Illustration inspired by the topic of the paper. Credit: Angela Shang.

Psychedelics, psychoactive substances that alter people’s perceptions, mood and thought patterns, have recently shown promise for the treatment of some mental health disorders, including depression and substance use disorders (SUDs). A psychedelic compound that has proved to be particularly promising for the treatment of depression is psilocybin, which is derived from some varieties of hallucinogenic mushrooms.

When ingested, psilocybin is converted into psilocin, an active substance that influences how neurons communicate with each other. Past studies suggest that it affects the functioning of multiple serotonin receptors, proteins on the surface of cells that receive the neurotransmitter serotonin, which is known to regulate sleep, appetite and mood.

Most earlier works focused on the effects of psilocybin on the serotonin 2A receptor, which is also responsible for the hallucinations induced by the compound. Yet the hallucinogenic properties of psychedelics are a key factor preventing their clinical use, as they pose risks for some patients and make predicting mental health outcomes more difficult.

Researchers at Dartmouth College in the U.S. recently carried out a study aimed at further investigating the biological mechanisms that could underpin psilocybin’s antidepressant effects. Their findings, published in Molecular Psychiatry, suggest that another serotonin receptor, which does not induce hallucinations when activated, could be responsible for some of the drug’s beneficial effects.

"There has been a lot of excitement around psilocybin’s clinical potential due to recent studies that highlight its therapeutic effects in various psychiatric conditions including depression and anxiety," said Katherine M. Nautiyal, co-author of the paper, told Medical Xpress.

"While clinical trials have shown encouraging results, psychedelic treatments remain costly and counter-indicated or aversive because of their hallucinogenic properties. Importantly, the mechanisms through which psilocybin has rapid and long-lasting effects on psychiatry are unclear. "

Delving deeper into the therapeutic effects of psychedelics

The main goal of the recent study by Nautiyal and her colleague Sixtine Fleury was to better understand how psilocybin could improve the symptoms of depression or reduce anxiety, as reported in some earlier studies. To achieve this, the researchers carried out a series of experiments involving adult mice that were fed psilocybin and observed in a laboratory setting.

"Psilocybin interacts with almost all of the 14 serotonin receptors, not just the one responsible for the hallucinogenic effects (serotonin 2A)," explained Nautiyal. "We were interested in understanding which of the other receptors are involved in the long-lasting antidepressant responses. This is important for the goal of developing non-hallucinogenic analogs and opening new avenues for drug development."

As part of their experiments, Nautiyal and Fleury blocked the activity of the serotonin 1B receptor in mice, using drugs that prevented psilocybin from binding to this receptor or genetic engineering tools. They then administered psilocybin to the mice, subsequently observing their behavior and recording activity in brain regions that support the processing of emotions and thinking processes.

"We injected psilocybin into these experimental mice or controls and measured behaviors acutely (1h) or post-acutely (1–4 days)," said Nautiyal. "We were most interested in examining the post-acute behaviors related to depression and anxiety. We found that psilocybin decreased these behaviors, but that these responses were blunted without the serotonin 1B receptor."

Towards safer and more effective psychedelics-based treatments

The data collected by the researchers suggest that the serotonin 1B receptor plays a key role in how psilocybin affects brain activity. In fact, when this receptor was made inactive, some common effects of the compound on the mice’s behavior were less pronounced. Specifically, after receiving psilocybin, mice in which the receptor was inactive tended to move more and appeared less interested in pleasurable stimuli than those in which the receptor was active.

"Our study shows that there are other important targets for psilocybin other than the serotonin 2A receptor also responsible for hallucinations, and that these targets contribute to the antidepressant and anxiolytic effects," said Nautiyal.

The recent work by Nautiyal and Fleury could soon inspire further research aimed at better understanding how specific serotonin receptors contribute to the different effects of psilocybin. These efforts could inform the future development of effective psychedelic-based treatments for depression or other mental health disorders that do not cause hallucinations and are thus safer or better suited for clinical settings.

"We now plan to dig deeper to understand how and where in the brain the serotonin 1B receptors are influencing behavioral responses to psilocybin," added Nautiyal.

"We are also starting to look at the role of the serotonin 1B receptors on the effects of psilocybin on different additional behaviors, including cognitive flexibility and risk taking. Lastly, we’re analyzing the variability in the behavioral response to psilocybin in mice to understand the covariates that influence the effect sizes so that we can improve our behavioral assays."

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Publication details

Sixtine Fleury et al, The serotonin 1B receptor is required for some of the behavioral effects of psilocybin in mice, Molecular Psychiatry (2025). DOI: 10.1038/s41380-025-03387-1.

Journal information: Molecular Psychiatry

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Citation: Psilocybin could treat depression via a non-hallucinogenic receptor (2026, January 21) retrieved 21 January 2026 from https://medicalxpress.com/news/2026-01-psilocybin-depression-hallucinogenic-receptor.html

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