Translational Psychiatry
October 2, 2021
Čestmír Vejmola, Filip Tylš, Václava Piorecká et al.
41 citations
Serotonergic psychedelics, including psilocin, LSD, mescaline, and DOB, all caused a time-dependent global decrease and desynchronization of EEG activity and functional disconnection in the 1–40 Hz range in freely moving rats, regardless of their chemical family. Major changes occurred in the frontal and sensorimotor cortex, with subtle spatial patterns unique to each substance. A rebound of occipital theta (4–8 Hz) activity appeared later after mescaline and LSD. Connectivity analyses revealed an overall decrease in global connectivity for both cross-spectral and phase-lagged coherence. These effects closely mirror those seen in human EEG/MEG studies, supporting the translational validity of this rodent model.
Translational Psychiatry
February 23, 2022
Trevor Sharp, Christopher W. Thomas, Cristina Blanco-Duque et al.
40 citations
Psilocin, a serotonergic psychedelic, alters sleep architecture and cortical activity in mice. Acute administration delays REM sleep onset, reduces NREM sleep maintenance for about three hours, and enhances a 4 Hz EEG oscillation. No long-term changes in sleep-wake quantity occur. Psilocin does not affect the overall homeostatic sleep rebound after sleep deprivation, but it slows the recovery of slow-wave activity in the medial prefrontal and surrounding cortex. These findings suggest psilocin influences both global vigilance state control and local sleep homeostasis, which may relate to its antidepressant effects.
Translational Psychiatry
February 12, 2024
Cheng Jiang, Ralph Dileone, Christopher Pittenger et al.
37 citations
A single dose of ketamine produces antidepressant-like effects in rats only when the brain's own opioid system is active in the medial prefrontal cortex (mPFC). Blocking opioid receptors with naltrexone—either throughout the body or directly in the mPFC—eliminates ketamine's behavioral effects. Ketamine rapidly increases levels of the opioid β-endorphin and expression of the μ-opioid receptor gene in the mPFC, and boosts production of β-endorphin's precursor in the hypothalamus. Neutralizing β-endorphin in the mPFC with a specific antibody also abolishes ketamine's behavioral and molecular effects, demonstrating that β-endorphin and opioid receptor activation in the mPFC are necessary for ketamine's antidepressant-like actions.
Translational Psychiatry
July 30, 2020
Ashish K Sahib, Joana Ra Loureiro, Megha M Vasavada et al.
37 citations
Ketamine produces rapid antidepressant effects even in people with treatment-resistant depression, but how it alters brain function is not fully understood. In this study, 47 patients with treatment-resistant depression and 32 healthy controls performed a brain-imaging task measuring response inhibition. After one and then four intravenous ketamine infusions, 37 patients repeated the task. Brain activation decreased in regions involved in inhibitory control, including prefrontal and parietal areas and visual cortex, following repeated treatment. Patients who achieved remission had lower activation in the supplementary motor area before treatment, which then normalized toward control levels after ketamine. These changes in the supplementary motor area during response inhibition were linked to reduced depressive symptoms and may predict treatment outcome.
Translational Psychiatry
November 29, 2024
Gustavo C Medeiros, Isabella Demo, Fernando S Goes et al.
32 citations
Treatment-resistant depression accounts for a large share of the burden of major depressive disorder. Intravenous ketamine and intranasal esketamine are rapid-acting antidepressants that can effectively treat this condition, but response varies. Reliable predictors of response are urgently needed. Clinical predictors of a robust response to ketamine include a family history of alcohol use disorder and a history of childhood trauma. A promising brain-based biomarker is an increase in gamma power in frontoparietal regions measured by EEG. Blood-based biomarkers have shown limited usefulness, with small-effect increases in BDNF being the most consistent indicator. Dissociative symptoms during treatment are not typically associated with response. Most predictors have modest effect sizes, so multivariate models will be needed.
Translational Psychiatry
November 11, 2023
Wan Lin Yue, Kwun Kei Ng, Amelia Jialing Koh et al.
32 citations
Mindfulness-based interventions improve cognition and emotion regulation, and this study examined how they change functional brain activity. Using a breath-counting task and resting-state fMRI, the researchers measured how efficiently the brain reconfigures its activity patterns between rest and task states. Elderly participants with sleep difficulties were assigned to either mindfulness-based therapy or a sleep hygiene active control. The mindfulness group showed improved self-reported mindfulness and greater brain functional reconfiguration efficiency in the executive control, default mode, and salience networks compared to the control group. However, these brain changes were not associated with behavioral improvements, suggesting that neuroplasticity from regular mindfulness practice may bring the brain's intrinsic functional configuration closer to a state required for mindful awareness.
Translational Psychiatry
May 2, 2022
Ruin Moaddel, Panos Zanos, Cristan A Farmer et al.
32 citations
Subanesthetic-dose ketamine produces rapid antidepressant effects, but its mechanism remains unclear. A targeted metabolomic analysis of plasma and cerebrospinal fluid from nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg), along with parallel analysis in mice given ketamine, (2R,6R)-hydroxynorketamine (HNK), or saline, found that both ketamine and HNK affect multiple inflammatory pathways. Some changes were unique to humans or mice, suggesting species differences. Consistently implicated mechanisms across both species and sample types include LAT1, IDO1, NAD+, nitric oxide signaling, and the sphingolipid rheostat.
Translational Psychiatry
June 10, 2024
ZuoYao Shen, DaiQuan Gao, Xue Lv et al.
31 citations
Ketamine rapidly reduces suicidal thoughts in people with depression, with effects lasting through the full treatment cycle. A network meta-analysis of 14 studies (1,380 participants) found that within the first day after treatment, suicidal ideation dropped significantly (risk ratio 10.02). Repeated doses produced greater improvement after the last dose than after the first (risk ratio 0.56). By the end of treatment, recovery was significantly better with ketamine than with placebo (risk ratio 4.29 at day 26). This is the first network meta-analysis to demonstrate ketamine's role in alleviating suicidal ideation and to compare drug effects at different time points.
Translational Psychiatry
September 3, 2021
Chao Huang, Yuanyuan Wang, Zifeng Wu et al.
29 citations
Ketamine acts as a rapid and long-lasting antidepressant, but its molecular mechanisms are unclear. In mice subjected to chronic social stress, microRNA miR-98-5p was downregulated in the prefrontal cortex and hippocampus. Overexpressing miR-98-5p with an agonist alleviated depression-like behaviors. Ketamine administration upregulated miR-98-5p, and inhibiting it with an antagonist blocked ketamine's antidepressant effect. This suggests a novel molecular mechanism for ketamine's action and that targeting miR-98-5p could be beneficial for depression treatment.
Translational Psychiatry
September 30, 2024
Aaron Klaiber, Yasmin Schmid, Anna M Becker et al.
27 citations
Mescaline produces dose-dependent subjective and physiological effects in healthy people, with doses above 100 mg increasing blood pressure and heart rate. Subjective effects lasted from 6.4 hours at 100 mg to 14 hours at 800 mg, and the drug reached peak concentration in blood after about 2 hours with a half-life of 3.5 hours. Nausea and vomiting were common at the highest dose. Blocking serotonin 5-HT2A receptors with ketanserin reduced the effects of 800 mg mescaline to levels similar to lower doses, indicating that mescaline's acute effects are primarily mediated by these receptors.
Translational Psychiatry
May 20, 2021
Rebeca Dı́ez-alarcia, Carolina Muguruza, Guadalupe Rivero et al.
27 citations
Serotonin 5-HT2A receptor density in the prefrontal cortex of people with schizophrenia depends on which radiotracer is used to measure it, because different tracers bind different receptor conformations. Using the inverse agonist [18F]altanserin, receptor density appeared decreased; using the agonist [3H]LSD, it appeared increased; and using the antagonist [3H]MDL100907, it was unchanged. These differences were more pronounced in schizophrenia subjects who were antipsychotic-free at death. The findings suggest a shift toward the active functional conformation of the 5-HT2A receptor in schizophrenia, consistent with increased cortical serotonin 2A receptor activity.
Translational Psychiatry
May 25, 2024
Marta Valenza, Roberta Facchinetti, Carola Torazza et al.
26 citations
Acute stress triggers a rapid response from glial cells—astrocytes and microglia—in the prefrontal cortex of rats, activating the NF-κB pathway and increasing inflammatory cytokines IL-18 and TNF-α. In vulnerable animals, this response persists alongside altered levels of glial proteins S100B, CD11b, and CX43, brain trophic factors BDNF and FGF2, and synaptic proteins MAP2 and PSD95. A single subanesthetic dose of ketamine given 24 hours after stress reversed many of these changes, suggesting it helps restore brain homeostasis. Reactive astrogliosis, changes in trophic factors, and neuronal damage appear to be key determinants of vulnerability to acute traumatic stress, and ketamine shows therapeutic potential against stress-related psychiatric disorders.
Translational Psychiatry
December 3, 2023
Laith Alexander, Peter C. T. Hawkins, Jennifer W. Evans et al.
26 citations
Ketamine's antidepressant effects involve changes in brain connectivity that depend on which part of the anterior cingulate cortex (ACC) is examined. In a double-blind, placebo-controlled crossover trial, patients with treatment-resistant depression and healthy volunteers received intravenous ketamine or placebo. Two days later, resting-state functional connectivity between ACC subregions and other brain areas differed between groups. Changes in perigenual ACC connectivity to the insula correlated with improved depression scores. Subgenual ACC connectivity was most altered by ketamine compared to placebo, and changes in its connectivity to other ACC subregions and the ventral striatum correlated with reduced anhedonia. Accurate ACC segmentation is needed to understand ketamine's effects.
Translational Psychiatry
December 14, 2023
Ivan Skorodumov, Rainer Spanagel, Jonathan R Reinwald et al.
25 citations
Psilocybin, a psychedelic compound, may help treat alcohol use disorder (AUD), but its brain effects in AUD are not well understood. In a placebo-controlled crossover study with healthy rats and a rat model of alcohol relapse, psilocybin broadly decreased functional connectivity across the brain while increasing connectivity between serotonin-related core regions and cortical areas. It also reduced connectivity within the default mode network (DMN), mirroring human findings. However, in rats with a history of alcohol relapse, this DMN hypoconnectivity was blunted, and the blunting correlated with relapse intensity. The results suggest that a standard psilocybin dose may be insufficient for severe AUD, a consideration for future clinical trials.
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.
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
February 27, 2024
Hanna M. Ollila, Nasa Sinnott-Armstrong, Katri Kantojärvi et al.
18 citations
Nightmares are vivid, negative dreams that awaken the dreamer. While occasional nightmares are common, frequent ones often indicate underlying emotional regulation problems. A genome-wide association study of 45,255 individuals found no single genetic variants linked to nightmare frequency, but estimated heritability at 5%. Genetic correlation analysis revealed strong correlations between nightmares and anxiety, depressive disorders, posttraumatic stress disorder, and the personality trait neuroticism. Mendelian randomization suggested that insomnia may causally increase the likelihood of frequent nightmares. These findings indicate that nightmares share genetic factors with psychiatric conditions and that insomnia may heighten susceptibility to nightmares, highlighting the need for systematic nightmare assessment in clinical settings.
Translational Psychiatry
December 4, 2024
Kenneth Shinozuka, Katarina Jerotic, Pedro A. M. Mediano et al.
17 citations
Serotonergic psychedelics such as LSD, psilocybin, and DMT alter consciousness and may help treat depression and addiction, but their mechanisms remain unclear. A systematic review and meta-analysis across three levels—subjective experience, neuroimaging, and molecular pharmacology—reveals that medium and high doses of LSD produce stronger visionary restructuring than psilocybin. Neuroimaging shows psychedelics generally strengthen connectivity between brain networks while weakening connectivity within networks. Pharmacologically, LSD triggers more inositol phosphate formation at the 5-HT2A receptor than DMT or psilocin, but no significant differences exist in receptor selectivity among the drugs. The analysis finds high heterogeneity and risk of bias, calling for standardized methods and more research.
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
July 15, 2024
Nadia R. P. W. Hutten, Conny W E M Quaedflieg, Natasha L. Mason et al.
16 citations
Repeated low doses of LSD (15 mcg) affect arousal, attention, and memory depending on a person's baseline cognitive state. In a randomized placebo-controlled trial with 53 healthy participants, LSD reduced resting-state EEG delta, theta, and alpha power (indicating stimulation) and enhanced pre-attentive processing during acute dosing sessions. LSD also blunted visual long-term potentiation (a marker of perceptual learning and memory) by the fourth dosing session. Stimulatory effects were strongest in individuals with low baseline arousal and attention, while inhibitory effects on memory were strongest in those with high baseline memory performance. Some EEG changes persisted at a one-week follow-up, suggesting possible neuroadaptations from repeated low-dose LSD.
Translational Psychiatry
June 4, 2024
Elizabeth D. Ballard, Deanna K Greenstein, Philip T Reiss et al.
16 citations
Ketamine, a drug that modulates the glutamate system, is linked to changes in sleep, depression, and suicidal thoughts. In a randomized, double-blind, crossover trial, 36 people with treatment-resistant major depression and 25 healthy volunteers underwent polysomnography before and after receiving ketamine or placebo. At baseline, those with depression had less total sleep time and shorter REM latency. Ketamine increased slow-wave (delta) brain activity early in the night and both alpha and delta activity later, compared to placebo. However, ketamine did not significantly alter sleep arousal metrics or mediate its antidepressant or anti-suicidal effects through sleep changes. The findings suggest sleep-related variables are part of broader neurobiological shifts after ketamine.
Translational Psychiatry
September 4, 2024
Patrick Vizeli, Erich Studerus, Friederike Holze et al.
15 citations
LSD dose is the strongest predictor of the drug's subjective and autonomic effects, but non-pharmacological factors also play a significant role. Pre-drug mood states—such as well-being, emotional excitability, and anxiety—predict subjective effects, heart rate, and body temperature. The personality trait openness to experiences correlates with stronger mystical-type effects and oceanic boundlessness. Prior hallucinogen use is linked to less anxious ego dissolution and a less intense overall altered state. Acute anxiety relates negatively to the functionality of the Cytochrome 2D6 enzyme. Sex and body weight do not significantly influence the drug experience.
Translational Psychiatry
April 15, 2024
Nathan Allen, Aron Jeremiah, Robin J Murphy et al.
15 citations
Microdosing LSD (10 µg every third day for six weeks) increased sleep duration in healthy adult male volunteers. On nights after dosing, the LSD group slept an extra 24.3 minutes per night compared to placebo, with no change in sleep on dosing days. Sleep stage proportions and physical activity remained unchanged. The findings indicate that microdosing LSD modifies physiological sleep requirements, and the objective changes are unlikely to be a placebo effect.
Translational Psychiatry
September 30, 2024
Elizabeth L. Fisher, Ryan Smith, Kyna Conn et al.
14 citations
Psilocybin treatment in rats performing a reversal learning task led to more rewards through increased task engagement, driven by changes in forgetting rates and reduced loss aversion. Computational modeling suggests psilocybin may induce an optimism bias by altering how beliefs are updated, which could have implications for clinical conditions marked by pessimism.
Translational Psychiatry
August 9, 2024
Yiheng Pan, Maria P Gorenflo, Pamela B Davis et al.
14 citations
Ketamine prescriptions are linked to a lower risk of suicidal thoughts in people with recurrent major depressive disorder compared to other common antidepressants. Analyzing electronic health records from over 500,000 patients, the risk of suicidal ideation was 37% lower within the first week, 33% lower within the first month, and 22% lower over nine months. The protective effect was strongest in adults over 24, females, males, and White patients. This real-world evidence suggests ketamine's long-term benefits for reducing suicidal ideation, though optimal dosing and mechanisms need further study.