LSD-Like Molecules Counter Depression Without the Trip

"Scientists have designed compounds that hit the same key receptor that LSD activates without causing hallucinations. A single dose produced powerful antidepressant and antianxiety effects in mice that lasted up to two weeks. The study was recently published in the journal Nature. UC San Francisco reports: The compounds were designed to fit into the 5HT2a receptor, which is the main target of psychedelics like LSD and psilocybin mushrooms. The receptor is also activated by serotonin, a naturally occurring hormone that regulates mood, cognition and many other functions in the body. The 5HT2a receptor is thought to play a role in schizophrenia and other psychotic disorders, as well as anxiety and depression, and a host of antipsychotic and antidepressant drugs block its activity. The new molecules activate it, but in a very different way than psychedelics. [...] Although it's been known for several decades that 5HT2a receptors activate different signaling pathways in cells, until now there were no compounds selective enough to see what each pathway did. The scientific team discovered the receptors could set off two different pathways, a hallucinatory pathway and an antidepressant/antianxiety one. LSD activates the first one more, while the new compounds activate the second one more. "The receptors are like antennae," said Brian Shoichet, PhD, professor of pharmaceutical chemistry in the UCSF School of Pharmacy. "They pick up a chemical signal, and downstream a bunch of things get activated in a cell." The compounds had been selected from a computational library of 75 million candidates. Jonathan Ellman, PhD, the Eugene Higgins Professor of Chemistry, and professor of pharmacology at Yale, synthesized them. And the UCSF, UNC, Yale team worked for more than a year to optimize them. "The final molecules were 100 times more potent than what we started with," Shoichet said, although they were still not nearly as strong as LSD. "In the animals they are very potent, much more potent than Prozac." The team expanded to test the designer molecules in mice, adding William Wetsel, PhD, who directs the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke. His lab looked for head twitch responses that are the tell-tale signs of psychedelic activity in mice. But the mice hardly twitched. Wetsel's lab ran the mice through a battery of tests to see if the molecules could ameliorate symptoms analogous to human anxiety and depression. And they were highly effective. After many years, what had begun as a science experiment arrived at a discovery with great clinical promise. "The team's next project will be optimizing the compounds, making them selective enough to be used in clinical trials," adds the report. "A key issue will be making molecules that have no affinity for 5HT2b. Drugs that hit this receptor, like the banned diet drug fen-phen, can cause valvular heart disease when taken chronically. That receptor is also hit by psychedelics, particularly LSD."

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