A team of scientists has developed LSD-like compounds that fit into the 5HT2a receptor – the main target of substances such as LSD and psilocybin.
Many people living with depression do not respond to current depression treatments such as SSRI’s. Research has shown that psychedelic compounds may offer a new and efficacious form of treatment for those who are resistant to current medication, however, these compounds can pose challenges when implementing them in classic healthcare systems.
As well as the ‘trip’ aspect of psychedelic substances, psychedelic treatments may take a few hours. Both of these aspects mean that clinical staff and clinical treatment rooms are needed, making scalability a hurdle, and some patients may also dislike the hallucinogenic nature of such treatments.
Now, scientists have designed compounds that hit the same key receptor that LSD activates without causing hallucinations. Results from a study, published in the journal Nature, showed that a single dose produced powerful antidepressant and anti-anxiety effects in mice that lasted up to two weeks.
The findings represent 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.
Psychedelics without the trip
The 5HT2a receptor is thought to play a role in schizophrenia and other psychotic disorders, as well as anxiety and depression. As well as psychedelics, this receptor is also activated by serotonin, a naturally occurring hormone that regulates mood, cognition and many other functions in the body.
A host of antipsychotic and antidepressant drugs block its activity, however, the newly designed molecules activate it – but in a very different way to 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.
Whether the trip aspect of this is an essential element to the treatment or not is currently under debate.
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 team of scientists has now discovered the receptors could set off two different pathways, a hallucinatory pathway and an antidepressant and anti-anxiety one.
LSD activates the first one more, while the new compounds activate the second one more.
Brian Shoichet, PhD, professor of pharmaceutical chemistry in the UCSF School of Pharmacy, commented: “The receptors are like antennae. 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 synthesise and, therefore, has been absent from virtual libraries, although it is common among FDA-approved drugs.
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.
With stated: “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.
“That really galvanised 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, synthesised them, and the UCSF, UNC, Yale team worked for more than a year to optimise them.
“The final molecules were 100 times more potent than what we started with,” Shoichet said, who highlighted that 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, however, 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, finding 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 optimising 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 Canadian 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.”
