Translational Psychiatry
October 6, 2025
Gavin P. Schmitz, Yi-Ting Chiu, Mia L. Foglesong et al.
13 citations
Psilocybin's active metabolite psilocin increases activity in the medial prefrontal cortex (mPFC), a brain region rich in 5-HT2A receptors. A specific population of neurons in the prelimbic/anterior cingulate mPFC that express these receptors becomes more excitable and fires more in response to psilocin and a selective 5-HT2A receptor compound, effects dependent on both the receptor and Gα q signaling. A novel non-hallucinogenic psychedelic compound produced similar effects. These results point to membrane-bound 5-HT2A receptors and intracellular Gα q signaling as potential therapeutic targets for psychedelic-associated plasticity.
Translational Psychiatry
July 27, 2024
Rubén Herzog, Florentine Marie Barbey, Md Nurul Islam et al.
13 citations
Ketamine increases redundancy in brain dynamics—copies of the same information retrievable from three or more electrodes—most notably in the alpha frequency band, as measured by portable low-density EEG. In a double-blind crossover trial with 30 male adults, racemic ketamine compared to saline infusion produced greater redundancy during resting state, linked to dissociative shifts in consciousness. During an auditory oddball task, the effect was stronger for predictable standard stimuli than for deviant ones. Associations between ketamine's high-order interactions and experiences of derealization were observed, suggesting these measures capture pharmacological alterations in consciousness.
Translational Psychiatry
September 12, 2024
Christopher R. Nicholas, Matthew I Banks, Richard C Lennertz et al.
10 citations
Psilocybin, a serotonergic psychedelic, can relieve symptoms in several psychiatric disorders and improve well-being, but it was unclear whether these benefits arise during the acute experience or depend on later memory of it. In 8 healthy participants, psilocybin (25 mg) was co-administered with the amnestic benzodiazepine midazolam at a dose that allowed a conscious psychedelic experience while partially impairing memory for it. Higher midazolam doses and greater memory impairment tended to associate with lower salience, insight, and well-being from psilocybin. These results suggest memory plays a role in therapeutically relevant behavioral effects of psilocybin.
Translational Psychiatry
August 29, 2025
Anton L. V. Avanceña, Linh N. Vuong, James G. Kahn et al.
8 citations
Psilocybin-assisted therapy (PAT) may offer economic value compared to standard care for treatment-resistant depression when its cost is $5000 or less. A simulation model of representative US adults with treatment-resistant depression found that adding PAT to standard care (pharmacotherapy, psychotherapy, electroconvulsive therapy, and esketamine nasal spray) over 12 months yielded an additional 0.031 quality-adjusted life years and $3639 in costs, resulting in an incremental cost-effectiveness ratio of $117,517 per QALY gained. At a $150,000 cost-effectiveness threshold, PAT had a 75% probability of being cost-effective. Results were sensitive to PAT's cost: at $10,000 the probability dropped to 1%, at $3000 it rose to 95%.
Translational Psychiatry
March 25, 2025
Brian H Silverstein, Nicholas Kolbman, Amanda Nelson et al.
8 citations
Psilocybin alters brain network organization in rats in a dose-dependent manner. Using electroencephalography from 27 cortical sites in 12 rats, the study found that psilocybin disrupted theta-gamma coupling, increased frontal high gamma connectivity and network density, and increased posterior theta connectivity and density. Medium gamma frontoparietal connectivity and behavioral activity showed an inverted-U relationship with dose. These results suggest that high-frequency network organization, decoupled from local theta-phase, may be a key signature of psilocybin-induced altered states of consciousness.
Translational Psychiatry
February 24, 2024
Rachael Sumner, Rebecca McMillan, Anna Forsyth et al.
7 citations
Ketamine's antidepressant effects may be driven by acute changes in brain connectivity and GABA receptor dynamics, not primarily by NMDA receptor blockade. In 30 patients with major depressive disorder, resting-state EEG was recorded before and during a 0.44 mg/kg ketamine infusion. Computational modeling revealed a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both changes correlated with antidepressant response. NMDA receptor changes did not survive correction and were not correlated with symptom improvement. The findings suggest that acute fronto-parietal connectivity and GABA-A/AMPA receptor dynamics mediate ketamine's antidepressant properties.
Translational Psychiatry
June 16, 2025
Ying Zhang, Lei Yang, Qiuyu Zhang et al.
6 citations
Psilocybin, a widely studied psychedelic, may help prevent suicide by interacting with specific proteins in the brain. Using computational methods, researchers identified 46 potential targets linking psilocybin to suicide treatment. Four key targets—HTR2A, HTR2C, HTR7, and PRKACA—showed strong binding to psilocybin. Enrichment analyses indicated that psilocybin might work by modulating serotonergic synapse and calcium signaling pathways. These findings suggest molecular mechanisms through which psilocybin could aid suicide prevention, providing a basis for further investigation.
Translational Psychiatry
December 5, 2024
Bettina Habelt, Dzmitry Afanasenkau, Cindy Schwarz et al.
6 citations
Alcohol use disorder (AUD) impairs prefrontal control mechanisms, leading to reduced inhibitory control and increased relapse risk. Using a biocompatible neuroprosthesis in a rat model of alcohol addiction, researchers measured neural oscillations and event-related potentials during abstinence. Alcohol-dependent rats showed reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity, along with a dominance in higher beta frequencies indicating hyperarousal prone to relapse. Treatment with psilocybin or LY379268 restored these electrophysiological impairments, with psilocybin particularly counteracting the hyperarousal state. These prefrontal markers may serve as indicators of relapse vulnerability and treatment response, especially for psychedelic drugs.
Translational Psychiatry
August 6, 2024
Chengyu Wang, Xiaofeng Lan, Weijian Liu et al.
6 citations
Non-improvement after four ketamine infusions, or three consecutive non-improvements after three infusions, reliably predicts overall non-response to a six-dose course of intravenous ketamine for depression. Among 135 individuals with major depressive or bipolar disorder in a current depressive episode, sensitivities for predicting non-response exceeded 90% using these early non-improvement criteria. Those who did not improve by these points showed no significant reduction in depressive symptoms from subsequent infusions. The findings suggest that early non-improvement can guide clinicians to discontinue treatment, avoiding ineffective continued dosing.
Translational Psychiatry
November 9, 2024
Tianwen Huang, Yangyang He, Ruijuan Cheng et al.
5 citations
In mice with cisplatin-induced acute kidney injury (AKI), a single dose of ketamine reduced kidney damage, pathological changes in other organs, and depression-like behaviors. The beneficial effects were reversed by blocking the TrkB receptor, and analysis implicated the TrkB and ERK-CREB signaling pathways and blood metabolites like C16-ceramide. The findings suggest ketamine may alleviate both kidney injury and associated depressive symptoms, though the role of the kidney-brain axis remains unclear.
Translational Psychiatry
January 19, 2024
Judit Biosca-Brull, Genís Ona, Lineth Alarcón-franco et al.
5 citations
A single oral dose of ibogaine significantly alters gene expression in the frontal cortex of mice four hours after administration. Genes involved in hormonal pathways and synaptogenesis were upregulated, while genes associated with apoptosis and endosomal transport were downregulated. Validation via qPCR did not fully confirm the hormonal pathway changes, possibly due to the specific brain region sampled. Female mice showed more pronounced gene expression changes than males, and high variability was observed across individual animals. These findings advance understanding of ibogaine's molecular actions and highlight sex differences that may influence its effects.
Translational Psychiatry
July 13, 2025
Xiaoqian Yu, Aki Tsuchiyagaito, Masaya Misaki et al.
4 citations
Adolescents who experienced early life adversity (ELA) show greater difficulty down-regulating the posterior cingulate cortex (PCC), a key node of the default mode network, compared to healthy controls. A neurofeedback-augmented mindfulness training combining breath focus with real-time fMRI neurofeedback targeting the PCC was tested in 43 ELA-exposed and 40 healthy adolescents. Those with ELA were randomly assigned to active or sham neurofeedback. Both active and sham groups showed similar PCC down-regulation, and all adolescents reported increased state mindfulness after training. ELA-exposed adolescents reported greater improvements in positive affect, negative affect, and stress at one-week follow-up relative to controls, but there was no difference between active and sham neurofeedback on self-reported measures. The approach was feasible and acceptable for ELA-exposed adolescents but may not enhance mindfulness training beyond sham.
Translational Psychiatry
October 14, 2024
Marvin S Meiering, David Weigner, Matti Gärtner et al.
4 citations
In healthy adults, a single dose of ketamine reduced activity in the hippocampus and the default mode network (DMN) and increased connections between frontal and limbic brain regions while participants viewed emotional faces. These effects occurred both during the infusion and 24 hours later. Pretreatment with lamotrigine, which blocks glutamate release, prevented the increase in brain connectivity and the delayed reduction in DMN activity, but did not affect the acute drop in hippocampal and DMN activity. The findings suggest that ketamine's acute changes in brain connectivity and its sustained effects on DMN activity depend on glutamate transmission, whereas its immediate suppression of limbic and DMN activity does not.
Translational Psychiatry
November 18, 2019
Zhongshan Cheng, Chureerat Phokaew, Yi-Ling Chou et al.
4 citations
A genome-wide association study of long-term cannabis users identified a significant signal at the CHRM3 gene linked to cannabis-induced hallucinations. The strongest association was found in European Americans, with the lead SNP rs115455482 reaching genome-wide significance. The risk allele was associated with lower CHRM3 expression in the thalamus, and CHRM3 was co-expressed with three psychosis risk genes in brain tissues. Findings did not replicate in an independent sample, though meta-analysis strengthened the association. No significant signals were found in African Americans. The results suggest CHRM3 may contribute to cannabis-induced hallucinations and point to the thalamus's potential role.
Translational Psychiatry
October 10, 2025
Wolfgang Emanuel Zürrer, Lionel Wettstein, Helena Aicher et al.
3 citations
Salvinorin A, the main psychoactive compound in Salvia divinorum, shows therapeutic potential for pain, addiction, and stroke in animal models, but its side effects—including anxiety, motor and cognitive impairment—may limit clinical use. A systematic review and meta-analysis of 82 studies found anti-nociceptive, anti-inflammatory, neuroprotective, and anti-addictive effects, though depression results were inconsistent. Doses ranged from 0.1 to 10 mg/kg, with rapid onset and a half-life of about one hour. Sixteen structurally distinct analogues were identified with potentially improved safety and pharmacokinetic profiles. Findings support further development of analogues to overcome the side effect profile.
Translational Psychiatry
February 6, 2025
Sumra Sajid, J John Mann, Michael F Grunebaum
3 citations
Ketamine and its enantiomers can reduce suicidal thoughts, but the effects are short-lived and vary by dose and route of administration. A systematic review of 16 clinical trials since 2020 found that multiple intravenous doses of ketamine or S-ketamine reduced suicidal ideation for several days to weeks, while single doses had shorter, less consistent effects. Intranasal and single intravenous doses produced less reliable results. R-ketamine showed fewer side effects but requires more research. No studies measured suicidal behavior as an outcome. The review highlights the need for personalized treatment and notes limitations such as small samples and study heterogeneity.
Translational Psychiatry
July 25, 2024
Ariela S. Buxbaum Grice, Laura Sloofman, Tess Levy et al.
3 citations
A single low-dose intravenous ketamine infusion (0.5 mg/kg) triggers immediate and profound changes in gene expression in the blood of individuals with ADNP syndrome, a rare neurodevelopmental disorder. These alterations include upregulation of immune and inflammatory processes and downregulation of RNA processing and metabolism, with specific enrichment in monocyte-related expression patterns. The changes are transient, returning to baseline within 24 hours to one week. The findings clarify ketamine's molecular effects and support further research into its therapeutic targets for ADNP syndrome and potentially autism spectrum disorder.
Translational Psychiatry
January 29, 2026
Rafael V Lima Da Cruz, Rêmullo B. G. De Miranda Costa, Gabriel M. De Queiroz et al.
2 citations
A single dose of the psychedelic DMT reversed depression-like behavior and restored cognitive performance in male mice exposed to chronic stress, outperforming chronic fluoxetine across most measures. When given during the stress period, DMT reduced anhedonia but did not rescue cognitive deficits, indicating domain-specific long-lasting effects. All DMT regimens increased the integration of adult-born granule cells and reduced abnormally integrated cells in the brain, suggesting structural circuit repair. The role of the psychedelic experience remains uncertain because isoflurane anesthesia may have confounded results.
Translational Psychiatry
November 18, 2025
Jenessa N Johnston, Peixiong Yuan, Bashkim Kadriu et al.
2 citations
In neurons derived from induced pluripotent stem cells of five women with treatment-resistant depression (average age 40.2 years), both the glycoprotein reelin and the ketamine metabolite (2R,6R)-hydroxynorketamine increased expression of several synaptic proteins (GluA1, PSD-95, Dab1, Synapsin I, and p-ERK) within one hour, with effects declining by 24 hours. Gene expression changes were similar for both compounds, though only reelin upregulated mTORC1 signaling. The findings suggest that iPSC-derived neurons may serve as a useful in vitro model for studying treatment-resistant depression and testing potential therapeutics.
Translational Psychiatry
October 31, 2025
Kristin L Dawson, Athena May Jean M. Carangan, Jessica Klunder et al.
2 citations
Ketamine infusions reduced symptoms of depression and PTSD in 20 participants with major depressive disorder or posttraumatic stress disorder. The treatment also lowered biological age as measured by three epigenetic biomarkers (OMICmAge, GrimAge V2, and PhenoAge), indicating a potential reversal of accelerated aging linked to these conditions. Changes in underlying epigenetic biomarker proxies and surrogate protein markers accompanied the age reduction. The findings align with prior research on ketamine's effects and suggest that these epigenetic clocks can capture signals related to clinical improvements.
Translational Psychiatry
June 13, 2025
Tom Ben-Tal, Ilana Pogodin, Alexander Botvinnik et al.
2 citations
Combining the psychedelic psilocybin with the NMDAR modulators D-serine or D-cycloserine reduced hallucinogenic-like effects and enhanced antipsychotic-like effects in male mice, while also promoting neuroplasticity-related synaptic protein expression. Psilocybin alone increased head twitch response, a surrogate for hallucinogenic effects, which was dose-dependently lowered by either modulator. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic action. The psilocybin-D-serine combination increased GAP43 expression across four brain regions and overall synaptic protein levels in the hippocampus; psilocybin-D-cycloserine elevated PSD95 across all regions. These results suggest that pairing serotonergic psychedelics with NMDAR modulators may improve therapeutic potential by reducing adverse effects and enhancing neuroplasticity.
Translational Psychiatry
May 26, 2026
Marvin M. Urban, Lea Zillich, Nathalie M. Rieser et al.
1 citation
In a pilot study of 37 detoxified patients with alcohol use disorder, psilocybin (25 mg) produced changes in DNA methylation across the genome compared to placebo. One methylation site in the TLE4 gene and a differentially methylated region in RASGRP4 were linked to psilocybin treatment. Co-methylation networks related to psilocybin were associated with reductions in depressive symptoms and drinking behavior, and gene analysis pointed to involvement in neuroplasticity and immune functions. The primary trial endpoints—duration of abstinence and mean alcohol use—were not reached, so the analysis focused on secondary psychometrics. The findings suggest immunomodulatory actions of psilocybin but are limited by the modest sample size.
Translational Psychiatry
May 20, 2026
Xin Ding, Rumi Murayama, Yi Cai et al.
1 citation
The drug combination KarXT (xanomeline plus trospium) reverses cognitive deficits caused by phencyclidine (PCP) in adult male mice, and this effect is linked to changes in gut and lung microbiota. PCP disrupted recognition memory and caused region-specific imbalances in microbes, especially in the small intestine and cecum. KarXT restored memory and normalized several bacterial species elevated by PCP, including Bacteroides fragilis and Veillonella ratti. Restoration of certain lung and gut microbes correlated with improved memory. The findings suggest that KarXT's cognitive benefits involve microbial modulation, which may guide efforts to reduce gastrointestinal side effects in muscarinic therapies for schizophrenia.
Translational Psychiatry
April 24, 2026
Matt Butler, Ellen Moore, James Rucker et al.
1 citation
Hallucinogen persisting perception disorder (HPPD) involves episodes of altered perception after past psychoactive drug use, causing distress and impairment. In a large retrospective cohort study using electronic health records from 25,778 individuals diagnosed with HPPD, high rates of prior comorbidities were found, including depressive episodes (29.2%), anxiety disorders (26.2%), chronic pain (15.9%), headache syndromes (14.7%), post-viral fatigue (12.3%), ADHD (6.6%), and fibromyalgia (6.7%). Anxiety and functional somatic syndromes were more common in HPPD patients than in psychedelic-using controls. Anxiety (odds ratio 1.5) and post-viral fatigue (odds ratio 1.9) predicted HPPD development among psychedelic users. After diagnosis, HPPD was associated with increased risk of subsequent functional somatic syndromes (odds ratio 2.0) and psychiatric disorders (odds ratio 1.4) compared to psychedelic-using controls.
Translational Psychiatry
February 27, 2026
Alex K. Gearin, Jennifer Docherty, Xiaofan Sun et al.
1 citation
Psychedelic-assisted therapies show clinical promise for reducing depression and anxiety in patients with life-limiting illness, but most protocols reflect Euro-American values. Using Chinese palliative care as an example, the commentary argues that cultural factors such as family-centered decision-making, spiritual beliefs, and stigma will shape how these therapies work in different settings. Cultural humility—ongoing self-reflection, sensitivity to power dynamics, and openness to diverse worldviews—is essential for psychedelic therapy, where patient experiences depend on context and meaning-making. Efficacy is not solely biochemical but also cultural; addressing this translational gap requires humility toward how situated beliefs, norms, and practices interact with psychedelic pharmacology.