Stripped-down LSD reveals structural features linked to hallucinogenic and therapeutic effects

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility: In this illustration, the chemical structure of LSD—represented by a rainbow—is being deconstructed into simplified analogs, which are portrayed as individual colors. Credit: Illustrated by Andras Domokos and Andrian G. Basargin/UC Davis University of California, Davis, researchers have stripped down LSD to the base features responsible for its hallucinogenic and therapeutic effects. In a study published in Proceedings of the National Academy of Sciences, the researchers whittled away at LSD's core multiring structure and synthesized new, simplified versions to probe its functionality. The researchers developed several compounds with reduced hallucinogenic and cardiotoxic effects while identifying one compound that produced antipsychotic-like effects. "By systematically deconstructing LSD, we have identified simplified cores that are better starting points for medicinal chemistry efforts," said study corresponding author David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics and a professor of chemistry and biochemistry and molecular medicine at UC Davis. LSD is among the many psychedelic drugs that researchers are investigating because of its ability to spur neuron growth and strengthen connections between neurons. A host of neuropsychiatric and neurodegenerative diseases are characterized by the withering of these connections. "We've known the structure of LSD for a long time, but the complexity of its core has really limited our ability to engineer optimized drugs based on its structure," Olson said. "If you can only modify a couple of spots, you're limited in what you can do." The study provides the psychedelic science research community with new launchpads for drug discovery. Finding function in the framework The research focused on LSD's ergoline core, a structure of four fused ring-like shapes that acts as its base molecular scaffold. This structure interacts with a suite of serotonin receptors in the brain, including serotonin receptors 5-HT2A, 5-HT2B and 5-HT2C, to produce LSD's various positive and negative effects. "We found that when you start deleting portions of LSD's molecular structure, you can retain some properties and eliminate others," Olson said. "By systematically deleting these rings, we can figure out what rings are important for what effects." An illustrated representation of the chemical structure of LSD being deconstructed. Credit: Illustrated by Andras Domokos and Andrian G. Basargin/UC Davis Olson described LSD's molecular framework as a mixture of the two major families of psychedelic compounds: the tryptamine family and the phenethylamine family. Molecularly, LSD possesses physical characteristics of both. "If you take those structures and overlap them, they basically produce LSD," Olson said. "The big question is, which one of those is more important for the hallucinogenic effects of LSD?" The answer, the researchers found, was the phenethylamine-like traits. When the researchers removed the tryptamine-like parts, the molecule retained its ability to stimulate the 5-HT2A receptor, producing hallucinogenic effects. But when the researchers removed other parts of the molecule, the hallucinogenic effects were reduced, as were the cardiotoxic effects. The cardiotoxic effects are mediated by the 5-HT2B receptor. In total, the research team synthesized nine modified versions of LSD's ergoline core, two of which showed improved safety profiles, with reduced hallucinogenic and cardiotoxic effects. The team named these compounds UCD0094 and UCD0076. A paradoxical quality While both UCD0094 and UCD0076 exhibited better safety profiles, UCD0076 also exhibited a high preference for binding to the 5-HT2C receptor. When tested in mouse behavioral assays, UCD0076 produced antipsychotic properties. "It's interesting that you could take LSD's structure, chop off a part of it and you're left with a molecule that is fundamentally antipsychotic," Olson said, noting that compounds that activate 5-HT2C receptors are being explored as treatment options for epilepsy and substance use disorders in addition to schizophrenia. "This is a great starting point for those conditions."