A single dose of psilocybin triggers heightened immediate behavioral reactions in mice bred to model aspects of schizophrenia, yet also produces a lasting improvement in sensory filtering among females. The findings suggest that the immediate psychedelic-like effects of the compound and its longer-term influence on brain function may operate through distinct biological pathways that vary by sex. The research was published in Neuropsychopharmacology.
Psilocybin is the primary psychoactive compound found in so-called magic mushrooms. Once consumed, the body converts it into psilocin, a molecule that alters perception, mood, and thought primarily by activating serotonin 2A receptors on the surface of brain cells. Although psilocybin is being widely tested in clinical trials for depression and anxiety, its effects in schizophrenia, a severe psychiatric disorder marked by hallucinations, delusions, social withdrawal, and trouble filtering sensory information, remain poorly understood.
Because psilocybin can temporarily mimic psychosis-like changes in perception and brain network connectivity in healthy people, modern clinical trials routinely exclude anyone with a personal or family history of psychotic disorders. According to a 2024 systematic review and meta-analysis of human studies, psychedelic-induced psychosis is rare: about 0.002 percent in population studies, 0.2 percent in uncontrolled trials, and 0.6 percent in randomized controlled trials.
The same analysis estimated a 3.8 percent rate of long-lasting psychotic symptoms among patients with schizophrenia, but that figure came from two small, uncontrolled LSD studies conducted more than fifty years ago and judged to have a high risk of bias, leaving open the question of how brains vulnerable to psychosis respond to psychedelics.
Understanding that vulnerability requires looking beyond serotonin to glutamate, the brain’s primary excitatory chemical messenger. Evidence from a 2008 study on brain receptor complexes indicated that serotonin 2A receptors can physically pair with a type of glutamate receptor on cortical neurons, shaping how the brain responds to hallucinogens. The new study focuses on a different member of the same receptor family, metabotropic glutamate receptor 5, which sits on nerve cells and helps regulate learning, emotional control, and the strength of connections between neurons.
Mice genetically engineered to lack this specific glutamate receptor display several traits relevant to human schizophrenia, including hyperactivity and impaired sensory filtering, which can be eased by standard antipsychotic medications. In a 2010 experiment in mice, animals missing this glutamate receptor showed exaggerated bursts of physical activity when given a synthetic hallucinogen that stimulates serotonin 2A receptors. At the same time, psilocybin has been shown in mice to promote the growth of new connections between brain cells, raising the possibility that it might ease certain schizophrenia-related deficits after its acute effects wear off.
Biological sex also shapes how animals react to psychedelics. For instance, an earlier experiment comparing male and female rats found that adult females displayed more psilocybin-induced head twitches than males, with responses fluctuating alongside estrogen levels. To explore how disrupted glutamate signaling and biological sex interact during and after psychedelic exposure, lead author James J. Gattuso, a PhD candidate at the University of Melbourne based at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, conducted the new study alongside senior authors Anthony J. Hannan and Thibault Renoir.
“Psilocybin’s effects on biology relevant to schizophrenia remain poorly understood, partly because people with schizophrenia have generally been excluded from modern psychedelic trials over concerns about worsening psychosis,” Gattuso told PsyPost. “At the same time, there is growing scientific interest in whether some of its longer-lasting effects might have therapeutic potential for particular aspects of the disorder. We wanted to investigate both the immediate responses and the longer-lasting effects of psilocybin in a mouse model that captures some features relevant to schizophrenia.”
The researchers worked with four-month-old male and female mice divided into two experimental cohorts, one for behavioral testing and another for brain tissue analysis. Each cohort included both mice genetically modified from conception to lack the metabotropic glutamate receptor 5 and a comparison group of genetically typical littermates.
The behavioral cohort consisted of 96 mice, with 10 to 14 animals per subgroup, that underwent a series of tests before and after receiving an abdominal injection of either 1 milligram per kilogram of psilocybin or an inactive saline solution. To prevent pre-existing differences in baseline nervousness from skewing the results, the authors balanced the treatment groups using exploration scores recorded one week prior and alternated testing across morning and afternoon hours.
Immediately after the injection, the mice were placed in an activity chamber for 30 minutes to track the total distance they moved. During the first 15 minutes in the chamber, overhead cameras recorded the animals so a researcher blinded to their group assignments could count their head-twitch responses, rapid side-to-side head movements that serve as a standard rodent indicator of hallucinogen-driven serotonin 2A receptor activation. Two weeks later, a subset of 47 mice received a second injection of psilocybin or saline to test whether repeated exposure altered their immediate reactions.
Because the active breakdown product of psilocybin clears from mouse blood in about four hours, the team scheduled follow-up tests over the next nine days to measure lingering effects after the drug had left the body. On days one and nine after the injection, the mice completed a prepulse inhibition test, which measures sensorimotor gating, the brain’s ability to filter out redundant sensory stimuli so it is not overloaded. In this assay, a quiet warning tone is played 30 or 100 milliseconds before a loud, startling noise; a healthy brain uses the quiet tone to dampen the physical flinch to the loud sound, whereas people with schizophrenia and mice lacking the glutamate receptor typically show less of this dampening.
On days three and seven, the mice were evaluated for anxiety-like and depressive-like behaviors. For the light-dark box test, animals spent 10 minutes in an arena split into a dark compartment and a brightly lit chamber; spending less time in the bright area reflects heightened anxiety-like avoidance. Thirty minutes later, the mice underwent the Porsolt swim test, commonly known as the forced swim test, in which they were placed in a beaker of water for six minutes while automated software tracked how much time they spent floating immobile during the final four minutes.
The second cohort of 61 behaviorally naive mice, with 5 to 10 animals per subgroup, was used to examine brain activity. These mice received the same psilocybin or saline injections and had their brains collected 90 minutes later to measure levels of c-Fos, a protein that marks recently active neurons, across four brain areas involved in psychedelic action and movement.
During the first 30 minutes after dosing, psilocybin triggered a sharp increase in physical movement among mice lacking the glutamate receptor, whereas the change in distance traveled among genetically typical mice was not statistically significant. Mice missing the receptor were also more active than typical mice overall regardless of treatment, and glutamate-deficient males moved more than glutamate-deficient females.
In the 15-minute video recordings, psilocybin increased head twitches across all groups compared to saline, peaking between five and 10 minutes after the injection. Male mice lacking the glutamate receptor exhibited a much larger surge in psilocybin-induced head twitches than genetically typical males, while the difference between the two female groups was not statistically significant.
The authors caution against reading this as a sex difference, however. Typical females already showed more head twitches than typical males, narrowing the gap between the two female groups, and knockout males and knockout females did not differ from each other, a pattern the authors interpret as a broadly heightened sensitivity in mice lacking the receptor.
“This behavior is an indicator of psychedelic-related serotonin-receptor activity in mice, but it is not a direct measure of hallucinations, psychosis, or harm,” Gattuso explained. “It points to altered sensitivity that warrants further investigation, and we hope our findings encourage continued attention to how sex and underlying biology shape responses to psychedelics.”
When the subset of 47 mice received a second dose two weeks later, with males and females analyzed together, psilocybin again increased movement and head twitches, though the larger head-twitch response in mice lacking the glutamate receptor emerged at the second dose only after one outlier was removed. Overall, the differences between the first and second injections were not statistically significant, suggesting no lasting tolerance or sensitization under these conditions.
In the brain tissue analysis conducted 90 minutes after dosing in small groups of 5 to 10 mice, the researchers focused first on the claustrum, a thin sheet of neurons tucked beneath the inner surface of the neocortex that is thought to act like a switchboard coordinating activity across distant brain networks. Psilocybin increased the density of active, c-Fos-positive neurons in the claustrum of genetically typical mice compared to saline, whereas the difference between psilocybin and saline in mice lacking the glutamate receptor was not statistically significant.
The authors suggest that intact signaling through this glutamate receptor contributes to psilocybin’s recruitment of the claustrum, and they propose, as a speculative idea that still needs to be tested, that weaker engagement of this coordinating hub could contribute to the exaggerated acute reactions seen in the receptor-deficient mice.
In the dorsomedial striatum, a deep brain region involved in goal-directed movement, mice lacking the glutamate receptor showed lower overall neuronal activity than typical mice, while the effect of psilocybin was not statistically significant. Effects of psilocybin in the dorsolateral striatum, prelimbic cortex, and infralimbic cortex were also not statistically significant, though male mice displayed higher overall neuronal activity than females across most of the examined regions.
In the post-acute tests on days three and seven, mice lacking the glutamate receptor spent less time exploring the brightly lit compartment of the light-dark box than typical mice, consistent with their baseline anxiety-like trait. However, the effect of psilocybin on time spent in the light, distance moved, or transitions between chambers was not statistically significant. In the Porsolt swim test, psilocybin-treated mice across both genotypes and sexes spent more time floating immobile than saline-treated mice.
Although increased floating is traditionally interpreted as a depressive-like passive reaction to stress, the authors propose an alternative explanation: because all mice had experienced a baseline swim session five days before receiving the drug, the extra floating may reflect adaptive learning and energy conservation in an inescapable situation. Among psilocybin-treated females on day seven, individual mice that had displayed more head twitches right after injection actually spent less time floating, whereas correlations on day three in females and on both days in males were not statistically significant.
The overall group increase in immobility stands in tension with an earlier study of depressive-like behavior in rats, which found that a single dose of psilocybin reduced swim-test immobility for up to 12 weeks alongside lasting increases in neuronal excitability in the medial prefrontal cortex. However, that earlier work examined long-term outcomes weeks later in a rat model of depression rather than post-acute responses in a mouse model of schizophrenia.
The most notable long-term change emerged in the sensorimotor gating tests on days one and nine. At the 100-millisecond warning interval, psilocybin improved prepulse inhibition across female mice compared to saline, whereas the effect in males was not statistically significant.
At the shorter 30-millisecond interval, saline-treated females lacking the glutamate receptor showed impaired sensory filtering compared to saline-treated typical females, and a single dose of psilocybin restored their filtering performance to a level where the difference from typical females was no longer statistically significant. This benefit persisted through day nine and held up after the researchers statistically accounted for differences in startle strength between the genotypes. In males, by contrast, saline-treated mice lacking the receptor did not show a statistically significant deficit at the 30-millisecond interval, and psilocybin’s effect was not statistically significant.
“That persistence and normalization to the control mice is an exciting feature of the findings,” Gattuso said. He described the main takeaway as “a promising lead for further research into psilocybin’s therapeutic potential, although improving one measure in mice does not establish that it will treat schizophrenia in people.”
“The sex differences were particularly striking: we observed a lasting improvement in sensorimotor gating in females, but not males,” he noted. “Finding this potentially beneficial effect was especially interesting given the concerns surrounding psychedelics and schizophrenia.”
When the team compared acute head twitches to day-nine sensory filtering in psilocybin-treated females, they found a negative correlation: females that had shown more head twitches immediately after dosing tended to have lower prepulse inhibition nine days later. Correlations on day one in females and on both days in males were not statistically significant. In the authors’ reading, this pattern supports the possibility that the immediate hallucinogen-like reaction and the lasting change in sensory filtering arise through separate mechanisms.
There are a few things to keep in mind when interpreting these results. First, the experiments were conducted in mice missing the metabotropic glutamate receptor 5 from conception, which models certain biological features of schizophrenia but does not capture the full complexity of the human disorder. Because the receptor was absent throughout brain development, some of the altered responses to psilocybin could stem from developmental compensations rather than the immediate absence of the receptor in adulthood. To sort this out, the researchers note that future experiments should test whether temporarily blocking this glutamate receptor with a drug in genetically typical adult mice produces the same heightened sensitivity to psilocybin.
Second, although the head-twitch response is a reliable marker of serotonin 2A receptor activation in rodents, it is not a direct measure of subjective hallucinations, psychosis, or mystical-type experiences in humans. The authors caution that the restoration of sensory filtering in female mice does not mean psilocybin acts as a broad antipsychotic, and the amplified acute reactions in receptor-deficient mice point to the need for continued caution regarding psychedelic use in people vulnerable to psychosis.
“Our findings do not establish whether psilocybin would benefit or harm people with schizophrenia, and they should not be interpreted as a recommendation for self-treatment,” Gattuso emphasized. “We examined one dose in one mouse model, and no animal model can reproduce the full complexity of the human disorder. Studying complementary models and a range of doses will help establish how robust and generalizable these findings are. That work could help inform whether, and under what conditions, carefully controlled clinical trials would be justified.”
Finally, the study tested only a single dose level of psilocybin and did not measure blood or brain concentrations of psilocin, leaving open the possibility that male and female mice or different genotypes metabolize the compound at different rates. The researchers suggest that future studies should test multiple doses and examine whether giving a compound that blocks serotonin 2A receptors prior to psilocybin eliminates the acute head twitches while preserving the long-term sensory filtering improvements in females.
“Ultimately, we want to understand where psilocybin might have therapeutic value, where it might carry risks, and which biological factors influence those outcomes,” Gattuso added. “Important next steps include investigating the mechanisms behind the sex differences and determining whether the longer-lasting improvements can be separated from the acute psychedelic-like responses. Our broader goal is to help advance psychedelic medicine through a clearer understanding of who might benefit, who might be vulnerable, and why.”
The study, “Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia,” was authored by James J. Gattuso, Ahmed Kamal, Jennyfer M. Payet, Kato Havaux, Jenna Hendey, Bilgenur Bezcioglu, Zoe J. Phelan, Maddy Orchard, Divyesh Bhanot, Matthew W. Hale, Anthony J. Hannan, and Thibault Renoir.