UC Davis researchers deconstruct LSD to identify molecular features linked to hallucinations, cardiotoxicity and therapeutic drug discovery

UC Davis researchers systematically deconstructed LSD's ergoline core to determine which molecular features drive its hallucinogenic, cardiotoxic and potentially therapeutic effects. They synthesized nine simplified analogues and found that phenethylamine-like features were more important for stimulating the 5-HT2A receptor and producing hallucinations than tryptamine-like features. Removing other structural elements reduced both hallucinogenic activity and cardiotoxic effects mediated by the 5-HT2B receptor. Two compounds, UCD0094 and UCD0076, showed improved safety profiles. UCD0076 also strongly bound to the 5-HT2C receptor and produced antipsychotic-like effects in mouse behavioral assays, suggesting possible starting points for medicines targeting conditions such as schizophrenia, epilepsy and substance use disorders. The findings provide simplified molecular scaffolds for further medicinal chemistry, but the reported antipsychotic properties remain preclinical.