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 27, 2026
Morgan Rose Healey, Yaser Sanchez-Gama, Mengyuan Ding et al.
Self-transcendence, the shift of experience away from the self toward others, nature, or broader meaning, is a key aspect of human psychology, but its neural basis was unclear. By applying lesion network mapping to 88 neurosurgical patients assessed before and after surgery for trait self-transcendence, a distributed brain network was identified whose disruption alters this capacity. This network overlapped with the default mode network and frontoparietal control subnetworks. Posterior midline regions were the most stable correlates of increased self-transcendence after lesions. The findings suggest that posterior midline hubs constrain, while brainstem and anterior midline regions facilitate, self-transcendent experience.
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 18, 2026
Jacinthe Cataldi, Andria Pelentritou, Sophie Schwartz et al.
The brain continuously processes signals from the outside world and from inside the body. How this balance shifts across different states of consciousness is not well understood. This study measured brain responses to external sounds (auditory evoked potentials) and to heartbeats (heartbeat evoked potentials) in 25 healthy participants during wakefulness and during two types of REM sleep: tonic REM and phasic REM, which have progressively lower responsiveness to the environment. Auditory responses decreased from wakefulness to tonic REM and were smallest during phasic REM. Heartbeat responses remained strong across REM sleep and were even larger than during wakefulness.
bioRxiv (Cold Spring Harbor Laboratory)
March 13, 2026
Emma Peters, Xinlin Wang, Kathrin Fischer et al.
Lucid dream induction using external sensory stimulation has often relied on lights or sounds, with mixed success. This study tested whether direct bodily stimulation—electrical muscle stimulation (EMS) and galvanic vestibular stimulation (GVS)—could induce lucid dreams. Twenty-eight participants completed two morning naps: one with stimulation during REM sleep and one with sham control. EMS and GVS did not increase stimulus incorporation. Lucidity rates were high in both EMS conditions, suggesting baseline lucidity, cognitive training, and expectations played a role. However, GVS significantly increased externally rated lucidity and DLQ questionnaire scores compared to control, indicating that galvanic vestibular stimulation can enhance dream lucidity.
bioRxiv (Cold Spring Harbor Laboratory)
March 12, 2026
Emma Peters, Johanna Heitmann, Nicolas Morath et al.
Lucid dreaming, where the dreamer knows they are dreaming, can be triggered in a lab by training people to associate the sleep laboratory with reflective awareness before sleep. In three studies with 101 participants, a morning nap followed verbal instructions and audio primes. Some conditions added immersive virtual reality rehearsal of the lab, haptic stimulation during REM sleep, or virtual reality with fake system errors. Across all conditions, 40-45% of dreams were rated lucid, and 11-32% were signal-verified lucid dreams. However, the extra virtual reality and haptic techniques did not increase lucidity compared to the basic lab training alone. This suggests that simply training people to recognize the lab context is a powerful method.
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 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 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)
February 10, 2026
Isaac N Treves, Clare Shaffer, Alexandra Decker et al.
Lapses in attention to internal bodily sensations, such as the breath, are predicted by behavioral and neural markers that overlap with those for lapses in external attention but also involve distinct brain systems. In 93 adolescents with depressive symptoms performing a breath-counting task during fMRI, the strongest predictors of attention lapses were the timing and variability of button responses. Breathing variability and coupling between breathing and behavior showed weaker predictive value. Brain connectivity models, incorporating default-mode, dorsal attention, ventral attention, and somatomotor networks, predicted lapses with modest accuracy and marginally outperformed behavior-only models. These findings suggest shared and unique mechanisms for interoceptive attention failures.
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
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 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 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 Dwiel, Mackenzi L. Prina, Elise 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.