bioRxiv (Cold Spring Harbor Laboratory)
June 12, 2026
Nikola Jajcay, Čestmír Vejmola, Jakub Korčák et al.
Psilocybin accelerates the temporal dynamics of large-scale brain activity while preserving access to the normal repertoire of brain states. In a double-blind, placebo-controlled crossover study of 15 healthy volunteers, EEG microstate analysis revealed that psilocybin increased the number of global field power peaks and reduced microstate lifespan while increasing their frequency of occurrence during peak intoxication (50–100 minutes after administration), indicating faster transitions between brain states. Microstate coverage was largely unchanged except for a transient difference in the 2–20 Hz bandwidth. Individual differences in these microstate dynamics correlated with both acute subjective experience intensity and self-reported psychological changes 28 days later, suggesting EEG microstates as candidate neural markers linking acute psychedelic effects to longer-term outcomes.
bioRxiv (Cold Spring Harbor Laboratory)
June 9, 2026
Morten L Kringelbach, Gustavo Deco
Brain dynamics can be described in three mathematical languages—connectome harmonics, turbulence, and complex harmonics (CHARM)—which are unified as a single self-adjoint operator and its spectral measure. The connectome Laplacian carries this measure; harmonics are its spectral projections, the turbulence smoothing kernel is its resolvent, and CHARM form is its unitary propagator. A shared control parameter, the spectral gap, yields cortical hierarchy, turbulent information cascade, and structured interference. Testing this with a pharmacological perturbation by LSD showed that one scalar coupling simultaneously predicts multi-scale turbulence shifts and macroscale harmonic energy redistribution, supporting the unified operator structure.
bioRxiv (Cold Spring Harbor Laboratory)
May 14, 2026
Shiva Khoshnoud, Federico Alvarez Igarzábal, Marc Wittmann
During flow, a state of full immersion in an activity, brain networks linked to self-referential thinking become less active. Using EEG microstate analysis of 43 people playing a video game, researchers found that two brain states associated with the default mode network (DMN) were shorter and occurred less often during flow compared to boredom or frustration. This suggests that flow reduces self-awareness by dampening DMN activity, similar to effects seen in meditation and psychedelic states.
bioRxiv (Cold Spring Harbor Laboratory)
April 22, 2026
Sabine Gnodde, Vlada Aslanov, Jolien C. Francken et al.
Perceptual awareness is linked to early, posterior brain activity rather than later frontal processes. Using electroencephalography with a cross-decoding method that minimized report-related confounds, participants viewed gratings in backward-masking and no-report tasks. Classifiers trained on stimulus location in the no-report task were tested on masked trials sorted by subjective visibility. Decoding revealed a reliable difference between subjectively visible and invisible stimuli from 130 to 170 milliseconds, driven by posterior sensors over occipital, temporal, and parietal regions. No corresponding effects were observed over frontal sensors, suggesting frontal activity in report-based paradigms reflects post-perceptual processing rather than awareness itself.
bioRxiv (Cold Spring Harbor Laboratory)
April 12, 2026
Ibrahim A. Akkouh, Jordi Requena Osete, N. W. Steen et al.
Activating GABA-A receptors with muscimol, a non-classic psychedelic, suppresses inflammatory signaling and promotes neuroplasticity in human cortical spheroids and astrocytes derived from patients with schizophrenia. Inflammatory stimulation triggered interferon-responsive gene programs, with astrocytes acting as key mediators. Muscimol reduced proinflammatory cytokine secretion, attenuated interferon signaling, and upregulated neuroplasticity-related genes such as NTRK2 and ELK1. It also restored impaired glutamate uptake in schizophrenia-derived astrocytes. These effects depended on GABA-A receptor activation. Proteomic analyses of spheroids and human brain tissue confirmed baseline dysregulation of GABAergic and neurotrophin signaling in schizophrenia, supporting the therapeutic potential of targeting astrocyte GABAergic signaling to restore neural homeostasis.
bioRxiv (Cold Spring Harbor Laboratory)
April 7, 2026
Benjamin Hänisch, Tobias Kaufmann, Sofie L. Valk
Combining pharmacodynamic profiles of four classic hallucinogens and ketamine with receptor density distributions from PET and autoradiography studies produces anatomical distribution profiles of drug action strength. Classic hallucinogens show high action strengths in association cortices and, based on autoradiography, in supragranular layers and multimodal temporal areas. Ketamine's affinity for high-affinity subtypes of 5-HT2a and D2 receptors generates classic hallucinogen-like neuroanatomical trends. High rapid-acting antidepressant action strengths in emotion-processing regions contribute to understanding the mechanism of rapid antidepressant action.
bioRxiv (Cold Spring Harbor Laboratory)
April 2, 2026
Maja Wójcik, Paweł Orłowski, Stanisław Adamczyk et al.
Long-term naturalistic psychedelic users who had abstained for at least 30 days showed largely no significant differences in brain oscillatory power, signal complexity, or network connectivity compared to non-users, contrary to patterns seen in acute administration studies. Complexity was unexpectedly lower in users during eyes-open conditions. Effective connectivity within and between key brain networks (Default Mode, Salience, Central Executive) showed no group differences after correction. These null findings suggest that repeated psychedelic use may not produce lasting neurophysiological changes detectable in resting-state EEG during abstinence, possibly due to homeostatic adaptation or individual variability.
bioRxiv (Cold Spring Harbor Laboratory)
March 23, 2026
Marco Taddei-Tardón, 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.
bioRxiv (Cold Spring Harbor Laboratory)
March 20, 2026
Jeremy Krohn, Larissa Breuer, Susanne Wegmann et al.
Astrocytes support brain functions like energy metabolism and synapse formation, and their calcium signals indicate cellular health and activity. A simple automated calcium imaging pipeline was developed to measure astrocyte calcium responses in mouse monocultures, mouse astrocyte-neuron cocultures, and human astrocytes from two stem-cell lines. The pipeline detected changes in response to ATP (increased activity), CPA (decreased activity), glutamate, and LSD (decreased activity in mouse cocultured astrocytes but increased in human astrocytes). Human recombinant Tau oligomers, modeling Alzheimer's pathology, decreased activity in both mouse and human astrocytes. This tool enables rapid screening of compounds affecting astrocyte function.
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.
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2026
Arina Nikitina, Christian Bustamante Toro, Raymond Gifford et al.
Ketamine rapidly silences population bursting in human forebrain organoids by disconnecting a subset of 'backbone' neurons that normally drive network activity, while individual neuron firing continues mostly unchanged. Acute exposure to 20 μg/mL ketamine abolished population bursts, reduced mean firing rates, and decreased functional connectivity globally, with backbone units losing their normally elevated connectivity. Re-exposure after chronic treatment no longer silenced bursting, indicating tolerance, though the network remained less active and less connected with fewer backbone units. The organoid-microelectrode array platform offers a scalable human-relevant system for studying circuit-level drug effects.
bioRxiv (Cold Spring Harbor Laboratory)
March 8, 2026
Nitzan Geva, Sarah J. Jefferson, Emi Krishnamurthy et al.
MDMA increases spine density and the formation of new spines in the medial prefrontal cortex of mice, as shown by two-photon microscopy. Calcium imaging in the infralimbic cortex during fear extinction revealed that neural activity in this region became more correlated with the suppression of freezing behavior, indicating a strengthened role in extinction. Longitudinal cell registration showed accelerated representational drift across days in MDMA-treated mice, especially in neurons that suppressed activity to conditioned cues. These findings indicate that MDMA facilitates structural and functional neuroplasticity, which may underlie its enhancement of extinction learning.
bioRxiv (Cold Spring Harbor Laboratory)
March 5, 2026
Venkatesh Subramani, Annalisa Pascarella, Jérémy Brunel et al.
Lysergic acid diethylamide (LSD) loosens the brain's usual alignment between anatomical structure and neural activity in a frequency-dependent way. Low-frequency brain waves (theta, alpha, beta) become less constrained by the structural connectome, indicating a global relaxation of large-scale dynamics. High-frequency gamma activity shows selective reorganization rather than uniform disruption. Greater gamma-band decoupling within core default-mode network regions predicts the intensity of ego dissolution across individuals. LSD does not cause indiscriminate disintegration but drives system-specific rebalancing: visual and attentional systems decouple while auditory networks strengthen coupling. These findings suggest psychedelic states emerge from frequency-dependent relaxation of structural constraints, with default-mode reorganization as a neural correlate of ego dissolution.
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.
bioRxiv (Cold Spring Harbor Laboratory)
February 10, 2026
Erdem Pulcu, Sara Costi, Pilar Artiach-Hortelano et al.
A single sub-anesthetic dose of ketamine reduces activity in the lateral habenula, a small midbrain structure involved in aversive learning, when healthy volunteers expect or experience unpleasant stimuli a day later. In a randomized trial with 70 adults, those who received ketamine showed attenuated habenula responses during an aversive Pavlovian conditioning task measured with 7-Tesla functional neuroimaging. Preliminary evidence suggests that reduced habenula activity during aversive learning may weaken the emotional impact of negative memories. These results support preclinical models of how ketamine may rapidly relieve depression by acting on the human habenula.
bioRxiv (Cold Spring Harbor Laboratory)
January 15, 2026
Justyna K. Hinchcliffe, Christopher W. Thomas, Gary Gilmour et al.
Psilocybin, a serotonergic psychedelic, can rapidly and lastingly reverse impaired reward processing in a rat model of depression. In rats with chronic interferon-alpha-induced depression, a single dose of psilocybin (0.3 mg/kg) restored reward-induced behavioral biases within 24 hours, and the effect persisted for at least 7 days. This suggests that restoring blunted reward processing may contribute to psilocybin's sustained antidepressant effects.
bioRxiv (Cold Spring Harbor Laboratory)
January 13, 2026
Iván Mindlin, Carlos Coronel-Oliveros, Jacobo Sitt et al.
A biologically grounded inhibitory homeostatic plasticity rule embedded into the Dynamic Mean Field (DMF) model creates a Homeostatic Dynamic Mean Field (HDMF) model that dynamically tunes local excitation-inhibition balance. The HDMF reproduces statistical observables of brain activity as well as the original DMF, can sustain neuromodulatory perturbations without overhead computations, and generates unprecedented sleep-like slow-wave activity that can coexist with wake-like asynchronous dynamics, permitting modeling of dissociated states of consciousness such as parasomnias. A single homeostatic rule broadens the stability and expressiveness of the DMF, providing a unified platform for studying how local adaptive processes shape the diverse global dynamics of the human brain.
bioRxiv (Cold Spring Harbor Laboratory)
January 2, 2026
Jason C. Slot, Alexander J. Bradshaw, Bryn T. M. Dentinger et al.
Psilocybe fuscofulva, a species of psychedelic mushroom, lacks the blue bruising and psilocybin found in other Psilocybe species. Genome sequencing and phylogenomic analysis placed P. fuscofulva as the earliest-diverging lineage in Clade I and found no psilocybin gene cluster (PGC) homologs in its genome, while all other examined Psilocybe genomes contained a single intact PGC. The PGC resides in two distinct, clade-specific genomic loci, with characteristic gene orders and orientations suggesting rearrangement through circular intermediates. Time-calibrated phylogenies estimated the Psilocybe crown group at about 28 million years ago, with major clade divergences in the Miocene. The absence of the PGC in P.
bioRxiv (Cold Spring Harbor Laboratory)
December 26, 2025
Jenna Houff, Andrew Williams, Obie Allen et al.
A single dose of psilocybin reduced preference for larger delayed rewards and increased the time rats took to choose them, measured 48 hours after administration. These effects were not related to changes in impulsivity, as they did not vary with delay length. Psilocybin also increased the density of activated parvalbumin inhibitory interneurons surrounded by perineuronal nets in the dorsomedial prefrontal cortex. The findings suggest psilocybin decreases reward seeking by activating these specific inhibitory neurons.
bioRxiv (Cold Spring Harbor Laboratory)
December 22, 2025
Sheida Shadani, Kaspar McCoy, Lina Ong et al.
A single dose of psilocybin (1.5 mg/kg) alters social behaviors in C57BL/6J mice in sex-specific ways. In females, psilocybin acutely triggers huddling linked to body temperature changes, enhances preference for social novelty 4 hours after administration lasting about 24 hours, but reverses to a preference for familiar over novel conspecifics 7 days later, associated with prolonged nucleus accumbens dopamine signaling during familiar sniffing. In males, psilocybin reduces stress-related behaviors at 24 hours and increases preference for familiar conspecifics, with blunted novelty-evoked dopamine responses at both 24 hours and 7 days. Both 5-HT1A and 5-HT2A receptors modulate these behaviors in sex-specific ways. The prosocial effects of psychedelics are not universal, emphasizing the need for sex-informed approaches.
bioRxiv (Cold Spring Harbor Laboratory)
December 22, 2025
Carla Pallavicini, Lorena Llobenes, Federico Cavanna et al.
Combining psilocybin with a compassion-focused imagery exercise produces long-term synergistic effects on cognitive absorption, self-compassion, and decentering. In a sample of 105 participants, those who received a compassion imagery prime before taking psilocybin showed distinct changes in brain network interactions—particularly among attentional, executive, and default mode networks—compared to those who simply focused on breathing. fMRI-based classifiers could distinguish the two priming conditions only at a high dose of psilocybin. The findings suggest that pairing psilocybin with compassion-based practices may amplify lasting psychological shifts and reorganize large-scale brain networks, though confirmatory studies are needed.
bioRxiv (Cold Spring Harbor Laboratory)
December 19, 2025
K.j Matthews Nicholass, I Flis, M.e Hanley et al.
Psilocybin, the psychedelic compound in 'magic' mushrooms, may have evolved as a chemical defense against insects. When fruit fly larvae were exposed to extracts from Psilocybe mushrooms, they showed reduced survival, lower pupation rates, and inhibited locomotion. Adults that developed from exposed larvae had smaller thoraxes and wings, along with increased fluctuating asymmetry, indicating developmental stress. Surprisingly, flies lacking 5HT2A receptors responded the same as normal flies, suggesting psilocybin's effects on insects involve different mechanisms than in vertebrates. DNA analysis showed that Psilocybe semilanceata hosts a distinct invertebrate community compared to most grassland fungi, though it overlapped with the non-psychedelic species Mycena epipterygia. This suggests psilocybin's ecological role may be more complex than simple defense.
bioRxiv (Cold Spring Harbor Laboratory)
December 19, 2025
Lucas L. Dwiel, Mackenzi L. Prina, Elise M. Bragg et al.
Pretreating rats with LSD before electrically stimulating the medial prefrontal cortex produces larger and longer-lasting changes in brain activity than stimulation alone. The combination activates the mTOR signaling pathway and alters perineuronal net integrity. Brain activity during stimulation does not predict the persistent brain state afterward. These findings support developing psychedelic-assisted brain stimulation to increase durability of stimulation effects, potentially reducing relapse rates in non-invasive stimulation treatments.
bioRxiv (Cold Spring Harbor Laboratory)
December 11, 2025
Caroline L. Alves, Fernanda Palhano-Fontes, Thaise G. L. de O. Toutain et al.
Ayahuasca alters conscious experience, and this study identifies EEG markers of its network-level effects using machine learning and complex-network analysis. In a randomized, double-blind, placebo-controlled trial with naïve ayahuasca users, resting-state EEG was recorded before dosing, 2 hours after, and 4 hours after. Connectivity was estimated with sliding windows; optimal classification performance occurred at 60–70 seconds (AUC and accuracy = 0.93). Network analysis revealed a bilateral decrease in eigenvector centrality (weaker hub influence), increased degree heterogeneity in the right hemisphere, and reduced global efficiency in the left. Posterior-left connections weakened acutely, while right temporal–central coupling transiently strengthened. The findings suggest that hub-centric shortcuts weaken, routing communication through more distributed, less efficient pathways with right-lateralized expression.
bioRxiv (Cold Spring Harbor Laboratory)
November 21, 2025
Joseph C. C. Chen, Gabriella Mace, Avery Ostrand et al.
preprint
Awe, a positive emotion linked to well-being and social behavior, was studied using EEG and autonomic physiology in 23 healthy older adults watching a nature film. Awe was the dominant emotion reported, though joy was also common. During awe events, skin conductance decreased, and EEG alpha and theta power decreased—changes associated with low arousal and positive emotion. Awe also increased Lempel Ziv Complexity (LZC), a measure of neural signal entropy linked to richer conscious experience. LZC correlated positively with awe intensity and negatively with skin conductance. Three additional datasets using different induction methods (video clips and DMT) showed similar occipital LZC increases, suggesting LZC may be a generalizable neurophysiological marker of awe.