Researchers systematically removed portions of LSD’s complex ring structure to create simpler analogues that retain beneficial neural effects while reducing hallucination and cardiotoxic signals. Two lead compounds point to new starting points for drug development.
The work maps which parts of LSD’s structure drive receptor-specific effects: phenethylamine-like features appear important for 5-HT2A-mediated hallucinations, while other portions influence 5-HT2B-mediated cardiotoxicity.
These simplified cores are presented as starting points for medicinal chemistry, not as proven therapies in people.
Researchers at the University of California, Davis performed a systematic "molecular autopsy" of lysergic acid diethylamide (LSD). They dismantled its ergoline core — a framework of four fused rings — and synthesized nine simplified analogues to see how removing specific structural elements changed biological activity.
LSD is being studied for its ability to promote growth and strengthening of connections between nerve cells, a property that could be useful against neuropsychiatric and neurodegenerative conditions. But LSD's complexity produces unwanted effects, including hallucinations and cardiotoxicity. The team wanted to identify simplified molecular cores that keep beneficial signaling while reducing adverse effects.
Two of the nine compounds, named UCD0094 and UCD0076, displayed improved safety profiles with reduced hallucinogenic and cardiotoxic properties. UCD0076 also showed strong preference for the serotonin receptor 5-HT2C and produced antipsychotic-like effects in behavioral tests in mice.
The researchers linked structural features to receptor activity. LSD resembles both tryptamine and phenethylamine families. When they removed tryptamine-like portions, remaining structures could still activate 5-HT2A and produce hallucinogenic effects. This pattern pointed to phenethylamine-like features as crucial drivers of LSD's 5-HT2A-mediated hallucinations. Removing other ring portions reduced activation of 5-HT2B, the receptor associated with cardiotoxicity.
Serotonin receptors 5-HT2A, 5-HT2B, and 5-HT2C mediate different effects. 5-HT2A activation is linked to psychedelic hallucinations. 5-HT2B activation is associated with heart-related adverse effects. 5-HT2C activity is being explored for therapeutic uses including epilepsy, substance use disorders, and schizophrenia. The study shows it's possible to shift a molecule's receptor preference by changing ring structure.
This work provides chemical starting points for drug discovery by identifying simpler cores that are easier to modify than LSD's complex ergoline scaffold. The authors describe these cores as better starting points for medicinal chemistry efforts.
These findings do not establish safety or efficacy in humans. The lead compounds are early-stage tools that helped the team map which molecular pieces drive specific pharmacological outcomes.
"By systematically deconstructing LSD, we have identified simplified cores that are better starting points for medicinal chemistry efforts," said David E. Olson, corresponding author and director of the Institute for Psychedelics and Neurotherapeutics at UC Davis.
Medicinal chemistry optimization, expanded preclinical safety testing, and receptor-selectivity studies will be required before any clinical conclusions can be drawn. The paper presents prioritized chemical scaffolds rather than candidate drugs ready for clinical testing.
In a result that is already sending ripples through the fields of neuroscience and drug design, chemists at the University of California, Davis have performed something akin to a molecular autopsy on lysergic acid diethylamide — better known as LSD — and lived to publish the findings. By systematically dismantling the
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