medRxiv Preprint Server
July 7, 2021
Or Duek, Yutong Li, Ben Kelmendi et al.
8 citations
preprint
A single low-dose infusion of ketamine, an NMDA receptor antagonist, given after recalling a traumatic memory can weaken the fear response associated with post-traumatic stress disorder. In the study, people who received ketamine showed lower activity in the amygdala and hippocampus when re-exposed to trauma memories, compared to those who received midazolam. Ketamine also reduced communication between the amygdala and hippocampus, without affecting connections to the prefrontal cortex. These changes lasted at least 30 days after treatment, suggesting that human traumatic memories can be altered during a reconsolidation window, potentially offering a new approach to treating PTSD.
Biological psychiatry. Cognitive neuroscience and neuroimaging
January 18, 2025
Brian J Roach, Judith M. Ford, Spero Nicholas et al.
7 citations
Abnormalities in the 40-Hz auditory steady-state response (ASSR), a measure of gamma-band brain activity, appear in schizophrenia and in animal models with reduced NMDA receptor function. This study compared 40-Hz ASSR deficits in schizophrenia patients to those induced by ketamine (an NMDA receptor antagonist) in healthy participants. Schizophrenia patients showed increased prestimulus broadband gamma power and reduced evoked power, total power, and phase-locking factor, replicating prior work, but no phase delay. Ketamine similarly increased prestimulus gamma power and reduced evoked power, total power, and phase-locking factor, while also advancing the ASSR phase. Direct comparison revealed significant differences only in phase, suggesting NMDA receptor hypofunction contributes to gamma oscillation abnormalities in schizophrenia.
bioRxiv Preprint Server
February 21, 2023
Naomi R. Driesen, Peter Herman, Margaret A. Rowland et al.
5 citations
preprint
Ketamine, an NMDAR antagonist, increased oxidative metabolism (CMRO2) and cerebral blood flow in the prefrontal cortex and other cortical regions, but did not alter resting-state cortical functional connectivity or brain-wide CBF-CMRO2 coupling. Higher baseline CMRO2 was associated with lower task-related prefrontal activation and greater working memory accuracy impairment under both saline and ketamine conditions. These findings suggest that CMRO2 and resting-state functional connectivity index distinct dimensions of neural activity, and that ketamine's impairment of working memory-related neural activity and performance relates to its induction of cortical metabolic activation.
bioRxiv Preprint Server
November 1, 2022
Flora Moujaes, Jie Lisa Ji, Masih Rahmati et al.
4 citations
preprint
Ketamine is a promising therapy for treatment-resistant depression, but why some people respond better than others remains unclear. The molecular mechanisms of ketamine are not yet connected to its effects on brain activity and behavior.
iScience
January 16, 2026
Amir Valizadeh, John D Roache, Xinyu Zhang et al.
2 citations
Post-traumatic stress disorder varies greatly in its clinical and biological features, making treatment difficult. The largest randomized trial of ketamine for PTSD found no overall benefit over placebo, highlighting the need to identify which patients might respond. Using pre-treatment blood DNA methylation profiles and clinical data from that trial, machine learning models predicted treatment response. A model based on 1,208 methylation sites outperformed models using only clinical variables, and combining both data types improved accuracy further. The methylation-derived score identified responders with 92.9% accuracy. Predictive methylation sites were near genes involved in glutamatergic signaling, immune regulation, and known PTSD risk loci, suggesting peripheral DNA methylation patterns can guide precision pharmacotherapy for PTSD.
JAMA Psychiatry
July 1, 2026
Sung Ryul Shim, Hye Su Jeong, Tanner J. Bommersbach et al.
1 citation
A systematic review and meta-analysis of 26 randomized clinical trials with 1,166 patients experiencing a major depressive episode found that intravenous ketamine infusions significantly reduce suicidal and depressive symptoms in the acute phase. A single ketamine infusion lowered suicidal symptoms at 24 hours and at 1 month, and repeated infusions produced similar reductions. Depressive symptoms decreased significantly from 4 hours through 1 week after a single infusion and after repeated infusions. Serious adverse events were unrelated to the interventions, and other side effects were transient. Longer-term outcomes remain unclear.
bioRxiv Preprint Server
February 10, 2025
Masih Rahmati, Flora Moujaes, Nina Purg Suljič et al.
1 citation
preprint
Working memory deficits in disorders like schizophrenia may stem from disrupted brain cell tuning. Using fMRI, researchers found that ketamine, which blocks NMDA receptors, broadens neural spatial tuning in healthy people, reducing the precision of brain responses across visual, parietal, and frontal areas and worsening spatial working memory accuracy. These tuning changes were more consistent across individuals and brain regions than overall activation changes and correlated with memory performance. The results link NMDA receptor disruption to altered brain circuit dynamics and memory impairment, offering a target for developing treatments.
medRxiv Preprint Server
April 10, 2020
Chadi G. Abdallah, Kyung-Heup Ahn, Lynnette A. Averill et al.
1 citation
preprint
A robust and reproducible brain connectivity fingerprint (CFP) was identified during ketamine infusion in healthy participants, characterized by reduced connectivity within primary cortices and the executive network, but increased connectivity between the executive network and the rest of the brain. This same CFP measured one week after treatment in major depressive disorder patients predicted response to eight weeks of sertraline, but not placebo. The findings suggest a brain network biomarker that links ketamine's acute effects to the mechanisms of conventional antidepressants.
Mol Psychiatry
July 7, 2026
Axel F. Rosado, Abigail L. Yu, Jen-Hau Yang et al.
Psilocybin and MDMA are both psychedelic drugs but produce different behavioral effects. MDMA, but not psilocybin, raises both serotonin and norepinephrine in the medial prefrontal cortex. Blocking norepinephrine release reveals head-twitch responses (a rodent correlate of psychedelic effects) from MDMA, suggesting that noradrenergic signaling opposes serotonin 2A receptor effects. Artificially raising norepinephrine also reduces psilocybin-induced head-twitch responses. Activating the noradrenergic alpha-2 receptor alone suppresses these responses, even in mice lacking the locus coeruleus, indicating action via heteroreceptors. Importantly, alpha-2 receptor activation does not block psilocybin's antidepressant-like effects in the forced swim test. This suggests that side effects of serotonin 2A activation can be reduced without losing therapeutic benefits.
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2026
Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau et al.
Combining psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) reduces psychedelic-like effects in mice—measured by head twitch response—while preserving antidepressant effects against chronic stress. Proteomic analysis of the medial prefrontal cortex revealed enhanced synaptogenesis and reduced GPCR signaling pathways with the combination versus psilocybin alone. This suggests a potential strategy for developing serotonergic antidepressants that maintain efficacy without the intense psychedelic experience, which currently limits scalability of psilocybin therapy.
bioRxiv (Cold Spring Harbor Laboratory)
March 8, 2026
Nitzan Geva, Sarah J. Jefferson, Emi Krishnamurthy et al.
MDMA increases spine density and the formation of new spines in the medial prefrontal cortex of mice, as shown by two-photon microscopy. Calcium imaging in the infralimbic cortex during fear extinction revealed that neural activity in this region became more correlated with the suppression of freezing behavior, indicating a strengthened role in extinction. Longitudinal cell registration showed accelerated representational drift across days in MDMA-treated mice, especially in neurons that suppressed activity to conditioned cues. These findings indicate that MDMA facilitates structural and functional neuroplasticity, which may underlie its enhancement of extinction learning.
bioRxiv : the preprint server for biology
August 22, 2025
Jose A Cortes-Briones, Juan Urrutia-Gandolfo, Pablo A Estevez et al.
preprint
The balance between excitatory and inhibitory (E/I) activity in the brain is important for normal function, and its disruption is linked to psychiatric disorders. In a randomized, double-blind, placebo-controlled study, healthy volunteers received low doses of ketamine (which shifts E/I balance toward excitation) and thiopental (which shifts it toward inhibition) while their brain activity was recorded with EEG. The drugs altered the aperiodic exponent of the power spectrum in opposite directions, matching computational predictions. Changes in the exponent correlated with subjective and cognitive effects, suggesting that this measure could serve as a noninvasive EEG biomarker for transient shifts in cortical E/I balance.
Schizophrenia Bulletin
September 1, 2012
Bita Moghaddam, John H. Krystal
Collaborative work since the late 1980s used NMDA receptor antagonists as a translational tool to move beyond the dopamine hypothesis of schizophrenia and understand glutamate synaptic dysfunction. The approach provided insights into disrupted cortical function in schizophrenia and identified potential new treatment targets, making clinical testing of the first target feasible. Advances in systems neuroscience enable new translational research, but obstacles in funding and academia-industry collaborations threaten future progress.