Molecular Psychiatry
March 13, 2018
P. Zanos, T. Gould
1,112 citations
A single low dose of the anesthetic ketamine can rapidly and lastingly relieve depression, but its abuse potential and dissociative side effects limit widespread use. This review examines proposed molecular mechanisms for ketamine's antidepressant action, including inhibition of specific N-methyl-D-aspartate receptors (NMDARs), effects on GABAergic interneurons, and suppression of burst firing in the lateral habenula. It also discusses downstream pathways involving brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mTOR, and GSK-3, as well as the roles of ketamine's (R)-ketamine enantiomer and the metabolite (2R,6R)-hydroxynorketamine. These mechanisms likely work together to trigger lasting changes in synaptic plasticity that underlie the antidepressant effects.
Molecular Psychiatry
October 3, 2018
M. Fava, M. Freeman, M. Flynn et al.
438 citations
Intravenous ketamine at 0.5 mg/kg and 1.0 mg/kg produces rapid antidepressant effects in adults with treatment-resistant depression, with most improvement seen one day after a single 40-minute infusion. Lower doses (0.1 mg/kg and 0.2 mg/kg) did not show consistent benefit. The study compared four ketamine doses against an active placebo (midazolam) in 99 outpatients across six U.S. sites. Higher doses caused more dissociative symptoms and temporary blood pressure increases, but infusions were generally well tolerated. The findings indicate a range of effective subanesthetic doses, with no clear advantage for doses below 0.5 mg/kg.
Molecular Psychiatry
April 15, 2021
J. Bonaventura, Sherry Lam, Meghan L. Carlton et al.
266 citations
Ketamine, a mixture of two mirror-image molecules called (S)-ketamine and (R)-ketamine, is used as an anesthetic and, more recently, as an antidepressant, but it carries a risk of abuse. The (S)-form is FDA-approved for treatment-resistant depression, while the (R)-form shows promise in animal models but has not been tested in people. In rats and mice, (S)-ketamine, but not (R)-ketamine, produced behaviors linked to abuse potential, such as self-administration, increased movement, and preference for places where the drug was given. (S)-ketamine also boosted activity and dopamine levels in a brain region called the medial prefrontal cortex, partly by activating opioid receptors. These findings indicate that the abuse liability of racemic ketamine stems mainly from its (S)-enantiomer.
Molecular Psychiatry
February 27, 2018
A. Nugent, Elizabeth D. Ballard, T. Gould et al.
254 citations
In a double-blind, placebo-controlled, randomized cross-over trial with 35 unmedicated people with major depressive disorder (MDD) and 25 healthy controls, ketamine (0.5 mg/kg) improved depressive symptoms in MDD subjects but caused modest, temporary increases in depressive symptoms in healthy controls. Both groups showed increased resting gamma power measured by magnetoencephalography. Among MDD subjects, gamma power did not directly predict the size of the antidepressant effect. However, baseline gamma power moderated the link between post-ketamine gamma and response: higher post-ketamine gamma was tied to better response in those with low baseline gamma, but the opposite pattern appeared in those with high baseline gamma. This suggests biological subtypes based on homeostatic dysregulation and cautions against inferring ketamine's mechanism solely from studies of healthy controls.
Molecular Psychiatry
May 7, 2021
Wei Yan, Lijia Chang, Kenji Hashimoto
242 citations
The antidepressant effects of the drug (R,S)-ketamine, a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), are not primarily due to blocking the N-methyl-D-aspartate receptor (NMDAR), despite initial assumptions. Preclinical studies in rodents show arketamine has more potent and longer-lasting antidepressant-like effects than esketamine, even though arketamine binds less strongly to NMDAR. Clinical trials with other NMDAR-blocking compounds failed to produce robust antidepressant effects in humans, indicating rodent findings do not always translate. The exact molecular mechanisms remain unclear. This review covers recent findings on these mechanisms, the possible roles of the brain-gut-microbiota and brain-spleen axes, and arketamine's potential for treating cognitive impairment, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
Molecular Psychiatry
October 15, 2013
Gerard Sanacora, Mark A. Smith, Sanjeev Pathak et al.
234 citations
NMDA channel blockers can produce antidepressant effects without the psychotomimetic and dissociative side effects seen with ketamine. Using quantitative electroencephalography to align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to ketamine, the antidepressant response was maintained with repeated and intermittent drug administration in placebo-controlled data. This provides a path for developing glutamatergic-based treatments for treatment-refractory mood disorders.
Molecular Psychiatry
November 24, 2021
W. Yao, Qianqian Cao, Shilin Luo et al.
208 citations
In a mouse model of depression, (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine. The study identifies a molecular pathway in microglia—cells in the brain's medial prefrontal cortex—that mediates these effects. (R)-ketamine activates the ERK-NRBP1-CREB-BDNF signaling cascade in microglia, increasing BDNF transcription. Blocking this pathway with specific inhibitors or depleting microglia prevented (R)-ketamine's antidepressant-like effects and its ability to restore reduced dendritic spine density. These findings suggest that microglial signaling is essential for (R)-ketamine's antidepressant actions.
Molecular Psychiatry
September 14, 2020
A. Mkrtchian, Jennifer W. Evans, C. Kraus et al.
110 citations
Ketamine increased fronto-striatal functional connectivity in people with treatment-resistant major depression toward levels seen in healthy volunteers, while shifting connectivity in healthy volunteers toward a state similar to depressed participants under placebo. These effects occurred largely without changes in inflammatory markers (C-reactive protein) and were associated with both acute and sustained symptom improvements in the depressed group. Ketamine thus normalized reward-related brain circuitry in depression but disrupted it in healthy individuals, highlighting the potential importance of this circuitry in ketamine's mechanism of action for motivational symptoms.
Molecular Psychiatry
May 25, 2021
Ju Lu, Michelle Tjia, Brian Mullen et al.
87 citations
A single dose of the psychedelic analog tabernanthalog (TBG) reduces anxiety and reverses stress-induced deficits in sensory processing and cognitive flexibility in mice exposed to unpredictable mild stress. TBG promotes regrowth of dendritic spines lost during stress, lowers baseline neuronal activity, and enhances whisking-related modulation in the somatosensory cortex. In a texture discrimination task, novel textures activate a greater proportion of cortical neurons than familiar ones; this differential response is diminished by stress and restored by TBG. The findings indicate TBG combats stress effects by modulating basal and stimulus-dependent neural activity in cortical networks.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Molecular Psychiatry
June 1, 2023
Jiahe Zhang, Jovicarole Raya, Francesca Morfini et al.
65 citations
Adolescents with a lifetime history of depression or anxiety (n = 9) participated in a proof-of-concept study using personalized mindfulness-based fMRI neurofeedback to reduce default mode network hyperconnectivity, a neural mechanism linked to depressive symptoms. After a resting state fMRI localizer to map each adolescent's default mode and central executive networks, a brief mindfulness training and neurofeedback session followed. The neurofeedback successfully engaged the target brain state, with participants spending more time with default mode network activation lower than central executive network activation. Within-default mode network connectivity decreased in all nine adolescents, correlating with increased state mindfulness after the session. Reduced within-default mode network connectivity mediated the link between better neurofeedback performance and increased state mindfulness, suggesting this non-invasive method can modulate networks involved in adolescent depression.
Molecular Psychiatry
January 1, 2023
Evan J. Kyzar, George H Denfield
62 citations
Psychiatric diseases alter subjective experience, yet neuroscience mostly studies objective behaviors. Phenomenology, a philosophical tradition examining lived experience, can generate hypotheses about the neurobiological basis of mental illness. Early 20th-century phenomenological psychiatrists made important contributions, but this approach faded with operationalized diagnoses. Recently, clinical-phenomenological research has re-emerged. Using examples from mania and psychosis, the authors show that phenomenological studies can produce fruitful neuroscientific proposals. They advocate integrating phenomenological methods with modern neuroscience, including cross-species research and human subjects work, to move toward a unified understanding of mental illness.
Molecular Psychiatry
December 1, 2024
Chloe E Page, C Neill Epperson, Andrew M Novick et al.
54 citations
Major depressive disorder (MDD) is better understood not as a serotonin deficit but as inflexibility in cognitive and emotional brain circuits that creates a persistent negativity bias. Effective treatments—including conventional antidepressants, ketamine, psychedelics, psychotherapy, and neuromodulation—work by enhancing neuroplasticity, restoring synaptic, network, and behavioral function to enable adaptive cognitive and emotional processing. The article provides accessible language and metaphors for clinicians and researchers to communicate this updated framework to patients and the public, aiming to improve understanding and trust.
Molecular Psychiatry
September 1, 2023
Alaina M Jaster, Javier González-Maeso
50 citations
Clinical trials show psychedelics can alleviate depression and anxiety and reduce nicotine and alcohol use, but the molecular mechanisms behind these lasting therapeutic effects remain poorly understood. Preclinical research is split between pathways dependent on the serotonin 5-HT2A receptor and those that are independent. Combining molecular, behavioral, and genetic techniques in neuropharmacology is beginning to clarify these mechanisms. The subjective experience during psychedelic-assisted therapy appears important, but without cross-validation between clinical and preclinical studies, the reasons for the experience and its translational validity may be lost.
Molecular Psychiatry
September 1, 2023
Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff et al.
48 citations
Repeated low doses of psilocybin, similar to human microdosing, were tested in rats. The regimen was well tolerated, causing no signs of anhedonia, anxiety, or altered movement, and did not downregulate or desensitize 5-HT2A receptors. The treatment increased resilience to injection stress, reduced self-grooming (a proxy for compulsive actions), and raised 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
Molecular Psychiatry
January 20, 2023
Jie Guo, Di Qiu, Han-Wen Gu et al.
46 citations
Perioperative intravenous ketamine reduces postoperative depression scores and pain scores on the first day after surgery but increases the risk of adverse effects including nausea, vomiting, headache, hallucination, and dizziness. The analysis of 15 randomized controlled trials with 1697 patients receiving ketamine and 1462 controls showed a reduction in depression scores on postoperative days 1, 3, and 7 and over the long term. Pain scores were lower only on the first postoperative day. The authors conclude that ketamine's benefits for postoperative depression and pain must be weighed against its increased adverse effects.
Molecular Psychiatry
April 1, 2024
Kyle A Brown, Todd D Gould
45 citations
The discovery that low doses of ketamine and esketamine can rapidly and persistently relieve depression in treatment-resistant patients has shifted thinking about how quickly depression can be treated. Impaired excitatory synapses in mood-regulating brain circuits likely contribute to depression. Metaplasticity—the process of priming neurons to alter their future capacity for plasticity—may be harnessed by drugs called metaplastogens to reverse depression's underlying pathophysiology. This review argues that diverse rapid-acting antidepressants, including ketamine mimetics and psychedelics, converge on common downstream molecular mediators to strengthen synapses and produce lasting effects. Targeting metaplastic mechanisms could reduce dosing frequency and side effects by eliminating the need for continuous drug presence.
Molecular Psychiatry
April 27, 2024
K Conn, L K Milton, K Huang et al.
44 citations
Psilocybin, currently in clinical trials for anorexia nervosa (AN), may improve cognitive inflexibility, a core feature of AN. Using the activity-based anorexia rat model, psilocybin post-acutely improved body weight maintenance in female rats and facilitated cognitive flexibility, specifically through better adaptation to reversed reward contingencies. The cognitive enhancing effects involved serotonin 5-HT1A and 5-HT2A receptor signaling; blocking 5-HT1A negated these benefits. Psilocybin transiently increased cortical Htr2a transcription and decreased Htr1a transcription, with further Htr2a reduction in anorexic rats. These findings suggest psilocybin could ameliorate cognitive inflexibility in AN and highlight therapeutic mechanisms beyond 5-HT2A receptor binding.
Molecular Psychiatry
March 31, 2015
Jordi Riba, Marta Valle, Frederic Sampedro et al.
41 citations
Chronic cannabis users, even after a period of abstinence, are more prone to false memories—mistaking events that never occurred for real ones. Using functional magnetic resonance imaging, the study found that abstinent cannabis users showed reduced brain activity in areas critical for memory processing, including the lateral and medial temporal lobe, as well as in parietal and frontal regions involved in attention and monitoring. Cannabis consumption was inversely correlated with medial temporal lobe activity, indicating a specific detriment to episodic memory. These results suggest long-lasting impairments in memory and cognitive control mechanisms that support reality monitoring.
Molecular Psychiatry
March 1, 2025
Michel Sabé, Adi Sulstarova, Alban Glangetas et al.
39 citations
A systematic review and meta-analysis assessed the risk of psychedelic-induced psychosis in people with schizophrenia. Among population studies, the incidence was 0.002%; in uncontrolled trials, 0.2%; and in randomized controlled trials, 0.6%. In uncontrolled trials that included individuals with schizophrenia, 3.8% developed long-lasting psychotic symptoms. Of those who experienced psychedelic-induced psychosis, 13.1% later developed schizophrenia. The evidence suggests schizophrenia might not be an absolute exclusion for clinical trials on psychedelics for treatment-resistant depression and negative symptoms, but low study quality and limited data warrant a conservative approach until more research is done.
Molecular Psychiatry
September 1, 2023
Matthew B. Wall, Rebecca Harding, Rayyan Zafar et al.
39 citations
Psychedelic therapy shows promise for treating depression, addiction, PTSD, and other psychiatric disorders. Classic serotonergic psychedelics like psilocybin and LSD act primarily at the 5-HT2A receptor, while ketamine, MDMA, and ibogaine also show potential. Modern neuroimaging techniques, especially PET and MRI, now allow precise measurement of brain effects. Key knowledge gaps remain: the link between acute drug effects and long-term clinical outcomes, detailed characterization of 5-HT2A receptor effects, and the role of neuroplasticity. Future studies combining PET with 5-HT2A-selective ligands like [11C]Cimbi-36 and MRI could bridge molecular, functional, and clinical understanding.
Molecular Psychiatry
July 1, 2024
Orr Shahar, Alexander Botvinnik, Amit Shwartz et al.
37 citations
Psilocybin-containing mushroom extract (PME) may have stronger and longer-lasting effects on synaptic plasticity than chemically synthesized psilocybin (PSIL) alone. In male mice, both PME and PSIL increased synaptic proteins GAP43 and synaptophysin in brain regions linked to learning and memory, but PME increased more proteins across more brain areas after 11 days. Metabolomic analysis of the frontal cortex revealed a distinct metabolic profile for PME, with a progressive decline in purines associated with oxidative stress from vehicle to PSIL to PME. These findings suggest that other compounds in the mushroom extract contribute to enhanced neuroplasticity, though further research is needed to identify them.
Molecular Psychiatry
January 17, 2024
Dotan Braun, Ayelet M Rosenberg, Elad Rabaniam et al.
32 citations
Psilocybin, a psychedelic serotonin receptor agonist, has two behavioral effects in larval zebrafish: it stimulates spontaneous exploration and prevents irregular swim patterns that normally follow stress exposure, indicating an anxiolytic effect. These effects resemble those of ketamine, not SSRIs. Neural imaging suggests psilocybin inhibits serotonergic neurons in the dorsal raphe nucleus by activating local GABAergic neurons, a mechanism consistent with findings in mammals.
Molecular Psychiatry
April 1, 2025
Mihai Avram, Lydia Fortea, Lea Wollner et al.
26 citations
Lysergic acid diethylamide (LSD), d-amphetamine, and MDMA each reduce the integrity (within-network connectivity) of several brain networks, with LSD uniquely reducing integrity in the default-mode network. Contrary to expectations, amphetamines reduced integrity in more networks than LSD. LSD produced more pronounced decreases in between-network segregation, while amphetamines also induced increases. Seed-based connectivity mostly increased between networks across all substances, with LSD showing stronger effects than both amphetamines. All substances decreased global connectivity in visual areas, but LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings clarify distinctive neurobiological effects of psychedelics and support further investigation of their therapeutic potential.
Molecular Psychiatry
October 11, 2024
Michal Brownstien, Michal Lazar, Alexander Botvinnik et al.
23 citations
In mice lacking the SAPAP3 gene, which display excessive self-grooming and anxiety similar to human obsessive-compulsive disorder, a single injection of psilocybin or psychedelic mushroom extract reduced self-grooming by about 15-19% over 21 days, while vehicle-treated mice showed a 119% increase. The effects lasted up to 7 weeks in responsive mice, and non-responsive mice later treated with psilocybin also improved. The mushroom extract was superior for reducing head-body twitches and anxiety. These results support clinical trials of psilocybin for OCD.