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 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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Argues that simplified ergoline analogues can retain LSD-like 5-HT2A agonism while offering improved safety profiles, identifying a 5-HT2C-preferring analogue with antipsychotic-like properties in mice.
Synthesized
Comparable studies
Other experimental studies on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Neural correlates of the LSD experience revealed by multimodal neuroimaging. Human participants | 2016 | Experimental study | |
| Crystal structure of an LSD-bound human serotonin receptor | 2017 | Experimental study with structural biology and molecular dynamics simulations | |
| Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe Midbrain neurons containing serotonin | 1968 | Experimental study | |
| Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD. Human brain | 2017 | Experimental study | |
| LSD-Assisted Psychotherapy in Patients with Terminal Cancer Cancer patients | 1973 | Experimental study | n = 60 |
Citations in the library
Cites 37
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- The Pharmacology of Lysergic Acid Diethylamide: A Review CNS Neuroscience & Therapeutics November 11, 2008
and 32 more in the library