{ "meta": { "tracker_site_url": "https://psilocybin-research.com", "publication_tracker_url": "https://psilocybin-research.com/", "generated_at_utc": "2026-07-02 19:51:05", "record_count": 125 }, "papers": [ { "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 06:56:32", "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" }, { "id": 3036, "title": "A Naturalistic Study on the Combined Neural and Psychological Effects of Psilocybin and Compassion Focused Imagery", "normalized_title": "a naturalistic study on the combined neural and psychological effects of psilocybin and compassion focused imagery", "authors": "Pallavicini C, Llobenes L, Cavanna F, de la Fuente LA, Muller S, Costa M, Gumiy N, Bruno N, D’Amelio T, Basran J, Plowright P, Stolkiner A, Namías M, Gilbert P, Tagliazucchi E.", "abstract": "Psilocybin is a classic psychedelic drug known to alter subjective experience and elicit long-term psychological changes, enhancing cognitive flexibility and reducing rigid self-related beliefs. Combined with compassion motivational primes that involve generating mental representations of compassion, it may increase the potential for activating the care-affiliative motivational systems, linked to several important biopsychosocial processes underpinning social safeness, social connection and mental wellbeing. We investigated the synergetic effects of psilocybin and compassion imagery with self-reported questionnaires and functional resonance imaging data (fMRI) in a sample of 105 participants. Participants were primed with either attention to breathing or a short compassion focused imagery prime. We found a long-term synergetic effect of compassion imagery and psilocybin on cognitive absorption, as well as changes relative to baseline self-compassion and decentering. Based on functional interactions between attentional, executive and default mode networks, fMRI-based classifiers detected participant engagement in compassion focused imagery before psilocybin intake and distinguished compassion imagery vs. attention to breathing priming only the high dose of psilocybin. Our results support the potential for synergistic effects from combinations of psilocybin and compassion-based interventions to induce long-term psychological changes, reshaping the functional organization of large-scale brain networks. Future confirmatory studies of our exploratory analyses should be conducted to determine whether the combination of psilocybin and compassion-based practices promotes increases in caring and contemplative abilities, enhanced psychological flexibility and well-being.", "journal": "bioRxiv", "publication_date": "2025-12-21", "publication_year": 2025, "doi": "10.64898/2025.12.17.694940", "pubmed_id": null, "source_url": "https://doi.org/10.64898/2025.12.17.694940", "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\":\"PPR1230558\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Default Mode Network,Aging,Wellbeing,Psychological Flexibility,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3044, "title": "Wherefore the magic? The evolutionary role of psilocybin in nature", "normalized_title": "wherefore the magic the evolutionary role of psilocybin in nature", "authors": "Matthews Nicholass K, Flis I, Hanley M, Knight M, Lane S, Littlejohn G, Thom M, Billington R, Boden R, Cummins R, Green B, Griffin C, Jones S, Salmon D, Sleep I, Smirnoff N, Ellis J.", "abstract": "Research into psychedelic compounds is in resurgence due to the exciting potential for their use in the treatment of psychiatric and mental health disorders. Despite this revival, remarkably little is known about their evolution. One of the most intriguing psychedelic compounds is psilocybin, the compound found in ‘magic’ mushrooms and used in ritual ceremonies in Central America for generations. Associated with agaricomycete fungi of the genus Psilocybe, psilocybin acts in a similar way to the neurotransmitter serotonin, yet how and why natural selection favoured its biosynthesis remains unclear. Given the resemblance to serotonin, modulation of invertebrate behaviour for defence is a likely explanation, but neither this nor alternative hypotheses have ever been formally tested. Here, we show that Drosophila larvae exposed to extracts from Psilocybe mushrooms exhibit reduced survival, pupation rates, and inhibited locomotion. Adults exposed during development show reduced thorax and wing size, along with increased fluctuating asymmetry, indicating developmental stress. Conversely, mutants lacking 5HT2A receptors showed the same response to Psilocybe extracts as wild-type flies. Furthermore, DNA metabarcoding revealed that while Psilocybe semilanceata demonstrates a distinct invertebrate community compared to most other grassland fungi, it overlapped with the non-psychedelic species Mycena epipterygia. This study provides a crucial first step toward understanding the evolutionary role of psilocybin-producing fungi and provides a grounding for future research into the molecular mechanisms, ecological interactions and evolutionary origins of psychedelic compounds in nature.", "journal": "bioRxiv", "publication_date": "2025-12-18", "publication_year": 2025, "doi": "10.64898/2025.12.17.694186", "pubmed_id": null, "source_url": "https://doi.org/10.64898/2025.12.17.694186", "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\":\"PPR1230910\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Mechanism of Action,Receptor Pharmacology,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3018, "title": "Unmixing the Psychedelic Connectome: Brain Network Traits of Psilocybin", "normalized_title": "unmixing the psychedelic connectome brain network traits of psilocybin", "authors": "Bhavaraju KP, Mason NL, Mallaroni P, Heinke D, Toennes SW, Ramaekers JG, Amico E.", "abstract": "Psilocybin induces profound alterations in consciousness, yet prevailing neural models often describe a monolithic change in brain connectivity that may not fully capture the multifaceted nature of the psychedelic state. To test the hypothesis of a composite neural state, this study applied a robust, data-driven framework, Connectome Independent Component Analysis (connICA) with multi-level resampling, to resting-state fMRI data from healthy volunteers. The analysis decomposed connectomes into statistically independent functional connectivity traits (\"FC-Traits\"), revealing a primary trait whose expression was significantly modulated by plasma psilocin concentration, providing a whole-cortical signature of the drug’s physiological action. Crucially, a second, distinct trait was also isolated, which independently associated with impaired performance on a visual divergent thinking task. These findings demonstrate that the acute psilocybin state is a composite of co-occurring neural processes. This validates the application of a decompositional connectomic framework to move beyond global descriptions and successfully disentangle the specific neural patterns underlying distinct pharmacological and cognitive correlates.", "journal": "bioRxiv", "publication_date": "2025-11-16", "publication_year": 2025, "doi": "10.1101/2025.11.17.688834", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.11.17.688834", "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\":\"PPR1121312\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Consciousness,Healthy Volunteers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3033, "title": "Ketamine and Psilocybin Differentially Impact Sensory Learning During the Mismatch Negativity", "normalized_title": "ketamine and psilocybin differentially impact sensory learning during the mismatch negativity", "authors": "Allohverdi SG, Soltanzadeh M, Schmidt A, Charlton CE, Hauke DJ, Karvelis P, Vollenweider FX, Diaconescu AO.", "abstract": "Ketamine and psilocybin show potential as therapies for various mental illnesses, including major depressive disorder. However, further investigation into their neural mechanisms is required to understand their effects on the brain. By combining computational modelling with electroencephalography (EEG), we examine the effects of ketamine and psilocybin on hierarchical sensory pwPE learning in the context of the auditory mismatch negativity, an event-related potential consistently shown to be reduced under psychotomimetic interventions. We employed a Bayesian framework and re-analyzed a previously acquired EEG dataset (Schmidt et al., 2012) by modelling single-trial EEG data using the Hierarchical Gaussian Filter. Using a placebo-controlled within-subject crossover design, healthy subjects were administered either S-ketamine or psilocybin during an auditory roving paradigm of pure sinusoidal tones. Our findings elucidate distinct neural impacts of ketamine and psilocybin on sensory learning: ketamine led to a larger reduction in the effect of sensory precision compared to placebo from 207 to 316 ms peaking at 277 ms in the frontal central channels, while psilocybin showed no significant effect. Both drugs reduced the expression of belief precision between 160 to 184 ms, peaking at 172 ms. For higher-level volatility pwPEs, ketamine reduced the expression at 312 ms while psilocybin had a null effect. For perception of elementary imagery, ketamine had a greater effect than psilocybin on sensory and volatility precision, while psilocybin had a greater effect on volatility pwPEs. Our findings suggest hallucinogens have distinct effects on sensory learning that could inform tailored therapies for major depression.", "journal": "bioRxiv", "publication_date": "2025-11-06", "publication_year": 2025, "doi": "10.1101/2025.11.06.687023", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.11.06.687023", "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\":\"PPR1116082\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Brain Imaging,Mechanism of Action", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3281, "title": "Simulated 5-HT2A receptor activation accounts for the high complexity of brain activity during psychedelic states", "normalized_title": "simulated 5 ht2a receptor activation accounts for the high complexity of brain activity during psychedelic states", "authors": "Martin HM, Cofre R, Destexhe A.", "abstract": "Serotonergic psychedelics, such as LSD, psilocybin, and DMT, have strong effects on human brain activity, yet their mechanisms of action at the whole-brain level are only partially understood. Here, we present a biophysically-based mean-field model that integrates cellular and network-level details to simulate the effects of these compounds at different spatial scales. By incorporating the brain-wide distribution of 5-HT2A receptors, our model mechanistically links receptor activation to a reduction in leak membrane potassium conductance, consistent with electrophysiological data. Our simulations reveal that this microscopic perturbation leads to the emergence of a brain state characterized by asynchronous and irregular dynamics with increased firing rates, as well as significant alterations in spectral power. Specifically, we find a robust decrease in power within the delta, theta, and alpha frequency bands, a result consistent with empirical findings. This change in dynamics is accompanied by an increase in spontaneous complexity, as quantified by the Lempel-Ziv complexity index, as observed experimentally. Furthermore, our model accurately replicates experimental findings regarding the Perturbational Complexity Index (PCI), demonstrating that PCI does not increase significantly by psychedelic drug administration. This crucial dissociation, where spontaneous complexity and spectral power are increased while perturbational complexity is preserved, highlights the distinct neurophysiological substrates underlying different metrics in psychedelic states. Our multiscale model provides a robust, mechanistic framework for understanding how serotoninergic psychedelics modulate global brain activity, offering new insights consistent with empirical neuroimaging and electrophysiological data.", "journal": "bioRxiv", "publication_date": "2025-10-19", "publication_year": 2025, "doi": "10.1101/2025.10.20.683366", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.10.20.683366", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:49", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR1104450\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Mechanism of Action,Receptor Pharmacology,Aging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3057, "title": "Psilocybin exerts differential effects on social behaviour and inflammation in mice in contexts of activity-based anorexia (ABA)", "normalized_title": "psilocybin exerts differential effects on social behaviour and inflammation in mice in contexts of activity based anorexia aba", "authors": "Shadani S, Greaves E, Andrews ZB, Foldi CJ.", "abstract": "Psychedelics, particularly psilocybin, have shown therapeutic potential across several psychiatric conditions, including depression, anxiety, obsessive-compulsive disorder, and anorexia nervosa (AN). These disorders often share social deficits that may be effectively alleviated by psychedelics considering their use has been linked with emotional empathy and enhanced social cognition. However, the mechanisms through which psychedelics alter social behaviour are unclear, and mechanistic studies in animal models have largely focused on male subjects. This is problematic for understanding the therapeutic effects relevant for disorders that predominantly affect females, such as AN. Here, we used the activity-based anorexia (ABA) mouse model to examine the effects of a single psilocybin dose on social behaviour in female mice and compared outcomes to mice exposed to food restriction (FR), exercise (RW) or standard housing (Controls). Together with these metabolic stressors, we also investigated the effects of psilocybin on the circulating proinflammatory cytokine interleukin-6 (IL-6), which is implicated in AN and is suppressed by psychedelics. Psilocybin did not alter sociability in ABA, RW, or FR mice but increased preference for familiarity in Controls. Novelty-seeking behaviour was elevated in both ABA and RW groups, although with distinct social patterns. Psilocybin elevated IL-6 levels in RW mice, which was positively correlated with preference for novelty. No such relationships were found in ABA or FR groups. These findings reveal subtle, context-dependent effects of psilocybin on social behaviour and inflammation in female mice, highlighting the need to clarify its temporal, neuroplastic, and immune-related mechanisms across sexes and disease models.", "journal": "bioRxiv", "publication_date": "2025-10-14", "publication_year": 2025, "doi": "10.1101/2025.10.14.682467", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.10.14.682467", "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\":\"PPR1102183\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,OCD,Eating Disorders,Mechanism of Action,Emotional Processing,Animal Study,Inflammation,Immune Function", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 474, "title": "Intravenous Administration of Serotonergic Psychedelics Produce Short-lasting Changes in Sleep-Wake Behavior and High Gamma Functional Connectivity in Rats", "normalized_title": "intravenous administration of serotonergic psychedelics produce short lasting changes in sleep wake behavior and high gamma functional connectivity in rats", "authors": "Kolbman N, Huels ER, Nelson A, Summerfield R, Byraju K, Groenhout T, Liu T, Hudetz AG, Vanini G, Pal D.", "abstract": "Background and Purpose Given the increase in recreational psychedelic use and ongoing efforts to explore psychedelics as therapeutic agents for mental health disorders, there is an urgent need to understand the effect of psychedelics such as psilocybin and N,N-dimethyltryptamine (DMT) on sleep-wake states, which share a bidirectional relationship with mental health. Here, we investigated the effects of intravenous psilocybin and DMT on sleep-wake states and EEG spectral power and functional connectivity in rats. Experimental Approach Sprague Dawley rats (n=25, 13 male) were surgically instrumented to record high-density EEG (27 electrodes) and EMG during 12-h light and 12-h dark cycle after intravenous psilocybin (2.5 mg/kg, 10 mg/kg), DMT (3.75 mg/kg, 7.5 mg/kg) or 0.9% saline. The EEG/EMG data were scored in 4-second epochs into wake, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. EEG spectral power and corticocortical coherence, a surrogate for functional connectivity, were computed in 12-second epochs. Key Results Psilocybin and DMT delayed the onset of SWS and REM sleep, and caused a short-lasting increase in wakefulness and decrease in SWS. Psilocybin also produced a 1) decrease in REM sleep, 2) decrease in theta power and coherence and increase in high gamma power and coherence during wake and SWS, and 3) increase in high gamma coherence during REM sleep. DMT increased gamma coherence only during wakefulness. Conclusions and Implications Serotonergic psychedelics have minimal effects on sleep-wake states. The enhanced high gamma functional connectivity suggests that the psychedelic-induced changes in EEG/neural dynamics can occur independent of the arousal states.", "journal": "bioRxiv", "publication_date": "2025-10-13", "publication_year": 2025, "doi": "10.1101/2025.10.12.681880", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.10.12.681880", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR1100688\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3250, "title": "Gestational LSD exposure in mouse rapidly reaches embryonic CSF and is associated with altered choroid plexus signaling, cerebral cortical development, and offspring behavior", "normalized_title": "gestational lsd exposure in mouse rapidly reaches embryonic csf and is associated with altered choroid plexus signaling cerebral cortical development and offspring behavior", "authors": "Courtney Y, Anderson JM, Lagares-Linares C, Wenthur CJ, Lehtinen MK.", "abstract": "Abstract Classic serotonergic psychedelics engage 5-HT receptors throughout the nervous system, but how maternal exposure intersects with embryonic brain interfaces is poorly defined. Here we tested in mice whether maternally administered lysergic acid diethylamide (LSD) accesses embryonic cerebrospinal fluid (CSF) and whether embryonic choroid plexus (ChP) - a CSF-secreting epithelium enriched for Htr2c - mounts an acute response. Following a single maternal injection (0.3 mg kg⁻¹, subcutaneous), LSD was detectable in embryonic CSF within 5-15 minutes at E12.5 and E16.5. Thirty minutes after maternal dosing, LSD induced Fos in embryonic ChP across ventricles and was accompanied by rapid apical remodeling and increased embryonic CSF protein. In parallel cohorts, psilocybin, 5-MeO-DMT, and the 5-HT₂C agonist WAY-161503 elicited a similar Fos response in ChP. Prenatal LSD exposure during mid-gestation was associated with altered S1 cortical cellularity and projection-neuron subtype marker composition at P8; regimen-dependent effects included male-biased changes in SATB2⁺ and CTIP2⁺ populations after repeated exposure. In adulthood, offspring exhibited modest, male-predominant reductions in prepulse inhibition and increased rotational stereotypy. Together, these data identify embryonic CSF as a rapidly accessible compartment for maternal LSD and support a model in which serotonergic agonists can acutely engage ChP epithelium during cerebral cortical development. Significance Psychedelic use during pregnancy is increasing, but the speed and extent to which these drugs access the embryonic CNS remain unknown. We show that a single maternal dose of LSD appears in mouse embryonic cerebrospinal fluid within five minutes and provokes an immediate response in the choroid plexus, a serotonin receptor-rich epithelium that regulates CSF composition. Psilocybin, 5-MeO-DMT, and a selective 5-HT₂C agonist trigger a similar response. Mid-gestational exposure alters cortical neuron composition in neonates and produces persistent behavioral abnormalities in adult offspring, including stereotypies evident from weaning. These data reveal that maternal serotonergic agonists rapidly access embryonic CSF, acutely activate choroid plexus epithelium, and are associated with lasting changes in cortical composition and offspring behavior.", "journal": "bioRxiv", "publication_date": "2025-09-30", "publication_year": 2025, "doi": "10.1101/2025.09.30.677638", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.09.30.677638", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:49", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR1094348\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Mechanism of Action,Receptor Pharmacology,Biomarkers,Observational Study,Animal Study", "study_type": "Observational Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3199, "title": "Psychedelics Relax Priors and Reshape Orbitofrontal Dynamics", "normalized_title": "psychedelics relax priors and reshape orbitofrontal dynamics", "authors": "Delgado-Sallent C, Ahmed SA, Khawaja-Lopez A, Lee BS, Senne R, Scott BB, Ramirez S.", "abstract": "Psychedelics such as psilocybin and ketamine are gaining attention as rapid-acting treatments for psychiatric disorders, yet the mechanisms by which they alter cognition remain unclear. A key hypothesis-the REBUS model-proposes that psychedelics relax high-level priors, allowing bottom-up sensory information to exert greater influence over perception and behavior. Here, we test this model in mice performing a free-response perceptual decision-making task that disambiguates prior-driven and sensory-driven decision strategies. Acute administration of psilocybin or ketamine significantly slowed decision times and improved accuracy. Behavioral modeling that combined drift diffusion and GLM-HMM frameworks revealed that these changes were mediated by increased decision thresholds and a marked shift into sensory-engaged cognitive states. Whole-brain c-Fos mapping identified a distributed decision-making network, with psychedelics selectively modulating cortical and subcortical nodes. Calcium imaging in the orbitofrontal cortex (OFC)-a key region for integrating priors and sensory inputs-revealed preserved decision-related selectivity under psychedelics, while exhibiting reduced neuronal correlations-population-level signatures of weakened top-down influence and relaxed priors. Together, these results provide circuit-level support for the REBUS model, showing that psychedelics reconfigure brain-wide and local dynamics to promote more deliberate, flexible, and sensory-driven decision policies.", "journal": "bioRxiv", "publication_date": "2025-09-18", "publication_year": 2025, "doi": "10.1101/2025.09.18.677110", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.09.18.677110", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR1088289\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Mechanism of Action,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": 3053, "title": "Psilocybin ameliorates neuropathic pain-like behaviour in mice and facilitates gabapentin-mediated analgesia", "normalized_title": "psilocybin ameliorates neuropathic pain like behaviour in mice and facilitates gabapentin mediated analgesia", "authors": "Askey T, Allen-Ross D, Luzyanin D, Lasrado R, Gilmour G, Hunt SP, Tamagnini F, Ahmed M, Stephens GJ, Maiarú M.", "abstract": "Chronic pain states are challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin can produce a sustained anti-nociceptive effect in a model of chronic neuropathic pain in male and female mice. Psilocybin anti-nociceptive effects were mediated by 5-HT2A receptors, although additional mechanisms might also be involved. Furthermore, a single dose of psilocybin caused a significant increase in the anti-nociceptive potential of gabapentin, a widely used treatment for neuropathic pain consistent with the establishment of longer lasting changes in network processing. Overall, these findings present the first preclinical evidence that psilocybin could be a valuable approach for treating chronic pain from nerve injury and serve as a new therapeutic addition for pain management.", "journal": "bioRxiv", "publication_date": "2025-09-16", "publication_year": 2025, "doi": "10.1101/2025.09.15.676273", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.09.15.676273", "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\":\"PPR1085617\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Chronic Pain,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": 3163, "title": "Effective connectivity of the human claustrum: Triple networks, subcortical circuits, and psychedelic modulation", "normalized_title": "effective connectivity of the human claustrum triple networks subcortical circuits and psychedelic modulation", "authors": "Masjedi NS, Razi A.", "abstract": "Decades of cross-species research highlight the claustrums extensive bidirectional connectivity with cortical and subcortical regions, implicating it in higher-order cognitive processes requiring synchronized brain states. Psychedelics may disrupt this synchrony by modulating claustro-cortical signaling, reflected by the dissolution of cortical network signatures. Using spectral dynamic causal modeling on resting-state fMRI data from the Human Connectome Project and PsiConnect datasets at 7T and 3T, we provide the first in vivo characterization of claustral effective connectivity with triple networks and subcortical regions in humans, both at rest and under the influence of psilocybin. Claustra displayed widespread bidirectional effective connectivity and a strong inhibitory influence on all target regions. Psilocybin enhanced claustral inhibition of cortical networks while disinhibiting subcortical areas, partially associated with psychedelic subjective effect scores. These findings are consistent with cellular and functional cross-species data, supporting the proposed mechanism of claustro-cortical inhibition in regulating network synchrony, while extending this influence to the subcortex, and revealing hierarchical and hemispheric asymmetries in claustral signaling modulation under psilocybin.", "journal": "bioRxiv", "publication_date": "2025-09-11", "publication_year": 2025, "doi": "10.1101/2025.09.07.674759", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.09.07.674759", "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\":\"PPR1083522\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Mechanism of Action", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3079, "title": "Context-dependent structurally informed effective connectivity under psilocybin", "normalized_title": "context dependent structurally informed effective connectivity under psilocybin", "authors": "Greaves MD, Barta T, Novelli L, Stoliker D, Razi A.", "abstract": "The extent to which anatomical connectivity constrains pharmacologically altered brain dynamics remains poorly understood. Here, we combined psilocybin administration with a structurally informed effective-connectivity model to examine how structural connectivity shapes directed inter-regional influences across experiential contexts. Using dynamic causal modeling embedded in a hierarchical empirical Bayes framework, we analyzed fMRI data acquired from a hippocampo-thalamo-cortical network during rest, guided meditation, music listening and movie viewing. Across contexts, psilocybin reorganized directed interactions while preserving structure-based scaling. Effects converged on efferents (outgoing influences) from the left hippocampus-a hub interfacing mnemonic and associative systems with the default-mode network and thalamus. Notably, the left-hippocampus-to-thalamus pathway showed a sign-reversed association with mystical-experience scores (downregulation during guided meditation and upregulation during music listening). In model-based leave-one-out cross-validation, left-hippocampal efferents predicted individual differences in mystical-experience intensity. A minimal model-free benchmark (hippocampal signal variability) also showed modest associations with mystical experience. Together, these findings link context-specific, structurally informed effective connectivity to individual differences in the acute psychedelic experience, providing a mechanistic bridge between anatomy, neurodynamics, and phenomenology.", "journal": "bioRxiv", "publication_date": "2025-08-21", "publication_year": 2025, "doi": "10.1101/2025.08.18.671000", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.08.18.671000", "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\":\"PPR1071263\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Mechanism of Action,Mystical Experience,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3060, "title": "Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks", "normalized_title": "psilocybin triggers an activity dependent rewiring of large scale cortical networks", "authors": "Jiang Q, Shao L, Yao S, Savalia NK, Gilbert AD, Davoudian PA, Nothnagel JD, Tian G, Hung TS, Lai H, Beier KT, Zeng H, Kwan AC.", "abstract": "SUMMARY Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin’s effect on connectivity is network-specific: strengthening the routing of inputs from perceptual and medial regions (homolog of default mode network) to subcortical targets, while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity, because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.", "journal": "bioRxiv", "publication_date": "2025-08-05", "publication_year": 2025, "doi": "10.1101/2025.08.06.668927", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.08.06.668927", "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\":\"PPR1065205\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Default Mode Network,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": 216, "title": "Psilocybin Prolongs the Neurovascular Coupling Response in Mouse Visual Cortex", "normalized_title": "psilocybin prolongs the neurovascular coupling response in mouse visual cortex", "authors": "Zirkel RT, Isaacson M, Liao C, Yi M, Yamaguchi K, Rivera D, Kuceyeski A, Nishimura N, Kwan AC, Schaffer CB.", "abstract": "Psilocybin has profound therapeutic potential for various mental health disorders, but its mechanisms of action are unknown. Functional MRI studies have reported the effects of psilocybin on brain activity and connectivity; however, these measurements rely on neurovascular coupling to infer neural activity changes and assume that blood flow responses to neural activity are not altered by psilocybin. Using two-photon excited fluorescence imaging in the visual cortex of awake mice to simultaneously measure neural activity and capillary blood flow dynamics, we found that psilocybin administration prolonged the increase in visual stimulus-evoked capillary blood flow - an effect which was reduced by pretreatment with a 5-HT2A R antagonist - despite not causing changes in the stimulus-evoked neural response. Multi-modal widefield imaging also showed that psilocybin extends the stimulus-evoked vascular responses in surface vessels with no observed effect on the population neural response. Computational simulation with a whole-brain neural mass model showed that prolonged neurovascular coupling responses can lead to spurious increases in BOLD-based measures of functional connectivity. Together, these findings demonstrate that psilocybin broadens neurovascular responses in the brain and highlights the importance of accounting for these effects when interpreting human neuroimaging data of psychedelic drug action.", "journal": "bioRxiv", "publication_date": "2025-07-30", "publication_year": 2025, "doi": "10.1101/2025.07.25.666803", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.07.25.666803", "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\":\"PPR1057821\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Mechanism of Action,Receptor Pharmacology,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": 3054, "title": "Electrophysiological effects of psilocybin co-administered with midazolam", "normalized_title": "electrophysiological effects of psilocybin co administered with midazolam", "authors": "Sutherland MH, Nicholas CR, Lennertz RC, Wenthur CJ, Krause BM, Sauder CJ, Riedner BA, Smith RF, Hutson PR, Raison CL, Banks MI.", "abstract": "The serotonergic psychedelic psilocybin induces neural plasticity and profoundly alters consciousness. The benzodiazepine midazolam blunts neural plasticity and induces conscious sedation and amnesia at low doses. In our recent open label pilot study, we administered oral psilocybin (25 mg) along with intravenous midazolam at doses allowing a full psychedelic experience while blunting memory for the experience. We previously reported preliminary results from high density scalp electroencephalography (EEG) recorded during the dosing session. Here, we examined changes in EEG band power, normalized Lempel Ziv complexity (LZCn), and spectral exponent. We used linear mixed effects models that incorporated time and the subjective effects of midazolam and psilocybin, measured with the Observer’s Assessment of Arousal and Sedation (OAA/S) and selected items from the Altered States of Consciousness (ASC) questionnaire, respectively. At 15-30 mins, when midazolam (but likely not psilocybin) was at its targeted effect site concentration, we observed increased beta power and decreased spectral exponent. As the subjective effects of psilocybin commenced and over the next six hours, we observed increased LZCn and spectral exponent and decreased broadband power. OAA/S improved model fits for alpha power while ASC improved model fits for LZCn and spectral exponent. These data are further evidence that the effects of psilocybin are maintained in the presence of midazolam, supporting its utility in mechanistic studies of psilocybin’s therapeutic activity.", "journal": "bioRxiv", "publication_date": "2025-07-28", "publication_year": 2025, "doi": "10.1101/2025.07.25.666887", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.07.25.666887", "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\":\"PPR1058017\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Brain Imaging,Consciousness", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3071, "title": "Epigenome-wide Association Study of Psilocybin-Induced Methylome Changes in Alcohol Use Disorder", "normalized_title": "epigenome wide association study of psilocybin induced methylome changes in alcohol use disorder", "authors": "Urban MM, Zillich L, Rieser NM, Herdener M, Vollenweider FX, Spanagel R, Preller KH, Meinhardt MW.", "abstract": "The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 40 patients with blood sampling and acquisition of psychometrics - at baseline, 24 hours after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. Our epigenome-wide association study (EWAS) identified one CpG site in TLE4 ( p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 ( pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance ( p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Furthermore, at p < 0.05, we found baseline differences between treatment responders (< 1 standard unit alcohol in 4-week follow-up) and non-responders in genes related to synaptic plasticity and different neurotransmitter systems. While these findings are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.", "journal": "bioRxiv", "publication_date": "2025-07-17", "publication_year": 2025, "doi": "10.1101/2025.07.18.664368", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.07.18.664368", "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\":\"PPR1052183\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Addiction,Neuroplasticity,Mechanism of Action,Epigenetics,Observational Study,Genomics,Immune Function", "study_type": "Observational Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 613, "title": "Psilocybin has no immediate or persistent analgesic effect in acute and chronic mouse pain models", "normalized_title": "psilocybin has no immediate or persistent analgesic effect in acute and chronic mouse pain models", "authors": "Gregory NS, Girard TE, Ram A, Casey AB, Malenka RC, Tawfik VL, Heifets BD.", "abstract": "The psychedelic psilocybin may have lasting therapeutic effects for patients with chronic pain syndromes. Some clinical and preclinical data suggest these putative benefits derive from direct analgesic effects. However, this possibility has not been comprehensively tested in preclinical models. Here, we show that psilocybin is not analgesic over a range of doses across multiple pain assays and models of acute and chronic inflammatory, neuropathic, or musculoskeletal pain in mice.", "journal": "bioRxiv", "publication_date": "2025-07-06", "publication_year": 2025, "doi": "10.1101/2025.07.06.663398", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.07.06.663398", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:00", "raw_json": "{\"europe_pmc_id\":\"PPR1047940\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Chronic Pain,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": 3216, "title": "Accurate and Interpretable Prediction of Antidepressant Treatment Response from Receptor-informed Neuroimaging", "normalized_title": "accurate and interpretable prediction of antidepressant treatment response from receptor informed neuroimaging", "authors": "Tolle HM, Luppi AI, Lawn T, Roseman L, Nutt D, Carhart-Harris RL, Mediano PAM.", "abstract": "Conventional antidepressants show moderate efficacy in treating major depressive disorder. Psychedelic-assisted therapy holds promise, yet individual responses vary, underscoring the need for predictive tools to guide treatment selection. Here, we present graphTRIP (graph-based Treatment Response Interpretability and Prediction) - a geometric deep learning architecture that enables three advances: 1) accurate prediction of post-treatment depression severity using only pretreatment clinical and neuroimaging data; 2) identification of robust biomarkers; and 3) causal analysis of treatment effects and underlying mechanisms. Trained on data from a clinical trial comparing psilocybin and escitalopram ( NCT03429075 ), graphTRIP achieves strong predictive accuracy ( r = 0.72, p = 6.8 ×10 −8 ), and shows clear generalization to both an independent dataset and across brain atlases. The model identifies stronger functional connectivity within sensory networks as a robust predictor of poorer response across both treatments. In contrast, causal analysis implicates frontoparietal and default mode networks as key moderators of differential response, with stronger 5-HT1A- and 5-HT2A-related signalling in the frontoparietal network predicting escitalopram response but psilocybin resistance. Overall, this work advances precision medicine and biomarker discovery in depression.", "journal": "bioRxiv", "publication_date": "2025-07-02", "publication_year": 2025, "doi": "10.1101/2025.07.02.662710", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.07.02.662710", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR1046304\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Brain Imaging,Mechanism of Action,Receptor Pharmacology,Default Mode Network,Biomarkers,Aging,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": 3081, "title": "Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin", "normalized_title": "converging pathways shared brain circuitry engaged by monoaminergic antidepressants ketamine and psilocybin", "authors": "Joseph K, Collins J, Genovese T, Maxwell M, Lieberman JA, Osten P.", "abstract": "Ketamine has transformed depression treatment by providing therapeutic relief within a single day, unlike monoaminergic antidepressants that require weeks to take effect. Here, we conducted whole-brain screening in mice to compare drug-evoked c-fos expression-acting as a marker of brain activity leading to protein synthesis-dependent forms of plasticity-following treatment with monoaminergic antidepressants, ketamine and psilocybin. Our findings reveal a shared limbic brain circuit comprising subcortical and frontal cortical regions, with a key distinction: c-fos-based activity in the prelimbic and infralimbic frontal cortex-areas strongly implicated in depression-was acutely induced by ketamine and high-dose psilocybin, but emerged only after chronic dosing with the selective serotonin reuptake inhibitor fluoxetine or psilocybin microdosing. These results suggest the existence of a core limbic subcortico-cortical circuit underlying antidepressant efficacy, provide mechanistic insight into the delayed therapeutic effects of monoaminergic antidepressants, and reveal a close similarity in brain activity evoked by monoaminergic antidepressants and psilocybin microdosing.", "journal": "bioRxiv", "publication_date": "2025-05-29", "publication_year": 2025, "doi": "10.1101/2025.05.26.655791", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.05.26.655791", "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\":\"PPR1028717\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Neuroplasticity,Mechanism of Action,Receptor Pharmacology,Biomarkers,Microdosing,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": 3083, "title": "Psilocybin-induced modulation of visual salience processing", "normalized_title": "psilocybin induced modulation of visual salience processing", "authors": "Muller S, Cavanna F, de la Fuente LA, Bruno N, D’Amelio TA, Pallavicini C, Tagliazucchi E.", "abstract": "Psychedelic compounds significantly reshape conscious perception, yet the implications of these alterations for complex visual-guided behaviors remain poorly understood. We investigated how psilocybin modulates visual salience processing during natural scene perception. Twenty-three participants completed eye-tracking tasks under self-blinded low and high doses of psilocybin, in a naturalistic design with experimental conditions unknown to participants and researchers. Subjects viewed natural scenes while their gaze patterns were recorded and analyzed in relation to normative computational saliency maps generated using a deep learning model of visual attention. Results revealed increased fixation on salient image regions and reduced inter-fixation distance under the high-dose condition, suggesting heightened sensitivity to visual salience and more localized gaze behavior. The Shannon entropy of fixations on high-saliency regions indicated a more exploratory and less predictable visual scanning of the images. Complementary EEG recordings showed broadband spectral power reductions and increased Lempel-Ziv complexity, with delta power negatively correlating with salience metrics. These findings suggest psilocybin enhances bottom-up attentional control while weakening top-down modulation, consistent with theoretical models positing facilitated bottom-up information flow under the acute effect of psychedelics.", "journal": "bioRxiv", "publication_date": "2025-05-11", "publication_year": 2025, "doi": "10.1101/2025.05.10.652897", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.05.10.652897", "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\":\"PPR1018727\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3288, "title": "Assessing the potential cardiovascular risk of microdosing the psychedelic LSD in mice", "normalized_title": "assessing the potential cardiovascular risk of microdosing the psychedelic lsd in mice", "authors": "Effinger DP, Schalk SS, King JL, Strong JR, O’Connell CK, Calderon JR, McCorvy JD, Thompson SM.", "abstract": "Summary Microdosing, the prolonged ingestion of psychedelics at sub-hallucinogenic doses, has gained popularity for its perceived cognitive and emotional benefits. Psychedelics have high affinity for 5-HT2B receptors, which cause heart disease with strong chronic activation. We investigated the effects of microdosed psychedelics on cardiovascular health in mice using electrocardiography after chronically administering either serotonin as a positive control or lysergic acid diethylamide (LSD) at two sub-hallucinogenic doses. Serotonin produced significant ventricular thickening at 4- and 8-weeks. No significant changes were observed in vehicle or LSD groups. We determined the affinity and potency of LSD, psilocybin, and norfenfluramine at mouse and human 5-HT2B Rs and observed no significant differences. We calculated that levels of 5-HT2B activation by low-dose LSD were substantial, but short-lived, compared to the cardiotoxin d -fenfluramine. Together, these data provide no evidence of cardiovascular risk associated with prolonged administration of low-dose LSD in mice.", "journal": "bioRxiv", "publication_date": "2025-04-13", "publication_year": 2025, "doi": "10.1101/2025.04.08.647757", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.04.08.647757", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:49", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR1003831\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Receptor Pharmacology,Microdosing,Emotional Processing,Animal Study,Safety", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3082, "title": "PsiConnect: A Multimodal Neuroimaging Study of Psilocybin-Induced Changes in Brain and Behaviour", "normalized_title": "psiconnect a multimodal neuroimaging study of psilocybin induced changes in brain and behaviour", "authors": "Novelli L, Stoliker D, Barta T, Greaves MD, Chopra S, Jackson J, Kwee J, Williams ML, Razi A.", "abstract": "ABSTRACT PsiConnect is a large-scale neuroimaging study designed to investigate the neural and subjective effects of psilocybin using multimodal neuroimaging. It combines functional, structural, and diffusion-weighted MRI with EEG to examine brain activity in 62 participants before and after a 19 mg dose of psilocybin. The design includes resting-state scans and three naturalistic conditions: guided meditation, music listening, and movie watching. Half of the cohort underwent an 8-week meditation training program, enabling the exploration of interactions among meditation, psilocybin, and brain function. The fMRI data was obtained through multi-echo fMRI, which enhances the signal-to-noise ratio and reduces susceptibility artifacts, thereby improving the reliability of the analyses. A comprehensive battery of behavioural and self-report measures captured both acute and longitudinal cognitive and subjective effects, with follow-ups extending to one year post-administration. The large sample size, multimodal neuroimaging, diversity of contexts, and longitudinal behavioural follow-ups enable the study of psilocybin-induced changes in brain and behaviour with an unprecedented level of detail and reliability. Furthermore, the data is curated according to open science principles to ensure accessibility and interoperability with established neuroimaging processing pipelines. These factors make PsiConnect a valuable and highly reusable resource for researchers in cognitive and computational neuroscience.", "journal": "bioRxiv", "publication_date": "2025-04-13", "publication_year": 2025, "doi": "10.1101/2025.04.11.643415", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.04.11.643415", "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\":\"PPR1003820\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Aging,Observational Study,Drug Interactions", "study_type": "Observational Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 744, "title": "A multi-institutional investigation of psilocybin’s effects on mouse behavior", "normalized_title": "a multi institutional investigation of psilocybin s effects on mouse behavior", "authors": "Lu OD, White K, Raymond K, Liu C, Klein AS, Green N, Vaillancourt S, Gallagher A, Shindy L, Li A, Wallquist K, Li R, Zou M, Casey AB, Cameron LP, Pomrenze MB, Sohal V, Kheirbek MA, Gomez AM, Lammel S, Heifets BD, Malenka R.", "abstract": "ABSTRACT Studies reporting novel therapeutic effects of psychedelic drugs are rapidly emerging. However, the reproducibility and reliability of these findings could remain uncertain for years. Here, we implemented a multi-institutional collaborative approach to define the robust and replicable effects of the psychedelic drug psilocybin on mouse behavior. Five laboratories performed the same experiments to test the acute and persistent effects of psilocybin (2 mg/kg, IP) on various behaviors that psychedelics have been proposed to affect, including anxiety-related approach-avoidance, exploration, sociability, depression-related behaviors, fear extinction, and social reward learning. Through this coordinated approach, we found that psilocybin had several robust and replicable acute effects on mouse behavior, including increased anxiety- and avoidance-related behaviors and decreased fear expression. Surprisingly, however, we found that psilocybin did not have replicable effects 24 hours post psilocybin administration on reducing anxiety- and depression-like behaviors or facilitating fear extinction learning. Additionally, we were unable to observe psilocybin-induced alterations in social preference or social reward learning. Overall, our comprehensive characterization of psilocybin’s acute and persistent behavioral effects using ∼200 total male and female mice per experiment spread across five independent labs demonstrates with unique certainty several acute drug effects and suggests that psilocybin’s persistent effects in mice may be more modest and inconsistent than previously suggested. We believe this unusual multi-laboratory, highly coordinated research effort serves as a model for facilitating the generation of replicable results and consequently will reduce efforts based on unreliable and spurious results.", "journal": "bioRxiv", "publication_date": "2025-04-08", "publication_year": 2025, "doi": "10.1101/2025.04.08.647810", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.04.08.647810", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR1001669\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,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": 3209, "title": "Psychedelics Align Brain Activity with Context", "normalized_title": "psychedelics align brain activity with context", "authors": "Stoliker D, Novelli L, Khajehnejad M, Biabani M, Greaves MD, Barta T, Williams M, Chopra S, Bazin O, Simonsson O, Chambers R, Barrett F, Deco G, Preller KH, Carhart-Harris R, Seth A, Sundram S, Egan GF, Razi A.", "abstract": "Psychedelics can profoundly alter consciousness by reorganising brain connectivity; however, their effects are context-sensitive. To understand how this reorganisation depends on context, we collected and comprehensively analysed the largest psychedelic neuroimaging dataset to date. Sixty-two adults were scanned with functional MRI and EEG during rest and naturalistic stimuli (meditation, music, and movie), before and after ingesting 19 mg of psilocybin (functional MRI ≈80 min post-dose; EEG ≈150 min post-dose). Half the participants ranked the experience among the most meaningful of their lives. Under psilocybin, functional MRI and EEG signals recorded during eyes-closed conditions became similar to those recorded during an eyes-open condition. Global functional connectivity increased in associative regions and decreased in sensory areas. Using machine learning to represent neural activity as low-dimensional trajectories, we found that psilocybin reorganised these into structured, context-sensitive patterns of brain activity that reflected both experimental condition and the quality of subjective experience, revealing an organisation that was missed by time-averaged connectivity measures. Under psilocybin, brain networks that ordinarily segregate internal and external processing coherently integrated and aligned neural dynamics with context. This context-alignment manifested as distinct and cohesive neural trajectories in participants reporting positively felt self- and boundary-dissolving effects, corresponding to the felt experience of being part of the environment, which we refer to as embeddedness -the subjective experience of being continuous with, rather than separate from, the surrounding environment. The strength of this context-alignment was associated with next-day mindset change, bridging the neural, experiential, and therapeutic dimensions of the psychedelic state. These findings show that the organisation of brain activity covaries with the experiential coherence of the psychedelic state, and provide a systems-level framework for how context-sensitive brain dynamics link neurobiology to subjective experience and behavioural change.", "journal": "bioRxiv", "publication_date": "2025-03-10", "publication_year": 2025, "doi": "10.1101/2025.03.09.642197", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.03.09.642197", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR987866\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Consciousness,Aging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 784, "title": "Lasting effect of psilocybin on sociability can be blocked by DNA methyltransferase inhibition", "normalized_title": "lasting effect of psilocybin on sociability can be blocked by dna methyltransferase inhibition", "authors": "Song C, Chang T, Buchborn T, Knöpfel T.", "abstract": "The recent renaissance in research on psychedelics such as psilocybin has highlighted their therapeutic potential including their lasting influences on brain function. Here we report that a single systemic administration of the serotonergic psychedelic psilocybin can durably promote social behaviour in the Cntnap2-knockout mouse model of autism. This effect can be blocked by pharmacological inhibition of DNA methyltransferase I, indicating an epigenetic mechanism underlying the long-lasting effect of psilocybin.", "journal": "bioRxiv", "publication_date": "2025-03-10", "publication_year": 2025, "doi": "10.1101/2025.03.10.642385", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.03.10.642385", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:00", "raw_json": "{\"europe_pmc_id\":\"PPR987875\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Epigenetics,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": 3116, "title": "Revealing Changes in Linear and Nonlinear Functional Connectivity After Psilocybin and Escitalopram Treatment in Patients with Depression", "normalized_title": "revealing changes in linear and nonlinear functional connectivity after psilocybin and escitalopram treatment in patients with depression", "authors": "Quah S, Glick C, Roseman L, Pasquini L, Carhart-Harris R, Saggar M.", "abstract": "Major Depressive Disorder (MDD) is typically characterized by altered linear functional connectivity (FC) across large-scale brain networks. Yet, it is unclear whether similar alterations are observed when nonlinear FC is examined. This study investigated how antidepressant treatment (i.e., psilocybin and escitalopram) modulates both linear FC and nonlinear FC in individuals with MDD. Here, we focused specifically on five key canonical brain networks: the Default Mode Network (DMN), Frontoparietal Network (FPN), Salience Network (SAL), Dorsal Attention Network (DAN), and Ventral Attention Network (VAN). Across both treatments, using resting-state fMRI data, we first compared changes in linear and nonlinear FC between responders and non-responders. Responders exhibited increased linear FC within the VAN and greater nonlinear FC within the DMN and VAN than non-responders. We also observed more between-network linear FC for DMN-DAN and nonlinear FC for DMN-VAN in responders than non-responders. Next, we compared treatments and observed that Psilocybin responders showed greater connectivity between FPN-VAN (linear FC), DMN-VAN (nonlinear FC), and SAL-VAN (nonlinear FC) integration than Escitalopram responders, reflecting enhanced coordination and integration between higher-order networks. Conversely, Escitalopram responders exhibited reduced within-network linear FC within the DMN and SAL and between the DMN and VAN, consistent with a dampening of self-referential and salience processing and altered attentional control. These findings highlight potentially distinct mechanisms of action for psilocybin and escitalopram. Incorporating both linear and nonlinear FC analyses provided a novel characterization of these effects, emphasizing the role of these different interactions in antidepressant response. Future studies should investigate the long-term stability of these network changes and their relationship to clinical outcomes.", "journal": "bioRxiv", "publication_date": "2025-03-09", "publication_year": 2025, "doi": "10.1101/2025.03.05.641592", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.03.05.641592", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR987622\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Brain Imaging,Mechanism of Action,Default Mode Network,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3062, "title": "Psilocybin alters visual contextual computations", "normalized_title": "psilocybin alters visual contextual computations", "authors": "Aqil M, de Hollander G, Vreugdenhil N, Knapen T, Dumoulin SO.", "abstract": "Psilocybin alters perception and brain dynamics. Contextual computations are ubiquitous in the brain. Here, we investigate the effects of psilocybin using psychophysics, ultra-high field functional MRI, and computational modeling. We find that 1) psilocybin alters contextual perception in the Ebbinghaus illusion, 2) psilocybin alters contextual modulation in cortical responses to visual stimuli, and 3) we propose a computational model capable of capturing and linking these changes. Leveraging vision as a beachhead, our findings highlight the alteration of contextual computations as a potential general mechanism underlying psychedelic action. Teaser Psilocybin alters visual-contextual computations, a potential general computational mechanism for psychedelic effects in the human brain.", "journal": "bioRxiv", "publication_date": "2025-02-07", "publication_year": 2025, "doi": "10.1101/2025.02.06.636848", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.02.06.636848", "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\":\"PPR976450\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Aging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3105, "title": "Dose-dependent changes in global brain activity and functional connectivity following exposure to psilocybin: a BOLD MRI study in awake rats", "normalized_title": "dose dependent changes in global brain activity and functional connectivity following exposure to psilocybin a bold mri study in awake rats", "authors": "Fuini E, Chang A, Ortiz RJ, Nasseef T, Edwards J, Latta M, Gonzalez E, Woodward TJ, Bradshaw HB, Axe B, Maheswari A, Cavallaro N, Kulkarni PP, Ferris CF.", "abstract": "Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. This is the first study to use MRI to follow functional changes in brain activity in response to different doses of psilocybin in fully awake, drug naive rats. Female and male rats were given IP injections of vehicle or psilocybin in doses of 0.03 mg/kg, 0.3 mg/kg, and 3.0 mg/kg while fully awake during the imaging session. Changes in BOLD signal were recorded over a 20 min window. Data for resting state functional connectivity were collected approximately 35 min post injection All data were registered to rat 3D MRI atlas with 173 brain regions providing site-specific changes in global brain activity and changes in functional connectivity. Treatment with psilocybin resulted in a significant dose-dependent increase in positive BOLD signal. The areas most affected by the acute presentation of psilocybin were the somatosensory cortex, basal ganglia and thalamus. Females were significantly more sensitive to the 0.3 mg/kg dose of psilocybin than males. There was a significant dose-dependent global increase in functional connectivity, highlighted by hyperconnectivity to the cerebellum. Brain areas hypothesized to be involved in loss of sensory filtering and organization of sensory motor stimuli such as the claustrum and the cortico-basal ganglia-thalamic-cortical loop were all affected by psilocybin in a dose-dependent manner. Indeed, the general neuroanatomical circuitry associated with the psychedelic experience was affected but the direction of the BOLD signal and pattern of activity between neural networks was inconsistent with the human literature.", "journal": "bioRxiv", "publication_date": "2025-02-05", "publication_year": 2025, "doi": "10.1101/2025.02.01.636078", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.02.01.636078", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR976027\",\"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": 820, "title": "Psilocybin as a Treatment for Repetitive Mild Head Injury: Evidence from Neuroradiology and Molecular Biology", "normalized_title": "psilocybin as a treatment for repetitive mild head injury evidence from neuroradiology and molecular biology", "authors": "Brengel EK, Axe B, Maheswari A, Abeer MI, Ortiz RJ, Woodward TJ, Walhof R, Utama R, Sawada C, Balaji S, Kulkarni PP, Bradshaw HB, Gitcho MA, Ferris CF.", "abstract": "Repetitive mild head injuries incurred while playing organized sports, during car accidents and falls, or in active military service are a major health problem. These head injuries induce cognitive, motor, and behavioral deficits that can last for months and even years with an increased risk of dementia, Parkinson’s disease, and chronic traumatic encephalopathy. There is no approved medical treatment for these types of head injuries. To this end, we tested the healing effects of the psychedelic psilocybin, as it is known to reduce neuroinflammation and enhance neuroplasticity. Using a model of mild repetitive head injury in adult female rats, we provide unprecedented data that psilocybin can reduce vasogenic edema, restore normal vascular reactivity and functional connectivity, reduce phosphorylated tau buildup, enhance levels of brain-derived neurotrophic factor and its receptor TrkB, and modulate lipid signaling molecules.", "journal": "bioRxiv", "publication_date": "2025-02-05", "publication_year": 2025, "doi": "10.1101/2025.02.03.636248", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.02.03.636248", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR975392\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Mechanism of Action,Receptor Pharmacology,Safety,Inflammation", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3086, "title": "Age- and estrous-dependent effects of psilocybin in rats", "normalized_title": "age and estrous dependent effects of psilocybin in rats", "authors": "Zylko A, Rakoczy R, Roberts B, Wilson M, Powell A, Page A, Heitkamp M, Fiest D, Jones J, McMurray M.", "abstract": "Psilocybin, a psychedelic compound in “magic” mushrooms, has promise as a novel treatment for psychiatric disorders, many of which are more prevalent in females and have onsets during adolescence. However, there is a lack of research about how factors such as sex and age affect responses to psilocybin, as well as potential safety concerns with developmental exposure. The primary objectives of this preclinical study were to determine if psilocybin-induced head twitch responses differ between adolescent and adult rats, and if estrous phase contributes to variation in female head twitch responses. Secondarily, this study sought to determine if treatment with psilocybin during adolescence has long-term effects on anxiety-associated behaviors and behavioral flexibility. Results showed that 1 mg/kg intraoral psilocybin failed to elicit head twitch responses in adolescents (P35 and P45) but elicited robust responses in adult rats. Further, adolescent psilocybin exposure did not cause long-term differences in performance on the elevated zero maze or probabilistic reversal learning tasks. Lastly, adult females in diestrus showed increased head twitch responses after 1 mg/kg psilocybin compared to females in proestrus. Head twitch responses are thought to be mediated by 5-HT2A receptors, but no age-or estrous-related differences in 5-HT2A receptor expression were observed in the medial prefrontal cortex. Collectively, these results highlight the existence of age-and sex-dependent differences in the effects of psychedelics, while finding no long-term effects on selected behaviors after adolescent exposure. These findings have implications on psychedelic study design, emphasizing the need for inclusive research considering age, sex, and hormonal status.", "journal": "bioRxiv", "publication_date": "2025-01-13", "publication_year": 2025, "doi": "10.1101/2025.01.10.632408", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.01.10.632408", "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\":\"PPR966388\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Anxiety,Receptor Pharmacology,Animal Study,Adolescents,Safety", "study_type": "Clinical Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3107, "title": "Cell-type specific transcriptional modulation by psilocybin induces sustained plasticity in mouse medial prefrontal cortex", "normalized_title": "cell type specific transcriptional modulation by psilocybin induces sustained plasticity in mouse medial prefrontal cortex", "authors": "Schuler H, Zhou D, Savignac C, Cvetkovska V, Tse Y, Meccia J, Lopez J, Harutyunyan AS, Ragoussis J, Bzdok D, Bagot RC.", "abstract": "Despite enormous interest in psychedelics for psychiatric interventions, potential underlying biological mechanisms remain unclear. Here, we confirm that a single dose of psilocybin increases synaptic transmission in mouse medial prefrontal cortex. Using scRNA-sequencing, we identify cell-type specific mechanisms of sustained neuroplastic effects. We show that, 24h post-psilocybin, expression of plasticity-related genes is increased in excitatory neurons and that transcription in a type of deep layer near projecting neuron, L5/6 NP, is robustly altered. Analyzing receptor expression patterns reveals that this cell-type specificity does not align with 5-HT2A expression but aligns with 5-HT2C expression patterns. Further, multivariate analyses identify psilocybin-induced gene expression patterns in L5/6 NP neurons predict 5-HT2C, but not 5-HT2A, transcript levels. Pharmacologic manipulation with a 5-HT2C antagonist attenuates the post-acute sustained effect of psilocybin on synaptic transmission, highlighting 5-HT2C signaling and L5/6 NP neurons as key mediators of psychedelic drug action’s sustained neuroplastic effects in mPFC.", "journal": "bioRxiv", "publication_date": "2025-01-07", "publication_year": 2025, "doi": "10.1101/2025.01.08.631940", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.01.08.631940", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR963790\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "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": 3102, "title": "Psilocybin induces sex- and context-specific recruitment of the stress axis", "normalized_title": "psilocybin induces sex and context specific recruitment of the stress axis", "authors": "Cook SG, Lee S, Ference E, Shi Y, Rojas-Carvajal M, Hen R, Bains JS, Füzesi T, Turi GF.", "abstract": "ABSTRACT Psychedelics have reemerged as potential treatments for mental health disorders, yet their impact on stress-related brain regions remains poorly understood. Here, we provide the first real-time, in vivo evidence of psilocybin-induced neuronal activation, specifically in hypothalamic corticotropin-releasing hormone neurons. Notably, psilocybin elicited more pronounced responses in female mice and produced context-related alterations in threat assessment. Our findings provide valuable insight into the impact of psychedelics on a key stress center in the brain.", "journal": "bioRxiv", "publication_date": "2025-01-05", "publication_year": 2025, "doi": "10.1101/2025.01.06.631556", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.01.06.631556", "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\":\"PPR963599\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "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": 872, "title": "Single-nucleus transcriptomics reveals cell type-specific and time-dependent effects of psilocybin and ketamine on gene expression", "normalized_title": "single nucleus transcriptomics reveals cell type specific and time dependent effects of psilocybin and ketamine on gene expression", "authors": "Liao C, O’Farrell E, Weiner AM, Qalieh Y, Savalia NK, Girgenti MJ, Kwan KY, Kwan AC.", "abstract": "ABSTRACT There is growing interest to investigate classic psychedelics and ketamine as therapeutics for mental illnesses. Previous studies have demonstrated that one dose of psilocybin or ketamine leads to persisting neural and behavioral changes. The durability of these effects suggests that there are likely alterations in gene expression at the transcriptional level. In this study, we performed single-nucleus RNA sequencing of the dorsal medial frontal cortex of male and female mice. Samples were collected at 1, 2, 4, 24, or 72 hours after psilocybin or ketamine administration and from control animals. At baseline, major subtypes of excitatory and GABAergic neurons selectively express particular serotonin receptor transcripts. The psilocybin-evoked differentially expressed genes in excitatory neurons are involved in synaptic plasticity, distinct from genes enriched in GABAergic neurons, which contribute to mitochondrial function and cellular metabolism, and non-neuronal glial cells. The effect of psilocybin on gene expression is time-dependent, including an early phase at 1 hour followed by a late phase at 72 hours of transcriptional response after administration, and differs from the changes following ketamine administration, which peaks at 2 - 4 hours. Collectively, the results provide a resource for understanding the cell type-specific and time-dependent changes in gene expression induced by psilocybin and ketamine in the mouse medial frontal cortex, which may underpin the drug’s long-term effects on neural circuits and behavior.", "journal": "bioRxiv", "publication_date": "2025-01-03", "publication_year": 2025, "doi": "10.1101/2025.01.04.631335", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.01.04.631335", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR962750\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Pharmacology,Receptor Pharmacology,Mitochondrial Function,Animal Study,Transcriptomics", "study_type": "Clinical Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3201, "title": "Perturbing whole-brain models of brain hierarchy: an application for depression following pharmacological treatment", "normalized_title": "perturbing whole brain models of brain hierarchy an application for depression following pharmacological treatment", "authors": "Socoró Garrigosa M, Sanz Perl Y, Kringelbach ML, Carhart-Harris R, Vohryzek J, Deco G.", "abstract": "Neural representation can extend beyond localised activity to encompass global patterns, where information is distributed across brain networks in a hierarchical manner. Recent research suggests that the hierarchy of causal influences shaping these patterns can serve as a signature of distinct brain states, with implications for neuropsychiatric disorders. Here, we first delve into how whole-brain models, guided by the Thermodynamics of Mind framework, can estimate the brain hierarchy of specific brain states, and how perturbations of such models can study the in-silico transitions to other states represented by static functional connectivity. We then show an application for major depressive disorder, where different brain hierarchical reconfigurations have been found following psilocybin and escitalopram treatments. We build whole-brain models of depressed patients before and after psilocybin and escitalopram interventions, and we carry a dynamic sensitivity analysis to explore the susceptibility of brain states and their drivability to healthier states. We show that susceptibility is on average reduced by escitalopram and increased by psilocybin, and that both treatments succeed in promoting healthier transitions. These results align with the post-treatment window of plasticity opened by serotonergic psychedelics, as well as with the similar clinical efficacy of both drugs observed in clinical trials. Graphical Abstract We apply whole-brain models of brain hierarchy based on the Thermodynamics of Mind framework to investigate state transitions in depression. Dynamic sensitivity analysis explores how psilocybin and escitalopram affect susceptibility and drivability to healthier states. Results show that psilocybin increases susceptibility, while escitalopram reduces it, with both enabling optimal transitions. This pipeline demonstrates the promise of in-silico approaches to inform neurostimulation protocols, potentially enhancing or complementing antidepressant therapies.", "journal": "bioRxiv", "publication_date": "2025-01-01", "publication_year": 2025, "doi": "10.1101/2025.01.01.631011", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2025.01.01.631011", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR962216\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Neuroplasticity,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": 3298, "title": "Brain dynamics of classical psychedelics show paradoxical hierarchical flattening with increased complexity", "normalized_title": "brain dynamics of classical psychedelics show paradoxical hierarchical flattening with increased complexity", "authors": "Vohryzek J, Garcia Guzman E, Kringelbach ML, Lopez-Sola E, Timmermann C, Roseman L, Tagliazucchi E, Ruffini G, Carhart-Harris R, Deco G, Sanz Perl Y.", "abstract": "Despite divergent behavioral and phenomenological profiles, both psychedelic states and reduced states of consciousness have been associated with a flattening of the brain's functional hierarchy. To address this apparent paradox, we developed a more specific definition of hierarchy based on the proximity of the brain to thermodynamic equilibrium and then applied it to investigate the changes to the functional hierarchy elicited by three classical serotonergic psychedelics: psilocybin, lysergic acid diethylamide, and dimethyltryptamine. We found that all three psychedelics consistently induced a global reduction in the functional hierarchy. In contrast to the flattening of the functional hierarchy observed during loss of consciousness, psychedelics displaced the brain towards equilibrium while simultaneously increasing the complexity of neural activity, indicating a unique mechanism linked to specific changes in the configuration and differentiation of resting-state networks. This work showcases how metrics based on statistical mechanics can be used for the specific characterization of different global brain states, contributing to the understanding of consciousness as a collective process emerging from complex neural interactions.", "journal": "bioRxiv", "publication_date": "2024-12-21", "publication_year": 2024, "doi": "10.1101/2024.12.21.629922", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.12.21.629922", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:50", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR958078\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Consciousness,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3114, "title": "Characterizing psilocybin as an antidepressant for adolescence in male and female rats", "normalized_title": "characterizing psilocybin as an antidepressant for adolescence in male and female rats", "authors": "García-Cabrerizo R, Beruete-Fresnillo I, García-Fuster MJ.", "abstract": "Adolescent depression is a significant public health concern, yet treatment options remain limited, particularly due to age- and sex-related differences in antidepressant efficacy. This study explored the rapid and long-lasting antidepressant-like potential of psilocybin in adolescent Sprague-Dawley rats, examining acute and repeated oral dosing effects while incorporating sex as a biological variable. An acute administration of psilocybin produced rapid antidepressant-like effects 30 minutes post-treatment in both male and female rats, demonstrated by reduced immobility and increased escape-related behaviour in the forced swim test. However, repeated daily administrations over 7 days revealed notable sex differences. In males, the antidepressant-like effects were sustained, at least, for up to 15 days post-treatment at both tested doses. In contrast, in females, the effects were dose-dependent and less enduring, persisting only up to 8 days at the highest dose tested. To the best of our knowledge, these results are the first ones to underscore psilocybin’s potential as a fast-acting and long-lasting antidepressant during adolescence, a developmental stage marked by high vulnerability to depression and reduced response to conventional treatments, while also emphasizing the importance of tailoring therapeutic approaches to individual biological factors such as sex.", "journal": "bioRxiv", "publication_date": "2024-12-21", "publication_year": 2024, "doi": "10.1101/2024.12.20.629571", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.12.20.629571", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR959351\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Adolescents", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3101, "title": "Psilocybin causes sex, time, and dose dependent alterations in brain signaling pathways", "normalized_title": "psilocybin causes sex time and dose dependent alterations in brain signaling pathways", "authors": "Barnett JH, Todd KT, Benetatos J, Rabichow BE, Gibson KA, Olney KC, Fryer JD.", "abstract": "Psilocybin is a psychedelic tryptamine that has emerged as a potential candidate for the treatment of a variety of conditions, including treatment resistant depression and post-traumatic stress disorder. Clinical trials which have assessed the efficacy of psilocybin for these conditions report a rapid and sustained improvement in patient- and clinician-rated depression scores. The established mechanism of action for psychedelics such as psilocybin is agonism of the serotonin 2A receptor (5HT 2A R), however, the downstream events that mediate their therapeutic effects remain uncertain. As high doses of psychedelics are known to induce strong perceptual alterations, an additional outstanding question is whether subperceptual doses induce similar molecular effects as psychoactive dosages. Here, we report the first analysis of dose- and sex-dependent transcriptional changes in forebrains of female and male mice at 3 timepoints (8 hours, 24 hours, and 7 days) following a single administration of psilocybin at low (0.25 mg/kg) or high (1 mg/kg) doses. Grouped analysis of both sexes reveals dose- and time-dependent transcriptomic alterations. We report more rapid transcriptional changes and attenuation of such changes in females following a single low-dose relative to males treated identically. Females also responded more robustly to high-dose administration relative to males at 8 and 24 hours, with signal attenuation in both sexes by 7 days. A notable observation was the persistent transcriptional effect of low-dose psilocybin at 7 days, which outlasted high-dose changes, and which suggests that low doses may have prolonged biological effects. A myriad of pathways were altered depending on sex and timepoint, but common features included functions related to neuronal differentiation, neurogenesis, and changes in receptor signaling. These data reveal dose- and sex-dependent molecular effects of psilocybin and support previous studies demonstrating its effect on dendritogenesis. Given ongoing clinical interest in psilocybin for treating mental health disorders, our results suggest that these sexually divergent changes should be considered when weighing treatment strategies. Additional consideration should be given to temporal effects of low vs high dosages on gene transcription, especially when timing psilocybin with adjuvant cognitive behavioral therapy.", "journal": "bioRxiv", "publication_date": "2024-12-16", "publication_year": 2024, "doi": "10.1101/2024.12.16.628764", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.12.16.628764", "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\":\"PPR961267\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,PTSD,Neurogenesis,Mechanism of Action,Receptor Pharmacology,Clinical Trial,Animal Study,Healthcare Workers,Transcriptomics", "study_type": "Clinical Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3111, "title": "Short- and long-term reconfiguration of rat prefrontal cortical networks following single doses of psilocybin", "normalized_title": "short and long term reconfiguration of rat prefrontal cortical networks following single doses of psilocybin", "authors": "Purple RJ, Gupta R, Thomas CW, Golden CT, Froudist-Walsh S, Jones MW.", "abstract": "SUMMARY We quantify cellular- and circuit-resolution neural network dynamics following therapeutically relevant doses of the psychedelic psilocybin. Using chronically implanted Neuropixels probes, we recorded local field potentials (LFP) alongside action potentials from hundreds of neurons spanning infralimbic, prelimbic and cingulate subregions of the medial prefrontal cortex of freely-behaving adult rats. Psilocybin (0.3mg/kg or 1mg/kg i.p.) unmasked 100Hz high frequency oscillations that were most pronounced within the infralimbic cortex, persisted for approximately 1h post-injection and were accompanied by decreased net pyramidal cell firing rates and reduced signal complexity. These acute effects were more prominent during resting behaviour than during a sustained attention task. LFP1-, 2- and 6-days post-psilocybin showed gradually-emerging increases in beta and low-gamma (20-60Hz) power, specific to the infralimbic cortex. These findings reveal features of psychedelic action not readily detectable in human brain imaging, implicating infralimbic network oscillations as potential biomarkers of psychedelic-induced network plasticity over multi-day timescales.", "journal": "bioRxiv", "publication_date": "2024-12-12", "publication_year": 2024, "doi": "10.1101/2024.12.10.627734", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.12.10.627734", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR954729\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Brain Imaging,Biomarkers,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": 3157, "title": "Synergistic Behavioral and Neuroplastic Effects of Psilocybin-NMDAR Modulator Administration", "normalized_title": "synergistic behavioral and neuroplastic effects of psilocybin nmdar modulator administration", "authors": "Ben-Tal T, Pogodin I, Botvinnik A, Lifschytz T, Heresco-Levy U, Lerer B.", "abstract": "The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. Using ICR male mice, we examined head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. Our results indicate that PSIL significantly increased HTR-a surrogate measure for hallucinogenic effects-which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions, suggesting a synaptogenic synergy. These findings support the hypothesis that combinations of SP with NMDAR modulators could optimize the therapeutic potential of SP by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.", "journal": "bioRxiv", "publication_date": "2024-11-27", "publication_year": 2024, "doi": "10.1101/2024.11.28.625811", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.11.28.625811", "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\":\"PPR947201\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Neuroplasticity,Receptor Pharmacology,Animal Study,Safety", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3108, "title": "Long-term effects of psilocybin on dynamic and effectivity connectivity of fronto-striatal-thalamic circuits", "normalized_title": "long term effects of psilocybin on dynamic and effectivity connectivity of fronto striatal thalamic circuits", "authors": "Pasquini L, Vohryzek J, Escrichs A, Sanz Perl Y, Ponce-Alvarez A, Idesis S, Girn M, Roseman L, Mitchell JM, Gazzaley A, Kringelbach M, Nutt DJ, Lyons T, Carhart-Harris RL, Deco G.", "abstract": "Psilocybin has been shown to induce fast and sustained improvements in mental well-being across various populations, yet its long-term mechanisms of action are not fully understood. Initial evidence suggests that longitudinal functional and structural brain changes implicate fronto-striatal-thalamic (FST) circuitry, a broad system involved in goal-directed behavior and motivational states. Here, we apply empirical methods and computational modeling to resting-state fMRI data from a within-subject longitudinal psilocybin trial in psychedelic-naïve healthy volunteers. We first show increases in FST dynamic activity four weeks after a full dose of psilocybin. We then proceed to mechanistically account for these increased dynamics, by showing that reduced structural constraints underlie increased FST dynamic activity post psilocybin. Further, we show that these reduced structural constraints come along with increased bottom-up and reduced top-down modulation of FST circuits. While cortical reductions in top-down modulation are linked to regional 5-HT2A receptor availability, increased information outflow via subcortical and limbic regions relate to local D2 receptor availability. Together, these findings show that increased FST flexibility weeks after psilocybin administration is linked to serotonergic-mediated decreases in top-down information flow and dopaminergic-mediated increases in bottom-up information flow. This long-term functional re-organization of FST circuits may represent a common mechanism underling the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia. Significance Statement Fronto-striatal-thalamic systems, which underlie motivation and reward, go through profound functional and structural changes following psilocybin administration. We leveraged longitudinal fMRI data from a within-subject psilocybin trial in psychedelic-naïve healthy participants to show that psilocybin increases fronto-striatal-thalamic dynamic activity as well as flexibility four weeks after dosing. Computational modeling revealed that this increased flexibility is mechanistically caused by reduced structural constraints on functional dynamics. Further long-term changes included increased bottom-up and reduced top-down information flow mediated by the serotonergic and dopaminergic systems. This long-term functional re-organization of fronto-striatal-thalamic circuits may reflect a common mechanism underlying clinical symptoms improvements across diagnostic groups, such as increased openness, improved well-being, and reductions in anhedonia, apathy, and substance craving.", "journal": "bioRxiv", "publication_date": "2024-11-06", "publication_year": 2024, "doi": "10.1101/2024.11.06.622302", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.11.06.622302", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR936542\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Eating Disorders,Brain Imaging,Mechanism of Action,Receptor Pharmacology,Wellbeing,Healthy Volunteers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 967, "title": "Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action", "normalized_title": "pyramidal cell types and 5 ht2a receptors are essential for psilocybin s lasting drug action", "authors": "Shao L, Liao C, Davoudian PA, Savalia NK, Jiang Q, Wojtasiewicz C, Tan D, Nothnagel JD, Liu R, Woodburn SC, Bilash OM, Kim H, Che A, Kwan AC.", "abstract": "Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses 1-4. At the cellular level, psychedelics induce structural neural plasticity 5,6, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells 7-9. A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics’ behavioral actions 10. Here, we use in vivo optical imaging, chemogenetic perturbation, and cell type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increased the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviorally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behavior and structural plasticity. Collectively these results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as playing essential roles for psilocybin’s long-term drug action.", "journal": "bioRxiv", "publication_date": "2024-11-02", "publication_year": 2024, "doi": "10.1101/2024.11.02.621692", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.11.02.621692", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR934425\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Brain Imaging,Receptor Pharmacology,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": 3100, "title": "Psilocybin Reduces Grooming in the SAPAP3 Knockout Mouse Model of Compulsive Behaviour", "normalized_title": "psilocybin reduces grooming in the sapap3 knockout mouse model of compulsive behaviour", "authors": "Gattuso JJ, Wilson C, Hannan AJ, Renoir T.", "abstract": "Psilocybin is a serotonergic psychedelic compound which shows promise for treating compulsive behaviours. This is particularly pertinent as compulsive disorders require research into new pharmacological treatment options as the current frontline treatments such as selective serotonin reuptake inhibitors, require chronic administration, have significant side effects, and leave almost half of the clinical population refractory to treatment. In this study, we investigated psilocybin administration in male and female SAPAP3 knockout (KO) mice, a well-validated mouse model of obsessive compulsive and related disorders. We assessed the effects of acute psilocybin (1 mg/kg, intraperitoneal) administration on head twitch and locomotor behaviour as well as anxiety- and compulsive-like behaviours at multiple time-points (1-, 3- and 8-days post-injection). While psilocybin did not have any effect on anxiety-like behaviours, we revealed for the first time that acute psilocybin administration led to enduring reductions in compulsive behaviour in male SAPAP3 KO mice and reduced grooming behaviour in female WT and SAPAP3 KO mice. We also found that psilocybin increased locomotion in wild-type littermates but not in SAPAP3 KO mice, suggesting in vivo serotonergic dysfunctions in KO animals. On the other hand, the typical head-twitch response following acute psilocybin (confirming its hallucinogenic-like effect at this dose) was observed in both genotypes. Our novel findings suggest that acute psilocybin may have potential to reduce compulsive-like behaviours (up to 1 week after a single injection). Our study can inform future research directions as well as supporting the utility of psilocybin as a novel treatment option for compulsive disorders.", "journal": "bioRxiv", "publication_date": "2024-10-23", "publication_year": 2024, "doi": "10.1101/2024.10.23.619763", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.10.23.619763", "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\":\"PPR930010\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Anxiety,Receptor Pharmacology,Animal Study,Adverse Events", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3123, "title": "The forgotten psychedelic: Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin", "normalized_title": "the forgotten psychedelic spatiotemporal mapping of brain organisation following the administration of 2c b and psilocybin", "authors": "Mallaroni P, Singleton P, Mason NL, Satterthwaite TD, Ramaekers JG.", "abstract": "As psychedelic-assisted psychotherapy gains momentum, clinical investigation of next-generation psychedelics may lead to novel compounds tailored for specific populations. 2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenethylamine reported to produce less dysphoria and subjective impairment than the psychedelic tryptamine psilocybin. Despite its popularity among recreational users and distinct pharmacodynamics, the neural correlates of 2C-B remain unexplored. Using 7T resting−state functional MRI in 22 healthy volunteers, we mapped out the acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin and placebo across spatiotemporal benchmarks of functional brain organisation. In a within-subjects, double-blind, placebo-controlled crossover design, we evaluated the neuropharmacological and neurobehavioural correlates of an array of connectivity measures - including static (sFC) and global connectivity (gFC), dynamic connectivity variability (dFC), and spontaneous brain complexity. Compared to placebo, 2C-B and psilocybin selectively reduced intra-network sFC, while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B exhibited less pronounced reductions in between-network FC but elicited elevations in transmodal sFC. Both compounds yielded spatially divergent increases in gFC yet produced similar increases in brain complexity. Using PET density modelling, the spatial distribution of neural effects aligned with documented differences in monoaminergic transporter and serotonergic receptor binding affinity beyond 5-HT2A, highlighting the role of pharmacology in shaping functional dynamics. Lastly, we show behavioural markers of psychedelic effects are non-linearly reflected by the desynchronisation of the transmodal axis of functional brain organisation. Together, our findings highlight 2C-B as a useful new addition to the study of psychedelic neuroscience and may motivate new pharmacotherapy strategies.", "journal": "bioRxiv", "publication_date": "2024-10-21", "publication_year": 2024, "doi": "10.1101/2024.10.22.619393", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.10.22.619393", "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\":\"PPR929517\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Pharmacology,Receptor Pharmacology,Biomarkers,Healthy Volunteers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3098, "title": "The serotonin 1B receptor is required for some of the behavioral effects of psilocybin in mice", "normalized_title": "the serotonin 1b receptor is required for some of the behavioral effects of psilocybin in mice", "authors": "Fleury S, Nautiyal KM.", "abstract": "Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR mediates some of the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotion to psilocybin. We also measured the persisting effects of psilocybin on anhedonia and anxiety-like behavior using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B is involved in mediating the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a mediator of the behavioral and neural effects of psilocybin in mice.", "journal": "bioRxiv", "publication_date": "2024-10-20", "publication_year": 2024, "doi": "10.1101/2024.10.18.618582", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.10.18.618582", "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\":\"PPR928116\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,Neuroplasticity,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": 3106, "title": "Human brain changes after first psilocybin use", "normalized_title": "human brain changes after first psilocybin use", "authors": "Lyons T, Spriggs M, Kerkelä L, Rosas F, Roseman L, Mediano P, Timmermann C, Oestreich L, Pagni B, Zeifman R, Hampshire A, Trender W, Douglass H, Girn M, Godfrey K, Kettner H, Sharif F, Espasiano L, Gazzaley A, Wall M, Erritzoe D, Nutt D, Carhart-Harris R.", "abstract": "ABSTRACT Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is unknown. In a placebo-controlled, within-subjects, electroencephalography, and magnetic resonance imaging study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain changes were detected from one-hour to one-month after a single high-dose (25 mg) of psilocybin. Increases in cognitive flexibility, psychological insight, and well-being were seen at one-month. Diffusion imaging done before and one-month after 25mg psilocybin revealed decreased axial diffusivity bilaterally in prefrontal-subcortical tracts that correlated with decreased brain network modularity over the same time period. Decreased modularity also correlated with improved well-being. Increased cortical signal entropy at 1- and 2-hours post-dosing predicted improved psychological well-being at one-month. Next-day psychological insight mediated the entropy to well-being relationship. All effects were exclusive to 25mg psilocybin; no effects occurred with a 1mg psilocybin ‘placebo’ dose.", "journal": "bioRxiv", "publication_date": "2024-10-13", "publication_year": 2024, "doi": "10.1101/2024.10.11.617955", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.10.11.617955", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR924123\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Aging,Wellbeing", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 993, "title": "Snapshot of 5-HT2A receptor activation in the mouse brain via IP1 detection", "normalized_title": "snapshot of 5 ht2a receptor activation in the mouse brain via ip1 detection", "authors": "de la Fuente Revenga M, González-Maeso J.", "abstract": "The distinct subjective effects that define psychedelics such as LSD, psilocybin or DOI as drug class are causally linked to activation of the serotonin 2A receptor (5-HT2A R). However, some aspects of 5-HT2A R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from non-psychedelic 5-HT2A R agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT2A R engagement of the canonical G q/11 pathway in native tissue. This non-radioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP1 ) in the mouse brain. The specificity of this method was assessed by comparing IP1 levels in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT2A R-KO animals compared to other brain regions, namely striatum and cerebellum. Furthermore, we encountered that head-twitch response (HTR) counts and IP1 in the frontal cortex were correlated. We observed that IP1 levels in frontal cortex homogenates from mice treated with LSD and lisuride vary in magnitude, consistent with LSD’s 5-HT2A R agonism and psychedelic nature, and lisuride’s lack thereof. MDMA evoked an increase of IP1 signal in the frontal cortex that were not matched by the serotonin precursor 5-HTP or the serotonin reuptake inhibitor fluoxetine. We attribute differences in the readout primarily to the indirect stimulation of 5-HT2A R by MDMA via serotonin release from its presynaptic terminals. This methodology enables capturing a snapshot of IP1 turnover in the mouse brain that can provide mechanistic insights in the study of psychedelics and other serotonergic agents pharmacodynamics.", "journal": "bioRxiv", "publication_date": "2024-10-11", "publication_year": 2024, "doi": "10.1101/2024.10.11.617861", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.10.11.617861", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR923549\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "End-of-Life Distress,Neuroplasticity,Pharmacology,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": 3124, "title": "Psilocybin prevents habituation to familiar stimuli and preserves sensitivity to sound following repeated stimulation in mouse primary auditory cortex", "normalized_title": "psilocybin prevents habituation to familiar stimuli and preserves sensitivity to sound following repeated stimulation in mouse primary auditory cortex", "authors": "Lane CP, Tarka VM, Valentin O, Lehmann A, Hamel E, de Villers-Sidani E.", "abstract": "Psilocybin, a psychoactive substance derived from fungi, has been utilized historically by diverse cultures for both medicinal and non-medicinal purposes, owing to its ability to elicit profound sensory and cognitive alterations and sustain long-term changes in mood and cognition. Promising results from recent clinical studies have generated a wave of interest in employing psilocybin to treat neuropsychiatric and neuro-degenerative conditions. How psychedelics cause acute perceptual effects, and how these relate to long-lasting alterations is still debated. Whereas it is thought that perceptual disturbances may be caused by disrupted flow of information between sensory and higher order areas, in vivo studies have focused mostly on the latter. In particular, there has been little study of how psilocybin affects sensory representations in primary auditory cortex (A1). We used two-photon microscopy and wide field calcium imaging to examine how psilocybin affects A1 neuron response properties in the mouse. Administration of 1 mg/kg psilocybin prevented habituation of sound-evoked responses to repeated stimuli, maintaining overall responsiveness, bandwidth, and sound-level response thresholds after repeated stimulation. This was in contrast to marked habituation of responses and narrowing of tuning in controls. We observed no effect on overall distribution of best frequencies at the cortical level, suggesting psilocybin in A1 disrupts normal sensory gating, rather than tonotopic organization. This supports models of psychedelic action in which perceptual disturbances are driven by disrupted hierarchical sensory gating. With further research, influences of psychedelics on sensory representations could be harnessed to target maladaptive sensory processing in conditions such as tinnitus. Significance Statement Despite its role in altering auditory sensory perception, the impact of psilocybin on modulating neuronal activity in the auditory cortex remains understudied. This study is the first to identify an inhibition of normal auditory habituation to repeated stimuli with single-neuron resolution. We identify a role for psilocybin in the targeted, context-dependent modulation of auditory sensory neural tuning properties, which may help to explain how disruption of hierarchical control of sensory representations leads to perceptual disturbances. With further work, this influence on sensory representations could be used to target conditions where maladaptive sensory processing leads to deleterious health outcomes.", "journal": "bioRxiv", "publication_date": "2024-09-29", "publication_year": 2024, "doi": "10.1101/2024.09.27.614985", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.09.27.614985", "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\":\"PPR917832\",\"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": 3151, "title": "Distinct classes of antidepressants commonly act to shape pallidal structure and function in mice", "normalized_title": "distinct classes of antidepressants commonly act to shape pallidal structure and function in mice", "authors": "Abe Y, Sugiura Y, Maeda R, Taira S, Yoshida K, Ibi D, Moritoh S, Hashimoto K, Yagishita S, Tanaka KF.", "abstract": "Antidepressants including selective serotonin reuptake inhibitors, ketamine, and psilocybin are all effective for treating depression despite their distinct primary mechanisms. We hypothesized that these drugs may share a common mechanism that underlies their therapeutic actions. We treated mice with one of the following: escitalopram, R- / S -/ RS- ketamine, or psilocin. Additionally, groups exposed to electroconvulsive stimulation and a saline control were included. Following treatment, fixed brains underwent structural magnetic resonance imaging, and voxel-based morphometry was performed to evaluate brain-wide volumetric changes. Compared with control treatment, we observed greater volumes in the nucleus accumbens, ventral pallidum, and external globus pallidus across all antidepressant treatments, and a smaller volume in the mediodorsal thalamus. Specifically, R -ketamine, RS -ketamine, and psilocin induced more pronounced hypertrophy of the ventral pallidum, whereas selective serotonin reuptake inhibitors and S -ketamine predominantly increased the volume of the external globus pallidus. Further analyses using super-resolution microscopy and imaging mass spectrometry revealed corresponding microstructural and molecular changes. Greater pallidal volume was associated with striatal medium spiny neuron terminal hypertrophy and elevated γ-aminobutyric acid (GABA) levels. Interestingly, all antidepressants were also associated with higher striatal dopamine content. Moreover, striatal vesicular GABA transporter overexpression reproduced the medium spiny neuron terminal hypertrophy and increased pallidal GABA content, and was associated with a reduction in innate anxiety. These findings indicate that despite their pharmacological diversity, antidepressant treatments lead to shared pallidum-centered structural and molecular changes. We propose that these shared changes may potentiate the striato-pallidal inhibitory circuit, thereby contributing to the overall antidepressant effect.", "journal": "bioRxiv", "publication_date": "2024-09-23", "publication_year": 2024, "doi": "10.1101/2024.09.23.614626", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.09.23.614626", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:47", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR914838\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,End-of-Life Distress,Brain Imaging,Mechanism of Action,Receptor Pharmacology,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": 3144, "title": "Premorbid Characteristics of the SAPAP3-Mouse Model of Obsessive-Compulsive Disorder: Behavior, Neuroplasticity, and Psilocybin Treatment", "normalized_title": "premorbid characteristics of the sapap3 mouse model of obsessive compulsive disorder behavior neuroplasticity and psilocybin treatment", "authors": "Lazar M, Brownstien M, Botvinnik A, Shevakh C, Shahar O, Lifschytz T, Lerer B.", "abstract": "Background SAPAP3-knockout (KO) mice develop excessive self-grooming behavior at 4-6 months of age, serving as a model for obsessive-compulsive disorder (OCD). Given that anxiety often precedes OCD diagnosis in humans, this study investigated whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype, and whether such behaviors respond to psilocybin treatment. The study also examined four key neuroplasticity-related synaptic proteins-GAP43, PSD95, synaptophysin, and SV2A - as SAPAP3 is a postsynaptic scaffold protein that interacts with PSD95 and may affect synaptic function. Methods Two studies were conducted using male and female juvenile (10-13 weeks) SAPAP3- KO mice. Study 1 compared behavioral phenotypes between homozygous (HOM), heterozygous (HET), and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of psilocybin (4.4 mg/kg) on identified behavioral differences. Both studies included comprehensive behavioral testing focused on anxiety, social interaction, and cognitive function. Additionally, levels of four synaptic proteins were measured by western blots in the frontal cortex, hippocampus, amygdala, and striatum of juvenile and adult SAPAP3-KO mice. Results In both studies, juvenile HOM SAPAP3-KO mice showed significant anxiety-like behaviors compared to WT mice, spending less time in open field center, and elevated plus maze open arms. They also buried fewer marbles and found fewer buried Oreos than WT mice. Psilocybin treatment did not improve these behavioral manifestations. Analysis of synaptic proteins revealed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions in adult male HOM mice and of SV2A in the frontal cortex of HOM females compared to WT, but not in juvenile mice of either sex. Conclusions Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling the prodromal anxiety often seen in human OCD. Unlike in adult SAPAP3-KO mice, these early manifestations were not responsive to psilocybin treatment. The age-dependent increases in synaptic proteins observed in adult but not juvenile male SAPAP3-KO mice and to a lesser extent in females, may represent compensatory plasticity changes in response to the phenotype. These results provide insights into the developmental trajectory of OCD-like behaviors and associated neuroplastic adaptations. Significance Statement Obsessive-compulsive disorder (OCD) frequently emerges during adolescence, with anxiety as a common prodromal symptom. This study investigated behavioral and molecular characteristics of juvenile SAPAP3 knockout (KO) mice, an established preclinical model of OCD, prior to manifestation of their characteristic excessive grooming phenotype. Juvenile SAPAP3 KO mice exhibited significant anxiety-like behaviors on multiple behavioral measures. While psilocybin treatment reduces OCD-like behaviors in adult SAPAP3 knockout mice, it did not ameliorate anxiety-like behaviors in juvenile mice, indicating age-dependent therapeutic effects. Notably, adult male SAPAP3 KO mice showed elevated levels of synaptic plasticity-related proteins in emotion-regulatory brain regions, whereas juvenile KO showed no such alterations. These findings demonstrate that anxiety precedes compulsive behaviors in this model and reveal age- dependent neuroplasticity changes. This developmental trajectory parallels clinical observations in OCD and provides a framework for investigating early intervention strategies.", "journal": "bioRxiv", "publication_date": "2024-09-22", "publication_year": 2024, "doi": "10.1101/2024.09.22.614317", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.09.22.614317", "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\":\"PPR914309\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Anxiety,OCD,Neuroplasticity,Emotional Processing,Animal Study,Drug Interactions", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3268, "title": "A virtual clinical trial of psychedelics to treat patients with disorders of consciousness", "normalized_title": "a virtual clinical trial of psychedelics to treat patients with disorders of consciousness", "authors": "Alnagger NL, Cardone P, Martial C, Sanz Perl Y, Mindlin I, Sitt JD, Roseman L, Carhart-Harris R, Nutt D, Mallaroni P, Mason NL, Ramaekers JG, Bonhomme V, Laureys S, Deco G, Gosseries O, Nunez P, Annen J.", "abstract": "Disorders of consciousness (DoC), including the unresponsive wakefulness syndrome (UWS) and the minimally conscious state (MCS), have limited treatment options. Recent research suggests that psychedelic drugs, known for their complexity-enhancing properties, could be promising treatments for DoC. This study uses whole-brain computational models to explore this potential. We created individualised models for DoC patients, optimised with empirical fMRI and diffusion-weighted imaging (DWI) data, and simulated the administration of LSD and psilocybin. We used an in-silico perturbation protocol to distinguish between different states of consciousness, including DoC, anaesthesia, and the psychedelic state, and assess the dynamical stability of the brains of DoC patients pre- and post-psychedelic simulation. Our findings indicate that LSD and psilocybin shift DoC patients' brains closer to criticality, with a greater effect in MCS patients. In UWS patients, the treatment response correlates with structural connectivity, while in MCS patients, it aligns with baseline functional connectivity. This virtual clinical trial lays a computational foundation for using psychedelics in DoC treatment and highlights the future role of computational modelling in drug discovery and personalised medicine.", "journal": "bioRxiv", "publication_date": "2024-08-18", "publication_year": 2024, "doi": "10.1101/2024.08.16.608251", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.08.16.608251", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:49", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR897826\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Consciousness,Aging,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": 3202, "title": "Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression - comparison with ketamine, fluoxetine and lithium", "normalized_title": "effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression comparison with ketamine fluoxetine and lithium", "authors": "Vella Y, Syrova K, Petruskova A, Koutrouli I, Kutna V, Pala J, Nikolic M, Sichova K, Mazoch V, Jurok R, Kuchar M, Bendova Z, Palenicek T.", "abstract": "Background: Recent evidence suggests that psychedelics are able to induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although exact underlying molecular mechanisms remain unclear. Aims: This study investigates selected neuroplastic effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro. Methods: Rat primary cortical cultures were treated with 10 uM psilocin, 1 uM lysergic acid diethylamide (LSD), 90 uM N, N-dimethyltryptamine (DMT), 1 uM ketamine, 10 uM fluoxetine and 5 mM lithium. Analysis of synaptic puncta was performed; puncta of presynaptic marker synapsin I/II, postsynaptic density protein 95 (PSD-95), and their co-localization (established synapse) were assessed 24 h after drug treatment. Next, expressions of immediate early genes (IEGs) encoding activity-regulated cytoskeleton-associated protein (Arc), early growth response 1 (Egr1), and neuronal PAS (Per-ArntSim) domain protein 4 (Npas4) were analysed 1 and 24 h after drug treatments. Results: Psilocin increased synaptic puncta count and induced Arc expression. The effect to promote synaptogenesis was comparable to ketamine and lithium; ketamine additionally increased PSD-95 puncta count. LSD and DMT didn't induce any significant effect. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated Egr1 and Npas4. Conclusions: Psilocin demonstrated a significant neuroplastic effect comparable to that of ketamine and lithium, adding another piece of evidence to its profile as a promising therapeutic agent.", "journal": "bioRxiv", "publication_date": "2024-08-08", "publication_year": 2024, "doi": "10.1101/2024.08.07.606965", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.08.07.606965", "keywords": "", "substance_tags": "psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR892617\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Mechanism of Action,Biomarkers,Animal Study,In Vitro Study", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3119, "title": "Molecular insights into the modulation of the 5HT 2A receptor by serotonin, psilocin, and the G protein subunit Gqα", "normalized_title": "molecular insights into the modulation of the 5ht 2a receptor by serotonin psilocin and the g protein subunit gqα", "authors": "Viohl N, Zanjani AAH, Khandelia H.", "abstract": "SUMMARY The 5HT 2A receptor (5HT 2A R) is a G protein-coupled receptor that drives many neuronal functions and is one of the primary targets for psychedelic drugs, which have recently shown promise in treating mental disorders. Understanding ligand interactions and conformational transitions is essential for developing effective pharmaceuticals, but mechanistic details of 5HT 2A R activation and ligand binding modes remain poorly understood. We conducted all-atom molecular dynamics simulations and free energy calculations of the active and inactive forms of 5HT 2A R with psilocin and serotonin. Both serotonin and psilocin have higher binding affinities for the orthosteric binding pocket than the extended binding pocket. Active state 5HT 2A R collapses to a closed state in the absence of Gqα. We also discover a ‘partially-open’ receptor conformation that is intermediate between the active and inactive states. Our discoveries can inform the design of new pharmaceuticals that target specific receptor conformations, potentially leading to more effective treatments for mental disorders.", "journal": "bioRxiv", "publication_date": "2024-07-23", "publication_year": 2024, "doi": "10.1101/2024.07.23.604750", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.07.23.604750", "keywords": "", "substance_tags": "psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:47", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR886272\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Receptor Pharmacology,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 45, "title": "Psychedelics relax predictive processing in the post-acute period by remodeling cortico-cortical feedback circuits", "normalized_title": "psychedelics relax predictive processing in the post acute period by remodeling cortico cortical feedback circuits", "authors": "West CL, Imai F, Bastos G, Hornick MA, Rachmany L, Duran A, Nadeem S, Ricci D, Rader Groves AM, Wargo JA, Van Leeuwen N, Sershen H, Yaragudri Vinod K, Peterka DS, Hamm JP.", "abstract": "Serotonergic psychedelics (e.g., psilocybin, LSD) have potential to treat psychiatric disorders, with therapeutic effects lasting days to weeks after a single dose. Prominent theories suggest that psychedelics have a lasting effect on hierarchical brain circuits, reducing top-down influence on information processing to facilitate an unbiased, bottom-up reassessment of the world, but direct and concrete evidence for such an effect is lacking. Here we directly tested this hypothesis in both humans and mice, assessing predictive processing in the fronto-visual system in the days after a single psychedelic exposure. Individuals who recently (", "journal": "bioRxiv", "publication_date": "2024-07-05", "publication_year": 2024, "doi": "10.1101/2024.07.03.601959", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.07.03.601959", "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\":\"PPR877954\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "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": 812, "title": "Striking Long Term Beneficial Effects of Single Dose Psilocybin and Psychedelic Mushroom Extract in the SAPAP3 Rodent Model of OCD-Like Excessive Self-Grooming", "normalized_title": "striking long term beneficial effects of single dose psilocybin and psychedelic mushroom extract in the sapap3 rodent model of ocd like excessive self grooming", "authors": "Brownstien M, Lazar M, Botvinnik A, Shevakh C, Blakolmer K, Lerer L, Lifschytz T, Lerer B.", "abstract": "Obsessive compulsive disorder (OCD) is a highly prevalent disorder that causes serious disability. Available treatments leave 40% or more of people with OCD significantly symptomatic. There is an urgent need for novel therapeutic approaches. Mice that carry a homozygous deletion of the SAPAP3 gene (SAPAP3 KO) manifest a phenotype of excessive self-grooming, tic-like head-body twitches and anxiety. These behaviors closely resemble pathological self-grooming behaviors observed in humans in conditions that overlap with OCD. Following a preliminary report that the tryptaminergic psychedelic, psilocybin, may reduce symptoms in patients with OCD, we undertook a randomized controlled trial of psilocybin in 50 SAPAP3 KO mice (28 male, 22 female). Mice that fulfilled inclusion criteria were randomly assigned to a single intraperitoneal injection of psilocybin (4.4 mg/kg), psychedelic mushroom extract (encompassing the same psilocybin dose) or vehicle control and were evaluated after 2, 4 and 21 days by a rater blind to treatment allocation for grooming characteristics, head-body twitches, anxiety and other behavioral features. Mice treated with vehicle (n=18) manifested a 118.71 + 95.96 % increase in total self-grooming (the primary outcome measure) over the 21-day observation period. In contrast, total self-grooming decreased by 14.60% + 17.90% in mice treated with psilocybin (n=16) and by 19.20 + 20.05% in mice treated with psychedelic mushroom extract (n=16) (p=.001 for effect of time; p=.0001 for time X treatment interaction). 5 mice were dropped from the vehicle group because they developed skin lesions; 4 from the psilocybin group and none from the psychedelic mushroom extract group. Secondary outcome measures such as head-body twitches and anxiety all showed a significant improvement over 21 days. Notably, in mice that responded to psilocybin (n=12) and psychedelic mushroom extract (n=13), the beneficial effect of a single treatment persisted up to 7 weeks. Mice initially treated with vehicle and non-responsive, showed a clear and lasting therapeutic response when treated with a single dose of psilocybin or psychedelic mushroom extract and followed for a further 3 weeks. While equivalent to psilocybin in overall effect on self-grooming, psychedelic mushroom extract showed superior effects in alleviating head-body twitches and anxiety. These findings strongly justify clinical trials of psilocybin in the treatment of OCD and further studies aimed at elucidating mechanisms that underlie the long-term effects to alleviate excessive self-grooming observed in this study. Graphical Abstract Prepared with BioRender ( https://www.biorender.com/ )", "journal": "bioRxiv", "publication_date": "2024-06-28", "publication_year": 2024, "doi": "10.1101/2024.06.25.600634", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.06.25.600634", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR875056\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Anxiety,OCD,Mechanism of Action,Clinical Trial,Randomized Controlled Trial,Animal Study,Drug Interactions", "study_type": "Randomized Controlled Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3353, "title": "Ketamine-Induced Unresponsiveness Shows a Harmonic Shift from Global to Localised Functional Organisation", "normalized_title": "ketamine induced unresponsiveness shows a harmonic shift from global to localised functional organisation", "authors": "Van Maldegem M, Vohryzek J, Atasoy S, Alnagger N, Cardone P, Bonhomme V, Vanhaudenhuyse A, Demertzi A, Jaquet O, Bahri MA, Kringelbach ML, Stamatakis EA, Luppi AI.", "abstract": "Ketamine is classified as a dissociative anaesthetic that, in sub-anaesthetic doses, can produce an altered state of consciousness characterised by dissociative symptoms, visual and auditory hallucinations, and perceptual distortions. Given the anaesthetic-like and psychedelic-like nature of this compound, it is expected to have different effects on brain dynamics in anaesthetic doses than in low, sub-anaesthetic doses. We investigated this question using connectome harmonic decomposition (CHD), a recently developed method to decompose brain activity in terms of the network organisation of the underlying human structural connectome. Previous research using this method has revealed connectome harmonic signatures of consciousness and responsiveness, with increased influence of global network structure in disorders of consciousness and propofol-induced sedation, and increased influence of localised patterns under the influence of classic psychedelics and sub-anaesthetic doses of ketamine, as compared to normal wakefulness. When we applied the CHD analytical framework to resting-state fMRI data of volunteers during ketamine-induced unresponsiveness, we found increased prevalence of localised harmonics, reminiscent of altered states of consciousness. This is different from traditional GABAergic sedation, where instead the prevalence of global rather than localised harmonics seems to increase with higher doses. In addition, we found that ketamine’s harmonic signature shows higher alignment with those seen in LSD- or psilocybin-induced psychedelic states than those seen in unconscious individuals, whether due to propofol sedation or brain injury. Together, the results indicate that ketamine-induced unresponsiveness, which does not necessarily suppress conscious experience, seems to influence the prevalence of connectome harmonics in the opposite way compared to GABAergic hypnotics. We conclude that the CHD framework offers the possibility to track alterations in conscious awareness (e.g., dreams, sensations) rather than behavioural responsiveness - a discovery made possible by ketamine’s unique property of decoupling these two facets.", "journal": "bioRxiv", "publication_date": "2024-06-24", "publication_year": 2024, "doi": "10.1101/2024.06.20.599885", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.06.20.599885", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:51", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR872399\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Consciousness", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3338, "title": "Increased 5-HT2A receptor signalling efficacy differentiates serotonergic psychedelics from non-psychedelics", "normalized_title": "increased 5 ht2a receptor signalling efficacy differentiates serotonergic psychedelics from non psychedelics", "authors": "Ippolito A, Vasudevan S, Hurley S, Gilmour G, Westhorpe F, Churchill G, Sharp T.", "abstract": "ABSTRACT Background and Purpose Serotonergic psychedelic drugs are under renewed investigation for the potential treatment of several psychiatric disorders. While all serotonergic psychedelics have 5-HT2A receptor activity, the explanation for why some 5-HT2A receptor agonists are not psychedelic is unknown. To address this question, we investigated the 5-HT2A receptor signalling bias and efficacy of a panel of psychedelics and non-psychedelics. Experimental Approach G -coupled (Ca 2+ and IP) and β-arrestin2 signalling effects of eight chemically diverse psychedelics (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe and DOI) and non-psychedelics (lisuride and TBG) were characterised using SH-SY5Y cells expressing recombinant human 5-HT2A receptors. Measurements of signalling efficacy and bias were derived from dose-responses curves for each agonist, compared to 5-HT. Follow-up experiments sought to confirm the generality of findings using rat C6 cells expressing endogenous 5-HT2A receptors. Key Results In SH-SY5Y cells, all psychedelics were partial agonists at both 5-HT2A receptor signalling pathways and none showed significant signalling bias. In comparison, in SH-SY5Y cells the non-psychedelics lisuride and TBG were not distinguishable from psychedelics in terms of biased agonist properties, but both exhibited the lowest 5-HT2A receptor signalling efficacy of all drugs tested, a result confirmed in C6 cells. Conclusion and Implications In summary, all psychedelics tested were unbiased, partial 5-HT2A receptor agonists. Importantly, the non-psychedelics lisuride and TBG were discriminated from psychedelics, not through biased signalling but rather by relatively low efficacy. Thus, 5-HT2A receptor signalling efficacy and not bias provides a possible explanation for why some 5-HT2A receptor agonists are not psychedelic.", "journal": "bioRxiv", "publication_date": "2024-06-15", "publication_year": 2024, "doi": "10.1101/2024.06.13.594677", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.06.13.594677", "keywords": "", "substance_tags": "psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:51", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR868508\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "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": 3130, "title": "Co-administration of midazolam and psilocybin: Differential effects on subjective quality versus memory of the psychedelic experience", "normalized_title": "co administration of midazolam and psilocybin differential effects on subjective quality versus memory of the psychedelic experience", "authors": "Nicholas CR, Banks MI, Lennertz RL, Wenthur CJ, Krause BM, Riedner BA, Smith RF, Hutson PR, Sauder CJ, Dunne JD, Roseman L, Raison CL.", "abstract": "Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.", "journal": "bioRxiv", "publication_date": "2024-06-12", "publication_year": 2024, "doi": "10.1101/2024.06.13.598878", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.06.13.598878", "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\":\"PPR867616\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Wellbeing,Healthy Volunteers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 726, "title": "Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats", "normalized_title": "psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats", "authors": "Floris G, Dabrowski KR, Zanda MT, Daws SE.", "abstract": "Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2A R), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2A R agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2A R antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2A R antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ∼2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including Il17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.", "journal": "bioRxiv", "publication_date": "2024-05-31", "publication_year": 2024, "doi": "10.1101/2024.05.28.596205", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.05.28.596205", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR860490\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Addiction,Mechanism of Action,Receptor Pharmacology,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": 1128, "title": "Time-resolved coupling between connectome harmonics and subjective experience under the psychedelic DMT", "normalized_title": "time resolved coupling between connectome harmonics and subjective experience under the psychedelic dmt", "authors": "Vohryzek J, Luppi A, Atasoy S, Deco G, Timmermann C, Carhart-Harris RL, Kringelbach ML.", "abstract": "Exploring the intricate relationship between brain's structure and function, and how this affects subjective experience is a fundamental pursuit in neuroscience. Psychedelic substances offer a unique insight into the influences of specific neurotransmitter systems on perception, cognition and consciousness. Specifically, their impact on brain function propagates across the structural connectome, a network of white matter pathways linking different regions. To comprehensively grasp the effects of psychedelic compounds on brain function, we used a theoretically rigorous framework known as connectome harmonic decomposition. This framework provides a robust method to characterize how brain function intricately depends on the organized network structure of the human connectome. We show that the connectome harmonic repertoire under DMT is reshaped in line with other reported psychedelic compounds; psilocybin, LSD and ketamine. Furthermore, we show that the repertoire entropy of connectome harmonics increases under DMT, as with those other psychedelics. Importantly, we demonstrate for the first time that measures of energy spectrum difference and repertoire entropy of connectome harmonics indexes the intensity of subjective experience of the participants in a time-resolved manner reflecting close coupling between connectome harmonics and subjective experience.", "journal": "bioRxiv", "publication_date": "2024-05-30", "publication_year": 2024, "doi": "10.1101/2024.05.30.596410", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.05.30.596410", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR860621\",\"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": 819, "title": "Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression", "normalized_title": "classification of psychedelics and psychoactive drugs based on brain wide imaging of cellular c fos expression", "authors": "Aboharb F, Davoudian PA, Shao L, Liao C, Rzepka GN, Wojtasiewicz C, Indajang J, Dibbs M, Rondeau J, Sherwood AM, Kaye AP, Kwan AC.", "abstract": "Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.", "journal": "bioRxiv", "publication_date": "2024-05-25", "publication_year": 2024, "doi": "10.1101/2024.05.23.590306", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.05.23.590306", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR858281\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Brain Imaging,Biomarkers,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": 3118, "title": "Psilocybin increases optimistic engagement over time: computational modelling of behavior in rats", "normalized_title": "psilocybin increases optimistic engagement over time computational modelling of behavior in rats", "authors": "Fisher EL, Smith R, Corcoran AW, Milton LK, Conn K, Hohwy J, Foldi CJ.", "abstract": "Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit computational models of underlying decision-making mechanisms to behaviour in rats. The model revealed that rats treated with psilocybin achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.", "journal": "bioRxiv", "publication_date": "2024-05-16", "publication_year": 2024, "doi": "10.1101/2024.05.16.594614", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.05.16.594614", "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\":\"PPR853997\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Mechanism of Action,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": 3129, "title": "Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors", "normalized_title": "psilocybin facilitates fear extinction importance of dose context and serotonin receptors", "authors": "Woodburn SC, Levitt CM, Koester AM, Kwan AC.", "abstract": "ABSTRACT A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for posttraumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin’s potential effect in fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin’s effect on fear extinction are not understood. In this study, we used an auditory delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, though these changes were sensitive to dose. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug’s effects. Co-treatment with a 5-HT2A receptor antagonist blocked psilocybin’s effects for extinction, extinction retention and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin’s ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.", "journal": "bioRxiv", "publication_date": "2024-05-05", "publication_year": 2024, "doi": "10.1101/2024.05.04.592469", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.05.04.592469", "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\":\"PPR848036\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "PTSD,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": 3311, "title": "Effects of Classical Psychedelics on Implicit and Explicit Emotional Empathy and Cognitive Empathy: A Meta-analysis of MET task", "normalized_title": "effects of classical psychedelics on implicit and explicit emotional empathy and cognitive empathy a meta analysis of met task", "authors": "Olami A, Peled-Avron L.", "abstract": "This meta-analysis investigates the effect of classic psychedelic drugs on empathy and focuses on cognitive and emotional empathy measured using the Multifaceted Empathy Test (MET). Empathy entails the ability to understand and share the feelings of another and is a significant component of social interaction. Several studies have examined the effects of psychedelic drugs such as LSD, psilocybin and ayahuasca on empathy, yet their overall effect has not been studied so far. In this meta analysis, we reviewed data from studies up to November 2023 with the aim of examining the effects of various psychedelic drugs on empathic abilities broadly. Our findings suggest that classical psychedelics significantly enhance explicit and implicit emotional empathy without affecting measures of cognitive empathy. The results emphasize the need to continue testing the therapeutic potential of classic psychedelic drugs.", "journal": "bioRxiv", "publication_date": "2024-05-04", "publication_year": 2024, "doi": "10.1101/2024.05.02.592231", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.05.02.592231", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:50", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR848109\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Emotional Processing,Meta-Analysis,Review Article,Drug Interactions", "study_type": "Meta-Analysis", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3366, "title": "The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents", "normalized_title": "the selective 5 ht2a receptor agonist lph 5 induces persistent and robust antidepressant like effects in rodents", "authors": "Jensen AA, Cecchi CR, Hibicke M, Bach AH, Kaadt E, Märcher-Rørsted E, Nichols CD, Elfving B, Kristensen JL.", "abstract": "ABSTRACT Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the results of an elaborate preclinical characterization of one such compound, LPH-5 [( S )-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2A receptor (5-HT2A R) and to exhibit pronounced selectivity for this receptor over the related 5-HT2B and 5-HT2C receptors in a range of functional assays. LPH-5 (0.375 - 12.0 mg/kg, i.p. ) dose-dependently induced head-twitch responses (HTR) in Sprague Dawley rats, with substantial 5-HT2A R engagement being observed at 0.5-1.0 mg/kg. Acute administration of LPH-5 (1.5 mg/kg, i.p.) induced robust antidepressant-like effects in Flinders Sensitive Line rats and adrenocorticotropic hormone-treated Sprague Dawley rats, and LPH-5 (0.3 and 1.5 mg/kg, i.p.) induced significant effects in a recently developed Wistar Kyoto rat model proposed to reflect the long-term antidepressant-like effects produced by psychedelics in humans. In conclusion, selective 5-HT2A R activation, as mediated here by LPH- 5, seems to hold antidepressant potential, suggesting that this activity component is key for the beneficial effects of classical psychedelics. Hence, we propose that LPH-5 and other 5-HT2A R- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.", "journal": "bioRxiv", "publication_date": "2024-04-21", "publication_year": 2024, "doi": "10.1101/2024.04.19.590212", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.04.19.590212", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:51", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR841168\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Receptor Pharmacology,Clinical Trial,Animal Study", "study_type": "Clinical Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3331, "title": "A dual-receptor model of serotonergic psychedelics", "normalized_title": "a dual receptor model of serotonergic psychedelics", "authors": "Juliani A, Chelu V, Graesser L, Safron A.", "abstract": "Serotonergic psychedelics have been identified as promising next-generation therapeutic agents in the treatment of mood and anxiety disorders. While their efficacy has been increasingly validated, the mechanism by which they exert a therapeutic effect is still debated. A popular theoretical account is that excessive 5-HT2a agonism disrupts cortical dynamics, relaxing the precision of maladaptive high-level beliefs and making them more malleable and open to revision. We extend this perspective by developing a simple energy-based model of cortical dynamics based on predictive processing which incorporates effects of neuromodulation. Using this model, we propose and simulate hypothetical computational mechanisms for both 5-HT2a and 5-HT1a agonism. Results from our model are able to account for a number of existing empirical observations concerning serotonergic psychedelics effects on cognition and affect. Using the findings of our model, we provide a theoretically-grounded hypothesis for the clinical success of LSD, psilocybin, and DMT, as well as identify the design space of biased 5-HT1a agonist psychedelics such as 5-MeO-DMT as potentially fruitful in the development of more effective and tolerable psychotherapeutic agents in the future.", "journal": "bioRxiv", "publication_date": "2024-04-14", "publication_year": 2024, "doi": "10.1101/2024.04.12.589282", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.04.12.589282", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:50", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR838073\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Anxiety,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": 1226, "title": "Psilocybin induces dose-dependent changes in functional network organization in rat cortex", "normalized_title": "psilocybin induces dose dependent changes in functional network organization in rat cortex", "authors": "Silverstein BH, Kolbman N, Nelson A, Liu T, Guzzo P, Gilligan J, Lee U, Mashour GA, Vanini G, Pal D.", "abstract": "Psilocybin produces an altered state of consciousness in humans and is associated with complex spatiotemporal changes in brain networks. Given the emphasis on rodent models for mechanistic studies, there is a need for characterization of the effect of psilocybin on brain-wide network dynamics. Previous rodent studies of psychedelics, using electroencephalogram, have primarily been done with sparse electrode arrays that offered limited spatial resolution precluding network level analysis, and have been restricted to lower gamma frequencies. Therefore, in the study, we used electroencephalographic recordings from 27 sites (electrodes) across rat cortex ( n =6 male, 6 female) to characterize the effect of psilocybin (0.1 mg/kg, 1 mg/kg, and 10 mg/kg delivered over an hour) on network organization as inferred through changes in node degree (index of network density) and connection strength (weighted phase-lag index). The removal of aperiodic component from the electroencephalogram localized the primary oscillatory changes to theta (4-10 Hz), medium gamma (70-110 Hz), and high gamma (110-150 Hz) bands, which were used for the network analysis. Additionally, we determined the concurrent changes in theta-gamma phase-amplitude coupling. We report that psilocybin, in a dose-dependent manner, 1) disrupted theta-gamma coupling [ p", "journal": "bioRxiv", "publication_date": "2024-02-11", "publication_year": 2024, "doi": "10.1101/2024.02.09.579718", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.02.09.579718", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR804295\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Consciousness,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": 673, "title": "Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles", "normalized_title": "psilocybin enhanced fear extinction linked to bidirectional modulation of cortical ensembles", "authors": "Rogers SA, Heller EA, Corder G.", "abstract": "The serotonin 2 receptor (5HT2R) agonist psilocybin displays rapid and persistent therapeutic efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. A single dose of psilocybin induced ensemble turnover between fear learning and extinction days while oppositely modulating activity in fearand extinctionactive neurons. The acute suppression of fear-active neurons and delayed recruitment of extinction-active neurons were predictive of psilocybin-enhanced fear extinction. A computational model revealed that acute inhibition of fear-active neurons by psilocybin is sufficient to explain its neural and behavioral effects days later. These results align with our hypothesis and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.", "journal": "bioRxiv", "publication_date": "2024-02-03", "publication_year": 2024, "doi": "10.1101/2024.02.04.578811", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.02.04.578811", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:04", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR800731\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Receptor Pharmacology,Aging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3125, "title": "Psilocybin biphasically modulates cortical and behavioral activity in mice", "normalized_title": "psilocybin biphasically modulates cortical and behavioral activity in mice", "authors": "Brockett AT, Francis NA.", "abstract": "SUMMARY Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted 2-photon imaging experiments in auditory cortex of awake mice and video analysis of mouse behavior, both at baseline and during psilocybin treatment. We found biphasic effects of psilocybin on behavioral and cortical activity. A2 mg/kg dose of psilocybin initially increased behavioral activity and neural responses to sound. 30 minutes post-dose, mice became behaviorally hypoactive and cortical responses to sound decreased, while neural response variance and noise correlations increased. In contrast, neuronal selectivity for auditory stimuli remained stable during psilocybin treatment. Our results suggest that psilocybin modulates the role of intrinsic versus stimulus-driven activity in sensory cortex, while preserving fundamental sensory processing. Graphical Abstract. Summary of psilocybin’s effect on auditory cortical responses to sound in mice. 30 minutes after injecting the inert vehicle saline, typical auditory responses occur within a relatively narrow range of possible amplitudes, i.e., each neuron’s response variance is weakly correlated with a neighboring neuron’s response variance. In contrast, 30 minutes after injecting 2 mg/kg of psilocybin, population response variance becomes more correlated between individual neurons, and the range of response amplitudes increases. These findings suggest that psilocybin modulates the role of intrinsic versus stimulus-driven neural activity in sensory perception, which may serve as a basis for auditory hallucination at the level of neuronal micro-circuits.", "journal": "bioRxiv", "publication_date": "2024-01-19", "publication_year": 2024, "doi": "10.1101/2024.01.18.576229", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.01.18.576229", "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\":\"PPR790246\",\"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": 3076, "title": "Psilocybin Promotes Cell-Type-Specific Changes in the Orbitofrontal Cortex Revealed by Single-Nucleus RNA-seq", "normalized_title": "psilocybin promotes cell type specific changes in the orbitofrontal cortex revealed by single nucleus rna seq", "authors": "Huang Z, Wei X, Wang Y, Tian J, Dong J, Liang B, Lu L, Zhang W.", "abstract": "Recent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT2A receptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC), a brain region vulnerable to psychological disorders such as depression. We showed that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and excitatory and inhibitory neurons collectively reduced circuit activity of the brain region. Knockdown of 5-HT2A receptor in deep layer excitatory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.", "journal": "bioRxiv", "publication_date": "2024-01-06", "publication_year": 2024, "doi": "10.1101/2024.01.07.573163", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.01.07.573163", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:00", "raw_json": "{\"europe_pmc_id\":\"PPR783465\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Addiction,OCD,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": 3066, "title": "Behavioural Investigations of Psilocybin in Animals 1962-2021: A Scoping Review", "normalized_title": "behavioural investigations of psilocybin in animals 1962 2021 a scoping review", "authors": "Shore R, Dobson K, Thomson N, Barnim N, Bergman H, Rideout K, McKeown S, Olmstead MC, Goldie C, Dumont E.", "abstract": "Background and Aims Psilocybin is a psychedelic drug that may hold promise for a wide range of human health conditions, yet the identification of therapeutic processes and mechanisms of action remains exploratory. We conducted a scoping review on pre-clinical behavioural investigations of psilocybin in non-human animals to help determine the behavioural effects of psilocybin in non-human animals, to identify studies completed, behavioural tests employed, and what dosing modalities had been studied. Methods A librarian-conducted literature search was performed using predefined key terms and search criteria and additional searching was conducted by reviewers, using electronic databases, grey literature sources, and reference lists of relevant articles or reviews. The final search updated occurred in October, 2021. Studies were reviewed, screened and selected against an a priori protocol using Covidence software by multiple reviewers with results plotted across the Research Domains Criteria construct. Results From 4124 records identified by database searching, 260 publications were subjected to full-text review with 77 studies included in this scoping review, published between 1962-2021. The preponderance of studies (n=64) investigated behavioural outcomes in rodents. Only 43 studies (55.8%) reported on housing conditions, and seventeen studies (22.1%) failed to report sample size. All studies reported behavioural outcomes following drug administration, with fifty-one studies (66.2%) using psilocybin, thirty studies (42.9%) psilocin, four studies (5.2%) administering whole mushroom extracts (WME), and a further eight studies investigating both psilocybin and psilocin and one study reporting the effects of both psilocin and WME. One hundred and thirty distinct behavioural investigations using fifty different behavioral paradigms were identified. Few adverse events were reported, and even exceedingly high doses were apparently well tolerated. Conclusion With seventy-seven publications spanning close to sixty years, there is huge variation in study design and quality. Overall psilocybin presents a unique and strong safety profile with no evidence of biological toxicity, is characterized by unique time and dose-dependent effects, and its pattern of drug action is significantly context and training-sensitive. Data suggest putative effects of psilocybin include acute arousal, dose-dependent sedation, reductions in fear conditioning at low doses, reduced aggression, improved valence, acute disruption of working memory, the rescuing of deficits from chronic stress, and improved learning when combined with repeated environmental exposure after resolution of drug effect.", "journal": "bioRxiv", "publication_date": "2024-01-04", "publication_year": 2024, "doi": "10.1101/2024.01.04.574146", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2024.01.04.574146", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:00", "raw_json": "{\"europe_pmc_id\":\"PPR782675\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Mechanism of Action,Review Article,Safety,Adverse Events,Toxicity", "study_type": "Review Article", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3152, "title": "Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms", "normalized_title": "psilocybin prevents activity based anorexia in female rats by enhancing cognitive flexibility contributions from 5 ht1a and 5 ht2a receptor mechanisms", "authors": "Conn K, Milton L, Huang K, Munguba H, Ruuska J, Lemus M, Greaves E, Homman-Ludiye J, Oldfield B, Foldi C.", "abstract": "Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors ( Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.", "journal": "bioRxiv", "publication_date": "2023-12-12", "publication_year": 2023, "doi": "10.1101/2023.12.12.571374", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.12.12.571374", "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\":\"PPR773743\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Eating Disorders,Mechanism of Action,Receptor Pharmacology,Clinical Trial,Animal Study", "study_type": "Clinical Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3342, "title": "Statistical diversity distinguishes global states of consciousness", "normalized_title": "statistical diversity distinguishes global states of consciousness", "authors": "Starkey J, Carhart-Harris RL, Pigorini A, Nobili L, Barrett AB.", "abstract": "Application of complexity measures to neurophysiological time series has seen increased use in recent years to identify neural correlates of global states of consciousness. Lempel-Ziv complexity is currently the de-facto complexity measure used in these investigations. However, by simply counting the number of patterns, this measure theoretically takes its maximum value for data that are completely random. Recently, a measure of ‘statistical complexity’ - which calculates the diversity of statistical interactions - has been devised which aims to account for and remove randomness seen in data. It was recently found that this measure decreases during anaesthesia in fruit flies. This paper investigates this statistical complexity measure on human neurophysiology data from different stages of sleep, and from individuals under the effects of three psychedelic substances: ketamine, lysergic acid diethylamide (LSD), and psilocybin. Results indicate that statistical complexity: (i) differentiates the different stages of sleep analogously to Lempel-Ziv complexity; (ii) increases relative to placebo for all three psychedelic substances. Thus, statistical complexity is a useful alternative measure for investigating the complexity of neural activity associated with different states of consciousness.", "journal": "bioRxiv", "publication_date": "2023-12-06", "publication_year": 2023, "doi": "10.1101/2023.12.05.570101", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.12.05.570101", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:51", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR770814\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Consciousness,Drug Interactions", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3351, "title": "The entropic heart: Tracking the psychedelic state via heart rate dynamics", "normalized_title": "the entropic heart tracking the psychedelic state via heart rate dynamics", "authors": "Rosas FE, Mediano PA, Timmermann C, Luppi AI, Candia-Rivera D, Abbasi-Asl R, Gazzaley A, Kringelbach ML, Muthukumaraswamy S, Bor D, Garfinkel S, Carhart-Harris RL.", "abstract": "A growing body of work shows that autonomic signals provide a privileged evidence-stream to capture various aspects of subjective and neural states. This work investigates the potential for autonomic markers to track the effects of psychedelics - potent psychoactive drugs with important scientific and clinical value. For this purpose, we introduce a novel Bayesian framework to estimate the entropy of heart rate dynamics under psychedelics. We also calculate Bayesian estimates of mean heart rate and heart rate variability, and investigate how these measures relate to subjective reports and neural effects. Results on datasets covering four drugs - lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), psilocybin, and sub-anaesthetic doses of the dissociative agent ketamine - show consistent increases in mean heart rate, high-frequency heart rate variability, and heart rate entropy during the psychedelic experience. Moreover, these effects have predictive power over various dimensions of the psychedelic experience. Changes in heart rate entropy were found to be correlated with increases in brain entropy, while other autonomic markers were not. Overall, our results show that a cost-efficient autonomic measure has the potential to reveal surprising detail about subjective and brain states, opening up a range of new research avenues to explore in both basic and clinical neuroscience.", "journal": "bioRxiv", "publication_date": "2023-11-08", "publication_year": 2023, "doi": "10.1101/2023.11.07.566008", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.11.07.566008", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:51", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR756922\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Biomarkers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 1169, "title": "Cultivation, chemistry, and genome of Psilocybe zapotecorum", "normalized_title": "cultivation chemistry and genome of psilocybe zapotecorum", "authors": "Miller DR, Jacobs JT, Rockefeller A, Singer H, Bollinger IM, Conway J, Slot JC, Cliffel DE.", "abstract": "Psilocybe zapotecorum is a strongly blue-bruising psilocybin mushroom used by indigenous groups in southeastern Mexico and beyond. While this species has a rich history of ceremonial use, research into its chemistry and genetics have been limited. Herein, we detail mushroom morphology and report on cultivation parameters, chemical profile, and the full genome sequence of P. zapotecorum. First, growth and cloning methods are detailed that are simple, and reproducible. In combination with high resolution microscopic analysis, the strain was barcoded, confirming species-level identification. Full genome sequencing reveals the architecture of the psilocybin gene cluster in P. zapotecorum, and can serve as a reference genome for Psilocybe Clade I. Characterization of the tryptamine profile revealed a psilocybin concentration of 17.9±1.7 mg/g, with a range of 10.6-25.7 mg/g (n=7), and similar tryptamines (psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, 4-HO-tryptamine, and tryptamine) in lesser concentrations for a combined tryptamine concentration of 22.5±3.2 mg/g. These results show P. zapotecorum to be a potent - and variable - Psilocybe mushroom. Chemical profiling, genetic analysis, and cultivation assist in demystifying these mushrooms. As clinical studies with psilocybin gain traction, understanding the diversity of psilocybin mushrooms will assure that psilocybin therapy does not become synonymous with psilocybin mushrooms.", "journal": "bioRxiv", "publication_date": "2023-11-01", "publication_year": 2023, "doi": "10.1101/2023.11.01.564784", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.11.01.564784", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR752679\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Genomics", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3162, "title": "Acute effects of psilocybin on the dynamics of gaze fixations during visual aesthetic perception", "normalized_title": "acute effects of psilocybin on the dynamics of gaze fixations during visual aesthetic perception", "authors": "Muller S, Cavanna F, de la Fuente L, Bruno N, D’Amelio TA, Pallavicini C, Tagliazucchi E.", "abstract": "Rationale Serotonergic psychedelics are remarkable for their capacity to induce variable yet reproducible modifications to human consciousness The most salient acute effects of these compounds include perceptual alterations, predominantly in the visual domain, yet to date these alterations have been mostly documented only by subjective reports. Objectives We used eye-tracking to quantify the effects of low vs. high doses of psilocybin mushrooms on the eye movements that underlie the exploration of complex visual stimuli, focusing on the particular case of aesthetic perception. Results Following a double-blind placebo-controlled design under semi-naturalistic conditions, we demonstrated that high doses of psilocybin result in a more local visual exploration of paintings, and thus in a less entropic fixation probability distribution. Participants reported heightened emotional response and state of flow under the high dose condition. Conclusions These findings are consistent with an effect of psilocybin on gaze fixation mediated by altered perception of low-level visual information, such as textures, shapes and colors. Our work also highlights the possibility of investigating psychedelics by addressing their effect on behavior under complex naturalistic conditions, which contributes to maintaining subject engagement while also increasing the ecological validity of the findings.", "journal": "bioRxiv", "publication_date": "2023-10-31", "publication_year": 2023, "doi": "10.1101/2023.10.27.564413", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.10.27.564413", "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\":\"PPR752096\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Chronic Pain,Consciousness,Emotional Processing", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3094, "title": "Pharmacological and behavioral effects of tryptamines present in psilocybin-containing mushrooms", "normalized_title": "pharmacological and behavioral effects of tryptamines present in psilocybin containing mushrooms", "authors": "Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Nguyen Q, Roberts BR, Sciortino JH, Gibbons WJ, Friedberg LM, Andrew Jones J, McMurray MS.", "abstract": "ABSTRACT Demand for more efficacious antidepressants, particularly those with a rapid onset of action, has resulted in a reevaluation of psychedelic drugs for their therapeutic potential. Several tryptamines found in psilocybin-containing ‘magic’ mushrooms share chemical similarities with psilocybin, and early work suggests they may also share receptor targets. However, few studies have explored their pharmacological and behavioral effects. To accomplish this, we compared baeocystin, norbaeocystin, and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, penetrate the blood brain barrier, serve as ligands for similar centrally located receptors, and modulate behavior in rodents similarly. We first assessed the stability and optimal storage and handling conditions for each compound. In vitro enzyme kinetics assays then found that all compounds shared nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin could cross a blood brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. Behaviorally, only psilocybin was found to induce head twitch responses in rats, a marker of 5HT2A agonism and indicator of the compound’s hallucinogenic potential. However, like psilocybin, norbaeocystin was also found to improve outcomes in the forced swim test. All compounds were found to cause minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Collectively, this work suggests that other naturally-occurring tryptamines, especially norbaeocystin, may share the same therapeutic potential as psilocybin, but without causing hallucinations. HIGHLIGHTS Baeocystin, norbaeocystin, and aeruginascin may have similar therapeutic value to psilocybin, but are understudied Compound stability varied widely, with dephosphorylated forms showing lowest stability Rates of metabolism by alkaline phosphatase and monoamine oxidase were similar across compounds Blood brain barrier penetration was limited to dephosphorylated forms of psilocybin, baeocystin, and norbaeocystin Rat behavioral testing suggested norbaeocystin may have therapeutic utility similar to psilocybin, without causing hallucinations", "journal": "bioRxiv", "publication_date": "2023-10-22", "publication_year": 2023, "doi": "10.1101/2023.10.19.563138", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.10.19.563138", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:00", "raw_json": "{\"europe_pmc_id\":\"PPR746275\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Pharmacology,Receptor Pharmacology,Biomarkers,Animal Study,In Vitro Study,Safety", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3188, "title": "Synergistic, Multi-level Understanding of Psychedelics: Three Systematic Reviews and Meta-analyses of Their Pharmacology, Neuroimaging and Phenomenology", "normalized_title": "synergistic multi level understanding of psychedelics three systematic reviews and meta analyses of their pharmacology neuroimaging and phenomenology", "authors": "Shinozuka K, Jerotic K, Mediano P, Zhao AT, Preller KH, Carhart-Harris R, Kringelbach ML.", "abstract": "Serotonergic psychedelics induce altered states of consciousness and have shown potential for treating a variety of neuropsychiatric disorders, including depression and addiction. Yet their modes of action are not fully understood. Here, we provide a novel, synergistic understanding of psychedelics arising from systematic reviews and meta-analyses of three hierarchical levels of analysis: 1) subjective experience (phenomenology), 2) neuroimaging and 3) molecular pharmacology. Phenomenologically, medium and high doses of LSD yield significantly higher ratings of visionary restructuralisation than psilocybin on the 5-dimensional Altered States of Consciousness Scale. Our neuroimaging results reveal that, in general, psychedelics significantly strengthen between-network functional connectivity (FC) while significantly diminishing within-network FC. Pharmacologically, LSD induces significantly more inositol phosphate formation at the 5-HT2A receptor than DMT and psilocin, yet there are no significant between-drug differences in the selectivity of psychedelics for the 5-HT2A, 5-HT2C, or D2 receptors, relative to the 5-HT1A receptor. Our meta-analyses link DMT, LSD, and psilocybin to specific neural fingerprints at each level of analysis. The results show a highly non-linear relationship between these fingerprints. Overall, our analysis highlighted the high heterogeneity and risk of bias in the literature. This suggests an urgent need for standardising experimental procedures and analysis techniques, as well as for more research on the emergence between different levels of psychedelic effects.", "journal": "bioRxiv", "publication_date": "2023-10-06", "publication_year": 2023, "doi": "10.1101/2023.10.06.561183", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.10.06.561183", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR738055\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Addiction,Brain Imaging,Pharmacology,Receptor Pharmacology,Consciousness,Aging,Systematic Review,Review Article,Safety", "study_type": "Systematic Review", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 1369, "title": "A suite of engineered mice for interrogating psychedelic drug actions", "normalized_title": "a suite of engineered mice for interrogating psychedelic drug actions", "authors": "Chiu Y, Deutch AY, Wang W, Schmitz GP, Huang KL, Kocak DD, Llorach P, Bowyer K, Liu B, Sciaky N, Hua K, Chen C, Mott SE, Niehaus J, DiBerto JF, English J, Walsh JJ, Scherrer G, Herman MA, Wu Z, Wetsel WC, Roth BL.", "abstract": "ABSTRACT Psychedelic drugs like lysergic acid diethylamide (LSD) and psilocybin have emerged as potentially transformative therapeutics for many neuropsychiatric diseases, including depression, anxiety, post-traumatic stress disorder, migraine, and cluster headaches. LSD and psilocybin exert their psychedelic effects via activation of the 5-hydroxytryptamine 2A receptor (HTR2A). Here we provide a suite of engineered mice useful for clarifying the role of HTR2A and HTR2A-expressing neurons in psychedelic drug actions. We first generated Htr2a -EGFP-CT-IRES-CreERT2 mice (CT:C-terminus) to independently identify both HTR2A-EGFP-CT receptors and HTR2A-containing cells thereby providing a detailed anatomical map of HTR2A and identifying cell types that express HTR2A. We also generated a humanized Htr2a mouse line and an additional constitutive Htr2A -Cre mouse line. Psychedelics induced a variety of known behavioral changes in our mice validating their utility for behavioral studies. Finally, electrophysiology studies revealed that extracellular 5-HT elicited a HTR2A-mediated robust increase in firing of genetically-identified pyramidal neurons--consistent with a plasma membrane localization and mode of action. These mouse lines represent invaluable tools for elucidating the molecular, cellular, pharmacological, physiological, behavioral, and other actions of psychedelic drugs in vivo.", "journal": "bioRxiv", "publication_date": "2023-09-25", "publication_year": 2023, "doi": "10.1101/2023.09.25.559347", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.09.25.559347", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR730960\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,PTSD,Headache / Migraine,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": 959, "title": "Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling.", "normalized_title": "psychedelic 5 ht2a receptor agonism neuronal signatures and altered neurovascular coupling", "authors": "Padawer-Curry JA, Krentzman OJ, Kuo C, Wang X, Bice AR, Nicol GE, Snyder AZ, Siegel JS, McCall JG, Bauer AQ.", "abstract": "Psychedelics hold therapeutic promise for mood disorders due to rapid, sustained results. Human neuroimaging studies have reported dramatic serotonin-2A receptor-(5-HT2AR)-dependent changes in functional brain reorganization that presumably reflect neuromodulation. However, the potent vasoactive effects of serotonin have been overlooked. We found psilocybin-mediated alterations to fMRI-HRFs in humans, suggesting potentially altered NVC. To assess the neuronal, hemodynamic, and neurovascular coupling (NVC) effects of the psychedelic 5-HT2AR agonist, 2,5-Dimethoxy-4-iodoamphetamine (DOI), wide-field optical imaging (WFOI) was used in awake Thy1-jRGECO1a mice during stimulus-evoked and resting-state conditions. While DOI partially altered tasked-based NVC, more pronounced NVC alterations occurred under resting-state conditions and were strongest in association regions. Further, calcium and hemodynamic activity reported different accounts of RSFC changes under DOI. Co-administration of DOI and the 5-HT2AR antagonist, MDL100907, reversed many of these effects. Dissociation between neuronal and hemodynamic signals emphasizes a need to consider neurovascular effects of psychedelics when interpreting blood-oxygenation-dependent neuroimaging measures.", "journal": "bioRxiv", "publication_date": "2023-09-23", "publication_year": 2023, "doi": "10.1101/2023.09.23.559145", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.09.23.559145", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR730039\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Receptor Pharmacology,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": 3148, "title": "Dynamic Functional Hyperconnectivity after Psilocybin Intake is Primarily Associated with Oceanic Boundlessness", "normalized_title": "dynamic functional hyperconnectivity after psilocybin intake is primarily associated with oceanic boundlessness", "authors": "Mortaheb S, Fort LD, Mason NL, Mallaroni P, Ramaekers JG, Demertzi A.", "abstract": "To provide insights into neurophenomenological richness after psilocybin intake, we investigated the link between dynamical brain patterns and the ensuing phenomenological pattern after psilocybin intake. Healthy participants received either psilocybin (n=22) or placebo (n=27) while in ultra-high field 7T MRI scanning. Changes in the phenomenological patterns were quantified using the 5-Dimensional Altered States of Consciousness (5D-ASC) Rating Scale, revealing alterations across all dimensions under psilocybin. Changes in the neurobiological patterns displayed that psilocybin induced widespread increases in averaged functional connectivity. Time-varying connectivity analysis unveiled a recurrent hyperconnected pattern characterized by low BOLD signal amplitude, suggesting heightened cortical arousal. In terms of neurophenomenology, canonical correlation analysis primarily linked the transition probabilities of the hyperconnected pattern with feelings of oceanic boundlessness (OBN), and secondly with visionary restructuralization. We suggest that the brain’s tendency to enter a hyperconnected-hyperarousal pattern under psilocybin represents the potential to entertain variant mental associations. For the first time, these findings link brain dynamics with phenomenological alterations, providing new insights into the neurophenomenology and neurophysiology of the psychedelic state.", "journal": "bioRxiv", "publication_date": "2023-09-17", "publication_year": 2023, "doi": "10.1101/2023.09.18.558309", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.09.18.558309", "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\":\"PPR727205\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Consciousness,Healthy Volunteers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 1032, "title": "Rapid, biochemical tagging of cellular activity history in vivo", "normalized_title": "rapid biochemical tagging of cellular activity history in vivo", "authors": "Zhang R, Anguiano M, Aarrestad IK, Lin S, Chandra J, Vadde SS, Olson DE, Kim CK.", "abstract": "ABSTRACT Intracellular calcium (Ca 2+ ) is ubiquitous to cell signaling across all biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca 2+ levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely-behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca 2+ in vivo. Ca 2+ -activated Split-TurboID (CaST) labels activated cells within 10 minutes with an exogenously-delivered biotin molecule. The enzymatic signal increases with Ca 2+ concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca 2+ activity. Furthermore, the CaST read-out can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice.", "journal": "bioRxiv", "publication_date": "2023-09-07", "publication_year": 2023, "doi": "10.1101/2023.09.06.556431", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.09.06.556431", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR721525\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Mechanism of Action,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": 3149, "title": "Intravenous psilocybin administration attenuates mechanical hypersensitivity in a rat model of chronic pain", "normalized_title": "intravenous psilocybin administration attenuates mechanical hypersensitivity in a rat model of chronic pain", "authors": "Kolbman N, Liu T, Guzzo P, Gilligan JP, Mashour GA, Vanini G, Pal D.", "abstract": "There is a renewed interest in the therapeutic potential of psychedelics, including psilocybin, in treating mental health disorders. However, there are no data on the efficacy of psilocybin in alleviating chronic pain. In this study, we investigated the effect of psilocybin on mechanical hypersensitivity and thermal hyperalgesia in a rat model of formalin-induced chronic pain. Adult male and female rats were surgically implanted with a jugular vein catheter for psilocybin or saline administration. After two weeks of post-surgical recovery and conditioning, baseline responses to mechanical (von Frey assay) and thermal (hot plate assay) stimuli were measured. Twenty-four hours after baseline measurements, rats received a subcutaneous injection of formalin (5%, 50µL) into one of the hind paws and 2h later, responses to the mechanical and thermal stimuli were measured. Twenty-four hours after formalin injection, rats received an intravenous bolus of 1 mg/kg psilocybin (n=14) or 10 mg/kg psilocybin (n=12) or saline (n=13), and approximately 3h later, responses to the mechanical and thermal stimuli were measured. Rats were tested every other day during week 1, and then weekly for the next 3 weeks. Formalin injection induced thermal hyperalgesia and bilateral mechanical hypersensitivity in the hind paws of all rats. Intravenous psilocybin produced significant attenuation (p", "journal": "bioRxiv", "publication_date": "2023-08-27", "publication_year": 2023, "doi": "10.1101/2023.08.26.554802", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.08.26.554802", "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\":\"PPR704236\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Chronic Pain,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": 3063, "title": "Novel psilocin prodrugs with altered pharmacological properties as candidate therapies for treatment-resistant anxiety disorders", "normalized_title": "novel psilocin prodrugs with altered pharmacological properties as candidate therapies for treatment resistant anxiety disorders", "authors": "Raithatha SA, Hagel JM, Matinkhoo K, Yu L, Press D, Cook SG, Sharma G, D D, Jensen G, Lee JB, Cai C, Gallant J, Bains JS, Tucker JE, Facchini PJ.", "abstract": "The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screened in vitro for metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocin in vitro, with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT2A receptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing.", "journal": "bioRxiv", "publication_date": "2023-05-17", "publication_year": 2023, "doi": "10.1101/2023.05.16.540994", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.05.16.540994", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:46", "last_checked": "2026-07-01 11:22:00", "raw_json": "{\"europe_pmc_id\":\"PPR661781\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,Pharmacology,Receptor Pharmacology,Biomarkers,Clinical Trial,Animal Study,In Vitro Study,Cancer Patients,Treatment-Resistant Depression", "study_type": "Clinical Trial", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 1487, "title": "Time-resolved network control analysis links reduced control energy under DMT with the serotonin 2a receptor, signal diversity, and subjective experience", "normalized_title": "time resolved network control analysis links reduced control energy under dmt with the serotonin 2a receptor signal diversity and subjective experience", "authors": "Singleton SP, Timmermann C, Luppi AI, Eckernäs E, Roseman L, Carhart-Harris RL, Kuceyeski A.", "abstract": "Psychedelics offer a profound window into the functioning of the human brain and mind through their robust acute effects on perception, subjective experience, and brain activity patterns. In recent work using a receptor-informed network control theory framework, we demonstrated that the serotonergic psychedelics lysergic acid diethylamide (LSD) and psilocybin flatten the brain’s control energy landscape in a manner that covaries with more dynamic and entropic brain activity. Contrary to LSD and psilocybin, whose effects last for hours, the serotonergic psychedelic N,N-dimethyltryptamine (DMT) rapidly induces a profoundly immersive altered state of consciousness lasting less than 20 minutes, allowing for the entirety of the drug experience to be captured during a single resting-state fMRI scan. Using network control theory, which quantifies the amount of input necessary to drive transitions between functional brain states, we integrate brain structure and function to map the energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Consistent with previous work, we find that global control energy is reduced following injection with DMT compared to placebo. We additionally show longitudinal trajectories of global control energy correlate with longitudinal trajectories of EEG signal diversity (a measure of entropy) and subjective ratings of drug intensity. We interrogate these same relationships on a regional level and find that the spatial patterns of DMT’s effects on these metrics are correlated with serotonin 2a receptor density (obtained from separately acquired PET data). Using receptor distribution and pharmacokinetic information, we were able to successfully recapitulate the effects of DMT on global control energy trajectories, demonstrating a proof-of-concept for the use of control models in predicting pharmacological intervention effects on brain dynamics.", "journal": "bioRxiv", "publication_date": "2023-05-11", "publication_year": 2023, "doi": "10.1101/2023.05.11.540409", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.05.11.540409", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR659698\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Pharmacology,Receptor Pharmacology,Consciousness", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3181, "title": "High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin", "normalized_title": "high resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin", "authors": "Braun D, Rosenberg A, Haruvi R, Malamud D, Barbara R, Kawashima T.", "abstract": "Serotonergic psychedelics are emerging therapeutics for psychiatric disorders, yet their underlying mechanisms of action in the brain remain largely elusive. Zebrafish have evolutionarily conserved serotonergic circuits and subcortical targets such as the brainstem regions and the cerebellum, providing a promising model for studying the subcortical effects of serotonergic drugs. Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic serotonin receptor agonist. Machine learning analyses of precise body kinematics identified latent behavioral states reflecting spontaneous exploration, visually-driven rapid swimming, and irregular swim patterns following stress exposure. Using this method, we identified two main behavioral effects of acute psilocybin treatment: [i] increased rapid swimming in the absence of visual stimuli and [ii] prevention of irregular swim patterns following stress exposure. Together, these effects indicate that psilocybin induces a brain state that is both stimulatory and anxiolytic. These findings pave the way for using larval zebrafish to elucidate subcortical mechanisms underlying the behavioral effects of serotonergic psychedelics.", "journal": "bioRxiv", "publication_date": "2023-04-13", "publication_year": 2023, "doi": "10.1101/2023.04.13.536830", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.04.13.536830", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:47", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR645777\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "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": 3171, "title": "The Unique Neural Signature of Your Trip: Functional Connectome Fingerprints of Subjective Psilocybin Experience", "normalized_title": "the unique neural signature of your trip functional connectome fingerprints of subjective psilocybin experience", "authors": "Tolle HM, Farah JC, Mallaroni P, Mason NL, Ramaekers JG, Amico E.", "abstract": "The emerging neuroscientific frontier of brain fingerprinting has recently established that human functional connectomes (FCs) exhibit fingerprint-like idiosyncratic features, which map onto heterogeneously distributed behavioural traits. Here, we harness brain-fingerprinting tools to extract FC features that predict subjective drug experience induced by the psychedelic psilocybin. Specifically, in neuroimaging data of healthy volunteers under the acute influence of psilocybin or a placebo, we show that, post psilocybin administration, FCs become more idiosyncratic due to greater inter-subject dissimilarity. Moreover, whereas in placebo subjects idiosyncratic features are primarily found in the frontoparietal network, in psilocybin subjects they concentrate in the default-mode network (DMN). Crucially, isolating the latter revealed an FC pattern that predicts subjective psilocybin experience and is characterised by reduced within-DMN and DMN-limbic connectivity, as well as increased connectivity between the DMN and attentional systems. Overall, these results contribute to bridging the gap between psilocybin-mediated effects on brain and behaviour, while demonstrating the value of a brain-fingerprinting approach to pharmacological neuroimaging. Author summary The trending field of brain fingerprinting focuses on characterising fingerprint-like idiosyncratic features of human functional connectomes (FCs), which have been shown to predict heterogeneously distributed behavioural traits. Here, we apply brain-fingerprinting methods to fMRI data from subjects who were administered the psychedelic psilocybin or a placebo. We find that, compared to the placebo condition, subjects under acute psilocybin effects exhibited more idiosyncratic FCs, with idiosyncratic features being largely concentrated in the default-mode network (DMN). Furthermore, we isolated an idiosyncratic FC pattern that predicted reports of subjective psilocybin experiences. This pattern was characterised by altered DMN connectivity, specifically by reduced within-DMN and DMN-limbic connectivity, and increased connectivity between the DMN and attentional systems. This work paves the way for exciting new research harnessing pharmacological brain fingerprinting.", "journal": "bioRxiv", "publication_date": "2023-03-20", "publication_year": 2023, "doi": "10.1101/2023.03.20.532894", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.03.20.532894", "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\":\"PPR633592\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Default Mode Network,Aging,Healthy Volunteers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 1350, "title": "UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice", "normalized_title": "unraveling the synergistic effects of psilocybin and environment on brain wide immediate early gene expression in mice", "authors": "Rijsketic DR, Casey AB, Barbosa DA, Zhang X, Hietamies TM, Ramirez-Ovalle G, Pomrenze M, Halpern CH, Williams LM, Malenka RC, Heifets BD.", "abstract": "The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos + cell density measurements. Psilocybin increased c-Fos expression in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus and decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum. Main effects of context and psilocybin-treatment were robust, widespread, and spatially distinct, whereas interactions were surprisingly sparse.", "journal": "bioRxiv", "publication_date": "2023-02-20", "publication_year": 2023, "doi": "10.1101/2023.02.19.528997", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.02.19.528997", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR619153\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Aging,Animal Study,Drug Interactions", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3180, "title": "Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition", "normalized_title": "assessment of the acute effects of 2c b vs psilocybin on subjective experience mood and cognition", "authors": "Mallaroni P, Mason NL, Reckweg JT, Paci R, Ritscher S, Toennes SW, Theunissen EL, Kuypers KP, Ramaekers JG.", "abstract": "2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it’s acute effects and distinctions from classical progenitors have yet to be characterised in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared to placebo, as indexed by the Digit Symbol Substitution Test (DSST), Tower of London (TOL) and Spatial Memory Task (SMT). Neither compound produced empathogenic effects on the Multifaceted Empathy Test (MET). 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorisation of 2C-B as a subjectively “lighter” psychedelic. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B’s experiential overlaps.", "journal": "bioRxiv", "publication_date": "2023-02-15", "publication_year": 2023, "doi": "10.1101/2023.02.16.528808", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.02.16.528808", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:47", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR617518\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Pharmacology,Consciousness,Emotional Processing,Observational Study,Animal Study", "study_type": "Observational Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 1478, "title": "Acute psilocybin enhances cognitive flexibility in rats", "normalized_title": "acute psilocybin enhances cognitive flexibility in rats", "authors": "Pacheco AT, Olson RJ, Garza G, Moghaddam B.", "abstract": "Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2A receptor antagonist ketanserin blocked psilocybin’s effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybin’s pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.", "journal": "bioRxiv", "publication_date": "2023-01-08", "publication_year": 2023, "doi": "10.1101/2023.01.09.523291", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2023.01.09.523291", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 06:48:05", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR593926\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,Pharmacology,Receptor Pharmacology,Healthcare Workers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3193, "title": "Phylogenomics of the psychoactive mushroom genus Psilocybe and evolution of the psilocybin biosynthetic gene cluster", "normalized_title": "phylogenomics of the psychoactive mushroom genus psilocybe and evolution of the psilocybin biosynthetic gene cluster", "authors": "Bradshaw AJ, Ramírez-Cruz V, Awan AR, Furci G, Guzmán-Dávalos L, Stamets P, Dentinger BT.", "abstract": "Psychoactive mushrooms in the genus Psilocybe have immense cultural value and have been used for centuries in Mesoamerica. Despite a recent surge in interest in these mushrooms due to emerging evidence that psilocybin, the main psychoactive compound, is a promising therapeutic for a variety of mental illnesses, their phylogeny and taxonomy remain substantially incomplete. Moreover, the recent elucidation of the psilocybin biosynthetic gene cluster is known for only five species of Psilocybe, four of which belong to only one of two major clades. We set out to improve the phylogeny for Psilocybe using shotgun sequencing of 71 fungarium specimens, including 23 types, and conducting phylogenomic analysis using 2,983 single-copy gene families to generate a fully supported phylogeny. Molecular clock analysis suggests the stem lineage arose ∼66 mya and diversified ∼53 mya. We also show that psilocybin biosynthesis first arose in Psilocybe, with 4-5 possible horizontal transfers to other mushrooms between 40 and 22 mya. Moreover, predicted orthologs of the psilocybin biosynthetic genes revealed two distinct gene orders within the cluster that corresponds to a deep split within the genus, possibly consistent with the independent acquisition of the cluster. This novel insight may predict differences in chemistry between the two major clades of the genus, providing further resources for the development of novel therapeutics.", "journal": "bioRxiv", "publication_date": "2022-12-14", "publication_year": 2022, "doi": "10.1101/2022.12.13.520147", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.12.13.520147", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR585520\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Genomics", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3248, "title": "Psychedelic compounds directly excite 5-HT2A Layer 5 Pyramidal Neurons in the Prefrontal Cortex through a 5-HT2A Gq -mediated activation mechanism", "normalized_title": "psychedelic compounds directly excite 5 ht2a layer 5 pyramidal neurons in the prefrontal cortex through a 5 ht2a gq mediated activation mechanism", "authors": "Schmitz GP, Chiu Y, König GM, Kostenis E, Roth BL, Herman MA.", "abstract": "Summary Psilocin, the active compound in Psilocybe sp. mushrooms, is a serotonergic psychedelic that has recently gained renewed interest due to its potential as a therapeutic tool. Despite promising clinical findings, the underlying signaling mechanisms and brain region-specific effects of psilocin and other psychedelic drugs remain unclear. Psilocin, like other psychedelic compounds, is an agonist at many serotonin and other biogenic amine receptors; however, activation of serotonin (5-Hydroxytryptamine, or 5-HT) 2A receptors (5-HT2A Rs) is understood as the main molecular target for the psychoactive effects in animals and humans. 5-HT2A Rs are abundantly expressed in the prefrontal cortex (PFC); however, the biochemical actions of psilocin on PFC neurons remain poorly understood. In this study, we used in vitro slice electrophysiology to examine how psilocin acutely alters the activity and electrophysiological properties of layer 5 pyramidal neurons in the mouse PFC. Focal application of psilocin (10 μ M) onto nonspecified Layer 5 Pyramidal neurons in the prelimbic PFC of C57BL/6J mice produced variable effects on firing (increase, decrease, or no change). 5-HT2A R layer 5 pyramidal neurons in the mouse prelimbic PFC were identified via labeling in a 5-HT2A-ERT2-Cre mouse crossed with an Ai9 tdTomato reporter. Focal application of psilocin increased firing in all identified 5-HT2A R neurons but did not result in any significant changes in synaptic transmission. Overall, the results demonstrate that psilocin evokes strong firing changes in the PFC that are 5-HT2A R and G α q dependent, thereby providing valuable insights into the effects of psilocin on a brain region implicated in mediating psychedelic drug actions.", "journal": "bioRxiv", "publication_date": "2022-11-14", "publication_year": 2022, "doi": "10.1101/2022.11.15.516655", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.11.15.516655", "keywords": "", "substance_tags": "psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:49", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR571939\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,Mechanism of Action,Receptor Pharmacology,Animal Study,In Vitro Study", "study_type": "Animal Study", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3314, "title": "5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice", "normalized_title": "5 meo dmt modifies innate behaviors and promotes structural neural plasticity in mice", "authors": "Jefferson SJ, Gregg I, Dibbs M, Liao C, Wu H, Davoudian PA, Sprouse JS, Sherwood AM, Kaye AP, Pittenger C, Kwan AC.", "abstract": "ABSTRACT Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early clinical studies. However relatively little is known about the behavioral effects and neural mechanisms of 5-MeO-DMT in animal models. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.", "journal": "bioRxiv", "publication_date": "2022-11-02", "publication_year": 2022, "doi": "10.1101/2022.11.03.515044", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.11.03.515044", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:50", "last_checked": "2026-07-01 11:22:04", "raw_json": "{\"europe_pmc_id\":\"PPR566748\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Anxiety,Neuroplasticity,Mechanism of Action,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": 3218, "title": "Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 receptors in the head twitch response induced by 5-hydroxytryptophan and psilocybin: Translational implications", "normalized_title": "role of 5 ht2a 5 ht2c 5 ht1a and taar1 receptors in the head twitch response induced by 5 hydroxytryptophan and psilocybin translational implications", "authors": "Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Wolf G, Lerer B, Lifschytz T.", "abstract": "There is increasing interest in the therapeutic potential of psilocybin in psychiatric disorders. In common with other serotonergic psychedelics, psilocybin is thought to act via the 5-HT2A receptor (5-HT2AR). Serotonin is the endogenous ligand of 5-HTR. In rodents, the serotonin precursor, 5-hydroxytryptophan (5-HTP), and psilocybin, induce a characteristic head twitch response (HTR), which is correlated with the human psychedelic trip in intensity and duration. We examined the role of other serotonergic receptors and the trace amine associated receptor 1 (TAAR1) in modulating HTR induced by 5-HTP and psilocybin. Male C57BL/6J mice (11 weeks old, ~30g) were administered 5-HTP, 50-250 mg/kg intraperitoneally (i.p.) or 200 mg/kg i.p. after pretreatment with 5-HT/TAAR1 receptor modulators. Psilocybin was administered at 0.1-51.2 mg/kg i.p. or at 4.4 mg/kg i.p. preceded by 5-HT/TAAR1 receptor modulators. HTR was assessed in a custom-built magnetometer. 5-HTP and psilocybin induced a dose dependent increase in the frequency of HTR over 20 minutes with attenuation by the 5-HT2AR antagonist, M100907 (volanserin), and the 5-HT1AR agonist, 8-OH-DPAT. The 5-HT2CR antagonist, RS102221, enhanced HTR at lower doses but reduced it at higher doses for 5-HTP and psilocybin. The TAAR1 antagonist, EPPTB, reduced 5-HTP-but not psilocybin-induced HTR. We have confirmed the key role of 5-HT2AR in HTR and have demonstrated an effect of 5-HT1AR and a bimodal contribution of 5-HT2CR as well as a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate HTR induced by psychedelics have a potentially important role in the emerging therapeutic use of these compounds. Significance Statement We have confirmed the key role of 5-HT2AR in in the induction of HTR by 5-HTP and psilocybin, have demonstrated the effect of a 5-HT1AR agonist to attenuate HTR and a bimodal contribution of 5-HT2CR as well as a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate HTR induced by psychedelics have a potentially important role in the emerging therapeutic use of these compounds. Visual Abstract", "journal": "bioRxiv", "publication_date": "2022-07-22", "publication_year": 2022, "doi": "10.1101/2022.07.22.501026", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.07.22.501026", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR522905\",\"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": 3195, "title": "Effect of psilocybin on marble-burying in ICR mice: Role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder", "normalized_title": "effect of psilocybin on marble burying in icr mice role of 5 ht1a receptors and implications for the treatment of obsessive compulsive disorder", "authors": "Singh S, Botvinnik A, Shahar O, Wolf G, Yakobi C, Saban M, Salama A, Lotan A, Lerer B, Lifschytz T.", "abstract": "Background Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble-burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. Aims To explore 1) the role of 5-HT2A and 5-HT1A receptors in the effect of psilocybin on marble-burying; 2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; 3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head-twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Methods Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-OH-DPAT2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the MBT. HTR was examined in a magnetometer-based assay. Results 1) Psilocybin and escitalopram significantly reduced marble-burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT reduced marble-burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. 2) Psilocybin injections over 3.5 hours had no effect on marble-burying and the effect of bolus injection was not persistent. 3) Co-administration of buspirone with psilocybin blocked its effect on HTR Conclusions Neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble-burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects.", "journal": "bioRxiv", "publication_date": "2022-07-13", "publication_year": 2022, "doi": "10.1101/2022.07.13.498401", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.07.13.498401", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR519282\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "OCD,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": 3372, "title": "Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape", "normalized_title": "mapping pharmacologically induced functional reorganisation onto the brain s neurotransmitter landscape", "authors": "Luppi AI, Hansen JY, Adapa R, Carhart-Harris RL, Roseman L, Timmermann C, Golkowski D, Golkowski D, Ranft A, Ilg R, Jordan D, Bonhomme V, Vanhaudenhuyse A, Demertzi A, Jaquet O, Bahri MA, Alnagger NL, Cardone P, Peattie ARD, Manktelow AE, de Araujo DB, Sensi SL, Owen AM, Naci L, Menon DK, Misic B, Stamatakis EA.", "abstract": "To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brain’s functional architecture.", "journal": "bioRxiv", "publication_date": "2022-07-12", "publication_year": 2022, "doi": "10.1101/2022.07.12.499688", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.07.12.499688", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:51", "last_checked": "2026-07-01 11:22:05", "raw_json": "{\"europe_pmc_id\":\"PPR518432\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Receptor Pharmacology,Aging", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3131, "title": "Brain dynamics predictive of response to psilocybin for treatment-resistant depression", "normalized_title": "brain dynamics predictive of response to psilocybin for treatment resistant depression", "authors": "Vohryzek J, Cabral J, Lord L, Fernandes HM, Roseman L, Nutt DJ, Carhart-Harris RL, Deco G, Kringelbach ML.", "abstract": "Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT2A and 5-HT1A, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.", "journal": "bioRxiv", "publication_date": "2022-07-03", "publication_year": 2022, "doi": "10.1101/2022.06.30.497950", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.06.30.497950", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:47", "last_checked": "2026-07-01 11:22:01", "raw_json": "{\"europe_pmc_id\":\"PPR521801\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Mechanism of Action,Receptor Pharmacology,Treatment-Resistant Depression", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3384, "title": "Synapses, predictions, and prediction errors: a neocortical computational study of MDD using the temporal memory algorithm of HTM", "normalized_title": "synapses predictions and prediction errors a neocortical computational study of mdd using the temporal memory algorithm of htm", "authors": "Sherif MA, Khalil MZ, Shukla R, Brown JC, Carpenter LL.", "abstract": "Background Synapses and spines are central in major depressive disorder (MDD) pathophysiology, recently highlighted by ketamine’s and psilocybin’s rapid antidepressant effects. The Bayesian brain and interoception perspectives formalize MDD as being “stuck” in affective states constantly predicting negative energy balance. We examined how synaptic atrophy relates to the predictive function of the neocortex and thus to symptoms, using temporal memory (TM), an unsupervised machine-learning algorithm. TM represents a single neocortical layer, learns in real-time using local Hebbian-learning rules, and extracts and predicts temporal sequences. Methods We trained a TM model on random sequences of upper-case alphabetical letters, representing sequences of affective states. To model depression, we progressively destroyed synapses in the TM model and examined how that affected the predictive capacity of the network. Results Destroying 50% of the synapses slightly reduced the number of predictions, followed by a marked drop with further destruction. However, reducing the synapses by 25% dropped the confidence in the predictions distinctly. So even though the network was making accurate predictions, the network was no longer confident about these predictions. Conclusions These findings explain how interoceptive cortices could be stuck in limited affective states with high prediction error. Growth of new synapses, e.g., with ketamine and psilocybin, would allow representing more futuristic predictions with higher confidence. To our knowledge, this is the first study to use the TM model to connect changes happening at synaptic levels to the Bayesian formulation of psychiatric symptomatology, making it possible to understand treatment mechanisms and possibly, develop new treatments. Graphical abstract", "journal": "bioRxiv", "publication_date": "2022-07-02", "publication_year": 2022, "doi": "10.1101/2022.06.29.498015", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.06.29.498015", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:52", "last_checked": "2026-07-01 11:22:06", "raw_json": "{\"europe_pmc_id\":\"PPR513414\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Neuroplasticity,Mechanism of Action", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3177, "title": "Electrical spiking of psilocybin fungi", "normalized_title": "electrical spiking of psilocybin fungi", "authors": "Gandia A, Adamatzky A.", "abstract": "Psilocybin fungi, aka “magic” mushrooms, are well known for inducing colourful and visionary states of mind. Such psychoactive properties and the ease of cultivating their basidiocarps within low-tech setups make psilocybin fungi promising pharmacological tools for mental health applications. Understanding of the intrinsic electrical patterns occurring during the mycelial growth can be utilised for better monitoring the physiological states and needs of these species. In this study we aimed to shed light on this matter by characterising the extra-cellular electrical potential of two popular species of psilocybin fungi: Psilo-cybe tampanensis and P. cubensis. As in previous experiments with other common edible mushrooms, the undisturbed fungi have shown to generate electric potential spikes and trains of spiking activity. This short analysis provides a proof of intrinsic electrical communication in psilocybin fungi, and further establishes these fungi as a valuable tool for studying fungal electro-physiology.", "journal": "bioRxiv", "publication_date": "2022-07-02", "publication_year": 2022, "doi": "10.1101/2022.07.02.498545", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.07.02.498545", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:47", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR513215\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "General", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3398, "title": "Unique Effects of Sedatives, Dissociatives, Psychedelics, Stimulants, and Cannabinoids on Episodic Memory: A Review and Reanalysis of Acute Drug Effects on Recollection, Familiarity, and Metamemory", "normalized_title": "unique effects of sedatives dissociatives psychedelics stimulants and cannabinoids on episodic memory a review and reanalysis of acute drug effects on recollection familiarity and metamemory", "authors": "Doss MK, Samaha J, Barrett FS, Griffiths RR, de Wit H, Gallo DA, Koen JD.", "abstract": "Despite distinct classes of psychoactive drugs producing putatively unique states of consciousness, there is surprising overlap in terms of their effects on episodic memory and cognition more generally. Episodic memory is supported by multiple subprocesses that have been mostly overlooked in psychopharmacology and could differentiate drug classes. Here, we reanalyzed episodic memory confidence data from 10 previously published datasets (28 drug conditions total) using signal detection models to estimate 2 conscious states involved in episodic memory and 1 consciously-controlled metacognitive process of memory: the retrieval of specific details from one’s past (recollection), noetic recognition in the absence of retrieved details (familiarity), and accurate introspection of memory decisions (metamemory). We observed that sedatives, dissociatives, psychedelics, stimulants, and cannabinoids had unique patterns of effects on these mnemonic processes dependent on which phase of memory (encoding, consolidation, or retrieval) was targeted. All drugs at encoding except stimulants impaired recollection, and sedatives, dissociatives, and cannabinoids at encoding impaired familiarity. The effects of sedatives on metamemory were mixed, whereas dissociatives and cannabinoids at encoding tended to enhance metamemory. Surprisingly, psychedelics at encoding tended to enhance familiarity and did not impact metamemory. Stimulants at encoding and retrieval enhanced metamemory, but at consolidation, they impaired metamemory. Together, these findings may have relevance to mechanisms underlying unique subjective phenomena under different drug classes, such as blackouts from sedatives or déjà vu from psychedelics. This study provides a framework for interrogating drug effects within a domain of cognition beyond the global impairments on task performance typically reported in psychopharmacology. Public significance statement This systematic review and reanalysis of several datasets indicate that sedatives (alcohol, zolpidem, triazolam), dissociatives (ketamine, dextromethorphan), psychedelics (psilocybin, MDMA), stimulants (dextroamphetamine, dextromethamphetamine), and cannabinoids (THC) can each have idiosyncratic effects on episodic memory, differentially impairing certain mnemonic processes while sparing or even facilitating others. Such findings inform how different drugs can produce unique subjective phenomena and provide a framework for future work to differentiate the effects of psychoactive drugs within a domain of cognition.", "journal": "bioRxiv", "publication_date": "2022-05-23", "publication_year": 2022, "doi": "10.1101/2022.05.20.492842", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.05.20.492842", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:52", "last_checked": "2026-07-01 11:22:06", "raw_json": "{\"europe_pmc_id\":\"PPR496762\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Pharmacology,Mechanism of Action,Consciousness,Systematic Review,Review Article", "study_type": "Systematic Review", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3194, "title": "Sex-Specific Effects of Psychedelic Drug Exposure on Central Amygdala Reactivity and Behavioral Responding", "normalized_title": "sex specific effects of psychedelic drug exposure on central amygdala reactivity and behavioral responding", "authors": "Effinger D, Quadir S, Ramage M, Cone M, Herman M.", "abstract": "ABSTRACT Psilocybin, and its active metabolite psilocin, have been shown to elicit rapid and long-lasting symptom improvements in a variety of affective psychiatric illnesses. However, the region-specific alterations underlying these therapeutic effects remain relatively unknown. The central amygdala (CeA) is a primary output region within the extended amygdala that is dysregulated in affective psychiatric disorders. Here, we measured CeA activity using the activity marker c-Fos and CeA reactivity using fiber photometry paired with an aversive air-puff stimulus. We found that psilocin administration acutely increased CeA activity in both males and females and increased stimulus specific CeA reactivity in females, but not males. In contrast, psilocin produced time-dependent decreases in reactivity in males, but not females as early as 2-days and lasting to 28-days post administration. We also measured behavioral responses to the air-puff stimulus and found sex-dependent changes in threat responding but not exploratory behavior or general locomotion. Repeated presentations of the auditory component of the air-puff were also performed and sex-specific effects of psilocin on CeA reactivity to the auditory-alone stimulus were also observed. This study provides new evidence that a single dose of psilocin produces sex-specific, time-dependent, and enduring changes in CeA reactivity and behavioral responding to specific components of an aversive stimulus.", "journal": "bioRxiv", "publication_date": "2022-04-28", "publication_year": 2022, "doi": "10.1101/2022.04.28.489882", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.04.28.489882", "keywords": "", "substance_tags": "psilocybin,psilocin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR487102\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Biomarkers", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3206, "title": "Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin", "normalized_title": "shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin", "authors": "Davoudian PA, Shao L, Kwan AC.", "abstract": "ABSTRACT Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b are predictive of whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.", "journal": "bioRxiv", "publication_date": "2022-03-19", "publication_year": 2022, "doi": "10.1101/2022.03.18.484437", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.03.18.484437", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR470947\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Neuroplasticity,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": 3226, "title": "Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity", "normalized_title": "psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity", "authors": "Gaddis A, Lidstone DE, Nebel MB, Griffiths R, Mostofsky SH, Mejia A, Barrett F.", "abstract": "ABSTRACT Background Serotonin 2A receptor (5-HT 2AR ) agonist psychedelics including psilocybin and LSD (“classic” psychedelics) evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been proposed to underlie these effects, which is supported by some functional MRI (fMRI) studies. Likely due to sample size limitations, these studies have treated the thalamus as a unitary structure, despite known differential 5-HT 2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been employed to generate functional subdivisions of the thalamus from resting state fMRI (rsfMRI) data. This report utilizes a novel data-sparing ICA approach in order to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity. Methods Baseline rsfMRI data (n=38) was utilized to generate a template, which was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in a smaller sample (n=18). Correlations with subjective reports of drug effect and comparisons with a previously reported analytic approach (treating the thalamus as a single functional unit) were conducted. Results Several intrathalamic components showed significant psilocybin-induced alterations in intrathalamic spatial organization, largely localized to the mediodorsal and pulvinar nuclei, and correlated with reported subjective effects. These same components demonstrated alterations in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance. Conclusions Utilization of a novel analytic approach demonstrated changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT 2AR. Given that these changes were not observed using whole-thalamus analyses, it seems that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.", "journal": "bioRxiv", "publication_date": "2022-03-01", "publication_year": 2022, "doi": "10.1101/2022.02.28.482395", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.02.28.482395", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR463548\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Receptor Pharmacology,Default Mode Network", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3223, "title": "Natural language signatures of psilocybin microdosing", "normalized_title": "natural language signatures of psilocybin microdosing", "authors": "Sanz C, Cavanna F, Muller S, de la Fuente L, Zamberlan F, Palmucci M, Janeckova L, Kuchar M, Carrillo F, García AM, Pallavicini C, Tagliazucchi E.", "abstract": "Serotonergic psychedelics are being studied as novel treatments for mental health disorders and as facilitators of improved well-being, mental function and creativity. Recent studies have found mixed results concerning the effects of low doses of psychedelics (“microdosing”) on these domains. However, microdosing is generally investigated using instruments designed to assess larger doses of psychedelics, which might lack sensitivity and specificity for this purpose. Following a double-blind and placebo-controlled experimental design, we explored natural language as a resource to identify speech produced under the acute effects of psilocybin microdoses, focusing on variables known to be affected by higher doses: verbosity, semantic variability and sentiment scores. Except for semantic variability, these metrics presented significant differences between a typical active microdose of 0.5 g of psilocybin mushrooms and an inactive placebo condition. Moreover, machine learning classifiers trained using these metrics were capable of distinguishing between conditions with high accuracy (AUC≈0.8). Our results constitute first proof that low doses of serotonergic psychedelics can be identified from unconstrained natural speech, with potential for widely applicable, affordable, and ecologically valid monitoring of microdosing schedules.", "journal": "bioRxiv", "publication_date": "2022-02-21", "publication_year": 2022, "doi": "10.1101/2022.02.20.481177", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.02.20.481177", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR459897\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Microdosing,Wellbeing,Creativity", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3227, "title": "Increased low-frequency brain responses to music after psilocybin therapy for depression", "normalized_title": "increased low frequency brain responses to music after psilocybin therapy for depression", "authors": "Wall MB, Lam C, Ertl N, Kaelen M, Roseman L, Nutt DJ, Carhart-Harris RL.", "abstract": "Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following psychedelic therapy. Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of the second of two psilocybin dosing sessions. Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Somewhat consistently, voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. These data suggest a specific effect of PT on the brain’s response to a hedonic stimulus (music), implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.", "journal": "bioRxiv", "publication_date": "2022-02-14", "publication_year": 2022, "doi": "10.1101/2022.02.13.480302", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2022.02.13.480302", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:48", "last_checked": "2026-07-01 11:22:02", "raw_json": "{\"europe_pmc_id\":\"PPR454661\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Depression,Brain Imaging,Aging,Emotional Processing,Treatment-Resistant Depression", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" }, { "id": 3273, "title": "Microevidence for microdosing with psilocybin mushrooms: a double-blind placebo-controlled study of subjective effects, behavior, creativity, perception, cognition, and brain activity", "normalized_title": "microevidence for microdosing with psilocybin mushrooms a double blind placebo controlled study of subjective effects behavior creativity perception cognition and brain activity", "authors": "Cavanna F, Muller S, de la Fuente LA, Zamberlan F, Palmucci M, Janeckova L, Kuchar M, Pallavicini C, Tagliazucchi E.", "abstract": "The use of low sub-hallucinogenic doses of psychedelics (“microdosing”) has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies limits our knowledge of microdosing and its effects. Moreover, research conducted in laboratory settings might fail to capture the motivation of individuals engaged in microdosing protocols. We recruited 34 individuals planning to microdose with psilocybin mushrooms ( Psilocybe cubensis ), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled design, we investigated the effects of 0.5 g dried mushrooms on subjective experience, behavior, creativity, perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, which could be explained by unblinding. For the other measurements, we observed either null effects or a trend towards cognitive impairment and, in the case of EEG, towards reduced theta band spectral power. Our findings support the possibility that expectation effects underlie at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.", "journal": "bioRxiv", "publication_date": "2021-12-06", "publication_year": 2021, "doi": "10.1101/2021.11.30.470657", "pubmed_id": null, "source_url": "https://doi.org/10.1101/2021.11.30.470657", "keywords": "", "substance_tags": "psilocybin", "source_name": "bioRxiv", "date_added": "2026-07-01 11:03:49", "last_checked": "2026-07-01 11:22:03", "raw_json": "{\"europe_pmc_id\":\"PPR429397\",\"source\":\"PPR\",\"pub_type\":null,\"publisher\":\"bioRxiv\",\"importer\":\"Europe PMC\"}", "topic_tags": "Brain Imaging,Microdosing,Creativity", "study_type": "Other", "hidden": 0, "false_positive": 0, "curation_notes": null, "merged_into_id": null, "curation_locked": 0, "publication_status": "preprint" } ] }