LSD atom swap tunes out hallucinations

By simply trading the positions of a carbon and a nitrogen within the skeleton of the psychedelic compound LSD, chemists have created a molecule that promotes neuron growth and alleviates depression in mice but does not prompt the animals to behave as though they are experiencing hallucinations. The new molecule could lead to treatments for mental illnesses like depression and schizophrenia, neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, traumatic brain injury, and stroke (Proc. Natl. Acad. Sci. U.S.A. 2025, DOI: 10.1073/pnas.2416106122).

The work was led by David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics at the University of California, Davis. Scientists in Olson’s lab and at Delix Therapeutics, a company he cofounded, are specialists at tweaking psychedelic molecules. “We've taken every major psychedelic class—tryptamines, iboga compounds, amphetamines—and we've tinkered with them to try to make them better versions of themselves: to improve safety profiles and improve efficacy,” Olson says.

LSD has always been a source of fascination for Olson because of its outstanding ability to form and strengthen neural pathways. “We have consistently found that LSD is among the best neuroplasticity-promoting agents that we've studied. And we've studied many. It produces large effects, and it's very, very potent,” he says.

While others have made analogs of LSD, the resulting molecules have substantially different molecular skeletons or weights than LSD has. Olson wanted to make an analog that would simply swap the positions of two atoms—a carbon and a nitrogen.

LSD and many of its other analogs have been made by extracting lysergic acid from ergot fungus and then chemically altering its structure. The molecule Olson wanted to make required a completely new synthesis. He challenged Jeremy R. Tuck and Lee E. Dunlap, who did their graduate work in his lab, to make the new molecule—which is now known as JRT because Tuck was the first to synthesize it. “We didn't even know if the compound would work or not. So that was a huge leap of faith that this one chemical point mutation would really change the pharmacology of the molecule,” Olson says.

The carbon-nitrogen swap prevents JRT from making a key hydrogen bond that LSD makes to a serine residue in the active site of 5-hydroxytryptamine 2A (5-HT_2A), a key serotonin signaling receptor that psychedelics target. This means JRT is a partial agonist of 5-HT_2A—it activates the receptor, but not as well as a full agonist. Olson and colleagues think it changes the receptor’s conformation slightly when it binds compared with LSD and spends less time on the receptor than LSD does, which is why JRT doesn’t cause hallucinations. JRT is also less promiscuous than LSD, which also binds to dopamine receptors.

John McCorvy, who studies psychedelic pharmacology at the Medical College of Wisconsin, says it’s amazing that Olson and colleagues were able to achieve 5-HT_2A partial agonism by simply moving around a nitrogen in LSD's ring structure. “This study is a step in the right direction using receptor structure to design 5-HT_2A partial agonists rather than antagonists or full agonists. There is much potential for designing in partial agonists with various degrees of 5-HT_2A activation to see where this pharmacological mechanism may be useful medically," he says in an email.

Olson says his teams at UC Davis and Delix are looking to see if JRT or a similar molecule should be moved into the clinic. “The concept of using a small molecule to repair damaged neural circuitry has broad applicability,” Olson says. “There are a lot of conditions that could benefit from these types of agents.”