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 multi-ring structure and synthesized new, simplified versions of it to probe its functionality. The researchers successfully developed several compounds with reduced hallucinogenic and cardiotoxic effects while also 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 due to its ability to spur growth of neurons and strengthen connections between them. A host of neuropsychiatric and neurodegenerative diseases are characterized by these connections withering.
"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," said Olson. "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, which is a structure of four fused ring-like shapes that act 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."
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 showcased these improved safety profiles, with reduced hallucinogenic and cardiotoxic effects.
The team named these compounds UCD0094 and UCD0076.
A paradoxical-like quality
While both UCD0094 and UCD0076 exhibited better safety profiles, UCD0076 also exhibited 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," said Olson, 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."
The research was supported by the National Institutes of Health, the National Science Foundation, the Camille and Henry Dreyfus Foundation, and the Pershing Square Foundation.
