Deconstruction of lysergic acid diethylamide.
Andrian G Basargin, Andras Domokosa, Joseph J. Hennessey, Isak K Aarrestad, Rohini Sambyal, Yara A Khatib, Johanna Krüger, Lee E. Dunlap, Samuel J Carter, Isabella A Rebek, John L. McKee, Serena S. Schalk, Min Liu, James C Fettinger, Monica A. Gonzalez, Abhay Potluri, Dean J Tantillo, Oliver Fiehn, John D. Mccorvy, David E. Olson
Proceedings of the National Academy of Sciences of the United States of America September 8, 2026 DOI: 10.1073/pnas.2603412123 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Intervention | LSD |
| Topics | LSD Serotonin |
| Keywords | Function-oriented synthesis Psychedelic |
| Key points | Argues that simplified ergoline analogues can retain LSD-like 5-HT2A agonism while offering improved safety profiles. Identifies UCD0076 as a 5-HT2C-preferring ergolog with antipsychotic-like properties in mice, contrasting with LSD's hallucinogenic effects. |
Abstract
Of the classic psychedelics, lysergic acid diethylamide (LSD) is perhaps the best-known, but its complex chemical architecture has limited synthetic investigations aimed at generating analogues with improved safety and efficacy profiles. Here, we systematically deconstruct the tetracyclic ergoline core of LSD to create 9 simplified ergoline analogues (i.e., ergologs) and evaluate them in pharmacological assays relevant to 5-HT2A, 5-HT2B, and 5-HT2C receptor function. Our work revealed the key molecular features and minimal pharmacophore of LSD necessary to produce maximal agonism of 5-HT2A receptors and hallucinogenic behavioral effects. Furthermore, we established strategies for reducing the hallucinogenic and cardiotoxic potential of LSD and identified UCD0094 and UCD0076 as ergologs with improved safety profiles. In stark contrast to LSD, UCD0076 exhibits preference for activating 5-HT2C receptors over other 5-HT2 receptors and produces antipsychotic-like properties in mouse behavioral assays.