Scientists identify the LSD structural elements that trigger hallucinations and create a promising non-hallucinogenic antipsychotic analogue

Researchers systematically removed rings from LSD's four-ring ergoline core to determine which structural features drive hallucinations and which may support therapeutic effects. In cell and mouse experiments, the complete structure was needed for maximal activation of the hallucinogenic 5-HT2A receptor, while a two-ring combination remained sufficient to produce the mouse head-twitch response. Removing the D ring produced UCD0094, which showed reduced activity at 5-HT2A and the heart-risk 5-HT2B receptor while retaining activity at 5-HT2C, a target associated with antipsychotic effects. The simpler compound UCD0076 barely activated 5-HT2A, did not cause head twitches, blocked hallucinogen-induced twitches at a high dose, and reduced amphetamine-induced hyperactivity in mice. The findings are promising for developing non-hallucinogenic psychiatric medicines, but results differed between cells and animals, most compounds were racemic mixtures, and mouse behavior cannot establish human safety or efficacy. Broader receptor activity also requires further study.