Archives of General Psychiatry
March 1, 1994
John H. Krystal
3,339 citations
Ketamine, a drug that blocks a specific brain receptor called NMDA, produces a broad set of effects in healthy people that resemble schizophrenia and dissociative states. In a randomized, double-blind, placebo-controlled study with 19 healthy adults, ketamine caused behaviors similar to both positive and negative symptoms of schizophrenia, altered perceptions, and impaired performance on tests of attention, verbal fluency, and cognitive flexibility. It disrupted delayed recall of words while sparing immediate and postdistraction recall. Ketamine also increased blood pressure and dose-dependently raised cortisol and prolactin levels, but did not affect a measure of general mental status. These findings suggest that NMDA receptor dysfunction may contribute to psychotic disorders.
Journal of Traumatic Stress
January 1, 1998
J. Douglas Bremner, John H. Krystal, Frank W. Putnam et al.
826 citations
A new instrument, the Clinician Administered Dissociative States Scale (CADSS), was developed to measure present-state dissociative symptoms. Initial analyses showed good interrater reliability and construct validity. CADSS scores successfully discriminated patients with dissociative disorders from patients with other psychiatric disorders and from healthy subjects.
Archives of General Psychiatry
March 1, 2000
Amit Anand, Dennis S. Charney, Dan A. Oren et al.
425 citations
A drug that inhibits glutamate release, lamotrigine, reduced several effects of ketamine in healthy adults. Lamotrigine given before ketamine decreased perceptual abnormalities, positive and negative schizophrenia-like symptoms, and learning and memory impairment. However, it increased the immediate mood-elevating effects of ketamine. These findings suggest that glutamate release plays a role in some effects of NMDA receptor blockade and that drugs reducing glutamate release might help treat conditions like schizophrenia, though more research is needed.
Annual Review of Medicine
October 23, 2014
Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman et al.
420 citations
Ketamine, a glutamate-based antidepressant, can rapidly alleviate depression within hours of treatment. Replicated evidence shows its rapid and potent effects in treatment-resistant depression. Preclinical and biomarker studies have begun to explain the mechanism behind these rapid effects, offering new insights into depression's biology and identifying potential treatment targets. This article discusses ketamine's efficacy, safety, and tolerability, summarizes depression's neurobiology, reviews the mechanisms of ketamine's rapid antidepressant effects, and considers prospects for next-generation rapid-acting antidepressants.
Elife
October 25, 2018
Katrin H. Preller, Joshua B. Burt, Jie Lisa Ji et al.
416 citations
Lysergic acid diethylamide (LSD) reduces associative brain connectivity while increasing sensory-somatomotor and thalamic connectivity. These neural effects, along with the subjective experience, are fully blocked by ketanserin, a selective 5-HT2A receptor antagonist. The spatial pattern of LSD's effects across the brain matches the distribution of 5-HT2A receptor gene expression in humans. These results strongly implicate the 5-HT2A receptor in LSD's neuropharmacology, informing the neurobiology of psychedelics and guiding development of psychedelic-based therapeutics.
Archives of General Psychiatry
September 1, 2005
John H. Krystal, Edward Perry, Ralitza Gueorguieva et al.
323 citations
Ketamine and amphetamine produce different patterns of psychotic and cognitive effects in healthy people. Ketamine causes perceptual changes, negative symptoms, and memory disruption, while amphetamine triggers hostility, grandiosity, and somatic concern. Both drugs produce positive symptoms and euphoria, but their interaction reveals three patterns: amphetamine reduces ketamine-induced working memory impairment; the drugs additively increase thought disorder, arousal, and euphoria; and their combined effect on psychosis is less than additive. These results suggest that glutamate and dopamine systems contribute differently to psychosis, thought disorder, and euphoria, and that boosting prefrontal dopamine may help cognitive problems linked to glutamate dysfunction.
Cerebral Cortex
November 29, 2012
John D. Murray, Alan Anticevic, Mark G. Gancsos et al.
278 citations
Disruption of the balance between excitation and inhibition in the prefrontal cortex is thought to underlie cognitive problems in schizophrenia. A computational model of spatial working memory showed that disinhibition—caused by perturbing NMDA receptors on interneurons—broadens the tuning of memory-related neural activity, leading to more variable and less precise stored information and a reduced ability to filter out distractions. This prediction was tested with behavioral data from humans given ketamine, which induces disinhibition, and ketamine increased errors as the model predicted. The model also showed that restoring excitation-inhibition balance could reverse these working memory deficits, pointing to new experimental approaches for studying memory problems in schizophrenia.
Proceedings of the National Academy of Sciences
September 25, 2012
Alan Anticevic, Mark G. Gancsos, John D. Murray et al.
260 citations
Glutamate signaling through NMDA receptors is essential for brain computations that support cognition, and its disruption may contribute to schizophrenia. Using ketamine, an NMDA receptor antagonist, the study found that the normal anticorrelation between the default-mode and task-positive brain systems was disrupted during a working memory task. The degree of this disruption predicted task performance and produced schizophrenia-like symptoms. A computational model suggests that cortical disinhibition underlies this effect, linking glutamate's role in large-scale brain organization to cognition and psychiatric symptoms.
Hippocampus
October 1, 2001
John W. Newcomer, John H. Krystal
238 citations
Reduced activity of NMDA receptors in the brain, which can be experimentally induced by antagonist drugs, impairs memory by disrupting the encoding and consolidation of information into long-term storage. More severe NMDA receptor hypofunction produces symptoms resembling psychosis and dissociation, and sustained underactivation triggers a neurotoxic process with distinct neuropathological features. As the brain ages, NMDA receptor function naturally declines, contributing to age-related memory and learning deficits. Preventing NMDA receptor hypofunction or its downstream effects may offer therapeutic strategies for memory and behavioral dysfunction in neuropsychiatric conditions.
Depression and Anxiety
April 6, 2016
Chadi G. Abdallah, Thomas G. Adams, Benjamin Kelmendi et al.
204 citations
Major depressive disorder is a common psychiatric condition that often responds poorly to traditional antidepressants, which can take weeks to work. Over the past two decades, the NMDA receptor antagonist ketamine has attracted attention because a single low dose produces rapid antidepressant effects in people with treatment-resistant depression. Evidence from animal and human studies suggests that ketamine triggers a surge of glutamate, initiating a cascade that promotes synaptogenesis and reverses stress-related damage, especially in the prefrontal cortex. This review covers the neurobiology of stress-related depression, the safety and efficacy of ketamine, its mechanism of action, and predictors of treatment response, along with research limitations and future directions.
Biological Psychiatry
January 13, 2020
Katrin H. Preller, Patricia Duerler, Joshua B. Burt et al.
199 citations
Psilocybin reduces connectivity in associative brain regions while increasing connectivity in sensory regions, a pattern that emerges over time from administration to peak effects. Baseline connectivity predicts the extent of these changes. The shifts correlate with spatial gene expression patterns of the serotonin 2A and 1A receptors, pinpointing their critical role in the psychedelic state. These findings suggest that sensory integration and associative disintegration may underlie the psychedelic experience, and baseline connectivity could serve as a predictive marker for personalized psychedelic treatment.
The American Journal of Drug and Alcohol Abuse
January 1, 1992
John H. Krystal, Lawrence H. Price, Charles Opsahl et al.
171 citations
Chronic use of MDMA (ecstasy) is associated with mild-to-moderate impairments in memory, as measured by the Wechsler Memory Scale, even when no memory deficits are apparent on clinical examination. In a study of nine individuals with extensive MDMA use, eight showed at least mild impairment on one or more neuropsychological tests. Despite previous evidence suggesting serotonin deficits in this group, none reported depressed mood or met criteria for an affective disorder at the time of testing. These findings raise concern about potential detrimental effects of MDMA on cognitive function and highlight important issues regarding serotonin's role in cognition and mood regulation.
American Journal of Psychiatry
October 1, 2004
Ismene L. Petrakis, Diana Limoncelli, Ralitza Gueorguieva et al.
143 citations
A family history of alcoholism is linked to differences in how the brain responds to a drug that blocks NMDA glutamate receptors. Healthy young adults with at least two relatives who had ethanol dependence received intravenous infusions of a low or high dose of ketamine, an NMDA receptor antagonist, or a placebo. Compared to those with no family history of alcoholism, individuals with a family history reported fewer perceptual changes and less dysphoric mood during ketamine infusion. These findings suggest that inherited alterations in NMDA receptor function may influence the subjective effects of alcohol and contribute to the risk of developing alcoholism.
October 1, 1999
R. Andrew Chambers, J. Douglas Bremner, Bita Moghaddam et al.
140 citations
Dissociative symptoms during trauma and afterward in PTSD may be linked to stress-induced glutamate release in the brain. Animal studies show stress stimulates cortico-limbic glutamate release, affecting behavior and neural plasticity, and contributing to neural toxicity. NMDA receptor antagonists also trigger transient glutamate release and produce dissociative-like symptoms in animals and humans. A drug that reduces glutamate release lessens the perceptual effects of the NMDA antagonist ketamine in humans. Because hyperglutamatergic states may contribute to acute and long-term trauma effects, drugs that attenuate glutamate release warrant exploration for treating traumatized individuals with dissociative symptoms.
Annals of the New York Academy of Sciences
February 27, 2015
Chadi G. Abdallah, Lynnette A. Averill, John H. Krystal
117 citations
Ketamine produces rapid and robust antidepressant effects in patient populations that often show little or no response to traditional antidepressants, and it is generally well tolerated with only transient mild-to-moderate adverse effects during infusion. However, the optimal dosing, route of administration, and safety of chronic treatment remain uncertain. This review describes ketamine's clinical effects, its neurobiological mechanisms, and how these may illuminate the neurobiology of depression, relevant biomarkers, and treatment targets. The authors also suggest directions for future research to improve psychopharmacologic interventions for depressive and trauma-related disorders.
Expert Opinion on Drug Safety
April 13, 2022
Sina Nikayin, Eva Murphy, John H. Krystal et al.
114 citations
Ketamine and its derivative esketamine (Spravato) can rapidly relieve depression, but their long-term safety is reviewed here. Common side effects are temporary and mild, including dissociation, nausea, headache, and changes in heart rate and blood pressure. Esketamine may increase lower urinary tract symptoms, but severe bladder problems have not occurred at prescribed depression doses. High-dose ketamine can impair cognition long-term, but esketamine trials show cognition remains stable or improves, indicating no increased cognitive risk with appropriate use.
PLoS One
June 12, 2013
Philip R. Corlett, Victoria C. Cambridge, Jennifer M. Gardner et al.
104 citations
Delusions, the persistent bizarre beliefs characteristic of psychosis, may arise from disturbances in prediction error-dependent learning. In a placebo-controlled study with 18 human subjects, ketamine—an NMDA receptor antagonist that induces aberrant prediction error signals—was administered during re-exposure to a conditioned fear stimulus. This led to stronger subsequent fear memory compared to placebo, with the degree of strengthening correlating with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signals. A partial replication in an independent sample with an appetitive learning procedure (8 subjects) supported these findings. The results suggest a link between altered prediction error, memory strength, and psychosis, potentially explaining both the emergence and persistence of delusional beliefs.
Elife
July 12, 2021
Joshua B. Burt, Katrin H. Preller, Murat Demirtaş et al.
49 citations
A computational model that simulates how LSD affects human brain activity shows that the drug alters communication between cortical areas by increasing the sensitivity of pyramidal neurons via the serotonin-2A receptor. The model accurately reproduced changes in functional connectivity observed in brain scans, and fitting it to individual participants captured personal differences in drug response related to altered consciousness. This approach links molecular drug actions to large-scale brain network changes, offering a path toward personalized medicine.
The American journal of psychiatry
January 1, 2025
Aaron Wolfgang, Gregory A. Fonzo, Joshua C. Gray et al.
47 citations
MDMA-assisted therapy (MDMA-AT) using pharmaceutical-grade MDMA in controlled clinical settings is a safe and efficacious treatment for PTSD. After three MDMA administrations supported by psychotherapy, 67%–71% of individuals with PTSD no longer meet diagnostic criteria, compared with 32%–48% for placebo-assisted therapy, and effects persist at long-term follow-up. Unlike recreational use, which is confounded by adulterants and lack of precautions, MDMA-AT uniquely induces prosocial effects of trust and self-compassion while maintaining cognitive clarity. The review distinguishes evidence from recreational and therapeutic settings, describes neurobiological mechanisms, clinical evidence, public health and policy considerations, and future research directions.
Current Psychiatry Reports
April 1, 2024
John L. Havlik, Syed Wahid, Kayla M Teopiz et al.
30 citations
Treatment-resistant depression (TRD) has historically had very limited options, but recent advances have expanded knowledge of effective interventions. Psychotherapy can help as an add-on but not alone. Adjunctive non-antidepressant drugs like buprenorphine and antipsychotics show little recent support; side effects and high discontinuation rates may outweigh benefits. Strong recent evidence supports interventional approaches: electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation. Research on TRD should use internationally defined inclusion criteria for generalizable results.
Elife
April 17, 2024
Flora Moujaes, Jie Lisa Ji, Masih Rahmati et al.
23 citations
Ketamine is a promising treatment for treatment-resistant depression, but why people respond differently is poorly understood. In a single-blind placebo-controlled study, 40 healthy participants received acute ketamine. Using data-driven global brain connectivity, the neural and behavioral effects of ketamine were found to be multi-dimensional, reflecting robust inter-individual variability. Ketamine's principal neural gradient matched somatostatin and parvalbumin cortical gene expression patterns, while the mean effect did not. Behavioral symptom variation mapped onto distinct neural gradients resolvable at the single-subject level. These results highlight the importance of individual variation for developing precise pharmacological biomarkers in psychiatry.
American Journal of Psychiatry
January 1, 2025
Adrienne Grzenda, Gregory A. Fonzo, Aaron Wolfgang et al.
14 citations
Current evidence does not support recommending psilocybin combined with psychological support (PST) as a psychiatric treatment. More rigorous clinical trials are needed to confirm its effectiveness in larger and more diverse patient groups, determine appropriate dosing, improve blinding methods, and understand how it works and for whom it works best. Comparing it directly with other proven treatments will clarify its potential future role in treating major psychiatric disorders.
American Journal of Psychiatry
September 10, 2025
Songze Li, Kristina T. Kumpf, Julian Urrutia et al.
13 citations
Repeated or high-dose subanesthetic ketamine causes excitotoxic neuronal damage and lasting cognitive deficits in animals, especially perinates. Infrequent low-to-moderate doses (<1 mg/kg human intravenous equivalent) do not produce overt brain damage in rats and nonhuman primates. In humans, frequent high-dose (>1 g/day) recreational users show memory and executive function impairments. However, a large clinical trial found that intranasal esketamine at up to 84 mg weekly or every other week for several years is associated with maintained or slightly improved cognition in adults with major depression, though some elderly patients showed potential worsening in attention and processing speed. Direct comparisons of esketamine and off-label racemic ketamine at higher doses are lacking.
Cell Reports Medicine
August 1, 2021
John H. Krystal, Benjamin Kelmendi, Ismene L. Petrakis
13 citations
A Phase III trial of MDMA combined with psychotherapy for severe PTSD produced a 24.4-point (55.5%) reduction in PTSD severity, compared with 13.9 points (31.5%) for placebo, and 33% of the MDMA group achieved remission versus 5% of the placebo group. The effect size was large (d > 0.9). MDMA also improved depression and social disability. The commentary notes the study was small for a Phase III trial, raises concerns about unblinding due to MDMA's subjective effects, and calls for larger replication trials, active comparators, and better safety monitoring for neurotoxicity and addiction liability.
Journal of Psychopharmacology
November 30, 2016
Benjamin Kelmendi, Philip R. Corlett, Mohini Ranganathan et al.
11 citations
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