{"rows":[{"id":3026,"title":"Divergent changes in perturbation-induced brain reconfiguration following depression treatment with psilocybin and escitalopram","normalized_title":"divergent changes in perturbation induced brain reconfiguration following depression treatment with psilocybin and escitalopram","authors":"Dagnino, P. C.; Acero-Pousa, I.; Carhart-Harris, R.; Erritzoe, D.; Nutt, D. J.; Kringelbach, M. L.; Sanz Perl, Y.; Deco, G.","abstract":"A central challenge in neuroscience is understanding how the human brain is organised to support optimal functioning and adaptability. One approach to characterise complex brain dynamics is by artificially perturbing whole-brain models. Here, we asked whether whole-brain organisation under perturbation in major depressive disorder (MDD) changes after intervention with psilocybin and escitalopram. First, we built whole-brain models of pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) and obtained an initial generative effective connectivity (GEC) matrix for each individual. Then, we employed systematic and local artificial perturbations across intensities, re-optimised each model to create a response GEC (GECr), and assessed the extent of brain reorganisation by quantifying the brain network reconfiguration index (NRI). Our results showed that the global brain NRI increases with psilocybin and decreases with escitalopram. Across sessions and interventions, higher global NRI was related with localised perturbations in brain areas orchestrating the brains hierarchical dynamics. Traditional approaches complemented our investigation. Our findings suggest distinct neural changes following each treatment for MDD. The increase in brain reorganisation under perturbation following psilocybin is consistent with greater brain flexibility and changeability, whereas the decrease following escitalopram suggests more stabilised brain dynamics. Overall, perturbation-induced brain NRI may represent a useful approach for uncovering neural changes following different interventions for depression.","journal":"bioRxiv","publication_date":"2026-06-25","publication_year":2026,"doi":"10.64898/2026.06.22.733731","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.06.22.733731","keywords":"neuroscience","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:45","last_checked":"2026-07-02 22:00:54","raw_json":"{\"server\":\"biorxiv\",\"version\":\"1\",\"category\":\"neuroscience\",\"type\":\"new results\"}","topic_tags":"Depression,Brain Imaging,Aging","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3023,"title":"Distinct brain responses to psilocybin and escitalopram in depression captured by the Fluctuation-Dissipation Theorem","normalized_title":"distinct brain responses to psilocybin and escitalopram in depression captured by the fluctuation dissipation theorem","authors":"Dagnino PC, Acero-Pousa I, Zamora-López G, Escrichs A, Erritzoe D, Nutt DJ, Carhart-Harris RL, Sanz Perl Y, Kringelbach ML, Deco G.","abstract":"In recent decades, the psychedelic psilocybin has been studied as a potential treatment for major depressive disorder (MDD), offering an alternative to traditional antidepressants. However, the brain changes underlying the clinical effects of different interventions remain unclear. Here, we investigated the effects of psilocybin and a conventional antidepressant, escitalopram, from the double-blind randomised controlled trial (DB-RCT) - NCT03429075 - on the brain’s hierarchical organisation. Using pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) we built whole-brain models and obtained a generative effective connectivity (GEC) matrix for each patient. Based on the GEC, we measured the level of non-equilibrium brain dynamics by quantifying the deviation from the fluctuation-dissipation theorem (FDT) and performed complementary analysis on brain segregation and asymmetry. Our results showed opposite reconfigurations of the hierarchical non-equilibrium brain dynamics following each treatment. Additionally, baseline measures effectively distinguished responders from non-responders within each treatment. These findings suggest that the deviation of the FDT may serve as a marker for differentiating the effects of psilocybin and escitalopram in MDD treatment, overall, contributing to the understanding of therapeutic mechanisms of depression.","journal":"bioRxiv","publication_date":"2026-06-15","publication_year":2026,"doi":"10.64898/2026.06.12.731811","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.06.12.731811","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:45","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1253375\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Depression,Brain Imaging,Mechanism of Action,Biomarkers,Aging,Randomized Controlled Trial","study_type":"Randomized Controlled Trial","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3027,"title":"EEG microstate dynamics during psilocybin intoxication relate to acute experience and persisting psychological changes","normalized_title":"eeg microstate dynamics during psilocybin intoxication relate to acute experience and persisting psychological changes","authors":"Jajcay N, Vejmola Č, Korčák J, Tylš F, Viktorinová M, Viktorin V, Bravermanová A, Androvičová R, Balíková M, Horáček J, Brunovský M, Hlinka J, Páleníček T.","abstract":"Psilocybin and other serotonergic psychedelics show therapeutic promise for psychiatric disorders, yet objective neural correlates linking the acute psychedelic state to persisting psychological outcomes remain limited. Electroencephalography (EEG) microstate analysis characterizes the rapid spatiotemporal organization of large-scale brain activity, offering a millisecond-resolution window into neural dynamics. Here, we examined resting-state EEG microstates in 15 healthy volunteers who participated in a double-blind, randomized, placebo-controlled crossover study of psilocybin, using both data-driven (three-microstate) and canonical (four-microstate) analysis solutions. EEG was recorded at five time points spanning pre-drug baseline, peak intoxication, and recovery. Psilocybin significantly increased the number of global field power (GFP) peaks and reduced microstate lifespan while increasing frequency of occurrence during peak intoxication (50-100 min post-administration), consistent with accelerated transitions between brain states. Notably, microstate coverage was largely preserved, with only a transient difference at peak intoxication in the 2-20 Hz band-width, suggesting that access to the repertoire of canonical brain states is broadly maintained despite altered temporal dynamics. Critically, individual differences in microstate dynamics during peak intoxication correlated with both acute subjective experience intensity and self-reported psychological changes measured 28 days post-administration, providing exploratory evidence for a link between acute neural dynamics and longer-term experiential outcomes in healthy volunteers. These findings suggest that psilocybin is associated with altered temporal organization of large-scale brain dynamics with largely preserved microstate coverage, and identify EEG microstates as candidate neural markers for psychedelic-induced alterations in consciousness with potential relevance to therapeutic research.","journal":"bioRxiv","publication_date":"2026-06-11","publication_year":2026,"doi":"10.64898/2026.06.09.731183","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.06.09.731183","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:45","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1251659\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Brain Imaging,Consciousness,Biomarkers,Longevity,Healthy Volunteers","study_type":"Clinical Trial","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":76,"title":"Reorganization of Human Brain Waves Across Diverse States of Consciousness","normalized_title":"reorganization of human brain waves across diverse states of consciousness","authors":"Fotiadis P, Jang H, Dai R, Li D, Cofré R, Timmermann C, Mashour GA, Hudetz AG, Huang Z.","abstract":"Brain waves are ubiquitous phenomena of human brain activity. As they propagate, they coordinate neural communication, shaping conscious perception. Understanding how brain waves unfold across space and time is thus critical for uncovering the neural mechanisms that support and suppress consciousness. Here, we analyzed data from the Human Connectome Project alongside multiple independent human datasets of various states of consciousness collected during non-rapid eye movement sleep, propofol anesthesia, and psychedelic states produced by lysergic acid diethylamide, N,N-dimethyltryptamine, psilocybin, nitrous oxide, and ketamine. We then applied complex principal component analysis to map spatiotemporal propagation patterns of blood oxygen level-dependent activity across the human brain, under these diverse states of consciousness. We identified four dominant motifs of wave propagation: a global synchronized wave supporting unimodal-transmodal propagation, an anti-correlated unimodal-transmodal wave, an anti-correlated task-positive/task-negative wave, and an anti-correlated visual-somatomotor wave. Among them, the global wave exhibited the most pronounced state-dependent reconfiguration: in diminished states (sleep and anesthesia), the time needed for the wave to propagate across brain regions consistently increased and the distribution of regional contributions to the wave's power became more spatially concentrated and heterogeneous across individuals, indicating slower, more fragmented, and less stereotyped dynamics. In contrast, propagation duration decreased under psychedelic states, reflecting accelerated global wave dynamics alongside a trend towards more spatially distributed and uniform regional contributions, consistent with a more integrated global wave propagation pattern. Beyond this global mode, diminished states slowed propagation primarily along the unimodal-transmodal axis, whereas psychedelic states selectively accelerated propagation along the task-positive/task-negative axis. Together, our findings reveal that diminished (sleep and anesthesia) and psychedelic states alter the spatiotemporal structure of wave propagation across the brain in opposite and distinct ways, providing a unifying account of how macroscale brain dynamics are dynamically reshaped under pharmacological and endogenous perturbations of consciousness.","journal":"bioRxiv","publication_date":"2026-05-31","publication_year":2026,"doi":"10.64898/2026.05.27.728182","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.05.27.728182","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:03","raw_json":"{\"europe_pmc_id\":\"PPR1243454\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Mechanism of Action,Consciousness","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3021,"title":"Appetite for change: How psilocybin reshapes food reward learning through striatal dopamine function","normalized_title":"appetite for change how psilocybin reshapes food reward learning through striatal dopamine function","authors":"Conn K, Wong N, Sunnetci S, Al Siyabi A, McCoy K, Huang K, Greaves E, Milton LK, Kuhlmann L, Maguire S, Foldi CJ.","abstract":"Psilocybin has emerged as a promising therapeutic agent for psychiatric disorders characterised by cognitive rigidity and disrupted reward processing, including anorexia nervosa. While its pro-cognitive effects have been mechanistically probed almost exclusively through serotonin receptor subtype antagonism, the downstream contributions of dopaminergic systems to these outcomes remain poorly understood. Here, we examined how psilocybin (1.5 mg/kg) modulates striatal dopamine dynamics and cognitive flexibility across multiple operant paradigms in female rats, and whether nutritional state or prior activity-based anorexia (ABA) exposure moderate these effects. Calorie restriction selectively attenuated psilocybin-enhanced reversal learning, shifting the temporal profile of benefit without abolishing it, and was associated with exacerbated nucleus accumbens (NAc) cFos+ expression relative to ad libitum fed animals. In vivo fiber photometry revealed that psilocybin broadly amplified NAc dopamine transients time-locked to expected and unexpected outcomes during probabilistic reversal learning across 7 days. Computational modelling identified psilocybin-specific increases in learning rate and reductions in prior value weighting, consistent with strengthened feedback-driven updating. In touchscreen paradigms, psilocybin enhanced discrimination accuracy and accelerated reversal learning acquisition when administered prior to initial discrimination, but impaired serial reversal accuracy when administered at a later training stage. ABA exposure constrained psilocybin’s pro-cognitive effects, abolishing discrimination accuracy benefits and trending toward worsened reversal learning, likely reflecting ABA-induced reductions in cortical 5-HT2A receptor availability. These findings provide the first direct evidence that psilocybin modulates striatal dopamine prediction error signalling in a behaving animal and demonstrate that nutritional state and prior ABA exposure critically moderate its cognitive effects.","journal":"bioRxiv","publication_date":"2026-05-17","publication_year":2026,"doi":"10.64898/2026.05.14.725265","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.05.14.725265","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:45","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1209323\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Eating Disorders,Receptor Pharmacology","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3056,"title":"Characterizing Resting-State Brain Dynamics with Frequency-Resolved EEG Microstates: Parallel Analyses of Psilocybin Microdosing and Acute Inhaled DMT","normalized_title":"characterizing resting state brain dynamics with frequency resolved eeg microstates parallel analyses of psilocybin microdosing and acute inhaled dmt","authors":"Tarailis P, Griskova-Bulanova I.","abstract":"Electroencephalographic (EEG) microstates provide a compact framework for characterizing the temporal organization of large-scale brain activity, yet their sensitivity to altered brain states remains insufficiently explored. In this study, we applied broadband and frequency-resolved EEG microstate analysis to resting-state EEG data from two publicly available datasets acquired under markedly different altered-state conditions: psilocybin microdosing and acute inhaled N,N-dimethyltryptamine (DMT). The aim was to determine whether narrowband microstate analysis reveals structured alterations in resting-state brain dynamics beyond those captured by broadband analysis alone. Psilocybin microdosing was associated with relatively subtle effects, including reduced global field power and frequency-specific alterations in delta- and theta-band microstate parameters, while no significant broadband spatiotemporal changes were observed. In contrast, acute inhaled DMT was associated with broader microstate alterations spanning broadband, delta, theta, and alpha activity, indicating more extensive reorganization of temporal microstate expression. Across both datasets, a descriptive overlap was observed in the delta band, where microstate C showed increased duration and microstate D showed decreased occurrence. Given the substantial differences between datasets in dose, route of administration, temporal dynamics, and study context, these overlapping effects should be interpreted cautiously. Overall, the findings support frequency-resolved EEG microstate analysis as a useful approach for characterizing altered resting-state brain dynamics and for detecting frequency-specific effects that may be obscured in broadband summaries.","journal":"bioRxiv","publication_date":"2026-05-07","publication_year":2026,"doi":"10.64898/2026.05.05.723034","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.05.05.723034","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:46","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1211288\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Brain Imaging,Microdosing","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3137,"title":"Distinct Modulatory Effects on Affective Biases by Different Serotonergic Psychedelics and MDMA in Male Rats: Possible Implications for Antidepressant Effects","normalized_title":"distinct modulatory effects on affective biases by different serotonergic psychedelics and mdma in male rats possible implications for antidepressant effects","authors":"Hinchcliffe JK, Bartlett J, Thomas CW, Golden CT, Gilmour G, Bortolotto ZA, Robinson ES.","abstract":"Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.","journal":"bioRxiv","publication_date":"2026-04-21","publication_year":2026,"doi":"10.64898/2026.04.20.719483","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.04.20.719483","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:47","last_checked":"2026-07-01 11:22:01","raw_json":"{\"europe_pmc_id\":\"PPR1213772\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Pharmacology,Mechanism of Action,Receptor Pharmacology,Emotional Processing,Animal Study","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":160,"title":"Structural plasticity and enhanced fear extinction following psilocybin in chronically stressed mice","normalized_title":"structural plasticity and enhanced fear extinction following psilocybin in chronically stressed mice","authors":"Knox CA, Woodburn SC, Gilbert AD, Schlotzhauer JM, Kwan AC.","abstract":"The classic psychedelic psilocybin elicits long-lasting neural plasticity and behavioral effects, but prior studies largely examined stress-naive animals. Using longitudinal imaging, we show that psilocybin increases dendritic spine density in frontal cortical neurons and facilitates fear extinction after chronic restraint stress, demonstrating psilocybin’s effects in a translationally relevant mouse model.","journal":"bioRxiv","publication_date":"2026-04-21","publication_year":2026,"doi":"10.64898/2026.04.21.720014","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.04.21.720014","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1213850\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Neuroplasticity,Brain Imaging,Aging,Animal Study","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":166,"title":"Serotonergic Polypharmacology of 2-Halogenated Tryptamines","normalized_title":"serotonergic polypharmacology of 2 halogenated tryptamines","authors":"Yacoub J, Bray E, Bayyat J, Glatfelter GC, Leake A, Buitrago EM, Maitland AD, Partilla J, Cavalco NG, Schalk SS, Lammers JC, Baumann MH, McCorvy J, Leahy JW, Gulick D, Witowski CG, von Salm JL.","abstract":"Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized 2-halogenated derivatives of DMT and psilacetin to reduce 5-HT2A/5-HT2B activity while retaining engagement of therapeutically relevant targets, particularly 5-HT6, 5-HT2C, and 5-HT1B. This study demonstrated that 2-position halogenation decreased affinities, potencies, and efficacies at 5-HT2A and 5-HT1A receptors while preserving potent 5-HT6 agonism, especially for 2-Br-psilocin. The analogues exhibited reduced affinities at 5-HT2B and hERG ion channels, suggesting safer cardiac valve and cardiotoxic profiles. In C57BL/6J mice, 2-Br-psilacetin did not induce the head-twitch response and attenuated 2,5 dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch behavior, suggesting a reduced potential for inducing psychedelic effects. Behavioral assays further revealed improvements in stress-induced affective measures and hippocampus-independent cued learning at intermediate doses. These findings identify 2-halogenated tryptamines as polypharmacological serotonergic ligands with reduced psychoactivity and cardiac valve and toxic liabilities, supporting their potential as next-generation psychedelic-inspired therapeutics.","journal":"bioRxiv","publication_date":"2026-04-20","publication_year":2026,"doi":"10.64898/2026.04.16.718915","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.04.16.718915","keywords":"","substance_tags":"psilocybin,psilocin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1214370\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Pharmacology,Receptor Pharmacology,Animal Study,Toxicity","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":169,"title":"Psilocybin reshapes cortical inhibition through selective interneuron recruitment","normalized_title":"psilocybin reshapes cortical inhibition through selective interneuron recruitment","authors":"Davoudian PA, Jiang Q, Knox CA, Savalia NK, Shao L, Wilson J, Weiner AM, Chong CW, Liao C, Nothnagel JD, Sakurai T, Kwan AC.","abstract":"Psychedelics show therapeutic potential for treating psychiatric disorders. While studies have emphasized the roles of cortical pyramidal cells, GABAergic neurons also express serotonin receptors and are therefore likely targets of psychedelics. In this study, we determine the effect of psilocybin on the activity dynamics of major GABAergic cell types in the mouse medial frontal cortex. Psilocybin reduces the firing of somatostatin-expressing interneurons, but increases the activity of parvalbumin-expressing interneurons. This cell type-specific response is unlikely to involve vasoactive intestinal peptide-expressing interneurons. Instead, pharmacological blockade and conditional knockout experiments demonstrate that psilocybin acts on the 5-HT1A receptor at SST interneurons, which contributes to the drug's long-term behavioral effects. Collectively, the results reveal that the classic psychedelic psilocybin alters cortical inhibition in a cell type-specific manner.","journal":"bioRxiv","publication_date":"2026-04-16","publication_year":2026,"doi":"10.64898/2026.04.16.718963","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.04.16.718963","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1215011\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Receptor Pharmacology,Animal Study","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3015,"title":"Psilocybin acutely reduces low-frequency BOLD power and frequency-specific connectivity","normalized_title":"psilocybin acutely reduces low frequency bold power and frequency specific connectivity","authors":"Olsen AS, Larsen K, McCulloch DE, Ganz M, Madsen MK, Ozenne B, Knudsen GM, Rehman Nu, Fisher PM.","abstract":"Psilocybin and other serotonergic drugs acutely alter human brain function and large-scale connectivity as measured with BOLD fMRI, but whether these effects are frequency-specific remains unknown. We applied multitaper spectral and cross-spectral analyses to resting-state fMRI data from 28 healthy volunteers scanned multiple times acutely following oral psilocybin administration (0.2 - 0.3 mg/kg), together with plasma psilocin measurements, to estimate psilocin associations with temporal frequency-specific activity and connectivity. Psilocybin produced a selective reduction in low-frequency spectral power (0.01 - 0.06 Hz ) and an increase in spectral entropy, with the strongest effects in transmodal networks. We also observed a reduction in low-frequency connectivity energy explained by the unimodal/transmodal axis. These findings demonstrate that psilocin induces spatially distributed, frequency-dependent alterations, suggesting that broadband fMRI analyses may obscure low-frequency dynamics. Frequency-resolved approaches may offer greater sensitivity for characterizing psychedelic effects on brain activity.","journal":"bioRxiv","publication_date":"2026-04-12","publication_year":2026,"doi":"10.64898/2026.04.09.717379","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.04.09.717379","keywords":"","substance_tags":"psilocybin,psilocin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:45","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1215195\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Brain Imaging,Healthy Volunteers","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":40,"title":"Dissociating the Hallucinogenic and Neuroplastic Effects of Psilocybin","normalized_title":"dissociating the hallucinogenic and neuroplastic effects of psilocybin","authors":"Baker JJ, Kogan E, Ma S, Lu J, Zuo Y.","abstract":"It is unclear how serotonin 2A receptors (5-HT2A Rs) in cortical layer 5 pyramidal neurons (L5 PyrNs) differentially contribute to psilocybin-induced hallucinations versus neuroplasticity. Here we show that psilocybin promotes synapse formation and maturation while accelerating the elimination of pre-existing synapses. Cell type-specific manipulation further demonstrated that 5-HT2A R signaling in L5 PyrNs is necessary and sufficient for psilocybin-induced synaptic remodeling but dispensable for the head-twitch response, a rodent proxy of hallucination.","journal":"bioRxiv","publication_date":"2026-04-08","publication_year":2026,"doi":"10.64898/2026.04.06.716778","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.04.06.716778","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1215700\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Neuroplasticity,Mechanism of Action,Receptor Pharmacology","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":212,"title":"Psilocybin Attenuates Cortical Representations of Aversion in the Mouse Auditory Cortex","normalized_title":"psilocybin attenuates cortical representations of aversion in the mouse auditory cortex","authors":"Johnson JD, Tian R, Etemadi Y, Li Z.","abstract":"Psilocybin can produce sustained benefits in affective and trauma-related disorders, yet if and how it reshapes sensory representations of learned valence associations remains largely unclear. To address this, we used longitudinal two-photon calcium imaging in awake C57BL/6 mice to examine how psilocybin modulates layer 2/3 auditory cortex activity at single-cell and population levels. Evoked responses were measured for tones with or without prior associations with valenced stimuli, as well as for the valenced stimuli themselves. Most responsive neurons were selective for tones alone, while distinct subsets responded exclusively to reward or aversive stimuli, and a smaller population encoded both. Psilocybin selectively reduced responses to aversive stimuli and earlier-established aversive-associated tones, without affecting aversive association, reward responses, or responses to newly aversive-associated tones. At the population level, psilocybin acutely increased coordination across tone-responsive neurons, while later reducing it selectively among neurons encoding the aversive-associated tone. These results demonstrate that psilocybin preferentially dampens well consolidated aversive sensory representations in auditory cortex, rather than fresh associations, without broadly affecting auditory processing or new aversive learning.","journal":"bioRxiv","publication_date":"2026-03-26","publication_year":2026,"doi":"10.64898/2026.03.26.714498","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.03.26.714498","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1217790\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Brain Imaging,Aging,Animal Study","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":219,"title":"Integrated 5-HT2A -TrkB and G protein signaling in serotonergic psychedelic responses","normalized_title":"integrated 5 ht2a trkb and g protein signaling in serotonergic psychedelic responses","authors":"Taddei-Tardón M, Medina-Rodríguez L, Maltman JL, Hudson S, Potukanuma S, Jiménez JH, Martín-Guerrero SM, González-Maeso J, López-Giménez JF.","abstract":"Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT2A receptor silencing selectively impaired serotonergic psychedelic-induced plasticity and altered TrkB-dependent responses. Most serotonergic compounds also increased synaptogenesis and induced c-Fos and Egr-2 expression, although ligand-specific differences were evident, particularly for psilocin and the phenethylamines DOI and Ariadne. Uncoupling of G q/11 or G i/o protein-dependent signaling differentially modified neuroplastic and transcriptional responses, indicating a ligand and endpoint dependent contribution of both pathways. Serotonergic psychedelics further induced a 5-HT2A receptor dependent lactate response that was generally sensitive to disruption of either G q/11 or G i/o protein coupling. Taken together, these findings support a model in which serotonergic psychedelics recruit an integrated 5-HT2A -TrkB signaling network with distinct structural, transcriptional and metabolic outputs, and establish this neural stem cell-derived system as a valuable platform for screening and dissecting the signaling basis of psychedelic action.","journal":"bioRxiv","publication_date":"2026-03-22","publication_year":2026,"doi":"10.64898/2026.03.19.712961","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.03.19.712961","keywords":"","substance_tags":"psilocin","source_name":"bioRxiv","date_added":"2026-06-30 22:38:07","last_checked":"2026-07-01 11:22:02","raw_json":"{\"europe_pmc_id\":\"PPR1218591\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Neuroplasticity,Pharmacology,Mechanism of Action,Receptor Pharmacology,In Vitro Study","study_type":"In Vitro Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3028,"title":"Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response","normalized_title":"enhancing cgmp signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response","authors":"Floris G, Jefferson SJ, Rondeau J, Yu AL, Menniti FS, Kwan AC, De Aquino JP, Krystal JH, Pittenger C, Kaye AP.","abstract":"Psilocybin has antidepressant effects, but its 5-HT2 AR-mediated perceptual effects limit tolerability. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) and observed suppression of head-twitch response, but maintenance of antidepressant-like behavior. Proteomics showed that PDE9i-psilocybin reduced 5-HT2 AR-mediated pathways while enhancing synaptogenesis. These results suggest that PDE9i-psilocybin represents a promising therapeutic strategy.","journal":"bioRxiv","publication_date":"2026-03-09","publication_year":2026,"doi":"10.64898/2026.03.06.710108","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.03.06.710108","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:46","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1214698\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Neuroplasticity,Mechanism of Action,Receptor Pharmacology,Safety,Proteomics","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3016,"title":"Inhibition of cortico-amygdala projections underlies affective bias modification by psilocybin","normalized_title":"inhibition of cortico amygdala projections underlies affective bias modification by psilocybin","authors":"Claydon MDB, Hinchcliffe JK, Bartlett J, Golden CT, Thomas CW, Gilmour G, Mellor JR, Bortolotto ZA, Robinson ESJ.","abstract":"Psilocybin, a serotonergic psychedelic, can produce rapid and enduring antidepressant effects in patients with major depressive disorder (MDD)[1, 2], yet the neural mechanisms underlying these effects remain unclear. Negative affective biases are an important neuropsychological mechanism central to the development and perpetuation of MDD[3]. Using a translational rodent model, we previously demonstrated that psilocybin modulates negative affective biases which, we hypothesize, contribute to its antidepressant effects[4]. Here, we identify the prelimbic subregion (PrL) of the rat medial prefrontal cortex (mPFC) as a key locus for the modulation of affective biases by psilocin, the active metabolite of psilocybin, and reveal a cell-type-specific bidirectional regulation of synaptic transmission. Psilocin selectively suppressed excitatory synaptic input to cortico-amygdala (CA) projection neurons, but enhanced excitatory transmission to other, putatively cortico-cortical, targets. Interestingly, suppression of the excitatory input to CA cells by psilocin, and modulation of affective biases by psilocybin, were both dependent on 5HT 1A and 5HT 2A receptor signaling. Consistent with the long-term therapeutic effects of rapidly acting antidepressants[1, 2, 4, 5], psilocin produced sustained changes to affective biases evident 24 hours after PrL infusion. In parallel, the suppressed excitatory transmission shifted to enhanced inhibitory synaptic input selectively in CA cells. Finally, chemogenetic inhibition of CA neurons in PrL recapitulated both the acute and sustained modulation of negative affective biases by psilocybin, as well as positively biasing new reward memories. Together, these findings identify modulation of the PrL cortico-amygdala circuit as a key substrate for affective bias modification by psilocybin, an effect which could explain its rapid and sustained antidepressant actions.","journal":"bioRxiv","publication_date":"2026-03-03","publication_year":2026,"doi":"10.64898/2026.03.02.709133","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.03.02.709133","keywords":"","substance_tags":"psilocybin,psilocin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:45","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1221362\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Depression,Neuroplasticity,Mechanism of Action,Receptor Pharmacology,Animal Study","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3038,"title":"Psilocybin rapidly, but not immediately, reverses reward learning deficits in a durable manner in an inflammatory rat model of depressive symptoms","normalized_title":"psilocybin rapidly but not immediately reverses reward learning deficits in a durable manner in an inflammatory rat model of depressive symptoms","authors":"Hinchcliffe JK, Thomas CW, Gilmour G, Robinson ES.","abstract":"The serotonergic psychedelic, psilocybin, shows potential for rapid and sustained antidepressant effects but the underlying mechanisms remain unknown. Using a chronic interferon-alpha-induced rat model of depression, we show acute psilocybin (0.3 mg/kg) reverses impaired reward-induced biases within 24hrs, with effects enduring for at least 7 days. This suggests psilocybin can restore blunted reward processing, an effect which could significantly contribute to its sustained antidepressant effects.","journal":"bioRxiv","publication_date":"2026-01-14","publication_year":2026,"doi":"10.64898/2026.01.14.699553","pubmed_id":null,"source_url":"https://doi.org/10.64898/2026.01.14.699553","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:46","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1226195\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Depression,Mechanism of Action,Animal Study,Inflammation","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3068,"title":"The one that abstained: Psilocybe fuscofulva genome suggests two recent origins of the psilocybin gene cluster in Psilocybe","normalized_title":"the one that abstained psilocybe fuscofulva genome suggests two recent origins of the psilocybin gene cluster in psilocybe","authors":"Slot J, Bradshaw A, Dentinger B, Borovička J, Konkel Z, Rockefeller A, Bollinger I.","abstract":"Production of the psychoactive compound psilocybin is a defining feature of the genus Psilocybe, commonly referred to as “psychedelic mushrooms”. However, Psilocybe fuscofulva is a striking exception within Psilocybe sensu stricto as it lacks the stereotypical blue bruising characteristic of the genus, and psilocybin has not been detected in the species.To investigate the evolutionary events leading to differential psilocybin production among Psilocybe species, we produced genome assemblies two P. fuscofulva strains, one Psilocybe polytrichoides strain, and one Psilocybe tampanensis strain, complemented by reannotated public genomes and metagenome-derived assemblies from fungarium specimens. This sample represents both major Psilocybe clades (Clade I and Clade II) and the most closely related genera. Phylogenomic analysis based on 100 single-copy orthologs curated for high branch support strongly placed P. fuscofulva as the earliest-diverging lineage in Psilocybe Clade I. No psilocybin gene cluster (PGC) homologs, whether clustered or dispersed, were identified in P. fuscofulva, whereas a single intact PGC was present in all other examined Psilocybe genomes. The PGC resides in two distinct, clade-specific genomic loci: one conserved in Clade I and another in Clade II, each displaying characteristic gene orders and orientations consistent with rearrangement through circular intermediates. Time-calibrated phylogenies estimated the Psilocybe crown group at approximately 28 million years ago, with major clade divergences occurring in the Miocene. The absence of the PGC in P. fuscofulva, together with clade-specific structural conservation and the lack of remnant sequences at alternate loci, supports two independent origins of the PGC within Psilocybe: one in the ancestor of Clade II and a subsequent origin in Clade I following divergence from P. fuscofulva, most likely via horizontal gene transfer (HGT). Gene phylogenies provide weak support for transfer from Clade I to Clade II, although broader sampling is required for confirmation. These results constrain the timeframe of PGC emergence and dispersal to the Miocene, implying rapid HGT events possibly driven by ecological pressures in expanding grassland ecosystems. This study challenges the assumption of an ancestral psilocybin pathway in Psilocybe and its close relatives and underscores multiple recent acquisitions of the PGC that suggest it is an ecologically important metabolic trait in psychoactive fungi.","journal":"bioRxiv","publication_date":"2026-01-01","publication_year":2026,"doi":"10.64898/2025.12.30.697041","pubmed_id":null,"source_url":"https://doi.org/10.64898/2025.12.30.697041","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:46","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1229316\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Mechanism of Action,Genomics","study_type":"Other","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3043,"title":"Psilocybin decreases reward-seeking behavior accompanied by increased activity of parvalbumin neurons with perineuronal nets in the medial prefrontal cortex","normalized_title":"psilocybin decreases reward seeking behavior accompanied by increased activity of parvalbumin neurons with perineuronal nets in the medial prefrontal cortex","authors":"Houff J, Williams A, Allen O, Gisabella B, Pantazopoulos H, Del Arco A.","abstract":"ABSTRACT Clinical trials suggest that a single dose of psilocybin is an effective treatment for substance use disorders (SUDs). Choice impulsivity is a value-based decision-making bias that predicts drug-intake escalation and is commonly associated with SUDs. The dorsomedial prefrontal cortex (dmPFC) regulates choice impulsivity and is enriched with 5-HT2A receptors that mediate effects of psilocybin. We hypothesized that psilocybin has long-term (≥48 hours) effects on choice impulsivity in association with dmPFC inhibitory interneurons with perineuronal nets (PNNs). Male Long Evans rats were trained in a delay discounting task (DDT) where rats chose between delayed large rewards (LR) and immediate small rewards (SR). 48 hours after psilocybin or vehicle injections, DDT was assessed, and rats’ brains processed for microscopy analysis of extracellular matrix (PNNs) together with inhibitory parvalbumin (PV) interneurons and c-fos as a marker of neuronal activity. Psilocybin acutely increased head-twitch responses. Psilocybin decreased LR choices and increased the latency to LR choices 48 hours after administration. These effects were independent of delay and therefore not consistent with changes in impulsivity. Psilocybin also increased the density of PNN+PV+cFos triple-labeled neurons in the dmPFC. These results suggest that psilocybin decreases reward seeking through the increased activation of dmPFC PV interneurons with PNNs.","journal":"bioRxiv","publication_date":"2025-12-25","publication_year":2025,"doi":"10.64898/2025.12.22.696123","pubmed_id":null,"source_url":"https://doi.org/10.64898/2025.12.22.696123","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:46","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1230007\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Addiction,Receptor Pharmacology,Biomarkers,Clinical Trial","study_type":"Clinical Trial","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"},{"id":3052,"title":"Psilocybin modulates social behaviour in male and female mice in a time-dependent manner","normalized_title":"psilocybin modulates social behaviour in male and female mice in a time dependent manner","authors":"Shadani S, McCoy K, Ong L, Greaves E, Conn K, Andrews ZB, Foldi CJ.","abstract":"With the resurgence of psychedelic research and the growing interest in their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable (SABV) on the prosocial effects of psychedelics remains poorly understood. Indeed, enhanced connectedness, sociability and empathy are common outcomes of psychedelic use and these have shaped human social structures for millennia. Here, we investigated the sex-specific effects of a single dose of psilocybin (1.5 mg/kg) in C57BL/6J mice on various aspects of social behaviours. We show an intriguing connection between huddling behaviour and body temperature acutely elicited by psilocybin that was restricted to females. We also observe temporally distinct patterns of social behaviour alterations in female mice, whereby enhanced preference for social novelty was observed after acute effects subsided (4 h post-administration), which was maintained for ∼24 h. Longer-term, the impact of psilocybin was reversed and promoted preference for familiar over novel conspecifics when assessed 7d post-administration, which was associated with prolonged nucleus accumbens dopamine signalling during familiar sniffing. In males, psilocybin reduced stress-related behaviours at 24 h and increased preference for familiar conspecifics, along with blunted novelty-evoked dopamine responses at both 24 h and 7 days post-treatment. Both 5-HT1A and 5-HT2A receptors were involved in modulating these behaviours, though in sex-specific ways. These findings highlight that the prosocial effects of psychedelics are not universal and emphasize the importance of sex-informed approaches in both preclinical research and clinical application. Graphical Abstract","journal":"bioRxiv","publication_date":"2025-12-21","publication_year":2025,"doi":"10.64898/2025.12.18.695064","pubmed_id":null,"source_url":"https://doi.org/10.64898/2025.12.18.695064","keywords":"","substance_tags":"psilocybin","source_name":"bioRxiv","date_added":"2026-07-01 11:03:46","last_checked":"2026-07-01 11:22:00","raw_json":"{\"europe_pmc_id\":\"PPR1229283\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}","topic_tags":"Depression,Anxiety,Eating Disorders,Receptor Pharmacology,Animal Study","study_type":"Animal Study","hidden":0,"false_positive":0,"curation_notes":null,"merged_into_id":null,"curation_locked":0,"publication_status":"preprint"}],"total":142,"page":1,"per_page":20,"pages":8,"resource":"papers","filters":{"q":null,"author":null,"substances":["psilocybin","psilocin"],"topic":null,"study_type":null,"sources":[],"publication_statuses":[],"year":null,"journal":"bioRxiv","from":null,"to":null,"sort":"newest","page":1,"per_page":"20"}}