Translational Psychiatry
September 1, 2015
Chun Yang, Yukihiko Shirayama, J-C Zhang et al.
600 citations
R-ketamine, a stereoisomer of the anesthetic ketamine, produces a more potent and longer-lasting antidepressant effect than S-ketamine (esketamine) in mouse models of depression, without causing psychotomimetic side effects or abuse liability. In the social defeat stress and learned helplessness models, R-ketamine more effectively restored decreased dendritic spine density, brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in the prefrontal cortex, CA3, and dentate gyrus of the hippocampus. Neither isomer affected these measures in the nucleus accumbens. S-ketamine, but not R-ketamine, caused hyperlocomotion, prepulse inhibition deficits, rewarding effects, and loss of parvalbumin-positive cells in the medial prefrontal cortex and dentate gyrus. R-ketamine appears to be a safe, long-lasting antidepressant.
Translational Psychiatry
November 7, 2019
Chun Yang, Jianjun Yang, A. Luo et al.
189 citations
Ketamine's robust antidepressant effects in treatment-resistant depression are well established, but the exact molecular and cellular mechanisms remain unclear. While NMDAR inhibition and subsequent AMPAR activation have been proposed, (R)-ketamine, a weaker NMDAR antagonist than (S)-ketamine, produces more marked and longer-lasting antidepressant-like effects in animal models. Non-ketamine NMDAR antagonists lack similar effects in patients, suggesting other mechanisms are key. Evidence points to mTORC1 activation in the medial prefrontal cortex for (S)-ketamine, and extracellular signal-regulated kinase for (R)-ketamine. The BDNF–TrkB cascade is crucial for both enantiomers and their metabolites. This review discusses recent findings, questioning the primacy of NMDAR inhibition in ketamine's antidepressant action.
Translational Psychiatry
September 28, 2020
José Á. Morales-García, Javier Calleja‐conde, Jose Antonio López‐moreno et al.
139 citations
N,N-dimethyltryptamine (DMT), a component of the ayahuasca brew, activates the subgranular zone of the dentate gyrus in the hippocampus, the main adult neurogenic niche, promoting the generation of new neurons. Mice treated with DMT performed better on memory tests than control animals, suggesting a functional relevance for the newly produced neurons. The neurogenic effect appears to involve sigma-1 receptor activation, as a sigma-1 receptor antagonist blocked it. These findings demonstrate that DMT treatment enhances adult neurogenesis and improves spatial learning and memory.
Translational Psychiatry
September 15, 2015
Matthew B. Young, Raül Andero, Kerry J. Ressler et al.
137 citations
MDMA (ecstasy) enhances the extinction of fear memories in mice through a mechanism dependent on brain-derived neurotrophic factor (BDNF). When administered before extinction training, MDMA persistently improved long-term extinction of conditioned fear. The drug increased Fos expression in the amygdala and medial prefrontal cortex, while BDNF expression rose specifically in the amygdala after extinction training. Direct infusion of MDMA into the basolateral amygdala recapitulated the extinction enhancement, and blocking BDNF signaling abolished it. These findings suggest MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders involving altered fear learning.
Translational Psychiatry
April 8, 2021
Natasha L. Mason, Kim P. C. Kuypers, Johannes T. Reckweg et al.
132 citations
A double-blind, placebo-controlled experiment with 0.17 mg/kg psilocybin shows that the drug affects creative thinking in time-dependent and task-specific ways. Immediately after consumption, psilocybin increased spontaneous creative insights but decreased deliberate, task-based creativity. Seven days later, participants generated more novel ideas. Brain imaging revealed that both acute and persisting effects were predicted by connectivity within and between networks of the default mode network. These results support historical claims that psychedelics can influence aspects of the creative process and may serve as tools for investigating creativity and its neural basis.
Translational Psychiatry
August 2, 2022
Federico Cavanna, Stephanie Müller, Laura Alethia de la Fuente et al.
130 citations
A double-blind placebo-controlled trial tested the effects of a low (0.5 g) dose of dried psilocybin mushrooms on 34 individuals beginning a microdosing protocol. The active dose produced more intense acute subjective effects than placebo, but only among participants who correctly guessed their condition. These effects coincided with reduced EEG theta-band power and preserved Lempel-Ziv broadband signal complexity. No evidence was found for enhanced well-being, creativity, or cognitive function; instead, small changes toward cognitive impairment appeared. The findings suggest that expectation, not the drug itself, accounts for many anecdotal benefits attributed to psilocybin microdosing.
Translational Psychiatry
April 4, 2017
Felix Mueller, Claudia Lenz, Patrick C. Dolder et al.
124 citations
Lysergic acid diethylamide (LSD) reduces reactivity in the left amygdala and right medial prefrontal cortex when processing fearful faces, compared to a placebo. In a double-blind, randomized, crossover study, 20 healthy adults received either 100 μg of LSD or a placebo before undergoing functional magnetic resonance imaging (fMRI). Plasma LSD levels were measured before and after the scan. A significant negative correlation emerged between the reduced amygdala response to fearful stimuli and the subjective drug effects reported by participants. These findings indicate that LSD alters the engagement of brain regions involved in emotional processing.
Translational Psychiatry
January 27, 2020
Kai Zhang, Chun Yang, Lijia Chang et al.
120 citations
In mice with depression-like symptoms from chronic social defeat stress, (R)-ketamine produced more potent and longer-lasting antidepressant effects than (S)-ketamine. RNA sequencing of the prefrontal cortex showed that transforming growth factor (TGF)-β signaling may explain these differences. (R)-ketamine, but not (S)-ketamine, reversed reduced expression of Tgfb1 and its receptors in the prefrontal cortex and hippocampus. Blocking TGF-β1 with inhibitors or a neutralizing antibody prevented (R)-ketamine's antidepressant effects. Depleting microglia also blocked these effects. Recombinant TGF-β1 itself produced rapid and lasting antidepressant effects in mice, suggesting a microglial TGF-β1-dependent mechanism and potential for new human antidepressants.
Translational Psychiatry
June 26, 2020
P. Shiroma, P. Thuras, J. Wels et al.
112 citations
In treatment-resistant depression, repeated ketamine infusions showed greater antidepressant effects than the active placebo midazolam after five doses, but when compared head-to-head against a single ketamine infusion added to midazolam over two weeks, the difference was not statistically significant. Fifty-four participants completed all six infusions. The primary outcome, change in depression severity measured by the Montgomery-Åsberg Depression Rating Scale at 24 hours after the last infusion, did not differ significantly between the six-ketamine group and the single-ketamine group. Remission and response rates favored six ketamine after the fourth and fifth infusions, respectively, compared to midazolam before the single ketamine.
Translational Psychiatry
May 9, 2023
Jared M. Kopelman, T. Keller, Benjamin Panny et al.
57 citations
A single intravenous infusion of ketamine (0.5 mg/kg) in 98 adults with unipolar depression who had not responded to at least one antidepressant was associated with rapid changes in gray matter microstructure measured by diffusion tensor imaging (DTI) 24 hours later. Greater decreases in DTI mean diffusivity, a marker of neuroplasticity enhancement, in several brain regions (left and right BA10, left amygdala) correlated with larger improvements in depression scores, particularly in the ketamine group. In the hippocampus, the relationship was reversed for one depression scale. The findings suggest that ketamine's acute antidepressant effects may involve rapid neuroplastic changes detectable with brain imaging.
Translational Psychiatry
August 11, 2022
Nicole Fadahunsi, Jens Lund, Alberte Wollesen Breum et al.
47 citations
A single dose of psilocybin substantially alters the prefrontal cortex transcriptome in mice but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Sub-chronic microdosing also has no metabolic effects, does not augment GLP-1-induced weight loss, and does not enhance diet-induced weight loss. A single high dose reduces sucrose preference but fails to counter binge-like eating behavior. These preclinical data discourage clinical investigation, though nuances in psychedelic drug action may require human evaluation.
Translational Psychiatry
March 21, 2021
Jennifer L. Kruse, Megha M. Vasavada, Richard Olmstead et al.
47 citations
Lower baseline levels of the inflammatory marker interleukin-8 (IL-8) in females, but not males, trended toward predicting a better response to ketamine for depression. In 46 depressed patients receiving a single ketamine infusion, changes in IL-8 over time also differed by sex and treatment response: increasing IL-8 was associated with decreasing depression scores in females, while the opposite pattern appeared in males. Other inflammatory markers showed no significant relationships. These preliminary findings suggest that sex differences in IL-8 may help explain how ketamine works and could guide personalized depression treatment.
Translational Psychiatry
January 10, 2022
F. Cathomas, L. Bevilacqua, Aarthi Ramakrishnan et al.
44 citations
Ketamine rapidly and lastingly reduces depression in people with treatment-resistant depression (TRD), but how it works remains unclear. TRD is linked to inflammation, and ketamine may curb inflammatory processes. Whole blood gene expression was compared between 21 healthy controls and 26 TRD patients, and again in TRD patients 24 hours after a single ketamine infusion. Before treatment, TRD patients showed activation of interferon signaling pathways. Among TRD patients, those who later responded to ketamine had higher levels of two glutamate receptor genes (GRM2 and GRIN2D) before the infusion. Ketamine response produced a distinct gene expression signature, but no evidence of anti-inflammatory changes was found. More research is needed on the peripheral immune system's role.
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
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
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
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 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
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.