eLife March 31, 2026 Jessica L Maltman, Javier González-Maeso
Exposure to psilocin, the active metabolite of the psychedelic psilocybin, increases structural complexity and strengthens synaptic connections in human neurons derived from stem cells. These changes suggest enhanced neuroplasticity at the cellular level.
Psychiatry and Clinical Psychopharmacology March 30, 2026 Kenji Hashimoto, Feyza Arıcıoğlu, Mesut Çetin
Classical serotonergic psychedelics—psilocybin, DMT, 5-methoxy-DMT, and LSD—can produce rapid and sometimes durable improvements in mood under supervised conditions. The review synthesizes clinical evidence for these compounds in depression and related disorders, noting challenges such as small sample sizes, expectancy effects, and limitations in maintaining blinding. Mechanistic frameworks extend beyond 5-HT2A receptor activity, involving multiple serotonergic subtypes, glutamatergic modulation, synaptic plasticity, and brain network reorganization. Preclinical and clinical evidence points to neurotrophic mechanisms, particularly BDNF-TrkB signaling, as contributors to sustained effects. Acute mystical-type experiences may enhance response but are not strictly required, suggesting plasticity-promoting mechanisms can be partially dissociated from hallucinogenic effects. Peripheral contributions, including gut-brain axis interactions, may influence treatment durability.
eLife March 27, 2026 Malin Schmidt, Anne Hoffrichter, Mahnaz Davoudi et al. 3 citations
Psilocin, the psychoactive metabolite of psilocybin, increases BDNF abundance in human cortical neurons derived from induced pluripotent stem cells via the 5-HT2A receptor. Transcriptomic profiling shows gene expression changes that prime neurons for neuroplasticity. Morphologically, psilocin enhances neuronal complexity and increases synaptic proteins, especially in the postsynaptic compartment. Functionally, it leads to increased excitability and enhanced synaptic network activity. These findings suggest psilocin induces a state of enhanced neuronal plasticity, which may explain its therapeutic potential in neuropsychiatric disorders involving synaptic dysfunction.
Communications Biology March 26, 2026 Veronica Mäki-marttunen 1 citation
Psilocybin, a psychedelic compound that activates 5HT2a serotonin receptors, alters the speed and pattern of traveling waves of neural activity across the cortex. Using fMRI data from a publicly available dataset, researchers found that psilocybin increased the propagation speed of infraslow cortical activity, which was linked to greater overall functional connectivity and a contraction of the principal gradient—a measure of how brain regions are organized along a sensory-to-association axis. The distribution of 5HT2a receptors in the cortex may help explain these changes. The results connect large-scale brain activity patterns, global neural events, and receptor action, offering insights into how psychedelics produce their effects.
Frontiers in Cell and Developmental Biology March 25, 2026 Mizuki Yamamoto, Haruka Hirakata, Koji Toda 5 citations
Major depressive disorder affects many people across their lives, but its biological causes are still not fully understood. Older theories focused on imbalances in monoamine neurotransmitters like serotonin, leading to common antidepressants such as selective serotonin reuptake inhibitors. These drugs can take weeks to work, must be taken continuously, and fail to help about one-third of patients, while also carrying risks like increased suicidal thoughts in some groups. Newer findings show that ketamine and psychedelic compounds can produce rapid antidepressant effects by acting on glutamate signaling, synaptic plasticity, and immune-brain interactions, challenging the older models. This review covers both historical and emerging views on antidepressant development, describes major animal models of depression, and discusses recent translational research that is reshaping treatment approaches.
bioRxiv (Cold Spring Harbor Laboratory) March 23, 2026 Marco Taddei-Tardon, Lidia Medina-Rodríguez, Jessica L. Maltman et al.
Serotonergic psychedelics, including tryptamines, phenethylamines, and ergolines, promote structural and transcriptional changes in neurons through an integrated signaling network involving the 5-HT2A receptor and TrkB. Using a neural stem cell-derived model, the study shows that TrkB silencing blocks dendritogenesis induced by psychedelics, ketamine, and TrkB agonists, while 5-HT2A silencing selectively impairs psychedelic-induced plasticity. Most compounds increase synaptogenesis and immediate-early gene expression, though psilocin and the phenethylamines DOI and Ariadne show ligand-specific differences. Lactate production, dependent on 5-HT2A and both Gq/11 and Gi/o protein signaling, also occurs. These results establish a platform for dissecting psychedelic action.
Journal of psychoactive drugs March 20, 2026 Marina A M Portes, Leandro J Bertoglio
Endurance athletes face unique psychological and physical stressors, yet their knowledge and attitudes toward psychedelic therapies are largely unknown. A survey of 28 Brazilian endurance athletes (mean age 37) found that 64% reported a lack of mental health support in their athletic environments. Only 11% had prior psychedelic experience, while 79% were open to legal, supervised psychedelic therapies. However, 61% were unaware of evidence for psychedelics in treating mental health conditions, and 78% mistakenly believed psychedelics are addictive. Women more often reported pharmacological treatment for depression or anxiety. The findings highlight unmet mental health needs, knowledge gaps, and misconceptions, pointing to a need for targeted, evidence-based education.
ACS pharmacology & translational science March 13, 2026 Bo Jarrett Wood, M Frances Vest, Catharine Carfagno et al.
In male mice, chronic treatment with the SSRI fluoxetine (Prozac) reduced the head-twitch response—a behavioral sign of 5-HT2A receptor activation—caused by the psychedelic DOI, while acute fluoxetine had no effect on DOI. The reduced response reversed after a 14-day discontinuation of fluoxetine. Acute fluoxetine also weakened the efficacy (but not potency) of psilocybin, indicating that SSRI-psychedelic interactions may differ depending on the specific psychedelic compound. These results suggest that a history of SSRI use can alter sensitivity to psychedelics in a compound-specific manner, with implications for psychedelic-assisted therapy in people taking SSRIs.
Molecules and Cells March 10, 2026 Victoria N. Chang, Roberto Ogelman, R. Vargas et al. 1 citation
Serotonin (5-HT) is a key neuromodulator that directly influences plasticity at excitatory synapses on dendritic spines. It activates 14 subtypes of G-protein-coupled receptors, each with distinct expression and signaling. Disruptions in serotonergic transmission during development or adulthood cause lasting changes in behavior and neuronal structure, particularly in dendritic spines, indicating serotonin's critical role in excitatory synaptic plasticity. This review summarizes how 5-HT receptors contribute to the development and maturation of excitatory postsynaptic synapses, from spinogenesis through stabilization, potentiation, and depression. It also highlights recent advances showing how atypical serotonergic signaling and psychedelics alter spine structure and function.
Zenodo (CERN European Organization for Nuclear Research) March 10, 2026 Veronica Mäki-marttunen
Psilocybin alters how brain activity spreads slowly and globally across the cortex, following the spatial distribution of 5HT2a receptors. The accompanying code supports the analysis of these propagation patterns.
bioRxiv (Cold Spring Harbor Laboratory) March 10, 2026 Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau et al.
Combining psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) reduces psychedelic-like effects in mice—measured by head twitch response—while preserving antidepressant effects against chronic stress. Proteomic analysis of the medial prefrontal cortex revealed enhanced synaptogenesis and reduced GPCR signaling pathways with the combination versus psilocybin alone. This suggests a potential strategy for developing serotonergic antidepressants that maintain efficacy without the intense psychedelic experience, which currently limits scalability of psilocybin therapy.
Psychopharmacology March 4, 2026 Ava M. Mac, Srinivasu Kallakuri, Alixandria T. Mascarin et al.
Repeated low doses of MDMA (2.5 mg/kg) caused mild anxiety-like behavior in rats one day after exposure, but this effect was confounded by reduced movement and did not persist at 15 days. Higher doses (5 mg/kg) did not produce anxiety-like behavior. Sucrose preference, a measure of anhedonia, increased over time and was unaffected by MDMA or sex. Brain analysis showed reduced serotonin levels in the nucleus accumbens one day after both MDMA doses, but not in the prefrontal cortex or dorsal hippocampus. These transient effects suggest that low-dose MDMA used clinically may be tolerated without limiting therapeutic benefit.
bioRxiv (Cold Spring Harbor Laboratory) March 4, 2026 Matthew D. B. Claydon, Justyna K. Hinchcliffe, Julia M. Bartlett et al.
Psilocybin, the active compound in magic mushrooms, produces rapid and lasting antidepressant effects in people with major depressive disorder, but the underlying brain mechanisms are not fully understood. In rats, psilocin (the active metabolite of psilocybin) alters negative affective biases—a key feature of depression—by acting on a specific circuit in the medial prefrontal cortex. It suppresses excitatory signals to cortico-amygdala projection neurons while enhancing excitatory transmission to other targets, effects dependent on 5HT1A and 5HT2A receptors. These changes persist for at least 24 hours and shift from suppressed excitation to enhanced inhibition in those same cells. Chemogenetically inhibiting these neurons reproduced psilocybin's effects on affective biases and reward memories, identifying this circuit as a key substrate for its antidepressant actions.
ACS Chemical Neuroscience March 3, 2026 Samuel E. Williamson, Elise K. Burkhartzmeyer, Michael T. Faley et al.
To support ongoing clinical trials, the major human metabolites of psilocybin—psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA)—along with putative minor metabolites and several deuterium-labeled derivatives, were synthesized on a preparative scale. When assayed for engagement at seven serotonin receptor subtypes using a BRET-based binding assay, only psilocin exhibited any discernible binding. Given the high cost and challenging preparation of these compounds, the work provides a comprehensive guide for researchers to access these resources, advancing both basic and clinical research with psilocybin and its metabolites.
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.