Research published in Molecular Psychiatry

Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin

Molecular Psychiatry February 3, 2026 Pablo Mallaroni, S. Parker Singleton, Natasha L. Mason et al.

As psychedelic-assisted psychotherapy gains momentum, clinical investigation of next-generation psychedelics may lead to novel compounds tailored for specific populations. 2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenethylamine reported to produce less dysphoria and subjective impairment than the psychedelic tryptamine psilocybin. Despite its popularity among recreational...

DOI: 10.1038/s41380-026-03447-0 Psilocybin Serotonergic Serotonin Neuroplasticity +13

Exploring the therapeutic potential of psychedelics in treating substance use disorders.

Molecular Psychiatry December 1, 2025 Yuanpeng Li, Hongyuan Li, Hongshuang Wang et al.

Psychedelics, particularly psilocybin, have garnered significant attention as potential therapeutic tools for treating substance use disorders (SUDs), such as those related to alcohol, nicotine, heroin (an opioid), or cocaine. Traditional treatments often fall short, leading to high relapse rates and an urgent need for innovative approaches. This article explores the emerging role of...

DOI: 10.1038/s41380-025-03168-w Full text

Quantitative monitoring of ketamine's impact on synaptic density using 11C-UCB-J PET imaging in the corticosterone mouse model of anxiety/depression.

Molecular Psychiatry November 18, 2025 Cassandre Corvo, Sébastien Goutal, Indira Mendez-David et al. 1 citation

Ketamine was shown to promote synaptogenesis, which is thought to account for its antidepressant effects through the restoration of lost synaptic connections observed in depression. PET imaging using 11C-UCB-J, a radiotracer targeting the synaptic vesicle protein 2 A (SV2A), was investigated as a translational method to monitor ketamine-induced changes in synaptic density in the corticosterone...

DOI: 10.1038/s41380-025-03369-3 Full text Ketamine ketamine Single ketamine dose Repeated doses Neuroplasticity brain connections +14

Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice.

Molecular Psychiatry November 18, 2025 A. Arena, M. R. Rubinstein, A. M. Genaro et al.

Ketamine has emerged as a rapid and sustained treatment for Major Depressive Disorder (MDD) and an alternative for patients who have not responded to traditional therapies. Its effects have been partly attributed to the noncompetitive antagonism of the N-methyl-D-aspartate receptor (NMDAR) in the central nervous system, which enhances neuroplasticity. However, the etiopathology of MDD is...

DOI: 10.1038/s41380-025-03338-w Full text

The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents

Molecular Psychiatry November 14, 2025 Núria Nadal‐gratacós, Pol Puigseslloses, Laura Hernández‐guzmán et al.

Psychedelics have garnered significant interest for their therapeutic potential in mental health conditions such as depression, anxiety, and post-traumatic stress disorder. While research has primarily focused on well-studied psychedelics, phenethylamine derivatives have also gathered interest for their potential therapeutic applications. Thus, this study aims to investigate the pharmacological...

DOI: 10.1038/s41380-025-03341-1 Full text Phenethylamine Antidepressant Dopamine Reboxetine +8

The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects

Molecular Psychiatry November 5, 2025 Dino Luethi, Grant C. Glatfelter, Eline Pottie et al. 1 citation

Abstract Various ring-substituted α-methylphenethylamines (i.e., amphetamines) produce psychedelic-like effects that are primarily mediated by activity at 5-hydroxytryptamine 2A (5-HT 2A ) receptors. Small lipophilic substituents at the 4-position of the 2,5-dimethoxyamphetamine core structure can greatly enhance the clinical potency of such derivatives. Here, we studied the effects of various...

DOI: 10.1038/s41380-025-03325-1 Full text Serotonin In vivo Potency In vitro +10

Neuropharmacology of halogenated DMT analogs: psychoplastogenic and antidepressant properties of 5-Br-DMT, a psychedelic derivative with low hallucinogenic potential

Molecular Psychiatry October 21, 2025 Pol Puigseslloses, Núria Nadal‐gratacós, Berta Fumàs et al. 1 citation

Current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRI), often present a delayed onset of action and fail to effectively treat a large proportion of patients, leaving a gap in the treatment of mood disorders. Psychedelics have recently emerged as promising alternatives due to their ability to produce fast-acting antidepressant effects through neuroplastic...

DOI: 10.1038/s41380-025-03308-2 Full text Neuroplasticity Antidepressant Neuropharmacology Psychopharmacology +10

Short- and long-term modulation of rat prefrontal cortical activity following single doses of psilocybin

Molecular Psychiatry August 26, 2025 Ross J. Purple, Rahul Gupta, Christopher W. Thomas et al. 2 citations

Abstract We quantify cellular- and circuit-resolution neural network dynamics following therapeutically relevant doses of the psychedelic psilocybin. Using chronically implanted Neuropixels probes, we recorded local field potentials (LFP) alongside action potentials from hundreds of neurons spanning infralimbic, prelimbic and cingulate subregions of the medial prefrontal cortex of...

DOI: 10.1038/s41380-025-03182-y Full text Psilocybin Hallucinogen Prefrontal cortex Term time +2

Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects

Molecular Psychiatry August 23, 2025 Adam J. Drewko, Ron L. P. Habets, Tibor M Brunt 4 citations

Serotonergic psychedelics, including the recreationally used psilocybin and LSD, have become promising therapeutic agents for the treatment of treatment-resistant depression. While it is generally agreed that they exhibit their antidepressant effects by inducing rapid and sustained neuroplasticity, the molecular mechanisms responsible are widely debated. In particular, the role of the serotonin...

DOI: 10.1038/s41380-025-03169-9 Neuroplasticity Antidepressant Vortioxetine Psychotherapist +1

The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine.

Molecular Psychiatry July 7, 2025 Dongsun Park, Gwangho Lee, Won-Gyu Lee et al. 7 citations

Major depressive disorder is a debilitating condition, with many patients unresponsive to conventional monoaminergic antidepressants. Rapid-acting antidepressants such as ketamine and psilocybin offer promising alternatives, relieving symptoms within hours. Ketamine, an NMDA receptor antagonist, and psilocybin, a serotonergic psychedelic primarily targeting 5-HT2A receptors, both enhance...

DOI: 10.1038/s41380-025-03100-2 Full text Neuroplasticity Brain plasticity Synaptic plasticity Depression treatment +15

Psilocybin increases emotional empathy in patients with major depression.

Molecular Psychiatry June 1, 2025 Johannes Jungwirth, Robin von Rotz, Isabel Dziobek et al. 19 citations

Empathy plays a crucial role in interpersonal relationships and mental health. It is decreased in a variety of psychiatric disorders including major depression. Psilocybin, a promising candidate for treating depression, has been shown to acutely increase emotional empathy in healthy volunteers. However, no study has investigated this effect and its relevance for symptom improvement in a...

DOI: 10.1038/s41380-024-02875-0 Full text Mental health treatment Depression research Social connection Psilocybin therapy +1

Enduring modulation of dorsal raphe nuclei regulates (R,S)-ketamine-mediated resilient stress-coping behavior.

Molecular Psychiatry June 1, 2025 Anderson Camargo, Anna Nilsson, Reza Shariatgorji et al. 5 citations

Ketamine may be a novel pharmacologic approach to enhance resilience and protect against stress-related disorders, but the molecular targets underlying this response remain to be fully characterized. The multifunctional protein p11 is crucial in the pathophysiology of depression and antidepressant responses. However, it is still unclear whether p11 plays a role in the pro-resilience effects...

DOI: 10.1038/s41380-024-02853-6 Full text Mental health Psychopharmacology Stress resilience Ketamine therapy

Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises

Molecular Psychiatry April 26, 2025 Rebecca Harding, Neomi Singer, Talma Hendler et al. 4 citations

Abstract Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’....

DOI: 10.1038/s41380-025-03035-8 Full text Major depressive disorder Escitalopram Audiology Clinical psychology +1

Letter to the editor: Comments on ‘Striking long-term beneficial effects of single-dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming’ by Brownstien et al. (2024)

Molecular Psychiatry April 6, 2025 James J Gattuso, Carey Wilson, Anthony J. Hannan et al. 2 citations

The growing interest in psychedelic compounds for psychiatric disorders highlights the importance of well-designed preclinical studies [ 1 , 2 ]. In this context, Brownstein et al. [ 3 ] recently reported evidence of potential therapeutic benefits of psychedelic mushroom extract (PME) in the SAPAP3 knockout (KO) mouse model of obsessive-compulsive disorder (OCD)-like behaviours.

DOI: 10.1038/s41380-025-03005-0 Full text

Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3,4-methylenedioxyamphetamine.

Molecular Psychiatry April 1, 2025 Mihai Avram, Lydia Fortea, Lea Wollner et al. 26 citations

Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have...

DOI: 10.1038/s41380-024-02734-y Full text Psychedelics hallucinogens Psychoactive drugs Entheogens Brain networks +4

Neural mechanisms of psychedelic visual imagery.

Molecular Psychiatry April 1, 2025 Devon Stoliker, Katrin H. Preller, Leonardo Novelli et al. 19 citations

Visual alterations under classic psychedelics can include rich phenomenological accounts of eyes-closed imagery. Preclinical evidence suggests agonism of the 5-HT2A receptor may reduce synaptic gain to produce psychedelic-induced imagery. However, this has not been investigated in humans. To infer the directed connectivity changes to visual connectivity underlying psychedelic visual imagery in...

DOI: 10.1038/s41380-024-02632-3 Full text Psilocybin Psychedelics Brain imaging Visual perception

Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies.

Molecular Psychiatry March 1, 2025 Michel Sabé, Adi Sulstarova, Alban Glangetas et al. 39 citations

Persons with schizophrenia are excluded from psychedelic-assisted therapy due to concerns about the risk of triggering or worsening psychosis. However, there is limited meta-analytic data on the risk of psychedelic-induced psychosis in individuals with pre-existing psychotic disorders. We conducted a systematic review, meta-analysis, and overview of reviews to assess the incidence of...

DOI: 10.1038/s41380-024-02800-5 Full text Schizophrenia Psychedelics Mental health Drug safety +1

Allosteric inhibition of NMDA receptors by low dose ketamine.

Molecular Psychiatry March 1, 2025 Jamie A Abbott, Han Wen, Beiying Liu et al. 14 citations

Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology,...

DOI: 10.1038/s41380-024-02729-9 Full text Ketamine Antidepressants Mental health Psychopharmacology

The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors.

Molecular Psychiatry February 19, 2025 Arianna Rizzo, Maria Zelai Garçon-Poca, Amelie Essmann et al. 14 citations

Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors. Its precise mechanism of action for its antidepressant properties remains...

DOI: 10.1038/s41380-025-02931-3 Full text Psychopharmacology Depression treatment Brain chemistry Mental health

Psychedelics and schizophrenia: a double-edged sword.

Molecular Psychiatry February 1, 2025 Jacopo Sapienza, Francesca Martini, Stefano Comai et al. 11 citations

Psychedelics have shown promising effects in several psychiatric diseases as demonstrated by multiple clinical trials. However, no clinical experiments on patients with schizophrenia have been conducted up to date, except for some old semi-anecdotal studies mainly performed in the time-span '50s-'60s. Notably, these studies reported interesting findings, particularly on the improvement of...

DOI: 10.1038/s41380-024-02743-x Full text Schizophrenia treatment Mental health research Psychedelics Psychiatric medicine

Neurophysiological correlates of ketamine-induced dissociative state in bipolar disorder: insights from real-world clinical settings.

Molecular Psychiatry January 14, 2025 Claudio Agnorelli, Alessandra Cinti, Giovanni Barillà et al. 8 citations

Ketamine, a dissociative compound, shows promise in treating mood disorders, including treatment-resistant depression (TRD) and bipolar disorder (BD). Despite its therapeutic potential, the neurophysiological mechanisms underlying ketamine's effects are not fully understood. This study explored acute neurophysiological changes induced by subanesthetic doses of ketamine in BD patients with...

DOI: 10.1038/s41380-025-02889-2 Full text Ketamine Depression treatment Brain activity Mental health

Serotonergic psychedelic 5-MeO-DMT alters plasticity-related gene expression and generates anxiolytic effects in stressed mice.

Molecular Psychiatry 2025 Margareth Nogueira, Daiane C Ferreira Golbert, Richardson Menezes et al. 18 citations

Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. However, a comprehensive mechanism of action is still lacking. Here, we investigated how a single dose of the short-acting 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) acts on gene expression from microdissected...

DOI: 10.1038/s41380-024-02655-w Full text Psychopharmacology Anxiety research Natural compounds

Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression.

Molecular Psychiatry 2025 Pei-Chi Tu, Wan-Chen Chang, Tung-Ping Su et al. 13 citations

Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is...

DOI: 10.1038/s41380-024-02640-3 Full text Depression Ketamine therapy Brain connectivity Mental health treatment

Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder.

Molecular Psychiatry December 1, 2024 Chloe E Page, C Neill Epperson, Andrew M Novick et al. 54 citations

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1)...

DOI: 10.1038/s41380-024-02625-2 Full text Depression Brain plasticity Mental health Cognitive patterns

A working model of neural activity and phenomenal experience in psychosis.

Molecular Psychiatry December 1, 2024 Matteo Martino, Paola Magioncalda 13 citations

According to classical phenomenology, phenomenal experience is composed of perceptions (related to environmental stimuli) and imagery/ideas (unrelated to environmental stimuli). Intensity/vividness is supposed to represent the key phenomenal difference between perceptions and ideas, higher in perceptions than ideas, and thus the core subjective criterion to distinguish reality from imagination....

DOI: 10.1038/s41380-024-02607-4 Full text

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