Proceedings of the National Academy of Sciences of the United States of AmericaSep 8, 2026

Breaking Down the Chemical Structure of LSD

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Updated Sep 9, 2026

Abstract

UCD0094 and UCD0076 are identified as ergoline analogues with improved safety profiles compared to LSD.

Nine simplified ergoline analogues were created by deconstructing the tetracyclic ergoline core of LSD.
Key molecular features necessary for maximal activation of 5-HT2A receptors and hallucinogenic effects were revealed.
Strategies were established to reduce the hallucinogenic and cardiotoxic risks associated with LSD.
UCD0076 preferentially activates 5-HT2C receptors, unlike LSD, and shows antipsychotic-like effects in mouse behavioral tests.

Simplified

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.

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Breaking Down the Chemical Structure of LSD

Abstract

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