Summary: A new mouse study challenges the widely held belief that psilocybin’s antidepressant effects depend on its psychedelic experience. Blocking the receptor responsible for hallucinations did not prevent psilocybin from restoring reward-seeking behavior in stressed mice.
Source: University of Maryland
Researchers at the University of Maryland School of Medicine (UMSOM) report that psilocybin—the active compound in so‑called “magic mushrooms”—retains antidepressant-like effects in a mouse model even when the drug’s hallmark psychedelic signaling is pharmacologically blocked.
The findings suggest that psilocybin acts through multiple biological pathways. If the fast-acting antidepressant benefits can be separated from the intense psychedelic experience, treatments could become more widely accessible, less resource-intensive, and safer for people for whom a full psychedelic session is inappropriate.
Current clinical protocols for psilocybin-assisted therapy include lengthy, supervised sessions with trained guides who help patients through hallucinations, altered perception of time and space, and intense emotional or spiritual experiences. Many in the field have assumed that those profound subjective effects are essential to the therapeutic outcome.
“We do not understand the mechanisms that underlie the antidepressant actions of psilocybin and the role that the profound psychedelic experience during these sessions plays in the therapeutic benefits,” says Scott Thompson, Ph.D., Professor and Chair of the Department of Physiology at UMSOM and the senior author of the study.
“The psychedelic experience is incredibly powerful and can be life-changing, but that could be too much for some people or not appropriate.”
Practical and safety concerns have limited broader use of psychedelic therapies. People with a family history of psychotic disorders like schizophrenia or bipolar disorder are typically excluded from psilocybin studies out of concern that intense psychedelic experiences could trigger or worsen symptoms. The structure of current treatments—often requiring a dedicated guide, a private setting, and a full day for the experience—also creates logistical and cost barriers that can limit access.
Dr. Thompson notes that if the antidepressant effects of psilocybin can be achieved without producing a full psychedelic state, a treatment could potentially be administered more safely at home or in outpatient settings and made available to people who cannot take prolonged time off or afford an intensive guided session.
The UMSOM team, led in this study by MD/PhD student Natalie Hesselgrave, used a validated mouse model of chronic stress to mimic depression-like deficits. Mice were exposed to daily stress over two to three weeks, after which their preference for a sweet reward—sugar water versus plain water—was tested. Loss of interest in rewarding activities, or anhedonia, is a core symptom of depression in humans and is reflected in decreased preference for sweet solutions in stressed mice.
Twenty-four hours after a single dose of psilocybin, previously stressed mice recovered their preference for sugar water, indicating a restoration of reward-seeking behavior. To test whether activation of the serotonin 2A receptor—the receptor known to mediate psychedelic effects—was necessary for this benefit, researchers administered ketanserin, a drug that blocks serotonin 2A, together with psilocybin.
Even with the serotonin 2A receptor blocked, the mice showed the same recovery of sugar preference after psilocybin treatment. In other words, preventing the receptor that produces the psychedelic response did not abolish the drug’s antidepressant-like effect in this animal model.
“These findings show that activation of the receptor causing the psychedelic effect isn’t absolutely required for the antidepressant benefits, at least in mice,” Dr. Thompson says. He cautions, however, that the same question must be tested in humans. His team plans to investigate which of the other serotonin receptors—there are more than a dozen—mediate the antidepressant actions of psilocybin.
Albert E. Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs at the University of Maryland, and Dean of the University of Maryland School of Medicine, calls the study an important step toward understanding how psychedelic compounds work. “This new study has interesting implications, and shows that more basic research is needed in animals to reveal the mechanisms for how these drugs work, so that treatments for these devastating disorders can be developed,” he says.
Funding: The research was supported by the National Institute of Mental Health (R01 MH086828) and the National Institute of General Medical Sciences (T32 GM092237).
Although not yet an approved therapy, Dr. Thompson and the University of Maryland Baltimore have filed a patent on the concept of using psilocybin in combination with drugs that block serotonin 2A receptors as a treatment strategy for depression.
About this psychedelics and depression research news
Source: University of Maryland
Contact: Vanessa McMains – University of Maryland
Image: The image is in the public domain
Original Research: The study will appear in PNAS.