Mol Psychiatry
July 7, 2026
Axel F. Rosado, Abigail L. Yu, Jen-Hau Yang et al.
Classic serotonergic psychedelics such as psilocybin act as agonists at cortical serotonin (5-HT) 2A receptors (5-HT 2A R), inducing psychedelic effects in humans and head-twitch responses (HTRs) in rodents. Another class of psychedelic drugs called entactogens, exemplified by MDMA, function primarily as monoamine releasers and typically evoke minimal HTR despite causing serotonin release. The...
JAMA Psychiatry
July 1, 2026
Sung Ryul Shim, Hye Su Jeong, Tanner J. Bommersbach et al.
1 citation
While intravenous ketamine is not approved by the US Food and Drug Administration, it is increasingly used with off-label indications as a novel treatment for suicidal and depressive symptoms. To systematically review and metasynthesize the efficacy and safety data for intravenous ketamine in treating major depressive episodes (MDEs). PubMed, PsycInfo, Cochrane Library, and Embase were...
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2026
Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau et al.
Abstract New treatments for depression are needed that combine robust efficacy with improved scalability. Although psilocybin has demonstrated antidepressant effects in Phase 3 clinical trials, some of its psychedelic effects limit tolerability, necessitating administration in highly supervised clinical settings, and thus motivating development of serotonergic therapeutics that preserve...
bioRxiv (Cold Spring Harbor Laboratory)
March 8, 2026
Nitzan Geva, Sarah J. Jefferson, Emi Krishnamurthy et al.
Abstract Fear extinction requires dynamic updating of cortical representations, yet the neural mechanisms underlying successful extinction remain poorly understood. Some psychoactive substances induce structural plasticity in medial prefrontal cortex (mPFC), possibly underlying their therapeutic potential. Here we investigated whether MDMA, which enhances fear extinction, induces prefrontal...
iScience
January 16, 2026
Amir Valizadeh, John D Roache, Xinyu Zhang et al.
2 citations
Post-traumatic stress disorder (PTSD) exhibits extensive clinical and biological variability, making treatment challenging. The Consortium to Alleviate PTSD (CAP)-ketamine trial, the largest randomized study of ketamine for PTSD, found no overall benefit of ketamine over placebo, underscoring the necessity to identify responsive subgroups. Using pre-treatment blood DNA methylation profiles and...
American Journal of Psychiatry
September 10, 2025
Songze Li, Kristina T. Kumpf, Julian Urrutia et al.
13 citations
This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal...
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 is critical for brain function, and its disruption is implicated in neuropsychiatric disorders. Electrophysiological signals can be decomposed into periodic (oscillatory) and aperiodic components. In the power spectrum, the periodic component appears as narrowband peaks, while the aperiodic component underlies its characteristic 1 / f...
bioRxiv Preprint Server
February 10, 2025
Masih Rahmati, Flora Moujaes, Nina Purg Suljič et al.
1 citation
preprint
Deficits in working memory (WM) are a hallmark of neuropsy-chiatric disorders such as schizophrenia, yet their neurobiological basis remains poorly understood. Glutamate N-methyl-D-aspartate receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonist ketamine known to attenuate task-evoked activation and reduce sWM accuracy. Cortical microcircuit models hypothesize that NMDAR...
Biological psychiatry. Cognitive neuroscience and neuroimaging
January 18, 2025
Brian J Roach, Judith M. Ford, Spero Nicholas et al.
7 citations
Auditory steady-state response (ASSR) abnormalities in the 40-Hz (gamma band) frequency have been observed in schizophrenia and in rodent studies of NMDA receptor (NMDAR) hypofunction. However, the extent to which 40-Hz ASSR abnormalities in schizophrenia resemble deficits in 40-Hz ASSR induced by acute administration of ketamine, an NMDAR antagonist, is not yet known. To address this knowledge...
The American journal of psychiatry
2025
Aaron Wolfgang, Gregory A. Fonzo, Joshua C. Gray et al.
47 citations
MDMA (i.e., 3,4-methylenedixoymethamphetamine), commonly known as "Ecstasy" or "Molly," has been used since the 1970s both in recreational and therapeutic settings. The Food and Drug Administration (FDA) designated MDMA-Assisted Therapy (MDMA-AT) as a Breakthrough Therapy for posttraumatic stress disorder (PTSD) in 2017, and the FDA is requiring an additional phase 3 trial after rejecting the...
American Journal of Psychiatry
2025
Adrienne Grzenda, Gregory A. Fonzo, Aaron Wolfgang et al.
14 citations
The evidence is currently insufficient to recommend psilocybin with PST as a psychiatric treatment. Additional rigorously designed clinical trials are needed to definitively establish efficacy in larger and more diverse samples, address dosing considerations, improve blinding, and provide information on mechanisms of action and moderators of clinical response. Head-to-head comparisons with...
Elife
April 17, 2024
Flora Moujaes, Jie Lisa Ji, Masih Rahmati et al.
23 citations
Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition....
Current Psychiatry Reports
April 1, 2024
John L. Havlik, Syed Wahid, Kayla M Teopiz et al.
30 citations
Purpose of Review We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature. Recent Findings Recent...
Proceedings of the National Academy of Sciences of the United States of America
November 27, 2023
John H. Krystal, Alfred P. Kaye, Sarah J. Jefferson et al.
66 citations
Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action...
Neuropsychopharmacology
July 24, 2023
John H. Krystal, Ege T Kavalali, Lisa M Monteggia
229 citations
Ketamine is an open channel blocker of ionotropic glutamatergic N -Methyl- D -Aspartate (NMDA) receptors. The discovery of its rapid antidepressant effects in patients with depression and treatment-resistant depression fostered novel effective treatments for mood disorders. This discovery not only provided new insight into the neurobiology of mood disorders but also uncovered fundamental...
bioRxiv Preprint Server
February 21, 2023
Naomi R. Driesen, Peter Herman, Margaret A. Rowland et al.
5 citations
preprint
Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a...
JAMA Psychiatry
October 19, 2022
T. Rhee, S. Shim, B. Forester et al.
139 citations
Importance Whether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown. Objective To systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode. Data Sources PubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using...
Expert Opinion on Drug Safety
April 13, 2022
Sina Nikayin, Eva Murphy, John H. Krystal et al.
114 citations
INTRODUCTION: Ketamine can produce rapid-acting antidepressant effects. Esketamine (Spravato), the S-enantiomer of racemic ketamine, was approved by the FDA for treatment-resistant depression in 2019. Here we review what is known about the long-term safety of both racemic ketamine and esketamine as therapies for psychiatric disorders. AREAS COVERED: In this article, we conducted a safety review...
Journal of Affective Disorders
2022
L. Averill, C. Averill, R. Gueorguieva et al.
Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we...
Cell Reports Medicine
August 1, 2021
John H. Krystal, Benjamin Kelmendi, Ismene L. Petrakis
13 citations
A promising new Phase III study of MDMA plus psychotherapy for PTSD treatment by Mitchell and colleagues that appeared in Nature Medicine raises important new questions about the biology and optimal treatment of this disorder. A promising new Phase III study of MDMA plus psychotherapy for PTSD treatment by Mitchell and colleagues that appeared in Nature Medicine raises important new questions...
Elife
July 12, 2021
Joshua B. Burt, Katrin H. Preller, Murat Demirtaş et al.
49 citations
Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically induced effects. Previously, using pharmacological neuroimaging, we found that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to...
medRxiv Preprint Server
July 7, 2021
Or Duek, Yutong Li, Ben Kelmendi et al.
8 citations
preprint
NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be stored in an altered form. This concept might have significant clinical implications in treating PTSD. Using amygdala activity as a major biomarker of fear response, we tested the potential of a single...
JAMA Network Open
May 1, 2020
K. Beck, Guy Hindley, F. Borgan et al.
179 citations
This meta-analysis assesses the psychopathological outcomes in healthy volunteers and patients with schizophrenia treated with ketamine and the experimental factors associated with these findings.
medRxiv Preprint Server
April 10, 2020
Chadi G. Abdallah, Kyung-Heup Ahn, Lynnette A. Averill et al.
1 citation
preprint
Over the past decade, various N-Methyl-D-Aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance...
Neuropsychopharmacology
February 24, 2020
Chadi G. Abdallah, Lynnette A. Averill, Ralitza Gueorguieva et al.
181 citations
Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized...