bioRxiv (Cold Spring Harbor Laboratory)
December 19, 2025
K.j Matthews Nicholass, I Flis, M.e Hanley et al.
Psilocybin, the psychedelic compound in 'magic' mushrooms, may have evolved as a chemical defense against insects. When fruit fly larvae were exposed to extracts from Psilocybe mushrooms, they showed reduced survival, lower pupation rates, and inhibited locomotion. Adults that developed from exposed larvae had smaller thoraxes and wings, along with increased fluctuating asymmetry, indicating developmental stress. Surprisingly, flies lacking 5HT2A receptors responded the same as normal flies, suggesting psilocybin's effects on insects involve different mechanisms than in vertebrates. DNA analysis showed that Psilocybe semilanceata hosts a distinct invertebrate community compared to most grassland fungi, though it overlapped with the non-psychedelic species Mycena epipterygia. This suggests psilocybin's ecological role may be more complex than simple defense.
bioRxiv (Cold Spring Harbor Laboratory)
December 11, 2025
Caroline L. Alves, Fernanda Palhano-Fontes, Thaise G. L. de O. Toutain et al.
Ayahuasca alters conscious experience, and this study identifies EEG markers of its network-level effects using machine learning and complex-network analysis. In a randomized, double-blind, placebo-controlled trial with naïve ayahuasca users, resting-state EEG was recorded before dosing, 2 hours after, and 4 hours after. Connectivity was estimated with sliding windows; optimal classification performance occurred at 60–70 seconds (AUC and accuracy = 0.93). Network analysis revealed a bilateral decrease in eigenvector centrality (weaker hub influence), increased degree heterogeneity in the right hemisphere, and reduced global efficiency in the left. Posterior-left connections weakened acutely, while right temporal–central coupling transiently strengthened. The findings suggest that hub-centric shortcuts weaken, routing communication through more distributed, less efficient pathways with right-lateralized expression.
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2025
Gabrielle Allohverdi, Milad Soltanzadeh, André Schmidt et al.
preprint
Ketamine and psilocybin, two hallucinogenic compounds being explored as treatments for major depressive disorder, affect sensory learning in the brain differently. By combining computational modeling with electroencephalography (EEG) data from a prior experiment, researchers analyzed how these drugs alter the brain's processing of unexpected sounds during an auditory task. Ketamine produced a larger reduction in the influence of sensory precision between 207 and 316 milliseconds after a sound, peaking at 277 milliseconds in frontal central brain regions, while psilocybin showed no significant effect in that measure. Both drugs reduced the expression of belief precision between 160 and 184 milliseconds, peaking at 172 milliseconds.
bioRxiv (Cold Spring Harbor Laboratory)
October 15, 2025
Sheida Shadani, Erika Greaves, Zane B. Andrews et al.
preprint
A single dose of psilocybin did not alter sociability in female mice exposed to activity-based anorexia, food restriction, or exercise, but increased preference for familiarity in control mice. Novelty-seeking behavior rose in both anorexia-model and exercise mice, with distinct social patterns. Psilocybin elevated the inflammatory marker interleukin-6 in exercised mice, which correlated with novelty preference; no such link appeared in other groups. These context-dependent effects on social behavior and inflammation underscore the need to study psilocybin's mechanisms across sexes and disease models.
bioRxiv (Cold Spring Harbor Laboratory)
September 17, 2025
Matheus Gallas‐lopes, Dagobert Müller, Thailana Stahlhofer-Buss et al.
preprint
Ketamine, an NMDA receptor antagonist, produced concentration-dependent behavioral changes in adult zebrafish. Acute exposure reduced social interaction and increased swimming activity and rotational behavior. These effects did not intensify with repeated daily dosing over five days and were not present 48 hours after the final treatment, indicating no behavioral sensitization or lasting disruption. The findings support zebrafish as a model for acute schizophrenia-like behavioral phenotypes induced by NMDA receptor blockade, but the lack of sustained effects differs from rodent studies.
bioRxiv (Cold Spring Harbor Laboratory)
September 12, 2025
Navid Shams Masjedi, Adeel Razi
preprint
The claustrum, a brain region with extensive connections to both cortical and subcortical areas, may help synchronize brain networks. Psychedelics like psilocybin appear to disrupt this synchrony by altering claustral signaling. Using brain scans from the Human Connectome Project and PsiConnect datasets, this work provides the first in vivo description of how the claustrum communicates with key brain networks in humans, both at rest and under psilocybin. The claustrum showed widespread bidirectional connections and a strong inhibitory influence on target regions. Psilocybin increased this inhibition on cortical networks while reducing it on subcortical areas, partly linked to subjective psychedelic effects, supporting a role for claustro-cortical inhibition in regulating network synchrony.
bioRxiv (Cold Spring Harbor Laboratory)
August 22, 2025
Matthew D. Greaves, Tamrin Barta, Leonardo Novelli et al.
preprint
Psilocybin reorganizes directed influences between brain regions while preserving the underlying structural connectivity, according to fMRI data analyzed with a dynamic causal model. Across four contexts—rest, guided meditation, music listening, and movie viewing—effects converged on outgoing influences from the left hippocampus, a hub linking memory and association systems with the default-mode network and thalamus. The left-hippocampus-to-thalamus pathway showed a sign-reversed association with mystical-experience scores: downregulation during guided meditation and upregulation during music listening. Left-hippocampal efferents predicted individual differences in mystical-experience intensity in cross-validation, and a simpler measure of hippocampal signal variability showed modest associations.
bioRxiv (Cold Spring Harbor Laboratory)
July 29, 2025
May Kung Sutherland, Christopher R. Nicholas, Richard Lennertz et al.
preprint
Psilocybin, a serotonergic psychedelic, induces neural plasticity and alters consciousness, while midazolam, a benzodiazepine, blunts plasticity and causes sedation and amnesia. In an open-label pilot study, 25 mg of oral psilocybin was given alongside intravenous midazolam at doses that allowed a full psychedelic experience but reduced memory of it. EEG recordings showed that 15-30 minutes after dosing, when midazolam was at its target concentration, beta power increased and the spectral exponent decreased. As psilocybin's effects emerged over the next six hours, Lempel-Ziv complexity and spectral exponent increased while broadband power decreased. These findings suggest psilocybin's effects persist even with midazolam, supporting its use in mechanistic studies.
bioRxiv (Cold Spring Harbor Laboratory)
May 30, 2025
Pavel Osten, K Sunny Joseph, Jane Collins et al.
preprint
Ketamine relieves depression within a day, whereas standard monoaminergic antidepressants take weeks. In mice, whole-brain mapping of the activity marker c-fos after treatment with monoaminergic antidepressants, ketamine, and psilocybin revealed a shared limbic circuit involving subcortical and frontal cortical regions. Ketamine and high-dose psilocybin acutely activated the prelimbic and infralimbic frontal cortex—areas linked to depression—while the selective serotonin reuptake inhibitor fluoxetine and psilocybin microdosing activated these regions only after chronic dosing. This suggests a common limbic subcortico-cortical circuit underlies antidepressant efficacy, explains the delay of monoaminergic drugs, and shows that monoaminergic antidepressants and psilocybin microdosing evoke similar brain activity.
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2025
Shaun K.l. Quah, Cameron Glick, Leor Roseman et al.
preprint
People with major depression who responded to either psilocybin or escitalopram showed distinct changes in brain network connectivity compared to non-responders. Responders had increased linear connectivity within the ventral attention network and greater nonlinear connectivity within the default mode and ventral attention networks. Psilocybin responders showed enhanced coordination between higher-order networks, while escitalopram responders showed reduced connectivity within networks linked to self-referential thought and salience processing. These patterns suggest the two antidepressants work through different mechanisms, with nonlinear connectivity analyses revealing effects not captured by traditional linear measures.
bioRxiv (Cold Spring Harbor Laboratory)
January 14, 2025
Alexia L. Zylko, Ryan J. Rakoczy, Brianna F Roberts et al.
preprint
Psilocybin, the psychedelic compound in magic mushrooms, produced head twitch responses in adult rats but not in adolescent rats. Adult female rats in diestrus showed more head twitches after psilocybin than those in proestrus, indicating that hormonal phase influences the response. Adolescent exposure to psilocybin did not cause lasting changes in anxiety-like behavior or behavioral flexibility. No age- or estrous-related differences were found in 5-HT2A receptor expression in the medial prefrontal cortex. These results show age- and sex-dependent differences in psychedelic effects and emphasize the need for inclusive research that accounts for age, sex, and hormonal status.
bioRxiv (Cold Spring Harbor Laboratory)
January 2, 2025
Marcel Socoró Garrigosa, Yonatan Sanz Perl, Morten L. Kringelbach et al.
preprint
Using whole-brain models guided by the Thermodynamics of Mind framework, the authors estimated the brain hierarchy of specific brain states and simulated transitions between states. Applying this to major depressive disorder, they built models of depressed patients before and after psilocybin and escitalopram treatments. Dynamic sensitivity analysis showed that susceptibility to change was on average reduced by escitalopram and increased by psilocybin, and both treatments promoted healthier transitions. These results align with the post-treatment plasticity window opened by serotonergic psychedelics and with the similar clinical efficacy of both drugs observed in clinical trials.
bioRxiv (Cold Spring Harbor Laboratory)
November 28, 2024
T. Ben Tal, Ilana Pogodin, Alexaner Botvinnik et al.
preprint
Combining psilocybin with NMDAR modulators D-serine or D-cycloserine reduces hallucinogenic-like effects and enhances neuroplasticity in mice. Psilocybin alone increased head twitch response, a surrogate for hallucinogenic effects, which was dose-dependently reduced by either modulator. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic effects. The psilocybin-D-serine combination increased GAP43 expression across all four brain regions examined and overall synaptic protein expression in the hippocampus, while psilocybin-D-cycloserine elevated PSD95 levels in all four regions, indicating synaptogenic synergy. These results suggest that pairing serotonergic psychedelics with NMDAR modulators may improve therapeutic efficacy and safety.
bioRxiv (Cold Spring Harbor Laboratory)
November 3, 2024
Ling-Xiao Shao, Clara Liao, Pasha A Davoudian et al.
preprint
A single dose of psilocybin increased the density of dendritic spines in both subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) cell types in the mouse medial frontal cortex. Silencing PT neurons eliminated psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons had no detectable effect. In PT neurons only, psilocybin boosted synaptic calcium transients and elevated firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolished psilocybin's effects on stress-related behavior and structural plasticity. These results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential for psilocybin's long-term drug action.
bioRxiv (Cold Spring Harbor Laboratory)
September 23, 2024
Michal Lazar, Michal Brownstien, Alexander Botvinnik et al.
preprint
Juvenile mice lacking the SAPAP3 gene, a model of obsessive-compulsive disorder (OCD), show anxiety-like behaviors before they develop the excessive self-grooming that mimics OCD compulsions. Compared to normal mice, these knockout mice spent less time in open areas, buried fewer marbles, and found fewer hidden objects. A single dose of psilocybin (4.4 mg/kg) did not reduce these anxiety-like behaviors. In adult but not juvenile male knockout mice, levels of several synaptic proteins (GAP43, synaptophysin, SV2A) were elevated across brain regions, suggesting compensatory plasticity changes that emerge with age. The findings parallel the clinical observation that anxiety often precedes OCD in humans and indicate that psilocybin's therapeutic effects may be age-dependent.
bioRxiv (Cold Spring Harbor Laboratory)
March 31, 2024
David Martin, Á.v. Delgado, Donna J. Calu
preprint
Psychedelics may help treat neuropsychiatric disorders by disrupting entrenched associations and promoting new learning. In rats performing a Pavlovian task where sequential cues predict rewards, the psychedelic DOI (a 5-HT2A/2C agonist) increased dopamine signaling in the nucleus accumbens core to rewards and to cues immediately preceding them, but not to more distal predictive cues. This elevated dopamine occurred independently of changes in reward value and supports increased prediction error signaling. The findings suggest psychedelics could engage error-driven learning mechanisms to disrupt or form new associations.
bioRxiv (Cold Spring Harbor Laboratory)
October 23, 2023
Ryan J. Rakoczy, Grace N. Runge, Abhishek K. Sen et al.
preprint
Naturally occurring tryptamines in psilocybin-containing mushrooms—baeocystin, norbaeocystin, and aeruginascin—were compared with psilocybin for pharmacological and behavioral effects. All compounds showed nearly identical rates of dephosphorylation and metabolism. Only dephosphorylated forms of baeocystin and norbaeocystin crossed a blood-brain barrier model similarly to psilocin (psilocybin's active form). In rats, only psilocybin triggered head twitch responses (a marker of hallucinogenic potential), but norbaeocystin, like psilocybin, improved outcomes in the forced swim test. All compounds showed minimal effects on renal and hepatic health markers. The findings suggest norbaeocystin may share psilocybin's therapeutic potential without causing hallucinations.
bioRxiv (Cold Spring Harbor Laboratory)
August 28, 2023
Nicholas Kolbman, Tiecheng Liu, Peter R. Guzzo et al.
preprint
A single intravenous dose of psilocybin (1 mg/kg or 10 mg/kg) reduced mechanical hypersensitivity in rats for 28 days after formalin-induced chronic pain, but had only a limited effect on thermal hyperalgesia. Formalin injection caused thermal hyperalgesia and bilateral mechanical hypersensitivity in all rats. Psilocybin significantly attenuated the mechanical hypersensitivity throughout the 28-day testing period, while thermal hyperalgesia was reduced only on days 1, 3, 5, and 21. These results suggest psilocybin may have potential for treating chronic pain, though its effects on different pain types vary.
bioRxiv (Cold Spring Harbor Laboratory)
July 20, 2023
Rafael V Lima Da Cruz, Richardson N Leao, Thiago C Moulin
preprint
New neurons continue to be generated in the mammalian brain throughout life, a process linked to the HPA axis and mood disorders. Psychedelic compounds—including phenethylamines, tryptamines, cannabinoids, and others—have emerged as potential treatments for neuropsychiatric disorders, with evidence suggesting they increase adult neurogenesis. This systematic review examined 68 studies from a total of 205 articles, covering CB1 agonists, NMDA antagonists, harmala alkaloids, tryptamines, and entactogens. The findings describe how different psychedelics affect the birth of new neurons and brain plasticity, providing a comprehensive picture that may inform future therapeutic strategies for neuropsychiatric disorders.
bioRxiv (Cold Spring Harbor Laboratory)
June 5, 2023
Annie Da Costa Souza, Bryan Da Costa Souza, Arthur S. C. França et al.
preprint
The psychedelic 5-MeO-DMT increases delta power and decreases theta power in the hippocampus of freely moving rats, effects not explained by changes in locomotion. It also dose-dependently reduces slow and mid gamma power and theta phase modulation. The overall spectral profile of awake behavior after 5-MeO-DMT resembles electrophysiological states seen during slow-wave sleep and REM sleep. These findings suggest that classical psychedelics may integrate waking behaviors with sleep-like neural activity patterns.
bioRxiv (Cold Spring Harbor Laboratory)
May 22, 2022
Leonard Lerer, Eric C. Reynolds, Jeet Varia et al.
preprint
A sustainable source of 5-MeO-DMT, a promising compound for psychiatric treatment, has been developed using a cell line from the parotoid gland of the endangered Incilius alvarius toad. This innovative approach demonstrated successful biosynthesis of 5-MeO-DMT through chemical processes in vitro. Given that natural populations are under ecological threat due to habitat loss and demand, this method offers a cruelty-free alternative for producing 5-MeO-DMT, potentially supporting future psychedelics and drug studies while preserving biodiversity.
bioRxiv (Cold Spring Harbor Laboratory)
January 21, 2022
Konstantin A. Demin, Olga V. Kupriyanova, Вадим А. Шевырин et al.
preprint
Certain synthetic N-Benzyl-2-phenylethylamine (NBPEA) derivatives, related to hallucinogens like mescaline and MDMA, produce distinct behavioral and neurochemical effects in adult zebrafish. Substitutions on the N-benzyl fragment primarily affected locomotion, while those on the phenethylamine moiety influenced anxiety-like behavior. The compounds also modulated brain serotonin and/or dopamine turnover. Several behavioral clusters emerged: anxiogenic/hypolocomotor, behaviorally inert, anxiogenic/hallucinogenic-like, and anxiolytic/hallucinogenic-like. Two compounds reduced despair-like behavior. Artificial intelligence-driven phenotyping linked multiple compounds to NMDA antagonists and/or MDMA, suggesting hallucinogenic-like properties. In silico modeling indicated similarities between these NBPEAs, MDMA, and ketamine, implicating serotonin release, calcium channel activity, and serotonin receptor involvement.
bioRxiv (Cold Spring Harbor Laboratory)
July 24, 2020
Timo Torsten Schmidt, Simon Reiche, Caroline L. C. Hage et al.
preprint
Kambô, the secretion of the Giant Leaf Frog (Phyllomedusa bicolor), is ritually used by Amazonian ethnicities against bad luck in hunting and has spread to Western urban centers, often alongside ayahuasca. A retrospective study of 22 anonymous users (mean age 39 years, 45.5% female) assessed acute and subacute psychological effects with standardized questionnaires. Acutely, participants reported mild to moderate psychological effects without psychedelic-type perceptual or thinking distortions. Persisting effects were predominantly positive and pleasant, with surprisingly high personal and spiritual significance. Subacute and long-term effects overlapped with the 'afterglow' phenomena following serotonergic psychedelics.
bioRxiv (Cold Spring Harbor Laboratory)
January 23, 2020
Ca Hales, Jm Bartlett, R Arban et al.
preprint
Ketamine and other rapid-acting antidepressants (RAADs) like CP-101,606 and scopolamine produce a positive bias in decision-making in rodents, shifting choices toward more optimistic outcomes. This effect is localized to the medial prefrontal cortex (mPFC), as targeted infusions into this brain region replicate the bias. In contrast, other NMDA receptor antagonists that lack rapid antidepressant effects do not induce this positive bias. Temporary inactivation of the mPFC with muscimol caused general behavioral disruptions rather than the specific positive bias seen with RAADs. These findings suggest that ketamine and similar RAADs act through a distinct mechanism involving the mPFC to alter affective biases, which may underlie their therapeutic action in major depressive disorder.
bioRxiv (Cold Spring Harbor Laboratory)
February 13, 2017
Vanja Dakic, Juliana Nascimento, Rafaela Sartore et al.
preprint
5-MeO-DMT, a hallucinogenic molecule found in traditional Amerindian medicine, alters the proteome of human cerebral organoids. Of 6,728 identified proteins, 934 were differentially expressed after treatment. Systems biology analyses indicate anti-inflammatory effects and modulation of proteins linked to long-term potentiation, dendritic spine formation, cellular protrusion, microtubule dynamics, and cytoskeletal reorganization. These findings provide mechanistic insights into the neuropsychological changes associated with dimethyltryptamine ingestion.