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Trip-Free LSD-Like Molecules Produce Antidepressant Effects in Mice

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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, appearing Sept. 28, 2022, in Nature, may offer a way to develop new kinds of antidepressants that are more effective and have fewer side effects than current medications, which don’t work for many patients and must be taken every day. It represents the culmination of half a dozen years of work by a team that began at UC San Francisco, UNC-Chapel Hill and Yale, and later expanded to Duke and Stanford universities. 

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. 

Recent studies have found that when given in combination with psychotherapy, one or two high doses of psychedelics like psilocybin and MDMA can have significant long-term effects on depression, anxiety and PTSD. It’s not known if the trip is essential to the treatment, or if drugs could be developed that alleviate symptoms without it. 

The current study offers the possibility of disentangling these effects. 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.”   

Shoichet and others on the team did not set out to find molecules that could be used to make new drugs for depression. Their initial goal was to find a way to screen a type of molecule called a tetrahydropyridine that is difficult to synthesize and therefore has been absent from virtual libraries, although it is common among FDA-approved drugs. 

But another team member, Bryan Roth, MD, PhD, of UNC-Chapel Hill, thought the molecules might be an interesting way to test the function of the 5HT2b receptor, which he’d been studying along with 5HT2a since the 1980s. 

“There wasn’t really any sense that drugs like psychedelics that activate this receptor would be therapeutic until psilocybin was tried in clinical trials for depression and shown to have this remarkable effect,” he said. “That really galvanized our interest, which basically started this collaboration.” 

Roth, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine, and some other team members had recently solved the crystal structure of the 5HT2b receptor. They used that structure to model the 5HT2a until Roth’s group worked out the crystal structure of 5HT2a. 

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 work was aided by a $27 million grant that Shoichet and Roth received in 2020 from the Defense Advanced Research Projects Agency (DARPA) to develop new psychiatric medicines. 

The team’s next project will be optimizing the compounds, making them selective enough to be used in clinical trials. The approach has been patented by Yale, UNC-Chapel Hill and UCSF and licensed to Onsero, a Boston-based startup.

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.

“We weren’t looking for anything therapeutic,” Roth said. “After a huge amount of work, we ended up with these very selective compounds.” 


Kaplan AL, Confair DN, Kim K, et al. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature. Published online September 28, 2022:1-10. doi:10.1038/s41586-022-05258-z

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