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
Psychedelic compounds such as ketamine, MDMA, psilocybin, and LSD show promise as novel psychiatric treatments. Their therapeutic effects are thought to involve the serotonergic system (via 5-HT2A and 5-HT1A receptors) and the glutamatergic system (via NMDA and AMPA receptors). Key mechanisms include neuroplasticity through mTOR, BDNF, and early growth response pathways; immunomodulation via the HPA axis, NF-κB, and cytokines; and modulation of multiple neurotransmitter systems. While preliminary results are promising, larger studies are needed to confirm findings and address concerns about neurobiological changes, dependence, and immunosuppression.
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
Lysergic acid diethylamide (LSD) is a serotonergic psychedelic being studied for potential anxiety and depression treatments, but its brain mechanisms are unclear. In male mice exposed to chronic restraint stress, acute LSD at doses of 5, 15, 30, and 60 μg/kg did not reduce anxiety or depression in non-stressed mice. However, daily 30 µg/kg LSD for 7 days prevented stress-induced anxiety-like behavior and the stress-induced loss of cortical dendritic spines. Repeated LSD increased the baseline firing rate of serotonin neurons in the dorsal raphe nucleus, which had been lowered by stress, and reduced the neurons' inhibitory response to a 5-HT1A receptor agonist. These effects suggest that repeated LSD prevents stress-induced anxiety by enhancing serotonin transmission and cortical spine density, possibly through desensitization of 5-HT1A receptors.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
November 1, 2022
Marco Solmi, Chaomei Chen, Charles Dauré 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.
Transl Psychiatry
December 13, 2023
Marco Onofrj, Mirella Russo, Stefano Delli Pizzi et al.
42 citations
Psychosis in Parkinson's disease and Dementia with Lewy Bodies shares underlying mechanisms with altered states of consciousness seen in REM sleep, psychiatric disorders, and psychedelic drug use. Dysregulated activity in high-order thalamic nuclei, driven by ThalamoCortical Dysrhythmia (TCD), is proposed as a crucial trigger. TCD disrupts finely tuned cortico-cortical modulations normally supported by the thalamus, leading to aberrant Default Mode Network (DMN) activity. This process alters thalamic filtering of internal and external information, causing cortical input overload and DMN decoupling from task-positive networks. These changes destabilize brain metastability, producing dreamlike, dissociative, or altered states. Psychedelic drugs similarly modulate thalamic-cortical pathways. Understanding this pathophysiology bridges neurology and psychiatry, offering promising avenues for investigation and therapy.
Progress in Neuro-psychopharmacology and Biological Psychiatry
June 28, 2022
Antonio Inserra, Antonella Campanale, David Cheishvili et al.
39 citations
Repeated administration of lysergic acid diethylamide (LSD) to mice over seven days altered DNA methylation at 635 sites and changed the expression of 178 proteins in the prefrontal cortex. The affected genes and proteins are involved in nervous system development, axon guidance, synaptic plasticity, and cell viability. Four specific genes—Coro7, Pef1, Rps24, and Abhd6—showed both increased methylation and increased transcription. These results suggest that LSD modifies epigenetic and protein-expression pathways related to neuroplasticity, which may underlie its therapeutic effects in mental disorders.
The International Journal of Neuropsychopharmacology
July 23, 2020
Danilo de Gregorio, Joshua Dean Conway, Martha López-canul et al.
39 citations
Chronic exposure to a low dose of THC (1 mg/kg) during adolescence in rats leads to depressive-like behaviors (increased immobility in the forced swim test and anhedonia in the sucrose preference test) and anxiety-like behavior (fewer open-arm entries in the elevated plus maze). Adult exposure also produces anxiety but not depressive-like behaviors. Both adolescent and adult THC exposure reduce the activity of serotonin neurons in the dorsal raphe, while noradrenergic neurons in the locus coeruleus remain unaffected. These findings suggest that the serotonin system is vulnerable to chronic low-dose THC, and that adolescents are particularly susceptible to THC-induced depressive effects.
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.
Molecular Psychiatry
February 1, 2025
Jacopo Sapienza, Francesca Martini, Stefano Comai et al.
11 citations
Despite promising results in other psychiatric conditions, no modern clinical trials have tested psychedelics in patients with schizophrenia, except for semi-anecdotal studies from the 1950s and 1960s that noted improvements in negative symptoms and social cognition. Recent evidence suggests the mechanisms of psychedelics partially overlap with schizophrenia's pathology but in an opposite direction, providing a biological rationale for their use. This perspective paper reviews old experiments and recent molecular findings on neuroplasticity, connectivity, immune and TAARs systems, neurotransmitters, and neurotropic factors. The authors identify a therapeutic potential for negative symptoms and social cognition, proposing very low doses (microdosing) for a subpopulation of chronic patients predominantly burdened by negative symptoms, while carefully considering safety and feasibility to guide future trials.
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.
Front Hum Neurosci
June 19, 2024
Giuseppe Pasculli, Pierpaolo Busan, Eric S. Jackson et al.
5 citations
Developmental stuttering involves speech-motor disruptions linked to metabolic and network anomalies in the brain, particularly in the default mode and social-cognitive networks. These networks also influence social anxiety and avoidance, which often accompany persistent stuttering. Psychedelic compounds can modify brain metabolism and connectivity in these networks and have shown clinical benefits for conditions like depression and PTSD that share features such as rumination and social anxiety. Although no controlled trials have been conducted, anecdotal reports suggest psychedelics might alleviate stuttering and its associated symptoms. The authors argue that psychedelics warrant investigation in randomized clinical trials for developmental stuttering.
European Psychiatry
April 1, 2021
Athanasios Markopoulos, Antonio Inserra, Danilo de Gregorio et al.
5 citations
Repeated low doses of lysergic acid diethylamide (LSD) increase social behavior in male mice. This pro-social effect is mediated by the medial prefrontal cortex (mPFC), specifically through the 5-HT2A and AMPA receptors. Blocking either receptor in the mPFC prevented LSD's behavioral effects. LSD also potentiated the excitatory responses of mPFC neurons to agonists of these receptors. The findings suggest a mechanism by which LSD promotes sociability, relevant to understanding its potential therapeutic use for conditions involving social dysfunction, such as autism spectrum disorder and social anxiety disorder.
Progress in Neuro-psychopharmacology and Biological Psychiatry
October 1, 2025
Brandon Richardson, Antonio Inserra, Michael Pileggi et al.
2 citations
Psilocybin and lisuride both activate 5-HT2A receptors, but only psilocybin triggers the head twitch response (HTR) in mice, a proxy for hallucinogenic activity. In adult male C57BL/6N mice, psilocybin (0.3–3 mg/kg) inhibited serotonin neuron firing in the dorsal raphe nucleus via 5-HT2A receptors, while lisuride (0.1–0.5 mg/kg) did not. Both drugs reduced dopamine neuron firing in the substantia nigra, but lisuride's effect was more sensitive to 5-HT2A antagonism. Psilocybin elicited HTR; lisuride did not. Only high-dose lisuride reduced immobility in the forced swim test. Both drugs reduced locomotion in open field and elevated plus maze tests. Principal component analysis separated the drug effects, indicating distinct neurobiological pathways: psilocybin produces psychedelic-like, serotonin-dominant effects, while lisuride displays dopamine-linked improvements in coping behavior.
January 1, 2023
Antonio Inserra, Danilo de Gregorio, Gabriella Gobbi
1 citation
No Summary
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.