Study finds non-hallucinogenic psilocybin neural receptor

Psilocybin—the psychedelic compound that occurs naturally in certain "magic" mushroom species—has been shown in trials to provide long-term treatment for depression and anxiety. But the chemical's hallucinogenic effects can make developing treatments expensive and pose significant risks to people living with other psychiatric illnesses.

Now, a Dartmouth study identifies a neural receptor that promotes the therapeutic benefits of psilocybin but is non-hallucinogenic. The findings, reported in Molecular Psychiatry, may provide a new potential target for psilocybin-like medications that are safer and more cost-efficient. 

"When people think about psilocybin, they think about acute effects like hallucinations, which are attributed to the activation of a specific neuroreceptor. We thought that the beneficial effects reported for treating depression and anxiety may be found in other receptors," says Sixtine Fleury, the study's first author and a PhD candidate in the lab of senior author Katherine Nautiyal, an associate professor of psychological and brain sciences at Dartmouth. 

"We want to understand where exactly the therapeutic effects of psilocybin come from, whether we can administer this compound in a safe way, or develop non-hallucinogenic analogs," Fleury says. "These are powerful substances, and it's important to understand their mechanisms." 

In the United States, psilocybin is a Schedule 1 controlled substance, making its possession illegal at the federal level. But in the past decade, the FDA has granted psilocybin and related compounds Breakthrough Therapy designation for the treatment of major depressive disorder and depression that is resistant to treatment with standard-of-care pharmacotherapies such as antidepressants.

Its possession has been decriminalized in some states, and others have proposed or passed laws to regulate its production, sale, or supervised administration for clinical psychiatric use, according to the National Center for Complementary and Integrative Health at the National Institutes of Health.

Psilocybin acts on receptors for serotonin, a chemical in the central nervous system that regulates mood, appetite, and sleep. Serotonin is a common target for pharmaceuticals designed to treat depression and anxiety.

The psychedelic effects of psilocybin stem from the serotonin receptor 2A, Nautiyal explains. Research into reducing hallucinations has focused on blocking this receptor, but these studies are inconsistent when it comes to preserving the compound's therapeutic advantages, she says.

"Our study shows that there likely is another target," Nautiyal says. "Researchers have narrowly focused on the 2A receptor because we know it causes hallucinations, but the screening profiles of psilocybin show that these drugs bind to nearly all of the serotonin receptors." 

Fleury and Nautiyal developed a new model to study the antidepressant and anti-anxiety effects of psilocybin in mice. They used this model to study the brains and behavior of mice given psilocybin and found that the compound's positive behavioral effects are routed through serotonin receptor 1B in addition to 2A.

The serotonin system is similar across many species, including mice and humans, Nautiyal says, with the 1B receptor serving as a target for many anti-migraine medications. 

The study results could help overcome the significant obstacle to using psilocybin medically, Fleury and Nautiyal say. Studies have shown that even one dose of the compound can relieve symptoms of depression and anxiety for several weeks up to as long as 6 to 12 months, they say.

But many people who might benefit from those effects, such as those with schizophrenia spectrum disorders, or a family history of psychosis, are unable to take psilocybin because of "the risk of psychedelics to trigger psychosis," Nautiyal says.

At the same time, testing and administering drugs derived from psilocybin is weighed down by the cost of providing caretakers to safely guide people through the hallucinogenic experience, she says. 

"Even people without a history of psychotic disorders still have the propensity to enter a highly anxious state, and that's what is controlled in trials," Nautiyal says. "We know this can be done safely, but we still don't know which of the many safeguards deployed in these settings are necessary for the reductions in 'bad trips' and psychiatric treatment."

"These substances have the potential to open new avenues for clinical therapy and therapeutic drugs," Fleury says. "It's important to find better treatments that are more efficient and more effective for people, but it's also important that we have a safe way to do that."