Yale University, VA Connecticut Healthcare System
60 papers in the library · 9,385 citations · publishing 1992-2026
Current Biology October 19, 2026 John H. Krystal
Ketamine's robust antidepressant effects often appear twenty-four hours after a single dose. A new study now provides evidence suggesting that this timepoint coincides with a quieting of habenula activation and reductions in aversive learning in healthy subjects.
Molecular 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. preprint
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. preprint
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...
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 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...
Neuropsychopharmacology June 2023 Sarah K. Fineberg, Esther Y Choi, Rosa Shapiro-Thompson et al.
This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled...
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...
Neuropsychopharmacology July 2022 Chadi G. Abdallah, John D Roache, Ralitza Gueorguieva et al.
This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine....
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...
American Journal of Psychiatry February 2022 Kevin P Hill, Mark S. Gold, Charles B. Nemeroff et al.
The United States is in the midst of rapidly changing laws regarding cannabis. The increasing availability of cannabis for recreational and medical use requires that mental health clinicians be knowledgeable about evidence to be considered when counseling both patients and colleagues. In this review, the authors outline the evidence from randomized double-blind placebo-controlled trials for...
Journal of Affective Disorders 2022 Lynnette A. Averill, Christopher L. Averill, Ralitza 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.
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...