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Could Psilocybin Treat Depression without the Trip?

Could Psilocybin Treat Depression without the Trip?

A growing body of early evidence suggests the psychedelic psilocybin could be a powerful and effective treatment for people suffering from treatment-resistant depression. But psilocybin treatment requires a deep commitment on the part of both patients and physicians, as the drug engenders hours of sometimes intense distortions of perception, time, and self. The psychedelic experience, in other words. A trip.

It has long been assumed by researchers that the antidepressant effects of psilocybin are tightly connected to the psychedelic experience, and are likely a direct result of that experience, but the causal relationship between the two remains poorly understood. However, according to the authors of a new paper, preclinical research conducted in mice suggests it might be possible to disentangle the antidepressant and psychedelic effects of psilocybin. If the results hold up in further studies, the authors suggest that it could make a potentially life-changing treatment available to many more people. 

A team at the University of Maryland conducted the study using chronically stressed male mice as an animal model of depression, with the mice no longer responding normally to pleasurable stimuli. It’s believed the hallucinatory, psychedelic effects of psilocybin depend on the activation of a subtype of serotonin receptor in the brain, the 5-HT2A receptor, so the researchers pretreated mice with the 5-HT2A antagonist ketanserin to block psilocybin from activating the receptors. They then gave the mice a single injection of psilocybin.

Despite blocking the psychedelic effects of psilocybin, the researcher’s found the treated mice regained their responsiveness to pleasurable stimuli, a behavioral sign that psilocybin helped alleviate symptoms of depression. The treated mice also developed stronger neural connections in a part of the brain known as the hippocampus, similar to the strengthened connection seen in this region with the use of more traditional antidepressants. These strengthened neural connections, the researchers note in a paper published in April in the Proceedings of the National Academy of Sciences, are a potential mechanism of action for psilocybin’s antidepressant effects.

“The tentative conclusion of our study is that the trip is not necessary for the acute antidepressant effect,” says University of Maryland School of Medicine Ph.D. student and lead author of the study, Natalie Hesselgrave. “Of course, our results were obtained with mice and depression is a uniquely human condition.” It’s also not yet clear if the antidepressant effects will last as long without the psychedelic experience, she says.

Ketanserin has been used in human clinical trials to mitigate the psychedelic effects of psilocybin in people without depression, Hesselgrave notes, and so it could provide a safe way to extend her work in human subjects with depression. If confirmed to be effective, a non-psychedelic psilocybin treatment for depression could make a potentially life-changing treatment available to many more people. “One of the biggest potential patient populations that could benefit are those with a personal or family history of bipolar or psychotic disorders,” Hesselgrave says. “Preventing or minimizing the psychedelic experience would reduce fears about the triggering of latent psychotic responses.”

A recent study on psilocybin published in the New England Journal of Medicine, for instance, excluded 891 of the 1,000 applicants based on their personal or family history of mental illness, according to Hesselgrave. 

The ability to prescribe psilocybin without psychedelic effects could also improve health equity, Hesselgrave said. Typically, a psilocybin session requires a full day in the clinic and the assistance of one or two facilitators, she says, which “represents a significant cost barrier to wider participation.”

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Hesselgrave and her colleagues are not alone in their interest in determining whether the psychedelic experience is integral to the therapeutic effects of psilocybin. Researchers at the University of Wisconsin-Madison are also trying to disentangle psilocybin’s various effects, although with different pharmacological methods.

There is also early evidence from studies of psilocybin in disease states other than depression suggesting psilocybin can be beneficial without the need for a trip. A recent study at the Yale School of Medicine found low doses of psilocybin could help reduce the number of migraine headaches suffered by patients and also found no correlation between the intensity of the psychedelic experience and the reduction in headaches.

All such work is still in the early stages, however, and it will require larger definitive studies to determine if psilocybin can work as medicine without the psychedelia, according to Hesselgrave. It’s work that will be very exciting, she says, “if it can be confirmed.”

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