Proceedings of the National Academy of Sciences
December 13, 2005
Gabriella Gobbi, Francis Rodriguez Bambico, Regina A. Mangieri et al.
675 citations
Inhibiting the enzyme fatty-acid amide hydrolase (FAAH) with URB597, which prevents the breakdown of the endocannabinoid anandamide, produces antidepressant-like effects in mice and rats. URB597 reduced immobility in the tail-suspension and forced-swim tests, and increased firing of serotonin and norepinephrine neurons in brain regions linked to mood. These effects required CB1 receptor activation and were accompanied by higher brain anandamide levels. Unlike direct THC-like drugs, URB597 showed no rewarding or abuse-related effects. The findings suggest FAAH inhibition as a potential target for antidepressant drugs without the psychotropic side effects of cannabis.
Psychopharmacology
January 1, 2023
Valeria Buzzelli, Emilia Carbone, Antonia Manduca et al.
20 citations
Fragile X syndrome (FXS) is the most common inherited intellectual disability and the leading monogenic cause of autism spectrum disorder (ASD). Serotonin, involved in brain development and synaptic remodeling, may be insufficient during childhood in these disorders, worsening behavioral and emotional symptoms. This study tested psilocybin, a serotonin-modulating compound, in adolescent Fmr1-Δexon 8 rats—a model of both ASD and FXS. Systemic and oral microdoses of psilocybin normalized the rats' performance on the novel object recognition test, a measure of exploratory behavior, perception, and recognition. The results suggest that psilocybin may help ameliorate cognitive deficits associated with ASD and FXS.
Neuropsychopharmacology
February 13, 2026
Fabrizio Ascone, Valeria Buzzelli, Francesca Mottarlini et al.
2 citations
In a rat model of Fragile X Syndrome (FXS), psilocybin microdosing rescued deficits in novel object recognition memory. This benefit persisted even when serotonin receptors (5HT2AR or 5HT1AR) were blocked, but was abolished by blocking the TrkB receptor, indicating that the effect depends on BDNF/TrkB signaling rather than classical serotonergic pathways. At the molecular level, psilocybin normalized mature BDNF, increased TrkB, and restored downstream AKT signaling in the prefrontal cortex—pathways linked to synaptic plasticity and cognition. These results suggest psilocybin microdosing could be a promising therapeutic strategy for neurodevelopmental disorders like FXS and autism spectrum disorder, potentially dissociating therapeutic benefits from hallucinogenic effects.
Neuroscience and biobehavioral reviews
August 1, 2026
Fabrizio Ascone, Diletta Giangiacomo, Viviana Trezza
A review of preclinical studies finds that classic psychedelics affect behavioral domains overlapping with autism spectrum disorder (ASD), including social interaction, communication, repetitive behaviors, anxiety-like traits, and cognitive function. The neurobiological mechanisms involve serotonergic signaling, glutamatergic neurotransmission, neuroinflammatory processes, BDNF/TrkB pathways, and oxytocinergic and dopaminergic modulation. Mechanistic convergence with neurobiological alterations implicated in ASD is identified, but significant gaps constrain interpretation, including a scarcity of studies in established animal models of ASD, reliance on simplified behavioral assays, and uncertainty about how ASD-specific circuit alterations may influence responses to psychedelics.