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.
Frontiers in Pharmacology
April 5, 2018
Antonio Inserra
91 citations
Ayahuasca ingestion may help retrieve and reprocess traumatic memories in PTSD by activating sigma-1 receptors and monoamine oxidase inhibitors, which reverse amnesic deficits and enhance synaptic plasticity, neurogenesis, and dopaminergic neurotransmission. This process could destabilize traumatic memories, allowing fear responses to be reprogrammed or extinguished through reconsolidation. The hypothesis suggests that DMT-mediated sigma-1 receptor activation and MAOI effects facilitate memory retrieval and updating, potentially offering a unique pharmacological treatment for PTSD. The mechanisms may also apply to other conditions with dysregulated cellular memory, such as cancer, diabetes, autoimmune diseases, and addiction.
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.
Frontiers in Psychiatry
June 9, 2021
Simon Ruffell, Nige Netzband, WaiFung Tsang et al.
74 citations
A naturalistic study of 63 people who participated in ayahuasca ceremonies at a retreat in the Peruvian Amazon found significant improvements in depression, anxiety, and overall psychological distress, along with increased self-compassion, immediately after the retreat and sustained at six months. Depression scores on the Beck Depression Inventory dropped from 13.9 to 6.1, anxiety scores on the State-Trait Anxiety Inventory fell from 44.4 to 34.3, and scores on the Clinical Outcomes in Routine Evaluation-Outcome Measure decreased from 37.3 to 22.3. Changes in memory valence were linked to these improvements. Epigenetic results were inconclusive but suggested further research on the SIGMAR1 gene is warranted.
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.
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.
Translational Psychiatry
September 4, 2024
Antonio Inserra, Antonella Campanale, Tamim Rezai et al.
24 citations
Rapid-acting antidepressants, such as dissociative anesthetics, psychedelics, and empathogens, may improve psychiatric disorders by modulating neuroplasticity, neurotransmission, and immunity. Preliminary evidence suggests these drugs are accompanied by epigenetic changes—including alterations in DNA methylation, histone modifications, and non-coding RNA regulation—in stress-responsive brain regions, similar to those seen with conventional antidepressants. Whether these epigenetic changes causally contribute to therapeutic effects, are a consequence, or are unrelated remains unknown. Candidate mechanisms involve neuronal activity, serotonin and TRKB signaling, and direct interaction with chromatin. Causation, cell type-specificity, and mechanisms are largely unconfirmed.
Australian & New Zealand Journal of Psychiatry
January 25, 2019
Antonio Inserra
22 citations
No Summary
Progress in neuro-psychopharmacology & biological psychiatry
August 30, 2024
Antonella Campanale, Antonio Inserra, Stefano Comai
18 citations
The kynurenine pathway (KP) plays a crucial role in the altered gut-brain axis balance in severe mental illness (SMI), including depression, bipolar disorder, and schizophrenia, as well as in cardiometabolic comorbidities. Serotonergic psychedelics may hold therapeutic potential by modulating the KP, either directly through influencing rate-limiting enzymes and tryptophan levels, or indirectly via effects on the gut microbiome, metabolism, and immune system. Preliminary evidence suggests psychedelics improve outcomes in preclinical models of obesity, metabolic syndrome, and vascular inflammation. However, the mechanisms and outcomes remain largely unknown, and concerns about side effects in specific SMI cohorts require further investigation.
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 neurobiology
May 1, 2025
Rick Wilhiam de Camargo, Larissa Joaquim, Richard Simon Machado et al.
13 citations
Pretreatment with the psychoactive decoction Ayahuasca (AYA) for three days before inducing sepsis in rats reduced anxiety-like behaviors and neuroinflammation. AYA increased time spent in the open arms of an elevated plus maze and prevented excessive grooming and rearing, indicating anxiolytic effects. It raised levels of the anti-inflammatory cytokine interleukin-4 in the prefrontal cortex and cortex and brain-derived neurotrophic factor in the cortex. AYA also increased myeloperoxidase activity in the prefrontal cortex and hippocampus while decreasing nitrite/nitrate concentrations across multiple brain regions, suggesting enhanced neutrophil activation and reduced nitric oxide signaling. Additionally, AYA prevented lipid peroxidation in the prefrontal cortex, hippocampus, and cortex. These findings suggest AYA may protect against sepsis-induced neuroinflammation, oxidative stress, and anxiety-like symptoms.
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.
Behavioural brain research
May 8, 2025
Larissa da Silva Joaquim, Lara Rodrigues da Rosa, Yasmin Strickert et al.
5 citations
Ayahuasca, a decoction containing β-carbolines and DMT, reversed stroke-induced increases in the inflammatory markers IL-6, IL-10, and MPO activity in the prefrontal cortex and hippocampus of rats, and reduced oxidative stress markers TBARS in the prefrontal cortex and hippocampus. It also modulated mitochondrial enzyme activity in the hippocampus and cortex. However, ayahuasca did not improve neurological deficits, locomotion, anxiety-like behavior, or recognition memory. These molecular changes suggest a neuroprotective role against ischemia-induced neuroinflammation and oxidative stress, though without corresponding functional improvements in this three-day treatment study.
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.
Psychiatry Research
August 18, 2025
Ilenia Rosa, L. Padula, Francesco Semeraro et al.
2 citations
Treatment-resistant depression (TRD) challenges standard approaches, prompting a shift toward non-monoaminergic interventions like neuromodulation and glutamatergic agents. This narrative review examines the endocannabinoid system (ECS) as a potential common pathway for these treatments. Evidence indicates that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) increase endocannabinoids anandamide and 2-arachidonoylglycerol, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors, while psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions. These findings suggest ECS modulation may unify diverse antidepressant mechanisms in TRD, offering a promising target for novel therapies.
Schizophrenia research
April 1, 2025
Sofia de Almeida Queiroz, Linério Ribeiro de Novais Junior, Anita Beatriz Pacheco de Carvalho et al.
2 citations
In a rat model of schizophrenia induced by ketamine, cannabidiol (CBD) restored rearing behavior (a measure of exploratory activity) without causing anhedonia-like behavior, whereas risperidone further reduced rearing and induced anhedonia-like effects in control rats. CBD reversed ketamine-induced increases in myeloperoxidase activity in the prefrontal cortex and striatum and protein carbonyls in the hippocampus, while risperidone reduced protein carbonyls in the prefrontal cortex and lowered the nitrite/nitrate ratio in the hypothalamus. Both compounds reduced oxidative stress and neuroinflammation in the striatum, hippocampus, and prefrontal cortex, but CBD did so more broadly and without the side effects seen with risperidone. These findings suggest CBD's antipsychotic effects may stem from its antioxidant and anti-inflammatory properties.
Frontiers in psychiatry
January 1, 2023
Simon G D Ruffell, Nige Netzband, WaiFung Tsang et al.
1 citation
correction
This is a correction notice for a previously published article. It provides no new findings, arguments, or data.
January 1, 2023
Antonio Inserra, Danilo De Gregorio, Gabriella Gobbi
1 citation
No Summary
Progress in Neuro-Psychopharmacology and Biological Psychiatry
July 1, 2026
Guilherme Lodetti, Rafael Mariano de Bitencourt, Antonio Inserra et al.
A single dose of Ayahuasca reduced relapse-like alcohol drinking in alcohol-dependent rats, with effects varying by sex and alcohol concentration. It also lessened anxiety- and depression-like behaviors caused by alcohol withdrawal, increased dopamine in the striatum of both male and female rats, and restored serotonin levels in the cortex primarily in males. Ayahuasca partially reversed alcohol-related drops in brain-derived neurotrophic factor and reduced markers of oxidative stress in the frontal cortex, hippocampus, and striatum. However, antioxidant enzyme activities were not consistently altered, and some neurochemical and oxidative stress measures showed only partial normalization. The findings suggest Ayahuasca modulates multiple neurobiological pathways disrupted by chronic alcohol exposure, with region- and sex-dependent effects.
Clinical Neuropsychopharmacology and Addiction
June 25, 2026
Luca Persico, Giacomo D’andrea, Clara Cavallotto et al.
Intranasal esketamine substantially reduced depression severity in 210 patients with treatment-resistant depression treated in routine clinical practice. Depression scores improved markedly over three months, and men showed a modest advantage over women by the end of treatment, with lower depression ratings and higher rates of response and remission. Among patients under 65 years, sex differences were small and not statistically significant; among those 65 and older, men appeared to benefit more numerically, but this difference did not hold up after statistical correction and remains uncertain. Discontinuation rates and safety outcomes were similar between sexes. The authors call for future studies to examine hormonal, vascular, inflammatory, and other factors that might explain the observed sex differences.