Translational Psychiatry
May 3, 2022
Shira Arluk, Michael A. Matar, Lior Carmi et al.
19 citations
In a rat model of posttraumatic stress disorder (PTSD), a single dose of MDMA (5 mg/kg) paired with a trauma reminder cue reduced anxiety-like behaviors and normalized stress-induced changes in brain structure (dendritic complexity in the dentate gyrus and basolateral amygdala) two weeks later. The treatment was effective only when MDMA was combined with memory reactivation; without the trauma cue, no behavioral improvement occurred. Blocking the HPA axis or serotonin receptors (with RU486, ketanserin, or pindolol) prevented these effects, suggesting MDMA's action involves both stress hormone and serotonin systems. The findings indicate MDMA may help update traumatic memories through reconsolidation processes.
Translational Psychiatry
June 14, 2025
Ines Erkizia-Santamaría, Igor Horrillo, Nerea Martínez-Álvarez et al.
16 citations
In a mouse model of chronic unpredictable mild stress, two doses of psilocybin (1 mg/kg, given 7 days apart) reversed stress-induced anhedonia and behavioral despair, but not apathy-related behavior. Psilocybin also produced an anxiolytic-like effect. However, it did not reverse stress-induced physiological signs of a hyperactive HPA axis or restore decreased brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Psilocybin increased expression and function of serotonin-2A receptors in the cortex of both control and stressed mice, and selectively increased glucocorticoid receptor expression in the cortex of stressed mice. These findings suggest psilocybin can rescue certain depressive and anxiety-like behaviors without normalizing all stress-related physiological or neuroplasticity impairments.
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
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
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
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
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 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 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.
Translational Psychiatry
July 20, 2026
Yong‐Yu Yin, Si‐Rui Sun, Hui‐Ying Zhang et al.
Ketamine, a fast-acting antidepressant, works in part by blocking a signaling pathway between immune cells and neurons in the brain. In mice with depression-like symptoms caused by corticosterone, a single dose of ketamine (10 mg/kg) reversed behavioral deficits, reduced inflammation, and restored the structure of brain cells. Blocking the CX3CL1/CX3CR1 signaling pathway—either with a drug or by silencing the gene—eliminated both the behavioral and brain-cell benefits of ketamine. This suggests that this chemokine pathway is essential for ketamine's antidepressant effects and could be a new target for treating depression.
Translational Psychiatry
July 16, 2026
Celia Martín-Cuevas, Víctor Darío Ramos‐Herrero, Álvaro Flores‐Martínez et al.
A dual-hit mouse model combining prenatal immune activation with adolescent THC exposure produces schizophrenia-relevant behavioral and brain changes, particularly in males. Social deficits and repetitive behaviors emerged, along with reduced cortical thickness and decreased dendritic spine density in the prefrontal cortex and hippocampus. Reelin signaling pathway alterations occurred in a sex-dependent manner: males showed reduced Reelin levels mainly after THC exposure alone, while females had general reductions across treatment groups. The number of Reelin-positive cells also decreased. Adolescent THC exposure appears to be a major driver of Reelin alterations, with prenatal immune activation potentially modulating this effect. The findings highlight complex, domain-specific interactions between environmental risk factors in schizophrenia-related processes.
Translational Psychiatry
July 11, 2026
Moira G. Semple, Sarah E. Mennenga, Ryan Smith et al.
Ketamine and MDMA, compounds known as psychoplastogens, show therapeutic potential for mood and trauma-related disorders, but their molecular mechanisms are not fully understood. In a study analyzing blood samples from 20 ketamine-treated participants and saliva samples from 16 MDMA-treated participants, DNA methylation changes were examined using a Brain-Epigenome-Wide Association Study targeting brain-relevant genes. Ketamine was associated with 405 significantly altered genes and 169 functional networks, while MDMA was linked to 346 altered genes and 183 networks. Both compounds converged on pathways related to neuroplasticity and neuroimmune regulation, suggesting they induce peripheral epigenetic changes that engage molecular pathways relevant to psychiatric health.
Translational Psychiatry
July 4, 2026
Krisha Shah, Rubén Herzog, Alan C. Swann et al.
Ketamine rapidly reduces depression in some people with treatment-resistant depression, but the brain mechanisms are not fully understood. This analysis of a randomized, double-blind trial compared ketamine to midazolam in 30 older veterans with treatment-resistant depression. Using EEG data and a measure called O-information, which captures how brain regions interact in groups of three or more, the study found that ketamine caused dynamic changes in these interactions over time. The strongest effects occurred in alpha brain waves one hour after infusion, with changes shifting to theta waves by 24 hours and partially returning in beta and gamma waves by day 7.
Translational Psychiatry
June 24, 2026
Mauro Pettorruso, Giacomo D’andrea, Antonio Inserra et al.
Emerging clinical and preclinical evidence suggests that the therapeutic benefits of psychedelics for depression and anxiety may be separable from their consciousness-altering effects. Psychedelics produce profound brain changes, including suppression of the default mode network, leading to intense subjective experiences such as ego dissolution. These effects require extensive preparation and integration, exclude individuals with certain psychiatric vulnerabilities, and raise scalability concerns. Pharmacological strategies like serotonin 2A receptor antagonism and development of biased psychedelic analogues might retain therapeutic efficacy without psychedelic experiences. Preclinical data indicate that downstream molecular and network-level mechanisms could mediate therapeutic effects independently of subjective states. Confirming this dissociation could enable more scalable, accessible treatments for broader psychiatric populations.
Translational Psychiatry
June 13, 2026
Jillian L. King, Devin P. Effinger, Cameron Basquez-Pfeifer et al.
The head-twitch response (HTR) in mice, a standard test for hallucinogenic potential, fails to reliably indicate overall psychoactivity. Lisuride, which did not produce HTR, caused impaired movement, coordination, stress, cognitive disruption, and reduced prefrontal cortex EEG power. LSD, which triggered strong HTR, had minimal effects on these measures. Neither compound's effects beyond HTR depended on 5-HT₂A receptors. The HTR alone is insufficient and should be combined with other assessments.
Translational Psychiatry
June 4, 2026
Mélusine Humbert‐droz, Anna M. Becker, Jan Valenta et al.
A booster dose of MDMA prolongs the acute subjective drug effects compared with a single dose, without increasing peak effects. In a double-blind, randomized, placebo-controlled crossover study with 23 healthy volunteers, a 120 mg dose of MDMA followed by a 60 mg booster after 2 hours extended the duration of subjective effects to an average of 5.6 hours, versus 4.6 hours with a single dose. Adverse effects were more common after both MDMA conditions than placebo. Whether the prolonged effect translates into clinical benefit for MDMA-assisted psychotherapy remains unknown.
Translational Psychiatry
March 27, 2026
Livio Erne, Lorenz Mueller, Isabelle Straumann et al.
Bolus injections of DMT produce very strong subjective effects that peak within 2 minutes and subside completely within 12–30 minutes, consistent with a short elimination half-life of about 6–7 minutes. A ceiling effect for peak subjective effects occurred at the 15 mg dose, and no tolerance developed to the acute effects. Tolerability markedly improved when doses were escalated openly rather than given double-blind, and at equivalent doses the subjective effects were rated as less intense. These results indicate that blinding and expectancy influence the subjective experience and that individual dose-escalation may improve tolerability and guide dose selection in future DMT studies.
Translational Psychiatry
February 19, 2026
Luís Carlos Pereira, Wigínio Gabriel Lira-Bandeira, Andréa Silva Medeiros-Bandeira et al.
Chronic stress from social isolation in juvenile male marmosets reduces neuronal volume in the somatosensory cortex, a brain region implicated in depression. Ayahuasca, a psychedelic brew, given before and during isolation prevented this reduction, with treated animals showing neuronal volumes similar to non-stressed controls. Trends also suggested preserved cortical structure, though differences in neuronal density and overall cortical volume were not statistically significant. These results indicate ayahuasca may protect against stress-induced cortical atrophy and support further research into its therapeutic potential for stress-related psychiatric disorders, especially in adolescents.
Translational Psychiatry
January 31, 2026
Jesper L. Kristensen
Psilocybin is a prodrug that is rapidly converted in the body to psilocin, the active compound responsible for its subjective and therapeutic effects. The authors of the reviewed manuscript used computational network pharmacology and molecular docking to investigate how psilocybin might prevent suicide, but they incorrectly treated psilocybin as the active agent. In humans, psilocybin's effects correlate with psilocin plasma concentration and serotonin 2A receptor occupancy, and cryo-EM structures of psilocin bound to that receptor are available. Therefore, discussing psilocybin's binding to proteins is nonsensical for understanding its therapeutic actions in humans.
Translational Psychiatry
November 13, 2025
Bruna Giribaldi Cunha, David Nutt, Marieke Martens et al.
In a double-blind randomized trial, patients with long-standing moderate-to-severe depression received either two doses of 25 mg psilocybin plus daily placebo or two doses of 1 mg psilocybin plus daily escitalopram over six weeks. Both treatments comparably reduced negative bias in recognizing facial emotions, a measure of emotional information processing. However, changes in this bias were not linked to concurrent depression score changes. Only in the escitalopram group did a decrease in misclassifying positive faces as negative correlate with lower depression scores at a one-month follow-up. The findings suggest overlapping cognitive mechanisms between psilocybin and escitalopram, notable given psilocybin's short dosing regimen.
Translational Psychiatry
November 7, 2025
Nicole Fadahunsi, Jens Lund, Alberte Wollesen Breum et al.
correction
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Translational Psychiatry
August 10, 2021
D. Quattrone, U. Reininghaus, A. Richards et al.
Genetic risk for schizophrenia and cannabis use each contribute to specific symptom patterns across psychotic disorders, not just diagnostic categories. Among 617 first-episode psychosis patients, higher schizophrenia polygenic risk scores were linked to more severe negative and positive symptoms, regardless of diagnosis. In 979 controls, the same genetic risk was associated with all dimensions of psychotic experiences. Daily or current cannabis use was tied to more positive symptoms in both patients and controls, beyond the effect of genetic risk. The findings support a dimensional view of psychosis, where genetic liability relates to symptom severity and cannabis use specifically increases positive symptoms.
Translational Psychiatry
May 12, 2020
C. Hindocha, D. Quattrone, T. Freeman et al.
Heavy cannabis use is linked to psychosis, but it is unclear which users are susceptible. This study examined whether variations in three genes—AKT1, COMT, and FAAH—affect cannabis experiences, including psychotic-like and euphoric effects. Data came from 720 participants: first-episode psychosis patients, controls, and young adult cannabis users. Psychotic-like experiences were more common in patients, while euphoric experiences were more common in young users. However, none of the genetic variations were associated with these experiences, nor did they interact with participant group. The findings contradict previous research suggesting these genes modulate cannabis's psychotogenic effects.