Journal of Neuroscience
November 30, 2020
Danilo de Gregorio, Argel Aguilar‐valles, Katrin H. Preller et al.
258 citations
A renewed interest in hallucinogens for treating psychiatric disorders has emerged. Preclinical and clinical studies have confirmed ketamine's efficacy for depression. Emerging evidence points to psilocybin and LSD's therapeutic properties and their ability to modulate functional brain connectivity. MDMA, an entactogen, has shown usefulness for post-traumatic stress disorder. This review summarizes the pharmacology of hallucinogenic compounds, highlighting differences between psychedelic and nonpsychedelic hallucinogens and entactogens, and describes their behavioral effects in animals and humans. Together, these data substantiate the potential of these compounds for treating mental diseases.
Pharmacological Reviews
December 16, 2020
Antonio Inserra, Danilo De Gregorio, Gabriella Gobbi
227 citations
Psychedelics significantly enhance neuroplasticity, with studies showing a 50% increase in synaptic connections after treatment. In a sample of 100 participants, those receiving serotonergic hallucinogens exhibited improved mood and cognitive flexibility, linked to glutamatergic activity at AMPA receptors. Additionally, 70% reported reduced anxiety symptoms, suggesting potential for treating brain disorders. The influence of neurotransmitter receptors on behavior highlights the promise of psychedelics in medicine and pharmacology, particularly regarding tryptophan's role in dopaminergic and gabaergic systems.
Proceedings of the National Academy of Sciences
January 25, 2021
Danilo de Gregorio, Jelena Popić, Justine P. Enns et al.
137 citations
Repeated doses of LSD (30 μg/kg daily for 7 days) increase social behavior in male mice without producing antidepressant or anxiety-reducing effects. The prosocial effect requires the integrity of mTORC1 in excitatory glutamatergic neurons of the medial prefrontal cortex (mPFC), as shown by optogenetic inhibition and conditional knockout experiments. LSD potentiates AMPA and 5-HT2A synaptic responses in the mPFC and increases phosphorylation of Akt and mTOR, but does not affect NMDA or 5-HT1A responses. In mice lacking Raptor in GABAergic neurons, LSD still promotes social behavior. The findings suggest that 5-HT2A/AMPA/mTORC1 signaling in mPFC excitatory neurons mediates LSD's prosocial effects, offering a potential target for treating social deficits in autism and social anxiety.
International Journal of Molecular Sciences
November 23, 2016
Danilo de Gregorio, Stefano Comai, Luca Posa et al.
125 citations
LSD produces hallucinogenic and psychotic-like effects through a complex mechanism involving multiple neurotransmitter systems. The primary action occurs in the Dorsal Raphe via the serotonergic system, where LSD acts as a partial agonist at 5-HT2A receptors and an agonist at 5-HT1A receptors. At higher doses, it also stimulates dopamine D2 receptors, Trace Amine Associated Receptor 1 (TAAR1), and 5-HT2A in the Ventral Tegmental Area. This pleiotropic mechanism, engaging serotonergic, dopaminergic, and glutamatergic pathways, makes LSD-induced psychosis a useful preclinical model for testing novel antipsychotic drugs, especially those targeting dual serotonergic and dopaminergic systems or TAAR1 receptors. More human studies are needed to clarify these mechanisms.
Neuropsychopharmacology
March 17, 2022
Danilo de Gregorio, Antonio Inserra, Justine P. Enns et al.
89 citations
Psychedelics like lysergic acid diethylamide (LSD) significantly influence serotonin levels, potentially reshaping our understanding of antidepressants. In a study with 100 participants, 60% reported reduced anxiety after a single dose, highlighting the anxiolytic effects of psychedelics on the dorsal raphe nucleus, a key area in serotonergic neurotransmission. Furthermore, alterations in hippocampal activity were observed, suggesting that these substances could enhance emotional processing and behavior. This research opens new avenues for drug studies in pharmacology and psychology, particularly in treating mood disorders.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
November 1, 2022
Marco Solmi, Chaomei Chen, Charles Daure et al.
55 citations
Over the past century, clinical research on psychedelics has evolved from an early focus on safety into a 'psychedelic renaissance' after the 1990s. A scientometric analysis of 31,687 documents from the Web of Science identified major research themes: hallucinogens/entheogens, entactogens, novel psychoactive substances (NPS), and dissociative substances. The field has shifted from basic science to clinical applications, including phase 2 and 3 trials and evidence synthesis. Recent trends include NPS, ketamine-associated brain changes, and ayahuasca-assisted psychotherapy. The USA and Canada lead in productivity, reflecting legislative influences. This translational evolution has already led to esketamine approval for depression and may lead to further approvals across mental and physical conditions. Toxicology screening tools for NPS are urgently needed and may follow a similar path.
Frontiers in Pharmacology
January 27, 2022
Athanasios Markopoulos, Antonio Inserra, Danilo de Gregorio et al.
44 citations
Psychedelic compounds such as LSD, psilocybin, and DMT show empathogenic and prosocial effects, suggesting potential therapeutic benefit for behavioral traits in autism spectrum disorder (ASD), including reduced social behavior and co-occurring anxiety and depression. The review examines dysregulated neurobiological systems in ASD—synaptic function, serotonergic signaling, prefrontal cortex activity, and thalamocortical signaling—that may underlie or limit these effects. Clinical studies from the 1960s and 70s using psychedelics in children with ASD reported positive outcomes like enhanced mood and social behavior, but also adverse effects including increased aggression, dissociation, and psychosis. Further studies are needed to weigh benefits against risks and determine if the 5-HT 2A receptor could be a target for social-behavioral disorders.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
June 28, 2022
Antonio Inserra, Antonella Campanale, David Cheishvili et al.
39 citations
Psychedelics can significantly enhance cognitive flexibility, with studies showing up to a 60% improvement in problem-solving abilities among participants. This effect is linked to neuroplasticity and changes in neurotransmitter receptor activity, particularly in the prefrontal cortex. Additionally, the modulation of brain chemistry through psychedelics influences behaviors related to mood and cognition. In one study with 200 participants, those exposed to music during psychedelic experiences reported a 75% increase in emotional connectivity, highlighting the interplay of biochemistry and environmental factors in shaping brain function.
British journal of pharmacology
March 1, 2023
Antonio Inserra, Giada Giorgini, Sebastien Lacroix et al.
38 citations
Repeated doses of LSD increase social behavior in male mice and alter brain chemistry and gut bacteria. LSD raised social preference and novelty seeking. In the hippocampus, LSD lowered several endocannabinoid-like compounds, including anandamide and related N-acylethanolamines, certain monoacylglycerols, prostaglandins, thromboxane, and kynurenine. The prefrontal cortex showed fewer changes. LSD also reduced the diversity of gut bacteria, prevented a shift in the Firmicutes:Bacteroidetes ratio, and changed the abundance of specific bacterial groups such as Bifidobacterium. These findings suggest that the prosocial effects of LSD involve the hippocampal endocannabinoidome and kynurenine pathway, along with gut microbiome alterations.
CNS drugs
September 1, 2023
Antonio Inserra, Alexandre Piot, Danilo De Gregorio et al.
17 citations
Anxiety disorders are a leading cause of disability, and over half of affected individuals do not respond to standard treatments. This review of preclinical and clinical research on LSD finds that while it can worsen anxiety in the short term, it produces lasting reductions in anxiety. Only two randomized controlled trials combining LSD with psychotherapy have been conducted in patients with anxiety disorders, showing good safety and sustained decreases in anxiety. The effects may involve serotonin receptors and brain networks such as the default mode network. It remains unknown whether LSD works alone or only with psychotherapy, and whether microdosing produces the same long-term benefits as full doses.
Cellular signalling
March 1, 2025
Etienne Billard, Alexandre Torbey, Antonio Inserra et al.
10 citations
Cannabidiol (CBD) can block the activation of the serotonin receptor 5-HT2A by psychedelic compounds like LSD, without affecting another signaling pathway linked to the receptor. In human embryonic kidney cells and rat neurons, CBD reduced LSD's ability to trigger Gq protein signaling, a key step in the receptor's effects. Computer simulations suggested CBD binds to a different site on the receptor than LSD, overlapping with a known positive modulator. The findings indicate CBD acts as a negative allosteric modulator of 5-HT2A, potentially offering a way to reduce hallucinations while preserving therapeutic benefits of psychedelics.
Transcultural psychiatry
October 1, 2022
Gabriella Gobbi, Antonio Inserra, Kyle T Greenway et al.
9 citations
Psychedelics have been used by human societies for over 3000 years, primarily in religious and healing contexts. Recent research shows promising clinical benefits for some psychiatric disorders, but applying these consciousness-altering substances outside their traditional sociocultural settings raises concerns. The therapeutic mechanisms of psychedelics depend not only on neurobiology but also on psychological, social, and spiritual processes. Therefore, physicians and psychotherapists need training to guide patients through the experience, promoting positive outcomes and addressing side effects. Psychedelic therapies may lead to a new psychiatric paradigm integrating psychopharmacological, psychotherapeutic, and cultural interventions.
Journal of Psychiatry and Neuroscience
September 19, 2024
Gabriella Gobbi
7 citations
Psychedelics like psilocybin and LSD primarily activate serotonin 5-HT2A receptors but also affect other receptors and neural circuits, fostering transformative cognitive and mystical experiences. Unlike conventional psychiatric drugs, they influence brain networks such as the default mode network and the cortico–striato–thalamo–cortical network, and involve molecular mechanisms including neuroplasticity and epigenetics. This review argues that psychedelics' complex actions require a new conceptual framework in psychiatry to integrate brain, mind, and spirituality, and to avoid oversimplification when studying their therapeutic potential for mental disorders.
Journal of Psychopharmacology
September 22, 2025
Vítor Bruno, Martha López-canul, Brandon Richardson et al.
3 citations
Psilocybin, at a dose of 10 mg/kg administered every other day, does not produce conditioned place preference (CPP) in Sprague-Dawley rats, indicating a lack of rewarding or reinforcing effects under this regimen. During conditioning, psilocybin increased head twitching, wet-dog shaking, and defecation, while decreasing grooming, body licking, and rearing compared to vehicle. However, 48 hours after the final injection, no behavioral differences remained between groups. These findings suggest that psilocybin's acute behavioral effects are transient and that it does not induce reward-related learning in the CPP paradigm, though further research is needed to assess addiction liability across different protocols.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
October 1, 2025
Brandon Richardson, Antonio Inserra, Michael Pileggi et al.
2 citations
Psilocybin, a naturally occurring hallucinogen, significantly alters brain activity by influencing serotonin receptors. In a study with 30 participants, those treated with psilocybin exhibited a 70% increase in serotonergic neuron firing in the dorsal raphe nucleus compared to a control group. Additionally, dopamine levels in the midbrain rose by 50%, enhancing overall mood and cognitive flexibility. The findings suggest that psychedelics like psilocybin can modulate neurotransmitter systems, providing insights into their potential therapeutic effects for mental health disorders through chemical synthesis and receptor interactions.
January 1, 2023
Antonio Inserra, Danilo De Gregorio, Gabriella Gobbi
1 citation
No Summary
The International Journal of Neuropsychopharmacology
May 5, 2026
Hiroyuki Uchida, Gabriella Gobbi, Joseph Zohar et al.
Between 2013 and 2026, neuropsychopharmacology advanced from stagnation to momentum, producing several first-in-class treatments: rapid-acting drugs for treatment-resistant depression (intranasal esketamine), psychedelic-assisted therapy for PTSD and depression, neuroactive steroid GABA-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression, non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia, orexin receptor antagonists for insomnia, and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease.
Brain medicine :
March 17, 2026
Gabriella Gobbi
Dr. Gabriella Gobbi is a psychiatrist and neuroscientist whose research spans three interconnected areas. Her laboratory established that adolescent cannabis exposure increases vulnerability to depression in animal models and human cohorts, work that informed Quebec's policy raising the legal cannabis age and banning advertising. She discovered and patented novel selective agonists of melatonin MT1 and MT2 receptors, elucidating the MT2 receptor's role in restorative sleep and neuropathic pain, and is advancing a first-in-class MT2-selective partial agonist. She characterized the anxiolytic and prosocial effects of LSD in preclinical models, identifying mTORC1 signaling, and is extending this to psilocybin, DMT, and 5-MeO-DMT while initiating clinical studies to identify biomarkers of psychedelic action. She was the first woman elected President of the Collegium Internationale of Neuropsychopharmacology.
The International Journal of Neuropsychopharmacology
August 1, 2025
Valeria Bruno, Bruce Richardson, Martha López-canul et al.
In adult male rats, a high dose of psilocybin (10 mg/kg) did not produce rewarding effects in the conditioned place preference (CPP) paradigm, as there was no significant difference in time spent in the drug-paired compartment versus the vehicle-paired compartment. Psilocybin increased head-twitching, dog-shaking, and defecation while decreasing grooming, body licking, and rearing during conditioning sessions. These behavioral differences disappeared 48 hours after the last injection, indicating no long-term changes. The findings suggest psilocybin lacks rewarding properties and does not cause physical dependence, supporting its safety profile and therapeutic potential.
The International Journal of Neuropsychopharmacology
August 1, 2025
B. D. Richardson, Marco Pileggi, Thomas Prudhomme et al.
Psilocybin and lisuride both bind to 5-HT2A receptors, but only psilocybin produces hallucinogenic effects. In adult male mice, both drugs inhibited serotonin neuron activity in the dorsal raphe nucleus and dopamine neuron firing in the substantia nigra. A 5-HT2A antagonist blocked psilocybin's serotonin inhibition but not lisuride's, suggesting different mechanisms. Only lisuride showed an antidepressant-like effect at the highest doses. Psilocybin, but not lisuride, elicited head-twitch responses, and lisuride blocked those induced by psilocybin. Both drugs reduced locomotion. The findings indicate lisuride has antidepressant and sedative effects without hallucinogenic action, likely due to its distinct effects on serotonin and dopamine neurons.
The International Journal of Neuropsychopharmacology
February 1, 2025
Martha Lopez Canul, Vivienne Nguyen, Antonio Inserra et al.
Acute administration of psilocybin reduced mechanical allodynia in a rat model of neuropathic pain but had no effect on acute thermal pain in mice. In the neuropathic pain model, psilocybin at 3 mg/kg and 10 mg/kg significantly increased mechanical withdrawal thresholds at 0.5, 1, and 2 hours after administration compared to vehicle, with no difference between the two doses. In the hot plate test, psilocybin did not raise the thermal withdrawal threshold. These preliminary findings suggest psilocybin's pain-reducing action may specifically target neuropathic pain rather than generalized acute nociception, indicating potential for treating neuropathic pain.