Psilocybin restores social drive in an autism mouse model even under anesthesia

New research provides evidence that a single dose of psilocybin can durably increase social behavior in mice with genetic traits related to autism. The findings indicate that these behavioral benefits occur even if the mice are anesthetized during the drug’s acute effects, which suggests the subjective psychedelic experience is not strictly required. The study was published in Nature Communications.

Psilocybin is the primary psychoactive compound found in certain species of hallucinogenic mushrooms. In recent years, medical research has explored its potential to treat conditions like depression, anxiety, and addiction. Some experts also wonder if it could improve sociability, which refers to the innate drive and capacity to interact with others.

Reduced sociability is a prominent characteristic of autism spectrum disorder. It is also a feature sometimes observed in other conditions, such as schizophrenia and major depressive disorder. When considering how psychedelics alter brain function, scientists sometimes look at the idea of physiological set points. According to a 2026 review, psychedelics can push brain activity away from a rigid set point, making neural pathways more adaptable even after the drug wears off. This perspective suggests that psilocybin might help shift an out-of-balance behavioral state toward a more typical one.

Another ongoing debate in psychiatric research revolves around the psychedelic trip itself. The intense sensory and emotional alterations induced by psilocybin can be challenging to manage in clinical settings and sometimes provoke adverse psychological reactions. It has remained unknown whether this conscious experience is biologically necessary to achieve the drug’s long-lasting behavioral effects.

“We wanted to examine the lasting effects of a single dose of psilocybin beyond its established effect on depression as previously reported in the human literature,” Chenchen Song, a principal investigator at Nanyang Technological University Singapore, told PsyPost. Song led the research alongside Thomas Knöpfel, director of the JC STEM Laboratory for Neuronal Circuit Dynamics at Hong Kong Baptist University. “We conduct basic preclinical research, so we examined the lasting effects using a mouse model of altered sociability; the model was established by other labs and used by many independent labs internationally.”

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“A long-standing debate in the psychedelic field is whether an awake subjective experience is required during the acute psychedelic phase (commonly known as a ‘psychedelic trip’) to achieve the therapeutic effects,” the researchers explained. “Since bad psychedelic trips have been linked to unfavorable behavioral outcomes, understanding this may have real-world implications for how psychedelic-assisted therapies are delivered.”

The researchers utilized a well-established group of mice bred without the Cntnap2 gene. In humans, variations in this gene are associated with autism. Mice lacking this gene naturally display lower levels of social interaction, hyperactivity, and repetitive behaviors. The team injected 30 adult mice with a single dose of either psilocybin or a saline solution to serve as a baseline comparison.

“We use social behavior as a behavioral readout of altered brain state,” the researchers noted. “Therefore we needed a mouse model that show altered social behavior that can potentially show an improvement in behavior, if any, upon treatment. It is for this reason that we used an established mouse model of autism which is known to show altered social behavior in the hands of many independent laboratories internationally.”

They emphasized that their focus was on understanding brain flexibility, not discovering a cure for a specific human condition. “The goal of this study is not to find a therapeutic intervention for autism per se, and we are not suggesting that autism, in and of itself, should be treated,” the team added.

The team assessed the animals’ social behavior using a standard three-chamber test. This behavioral measure records how much time a mouse chooses to spend near a cup containing an unfamiliar mouse compared to an empty cup. The psilocybin-treated mice displayed an increased preference for the social cup compared to the saline-treated mice. This enhanced social drive was detectable one day after the injection and lasted for at least two weeks.

“The sociability promoting effect of psilocybin in mice that show a low baseline sociability was an original discovery of our lab (first in the prenatal valproate exposure mouse model of autism and now in a genetic model of reduced sociability),” Song pointed out.

The differences in the total amount of time the mice spent exploring both cups and their overall movement around the testing area were not statistically significant. This indicates that the drug specifically improved the animals’ social motivation rather than merely increasing their general desire to explore. To ensure the animals were not just learning how to navigate the test over time, the researchers tested a separate group of 19 mice for the very first time two weeks after treatment and observed the same social enhancements.

To determine if psilocybin acts as a universal social enhancer, the researchers repeated the exact same procedure with 18 isogenic wild-type mice. These are genetically identical control mice that possess normal Cntnap2 genes and exhibit typical social behaviors. In these animals, a single dose of psilocybin did not increase sociability. In fact, the treated control mice showed a tendency toward reduced social behavior one day after the injection.

“Even though we observed therapeutic effects in the model mice (of altered social behavior), we observed a lack of beneficial effects in control mice that do not have a deficit to begin with,” the researchers explained. “We therefore think that psychedelic use in the absence of behavioral alterations have limited beneficial effects.”

“Further, given that a significant portion of preclinical psychedelic research is done using wild-type mice, we should highlight that we think it important that the therapeutic effects of psychedelics should be examined using models of altered states as different effects/mechanisms may be involved,” they added.

The team also looked at other behaviors associated with this genetic model, specifically repetitive self-grooming and hyperactivity. During the observation periods, mice lacking the Cntnap2 gene groomed themselves much more frequently and traveled greater distances than the typical control mice. Psilocybin treatment did not alter these specific behaviors. The hyperactive and repetitive actions remained at the same elevated levels one day and one week after the drug was administered.

Psilocybin is known to exert its primary effects by activating a specific serotonin receptor in the brain, known as the 5HT2A receptor. To confirm this biological pathway, the researchers gave a group of mice a drug that blocks 5HT2A receptors fifteen minutes before administering the psilocybin. The blocking agent completely prevented the long-term increases in sociability.

The blocking agent also stopped the mice from exhibiting head twitches, which are rapid side-to-side head movements that scientists use as an indicator of a psychedelic hallucination in rodents. Interestingly, the frequency of a mouse’s head twitches right after receiving psilocybin had no correlation with how much its sociability improved weeks later. This hint led the researchers to a final, more definitive test.

To directly test if an active, awake experience is necessary for the long-term benefits, the researchers designed an experiment where mice were given psilocybin while unconscious. The animals were placed under light isoflurane anesthesia, maintaining a steady breathing rate with no movement or conscious awareness, for two hours. During this window, the animals received their injection and experienced the entirety of the drug’s acute chemical effects without an awake psychological trip.

When these anesthetized mice were later tested awake, they still exhibited the exact same long-lasting increases in sociability as the mice treated while awake. This provides evidence that the drug’s ability to rewire social behaviors is driven by basic chemical receptor interactions, rather than profound psychological realizations.

“Our observations suggest that psilocybin – even when given under anesthetized state – can have long-term therapeutic potential,” the researchers noted. However, they cautioned that “our preclinical work is no substitute for human studies. As far as we are aware of, human studies at various institutions are also underway for examining the therapeutic effects when psychedelics are given under anesthesia, for different psychedelic compounds.”

These animal findings are in line with research covered by PsyPost in 2025, which found that autistic adults often reported increased social engagement and reduced distress after impactful psychedelic experiences. However, that previous study relied on human self-reporting, whereas the current research measured physical approach behaviors in an animal model.

As with all research, there are a few things to keep in mind. Animal models cannot perfectly replicate complex human conditions like autism spectrum disorder. Additionally, the three-chamber test relies on measuring the physical time an animal spends near another mouse, but it cannot reveal the nuance of that interaction, meaning researchers cannot easily tell if an approach is driven by friendly interest or territorial aggression.

“The lasting effects of psychedelics remain understudied, especially at the mechanistic level,” Song said. “Nevertheless there is overwhelming evidence for the existence of lasting effects across species and across components of behavior. This is something that one should be generally aware of, especially with the increase of recreational psychedelic use.”

“Next we hope to look more mechanistically at how the lasting effects are achieved/sustained,” the researchers concluded. “Our preliminary observations suggest that epigenetic mechanisms are involved.”

The study, “Psilocybin enhances sociability only in altered behavioural state and does not need an awake experience to be effective,” was authored by Chenchen Song, Tinya Chang, Tobias Buchborn, and Thomas Knöpfel.