, and establishing a scheduling framework for easier research access.