“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. 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.īut 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. Shoichet and others on the team did not set out to find molecules that could be used to make new drugs for depression. “They pick up a chemical signal, and downstream a bunch of things get activated in a cell.” “The receptors are like antennae,” said Brian Shoichet, PhD, professor of pharmaceutical chemistry in the UCSF School of Pharmacy. LSD activates the first one more, while the new compounds activate the second one more. The scientific team discovered the receptors could set off two different pathways, a hallucinatory pathway and an antidepressant/antianxiety one. 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 current study offers the possibility of disentangling these effects. It’s not known if the trip is essential to the treatment, or if drugs could be developed that alleviate symptoms without it. 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. The new molecules activate it, but in a very different way than psychedelics. 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 receptor is also activated by serotonin, a naturally occurring hormone that regulates mood, cognition and many other functions in the body. The compounds were designed to fit into the 5HT2a receptor, which is the main target of psychedelics like LSD and psilocybin mushrooms. 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. 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. A single dose produced powerful antidepressant and antianxiety effects in mice that lasted up to two weeks. Scientists have designed compounds that hit the same key receptor that LSD activates without causing hallucinations. Scientists Discover Multiple Pathways of the Main Receptor Activated by Psychedelics LSD-Like Molecules Counter Depression Without the Trip
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