The International Journal of Neuropsychopharmacology
October 21, 2022
James J Gattuso, Daniel Perkins, Simon Ruffell et al.
233 citations
Classical psychedelics like LSD, psilocybin, and ayahuasca consistently disrupt resting-state connectivity within the Default Mode Network (DMN) and increase functional connectivity between canonical resting-state networks. The DMN, a set of brain regions active during self-referencing and mind wandering, is altered in various neuropsychiatric conditions. While DMN modulation is central to some cognitive models of psychedelics, its role in their therapeutic potential remains unclear. This systematic review provides a comprehensive overview to guide future research on the neurocognitive mechanisms of these agents.
Journal of Neurochemistry
November 29, 2023
James J Gattuso, Carey Wilson, Anthony J Hannan et al.
18 citations
Psilocybin, the psychoactive compound in magic mushrooms, shows promise for treating neuropsychiatric conditions like depression and anxiety, though its biological mechanisms remain unclear. A systematic review of 34 preclinical rodent studies found psilocybin most effective for depression, with potential to alter functional connectivity in the brain. Preclinical models allow controlled study of cellular mechanisms and minimize placebo effects, offering translatable insights for future therapies. The review highlights heterogeneity across studies and identifies avenues for further research.
European journal of pharmacology
March 15, 2025
James J Gattuso, Carey Wilson, Shanshan Li et al.
16 citations
Psilocybin, a serotonergic psychedelic, shows therapeutic potential for depression and anxiety disorders. In a study using serotonin transporter knockout mice—a model for anxiety and depression—a single dose of psilocybin (1 mg/kg) failed to produce head-twitch or hyperlocomotor responses in knockout animals, unlike wild-type mice. Psilocybin did not alter anxiety- or depressive-like behaviors in either genotype, though a trend toward reduced immobility in the Porsolt swim test appeared in female wild-type mice. Female knockout mice uniquely showed anhedonia-like behavior. The findings indicate that functional serotonin transporters are necessary for psilocybin's acute behavioral effects, with implications for pharmacogenetics in humans.
Neuropharmacology
January 1, 2025
James J Gattuso, Carey Wilson, Anthony J Hannan et al.
10 citations
A single injection of psilocybin reduced compulsive grooming in male SAPAP3 knockout mice—a model of obsessive-compulsive disorder—for up to one week, without affecting anxiety-like behaviors. The drug also decreased grooming in female knockout and wild-type mice and increased locomotion in wild-type but not knockout animals, indicating serotonergic dysfunction in the knockout mice. The typical head-twitch response confirmed psilocybin's hallucinogenic-like effect at the dose used. These findings suggest acute psilocybin may offer a novel treatment option for compulsive disorders, addressing the need for alternatives to current therapies that leave many patients unresponsive.
Neuropharmacology
August 21, 2025
James J Gattuso, Geraldine Kong, Bilgenur Bezcioglu et al.
7 citations
Chronic psilocybin given orally to mice at two doses (0.1 and 1 mg/kg) increased sociability in male wild-type mice but did not improve anxiety, compulsive, or depressive behaviors, nor did it induce psychosis-like effects. Psilocybin affected gut motility in a dose-dependent way. While overall gut microbiome diversity remained unchanged, specific bacterial species—Lactobacillus murinus, Lactobacillus animalis, and Alistipes dispar—decreased in male wild-type mice only. A cluster of these bacteria correlated with movement, head-twitch response, and gut motility, distinguishing psilocybin-treated from control mice, suggesting a feedback loop involving serotonin signaling. Other bacterial clusters were linked to startle response and sociability, indicating psilocybin engages distinct neural pathways. The findings underscore the roles of the microbiome and sex in psychedelic research.
Psychedelics.
October 28, 2025
James J Gattuso, Bilgenur Bezcioglu, Carey Wilson et al.
1 citation
Psilocybin, a serotonergic psychedelic, shows growing evidence for reducing obsessive-compulsive symptoms. A systematic review of 13 studies (4 clinical trials, 9 preclinical) found that single doses rapidly reduced symptoms in patients with OCD and body dysmorphic disorder. In wild-type mice, psilocybin briefly decreased marble-burying behavior only on the first day. In SAPAP3 knockout mice, a genetic model of compulsive behavior, a single dose produced robust, lasting reductions in excessive grooming, replicated across labs and doses. Chronic hallucinogenic doses did not improve anxiety or compulsive behavior in these mice, but chronic sub-hallucinogenic doses in rats reduced self-grooming and increased synaptic markers in the paraventricular thalamus. The evidence suggests transient clinical effects and lasting anti-compulsive effects in animal models, warranting larger placebo-controlled trials with neuroimaging.
bioRxiv (Cold Spring Harbor Laboratory)
October 24, 2024
James J Gattuso, Carey Wilson, Anthony J. Hannan et al.
1 citation
preprint
Acute psilocybin administration reduced compulsive grooming behavior in male SAPAP3 knockout mice, a model of obsessive-compulsive disorder, for up to eight days after a single injection. The compound did not affect anxiety-like behaviors. Psilocybin increased locomotion in wild-type mice but not in knockouts, suggesting underlying serotonergic differences. Both genotypes showed the typical head-twitch response, confirming the drug's hallucinogenic effect at the 1 mg/kg dose. The findings indicate psilocybin may have enduring anti-compulsive potential.
European Journal of Neuroscience
December 1, 2025
Nina Kleditzsch, James J Gattuso, Anthony J. Hannan et al.
Psilocybin, the active compound in psychedelic mushrooms, is being studied as a treatment for depression. Its metabolite psilocin binds to serotonin receptors and the serotonin transporter (5-HTT). In mice lacking 5-HTT, psilocybin failed to cause hyperactivity or head twitches, suggesting 5-HTT might be involved. To test this, researchers gave mice the selective 5-HTT inhibitor escitalopram before psilocybin. Escitalopram did not block psilocybin's effects on movement or head twitches. This indicates that acute blockade of 5-HTT does not directly mediate these behaviors, and the earlier findings in knockout mice likely stem from developmental changes or altered serotonin levels rather than acute transporter function.