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
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
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
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
September 1, 2024
Sanne Y Smith-Apeldoorn, Jolien K E Veraart, Jeanine Kamphuis et al.
23 citations
A randomized placebo-controlled trial tested whether a fixed low dose of oral esketamine (30 mg three times daily) could reduce depression severity in patients with treatment-resistant depression. Over six weeks, the drug showed no benefit compared to placebo on the Hamilton Depression Rating Scale. Dizziness and sleep hallucinations were more common with esketamine. In an open-label extension phase where doses were individually titrated up to 3.0 mg/kg twice weekly, depressive symptoms decreased substantially. The findings suggest that fixed low-dose oral esketamine is ineffective, but individually adjusted higher doses may hold promise for treatment-resistant depression.
Molecular psychiatry
June 1, 2025
J Jungwirth, R von Rotz, I Dziobek et al.
19 citations
Empathy is important for relationships and mental health but is often reduced in depression. Psilocybin, a potential depression treatment, acutely boosts emotional empathy in healthy people, but its effect in depressed patients was unknown. In a randomized, placebo-controlled trial, 51 depressed patients received either a single psilocybin dose (0.215 mg/kg) or placebo, alongside 4 weeks of psychological support. Empathy was tested at baseline and up to 2 weeks later. Psilocybin significantly improved explicit emotional empathy, especially toward positive stimuli, for at least two weeks. The findings suggest psychedelics may enhance social cognition in depression, though more research is needed on its link to clinical improvement.
Molecular psychiatry
April 1, 2025
Devon Stoliker, Katrin H Preller, Leonardo Novelli et al.
19 citations
Psilocybin, the active compound in magic mushrooms, alters visual perception by changing how brain regions communicate. Under psilocybin, early visual areas and higher visual-association regions showed increased self-inhibition, reducing sensitivity to incoming neural signals. At the same time, top-down feedback from visual-association areas to earlier visual regions was enhanced. This shift in balance—less bottom-up sensitivity and stronger top-down influence—may explain the vivid eyes-closed imagery characteristic of psychedelic experiences. The findings come from a double-blind, placebo-controlled study of 24 healthy adults using functional MRI and dynamic causal modeling, and they advance understanding of both basic visual perception and potential clinical applications.
Molecular psychiatry
January 1, 2025
Margareth Nogueira, Daiane C Ferreira Golbert, Richardson Menezes et al.
18 citations
A single dose of the short-acting psychedelic 5-MeO-DMT alters expression of genes related to plasticity and neuronal activity in specific brain regions of mice, including the anterior cingulate cortex, basolateral amygdala, and ventral hippocampus. Immediate early genes Arc and Zif268 changed within hours, while TRIP8b, a modulator of neuronal activity, increased in the ventral hippocampus after five days. Behaviorally, 5-MeO-DMT produced mixed anxiety-reducing and anxiety-increasing effects in standard tests, but mice pre-treated with the compound and then exposed to acute stress showed lower corticosterone levels and strong anxiety-reducing effects. The findings suggest molecular pathways through which 5-MeO-DMT may produce anxiolytic effects.
Molecular psychiatry
September 1, 2024
Brandi Quintanilla, Carlos A Zarate, Anilkumar Pillai
17 citations
Over 300 million people worldwide have major depressive disorder (MDD), but only 30-40% achieve remission with standard antidepressants. Ketamine offers rapid relief within hours, unlike weeks for conventional drugs. While many studies focus on ketamine's effects on glutamate, this review highlights its anti-inflammatory actions, especially through the complement system—a part of innate immunity involved in synaptic plasticity. The complement system is linked to depression, with increased complement component 3 (C3) expression found in the prefrontal cortex of suicidal individuals with depression. Given ketamine's anti-inflammatory properties and the complement system's role in glutamate modulation, the review suggests a common link between the complement system and ketamine's mechanism of action.
Molecular psychiatry
January 1, 2024
Uriel Heresco-Levy, Bernard Lerer
17 citations
Serotonergic psychedelics like psilocybin show promise for treating depression and other neuropsychiatric disorders, but their psychotomimetic effects may limit use. They enhance neuroplasticity through serotonin 2A receptor activation and interactions with glutamate receptors, TrkB, and mTOR. Drugs like ketamine, D-serine, and D-cycloserine share some of these mechanisms and have neuroplastic and antidepressant effects, with D-serine and D-cycloserine also showing procognitive effects. The authors hypothesize that combining a psychedelic with an NMDAR modulator could increase therapeutic impact, allow dose adjustments, and improve safety. They propose initial research on acute concurrent administration of psilocybin with D-serine or D-cycloserine for depression.
Molecular psychiatry
March 1, 2025
Jamie A Abbott, Han Wen, Beiying Liu et al.
14 citations
Ketamine produces rapid antidepressant effects at low doses, but the molecular targets responsible are debated. This study used electrophysiology, mutagenesis, and modeling to show that at nanomolar concentrations, ketamine binds to hydrophobic sites on NMDA receptors distinct from its known pore-blocking site. This binding stabilizes receptors in pre-open states, reducing gating in a voltage- and pH-dependent manner. Importantly, this allosteric inhibition spares brief synaptic activations but preferentially reduces currents from receptors activated tonically by ambient neurotransmitters. These hydrophobic sites may explain ketamine's unique clinical effects and offer targets for developing safer neuroactive drugs.
Molecular psychiatry
February 19, 2025
Arianna Rizzo, Maria Zelai Garçon-Poca, Amelie Essmann et al.
14 citations
Esketamine, a new antidepressant, works through a complex interaction with brain chemicals rather than a single target. In mice, esketamine increased movement and raised overall dopamine levels by slowing dopamine removal, not by boosting its release. It also reduced glutamate activity. However, it decreased spontaneous dopamine release events and blunted reward-triggered dopamine release, which lowered the mice's motivation to work for rewards. Some of these dopamine effects were partially blocked by naloxone, an opioid blocker, and depended on glutamate input. The findings suggest esketamine's effects on brain chemistry vary by brain circuit and behavioral state.
Molecular psychiatry
November 1, 2023
L. Taylor Flynn, Wen-Jun Gao
14 citations
Psychedelic compounds are being studied as potential treatments for psychiatric conditions, but their mechanism of action is not well understood. This review proposes that changes in DNA methylation, a form of epigenetic regulation, may underlie the therapeutic effects of psychedelics. The authors focus on the N-methyl D-aspartate receptor (NMDAR), which is important for synaptic plasticity and is known to be dysfunctional in schizophrenia and major depressive disorder. They review evidence linking abnormal DNA methylation to NMDAR dysfunction in these disorders and present a model suggesting that psychedelics may act through epigenetic mechanisms to provide therapeutic benefits.
Molecular psychiatry
January 1, 2025
Pei-Chi Tu, Wan-Chen Chang, Tung-Ping Su et al.
13 citations
In two clinical trials involving a total of 96 patients with treatment-resistant depression, a single low dose of ketamine altered specific connections between the thalamus and frontal brain regions, measured by resting-state functional MRI three days after infusion. Some thalamocortical connections increased and others decreased in the ketamine groups compared to placebo or midazolam groups. However, these brain connectivity changes were not statistically significantly linked to improvements in depression or suicidal thoughts after correcting for multiple comparisons. The results suggest that while ketamine may modify thalamocortical connectivity, whether these changes underlie its antidepressant and antisuicidal effects remains uncertain and requires further study.
Molecular psychiatry
December 1, 2024
Matteo Martino, Paola Magioncalda
13 citations
Psychosis, involving hallucinations and delusions, arises from a combination of sensory system deficits and overactivity in brain networks linked to internal thought, such as the default-mode network. Hallucinations are tied to transient activation in sensory cortices (e.g., superior temporal gyrus) and increased connectivity in associative areas like the temporoparietal junction. Delusions are linked to hyperactivity in the medial prefrontal cortex. These changes cause internally generated imagery to become as vivid as real perceptions, impairing the ability to distinguish reality from imagination, leading to a loss of contact with the environment.
Molecular psychiatry
February 1, 2025
Jacopo Sapienza, Francesca Martini, Stefano Comai et al.
11 citations
Despite promising results in other psychiatric conditions, no modern clinical trials have tested psychedelics in patients with schizophrenia, except for semi-anecdotal studies from the 1950s and 1960s that noted improvements in negative symptoms and social cognition. Recent evidence suggests the mechanisms of psychedelics partially overlap with schizophrenia's pathology but in an opposite direction, providing a biological rationale for their use. This perspective paper reviews old experiments and recent molecular findings on neuroplasticity, connectivity, immune and TAARs systems, neurotransmitters, and neurotropic factors. The authors identify a therapeutic potential for negative symptoms and social cognition, proposing very low doses (microdosing) for a subpopulation of chronic patients predominantly burdened by negative symptoms, while carefully considering safety and feasibility to guide future trials.
Molecular psychiatry
January 14, 2025
Claudio Agnorelli, Alessandra Cinti, Giovanni Barillà et al.
8 citations
In patients with bipolar disorder and treatment-resistant depression, a subanesthetic dose of ketamine alters brain activity patterns measured by EEG. Ketamine reduced low-frequency power and increased gamma oscillatory power, flattened the slope of power spectra, and increased brain signal entropy, especially in high-frequency bands. Patients who responded later to treatment showed greater EEG changes than early responders, suggesting underlying differences in treatment sensitivity. These neurophysiological effects may help explain ketamine's therapeutic mechanisms and could guide personalized treatment for mood disorders.
Molecular psychiatry
July 7, 2025
Dongsun Park, Gwangho Lee, Won-Gyu Lee et al.
7 citations
Ketamine and psilocybin both provide rapid relief from major depressive disorder by enhancing synaptic plasticity in mood-regulating circuits, but through distinct initial mechanisms: ketamine blocks NMDA receptors while psilocybin primarily activates 5-HT2A receptors. A shared downstream pathway involves BDNF-TrkB signaling, which promotes spinogenesis and synaptogenesis critical for sustained antidepressant effects. The review also discusses 5-HT2A receptor biased agonism as a potential strategy to separate therapeutic benefits from hallucinogenic effects. Understanding how serotonergic, glutamatergic, and neurotrophic systems converge may guide development of fast-acting, durable, and non-hallucinogenic antidepressants.
Molecular psychiatry
June 1, 2026
Charles F Zorumski, Joseph Cichon, Yukitoshi Izumi et al.
5 citations
Nitrous oxide (N2O), an inhalational anesthetic used for over 150 years, shows rapid and durable antidepressant effects in patients with major depressive disorder and treatment-resistant depression, according to recent clinical trials. Like ketamine, N2O inhibits N-methyl-D-aspartate receptors (NMDARs) but through distinct mechanisms. Cellular and neuronal circuit studies are early but suggest N2O shares some downstream mechanisms with ketamine while also having unique effects on neurophysiology and signaling. Human neuroimaging studies have begun identifying acute and persisting effects of N2O on brain circuits relevant to antidepressant responses. This review highlights current clinical and preclinical research, major unanswered questions, future directions, and potential barriers to clinical use.