Abstract Self-disturbance is a core feature of schizophrenia (SCZ) and may emerge during the prodromal phase. Temporal imprecision has recently been proposed as a core neural mechanism in schizophrenia, primarily demonstrated in faster EEG frequency ranges. Whether such imprecision extends to infraslow brain dynamics in functional magnetic resonance imaging (fMRI) and relates to...
Abstract Classic psychedelics, including lysergic acid diethylamide (LSD), are currently under investigation for the treatment of major depressive disorder (MDD). Cognitive dysfunction is common in MDD, but effects of psychedelic treatment on cognitive brain function, measured by magnetic resonance imaging, are sparsely reported. The present study investigated effects of LSD treatment on...
Insomnia and anxiety frequently co-occur with treatment-resistant depression (TRD). This study examined short-term changes in depression, anxiety, and insomnia symptoms post-ketamine in TRD and their inter-relationships. Seventy-one patients with TRD were assessed at baseline and 24 h after intravenous ketamine (0.5 mg/kg). Depression, anxiety, and insomnia were measured using the...
Obsessive-compulsive disorder (OCD) is a highly debilitating and often chronic condition. A large percentage of patients do not respond to first-line treatments with selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy (CBT), underscoring the need for novel therapeutic approaches. In this context, promising innovative treatments have recently emerged for OCD; these...
Abstract Ketamine induces a sequence of temporally distinct effects on brain function, yet its impact on reward processing beyond the acute post-administration phase remains unclear. In this single-blind, placebo-controlled, crossover study, 28 healthy participants received 0.5 mg/kg racemic ketamine or placebo via a 40 min intravenous infusion. Functional magnetic resonance imaging was...
Translational PsychiatrySeptember 14, 2026Muhammad Asim, Julia A. Galiza Soares, Jason M Tucciarone
Serotonin (5-hydroxytryptamine; 5-HT) modulates a vast array of brain functions via its diverse receptor subtypes. Among these, the serotonin 5-HT2A receptor (5-HT2AR) has garnered intense recent interest for its pivotal role in mediating the effects of psychedelic compounds. Substantial evidence indicates that psychedelics act as agonists at the 5-HT2AR, triggering profound alterations in...
Abstract Psychedelic drugs can induce intense changes in perception and thought, and some also promote long-lasting adaptations in brain circuits that are being explored for treatment of mood and anxiety disorders. How these compounds differ at the level of intracellular signaling, and how hallucinogenic drugs diverge from related non-hallucinogenic forms, is poorly understood. A central...
Rumination has been associated with aberrant dynamics of a coactivation pattern (CAP) comprising the default mode (DMN) and frontoparietal (FPN) networks. Ketamine exerts rapid antidepressant effects and may influence these dynamics via glutamatergic mechanisms. In a randomized, double-blind, placebo-controlled fMRI study, we investigated ketamine's effects on dynamic CAPs associated with...
Distressing dreams or nightmares about a traumatic experience are common among trauma-exposed individuals and contribute to the maintenance of posttraumatic stress disorder (PTSD) symptoms. Like other intrusive reexperiencing symptoms, trauma-related nightmares are characterized by vivid sensory details and heightened emotional intensity. However, little is known about their underlying...
Abstract Psychedelic drugs exert rapid and profound effects on human consciousness [1–7] and are increasingly being investigated for their therapeutic potential [8–14]. Yet the transcriptional programs through which they may reshape brain function and structure remain incompletely understood, in part because the available evidence is heterogeneous and largely preclinical [15, 16]. In a...
Ketamine, a non-competitive N-methyl-D-aspartate acid (NMDA) receptor antagonist, produces rapid and sustained antidepressant actions, but the underlying molecular mechanism remains unclear. The CX 3 CL1/CX 3 CR1 signaling is closely related to mood disorders, and this study aims to investigate its role in ketamine’s antidepressant actions. We pharmacologically (AZD8797, a selective CX 3 CR1...
Since the discovery of the first antipsychotic, pharmacological treatment of schizophrenia (SCZ) has primarily relied on dopamine D2 receptor antagonist. However, variability in treatment responses highlights the need for novel biomarkers and therapeutics targets. Here, we developed a dual-hit mouse model combining maternal immune activation (MIA) induced by polyinosinic-polycytidylic acid...
Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmental context remain unclear. Here, we tested whether a single dose of psilocybin (0.3 mg/kg) alters synaptic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen...
Psychoplastogen compounds such as ketamine and MDMA have shown therapeutic promise for mood and trauma-related disorders, yet the molecular mechanisms underlying their effects remain poorly understood. Here, we applied a Brain-Epigenome-Wide Association Study (BEWAS) targeting brain-relevant genes to examine DNA methylation changes following treatment. Pre- and post-treatment blood (ketamine, N...
Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (HOI) derived from multivariate information theory provide a framework for examining nonlinear dependencies among brain regions beyond pairwise connectivity. One such metric, the...
Clinical trials investigating psychedelic compounds for depression and anxiety-related disorders are yielding promising preliminary results. Psychedelics produce profound alterations in brain function—such as suppression of the default mode network and thalamocortical dysregulation—leading to intense subjective experiences including ego dissolution and mystical-type states. While often...
The head-twitch response (HTR) is widely used as a preclinical assay for the hallucinogenic potential of compounds, with its utility based on 5HT 2A R activation. Here, we examine how the polypharmacological agonists lisuride and lysergic acid diethylamide (LSD) influence behavioral and physiological outcomes in mice to test whether the HTR reliably reflects overall psychoactivity. Lisuride...
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in which prenatal stress and long-lasting disruptions of excitatory-inhibitory (E/I) balance have been implicated as key vulnerability factors. Although established pharmacological and behavioral treatments are effective for many individuals, they are not universally successful and do not directly target...
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AT) is being investigated as a treatment for several psychiatric disorders, particularly posttraumatic stress disorder. Phase 2 and 3 trials typically administered a first dose of MDMA followed by a second "booster" dose 1.5-2.5 h later, to extend the acute effect duration. However, the risks and benefits of the booster dose...
Affective biases shape cognitive and emotional behaviour and are important in major depressive disorder (MDD). Modulation of affective biases by the NMDA antagonist, ketamine, may underlie its antidepressant effects but not all NMDA antagonists are efficacious. Some studies suggest ketamine's efficacy involves non-NMDA mechanisms e.g. via its active metabolite HNK (2R, 6R)-hydroxynorketamine),...
The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a...
Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are two types of substituted amphetamines that share structural-chemical similarities but exhibit contrasting acute and chronic effects including addictive liability. Tryptophan (TRY) pathways are involved in pleiotropic physiological functions at the interface of brain-body connections. Preclinical...
), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripherally restricted antagonist trospium, effectively reduces psychosis but is associated with gastrointestinal adverse effects. Here, we tested whether KarXT reverses phencyclidine (PCP)-induced cognitive deficits through microbiota-associated mechanisms in adult male mice. Mice received saline or PCP (10...
Ketamine has demonstrated rapid antidepressant efficacy in treatment-resistant depression (TRD), but clinical decision-making is challenging due to variability in individual response. Current trial-and-error prescribing practices may expose patients to ineffective treatment and avoidable adverse effects, underscoring the need for reliable predictive tools to optimize treatment selection and...
Hallucinogen persisting perception disorder (HPPD) is characterised by episodes of altered perception linked to past psychoactive drug use, accompanied by distress and functional impairment. To date, clinical characterisation has been limited in scale. Using TriNetX, a global federated health research network of electronic health records, we conducted a retrospective cohort study comparing...