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
March 14, 2024
Pol Puigseslloses, Gabriel Ketsela, Nicola Weiss et al.
23 citations
All tested 5-MeO-tryptamines selectively bind to 5-HT1A receptors over 5-HT2A receptors, with computational docking predicting better interaction in the 5-HT1A binding pocket. These compounds also interact with the serotonin transporter (SERT), where molecular size of the amino group influences affinity. 5-MeO-pyr-T acts as the most potent partial 5-HT releaser. All tryptamines elicit the head twitch response in mice, indicating potential hallucinogenic effects primarily mediated by 5-HT2A receptors, but 5-HT1A activation attenuates this response. Tryptamines producing stronger hypothermic responses via 5-HT1A tend to show lower hallucinogenic effects, highlighting opposing roles of the two receptors. Some compounds with low hallucinogenic effects remain potent 5-HT2A agonists, offering insight into non-hallucinogenic therapeutic ligands.
Molecular Psychiatry
May 3, 2022
Aino Saarinen, Leo‐Pekka Lyytikäinen, Jarmo Hietala et al.
22 citations
A high polygenic risk score for schizophrenia predicts elevated magical thinking in adults who never develop a non-affective psychotic disorder. Among 1,292 participants from the Young Finns Study, those with high genetic risk showed higher scores on the Spiritual Acceptance Scale (beliefs in telepathy, miracles, mystical events, or sixth sense) across ages 20–50. While magical thinking typically decreased steadily from age 20 to 50 in low-risk individuals, high-risk individuals showed a plateau in middle age, leaving their magical thinking higher than expected. These patterns held after controlling for sex, childhood family environment, and adulthood socioeconomic factors. The finding suggests that high genetic psychosis risk can manifest as milder deviant thinking when full psychosis does not develop.
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
October 21, 2024
Gabriele Floris, Mary Tresa Zanda, Konrad Dabrowski et al.
19 citations
A single dose of psilocybin given to rats 4–24 hours before a relapse test reduced cue-induced heroin seeking, though it did not alter actual heroin taking. Blocking the serotonin 2A receptor with antagonists worsened relapse. Psilocybin regulated about twice as many genes in the prefrontal cortex at a higher dose, with ketanserin blocking over 90% of these gene changes, including the IL-17a cytokine receptor. Psilocybin also regulated four chemokine/cytokine genes, and selectively inhibiting IL-17a in the prefrontal cortex was enough to reduce heroin relapse. The findings suggest psilocybin reduces heroin relapse and point to IL-17a signaling as a possible downstream pathway.
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
February 6, 2024
Merima Šabanović, Alberto Lazari, Marta Blanco-Pozo et al.
17 citations
A single dose of the psychedelic compound (±)-DOI increased brain volume in sensory and association areas of young adult mice and improved cognitive flexibility one week later. Treated mice adapted faster to a reversal in a probabilistic learning task and began learning from reward omissions, a strategy mice normally do not use. The effects depended on the timing between drug administration and the reversal, as well as on intervening experiences. These findings suggest that psychedelics may aid treatment of conditions involving rigid thinking, such as depression or addiction, by enhancing neuroplasticity and enabling new learning strategies.
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
February 17, 2022
Guang Chen, G. Mannens, Marlies de Boeck et al.
14 citations
An open-label study of (R)-ketamine for depression cannot establish efficacy due to expectancy biases and large placebo effects, even in treatment-resistant patients. One patient showed clinically meaningful dissociation. The antidepressant efficacy and optimal dose of (R)-ketamine must be determined in randomized controlled trials. A study in healthy volunteers found that (R)-ketamine and (S)-ketamine produced similar frequency and character of dissociative and other central nervous system adverse effects when compared at doses equipotent for NMDAR antagonism.
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
November 29, 2024
Adrian Hase, Gregor Hasler, Abigail E. Calder
12 citations
A meta-analysis of 29 studies found no evidence that psychoplastogens—including ketamine, LSD, psilocybin, and MDMA—elevate peripheral brain-derived neurotrophic factor (BDNF) levels in humans. The overall effect size was negligible (SMD = 0.024) and not statistically significant. This null result held across different drugs, doses, blood fractions, participant ages, and psychiatric diagnoses. Better-controlled studies showed even smaller effects. The findings suggest that peripheral BDNF may not be a useful biomarker for rapid neuroplasticity changes in humans, or that preclinical findings on psychoplastogen-induced neuroplasticity may not translate to humans. More precise methods, such as neuroimaging, are recommended for future translational research.
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
March 1, 2026
Tyler G. Ekins, Chloe Rybicki-Kler, Tao Deng et al.
9 citations
Classic psychedelics can strengthen connections in the retrosplenial cortex, a brain region important for memory and spatial orientation that is impaired in Alzheimer's disease, even though its neurons lack the serotonin 2A receptors thought necessary for such effects. Using a new genetic tool in mice, the research shows that this strengthening depends on presynaptic serotonin 2A receptors on incoming nerve fibers from the anterior thalamus, not on the postsynaptic receptors of the retrosplenial cortex itself. The finding suggests psychedelics may have broader therapeutic potential than currently recognized, possibly aiding conditions like Alzheimer's disease and post-traumatic stress disorder by boosting retrosplenial circuit function.
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.
Molecular Psychiatry
June 1, 2025
Anderson Camargo, Anna Nilsson, Reza Shariatgorji et al.
5 citations
Prophylactic ketamine administration buffers passive stress-induced maladaptive behaviors caused by chronic stress exposure. It also prevents stress-induced disturbances of tryptophan metabolism in the dorsal raphe nuclei (DRN) and blocks the reduction of the protein p11 in that region. p11 deficiency increases susceptibility to stress-related depression-like behaviors, and these effects depend partly on p11 function in serotonergic neurons. Viral-mediated reduction of p11 in the DRN produces a stress-susceptible phenotype. The pro-resilience effect of ketamine is lost when p11 is selectively deleted in serotonergic neurons, revealing a previously unexplored role of the DRN circuit in regulating stress susceptibility and ketamine's resilience-enhancing actions.
Molecular Psychiatry
August 23, 2025
Adam J. Drewko, Ron L. P. Habets, Tibor M Brunt
4 citations
Serotonergic psychedelics like psilocybin and LSD show promise for treatment-resistant depression by rapidly inducing neuroplasticity, but the molecular mechanisms are debated. This narrative review examines evidence on whether the serotonin 5-HT2A receptor, which mediates hallucinogenic effects, is also required for neuroplasticity. It covers how decreased neuroplasticity relates to depression, how psychedelics promote dendrito-, spino-, and synaptogenesis, and whether these effects are regionally selective. The review critically assesses conflicting studies on the necessity of 5-HT2A signaling for neuroplastic effects and presents a model of the molecular mechanisms involved.
Molecular Psychiatry
April 26, 2025
Rebecca Harding, Neomi Singer, Talma Hendler et al.
4 citations
Psilocybin therapy reduces anhedonia more than the SSRI escitalopram in major depressive disorder, yet escitalopram dampens emotional responses to musical surprises while psilocybin therapy preserves them. Escitalopram increases brain activity in memory and emotion regions during musical surprises, whereas psilocybin therapy decreases activity in the ventromedial prefrontal cortex and angular gyrus and increases sensory region activation. These contrasting neural and behavioral effects suggest fundamentally different treatment mechanisms: psilocybin may maintain subjective responses by reducing the salience of prediction errors or strengthening hedonic expectations, while escitalopram may weaken hedonic priors.