bioRxiv (Cold Spring Harbor Laboratory)
May 6, 2024
Samuel C. Woodburn, Caleb M. Levitt, A. Koester et al.
3 citations
preprint
Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, with effects observed at all doses tested. It also produces long-term improvements in extinction retention and suppression of fear renewal in a novel context, though these effects depend on dose. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is required. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, extinction retention, and fear renewal, while blocking the 5-HT1A receptor only reduces the effect on fear renewal. These results indicate dose, timing, context, and serotonin receptors are critical for psilocybin's facilitation of fear extinction, supporting its potential as an adjunct to extinction-based therapy for PTSD.
bioRxiv (Cold Spring Harbor Laboratory)
February 12, 2024
Brian H Silverstein, Nicholas Kolbman, Amanda Nelson et al.
3 citations
preprint
Psilocybin disrupts the coupling between theta and gamma brain waves in rats and reorganizes brain networks in a dose-dependent manner. Using 27 electrodes across the cortex, the study found that psilocybin increased frontal high gamma connectivity and posterior theta connectivity, as well as network density in those regions. Medium gamma frontoparietal connectivity showed a nonlinear relationship with dose. Theta-gamma phase-amplitude coupling was disrupted. These changes suggest that high-frequency network organization, decoupled from local theta-phase, may be a signature of the altered state of consciousness induced by psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
January 7, 2024
Ziran Huang, Xiaoyan Wei, Xiaobin Wang et al.
3 citations
preprint
A single dose of psilocybin, a psychedelic whose metabolite psilocin activates 5-HT2A receptors, induces long-term genetic and functional changes in neurons of the orbitofrontal cortex (OFC), a brain region implicated in depression and other psychological disorders. Excitatory and inhibitory neurons together reduce circuit activity in the OFC. Knocking down the 5-HT2A receptor in deep-layer excitatory neurons diminishes these functional changes and the anti-depressant effect. These findings reveal cell type-specific mechanisms of psilocybin and highlight differences in how psychedelics affect distinct brain regions.
bioRxiv (Cold Spring Harbor Laboratory)
January 5, 2024
Ron Shore, K. Dobson, Nina Thomson et al.
3 citations
preprint
A scoping review of 77 pre-clinical studies (1962–2021) examined psilocybin's behavioral effects in non-human animals. Most studies used rodents. Psilocybin shows a strong safety profile with no biological toxicity, even at high doses. Effects include acute arousal, dose-dependent sedation, reduced fear conditioning at low doses, reduced aggression, improved valence, acute working memory disruption, reversal of chronic stress deficits, and improved learning when combined with repeated environmental exposure after drug effects resolve. Only 55.8% of studies reported housing conditions, and 22.1% failed to report sample size, indicating wide variation in study quality and design.
bioRxiv (Cold Spring Harbor Laboratory)
November 1, 2023
Stephanie Müller, Federico Cavanna, L. de la Fuente et al.
3 citations
preprint
High doses of psilocybin mushrooms cause people to explore paintings with more local, less random eye movements, making their gaze patterns less entropic. Participants also reported stronger emotional responses and a greater state of flow under the high dose. These effects are consistent with psilocybin altering the perception of low-level visual features like textures, shapes, and colors. The findings demonstrate that eye-tracking under naturalistic conditions can objectively measure psychedelic-induced perceptual changes, supporting greater ecological validity.
bioRxiv (Cold Spring Harbor Laboratory)
July 23, 2021
Václav Havel, Andrew C. Kruegel, Benjamin Bechand et al.
3 citations
preprint
A new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga skeleton to include a benzofuran group. These compounds act as potent kappa opioid receptor agonists but show atypical behavioral effects compared to standard kappa psychedelics. Oxa-noribogaine, a key oxa-iboga compound, demonstrated greater therapeutic efficacy in rat models of opioid use than noribogaine, with no cardiac pro-arrhythmic potential. A single dose produced long-lasting suppression of morphine and fentanyl intake, and a short treatment regimen persistently reduced morphine intake and reinforcing efficacy. It also suppressed drug seeking in relapse models and elevated neurotrophin proteins in brain regions linked to addiction, suggesting targeted neuroplasticity. Oxa-iboga compounds are candidates for a novel pharmacotherapy for opioid use disorder.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2020
Shreyas Bhat, Daryl A. Guthrie, Ameya Kasture et al.
3 citations
preprint
A novel tropane-based compound, 9b, corrects folding defects in the dopamine transporter (DAT) caused by specific mutations linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, researchers created analogs that bind to wild-type transporters and rescue two synthetic folding-deficient mutants, SERT-PG 601,602 AA and DAT-PG 584,585 AA. The most active analog, 9b, was effective as a pharmacochaperone in fruit flies carrying the DAT-PG 584,585 AA mutation and rescued six out of 13 disease-associated human DAT mutants in cell-based tests. This compound represents a promising lead for developing medications for patients with DAT mutations.
bioRxiv (Cold Spring Harbor Laboratory)
March 16, 2019
Christopher B. Germann
3 citations
preprint
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring psychoactive compound unique for its powerful ego-dissolving effects that can lead to nondual consciousness, similar to peak experiences in contemplative traditions like Advaita Vedānta and Mahāyāna Buddhism. Endogenous to the human brain, its psychological effects remain poorly understood due to a lack of controlled human trials. Its psychoactivity likely involves agonism of the 5-HT 2A serotonin receptor. Anthropological evidence shows millennia of use in various cultures. The paper argues this compound could serve as a neurochemical research tool to advance understanding of cognition and creativity, potentially by downregulating the default-mode network and increasing neuronal connectivity. The importance of unbiased research and potential abuse scenarios, including military torture, are discussed.
bioRxiv (Cold Spring Harbor Laboratory)
Sabine U. König, Caspar Goeke, Tobias Meilinger et al.
3 citations
preprint
Spatial knowledge about houses and streets is coded differently in the brain. Under time pressure, people are more accurate at pointing to the relative orientation of two houses than the absolute orientation of a single house toward north. Given unlimited time, accuracy for absolute house orientation improves greatly and surpasses the slight improvement for relative orientation. For streets, however, people perform better on absolute orientation even under time pressure. Pointing from one house to another yields the best performance overall. These results suggest that house orientation and location are primarily learned in an action-oriented, relational way, supporting enactive theories of cognition, whereas street orientation is preferentially coded in absolute, cardinal terms.
bioRxiv (Cold Spring Harbor Laboratory)
July 7, 2025
Akila Ram, Austen B. Casey, Robert C. Malenka et al.
2 citations
preprint
Psilocybin does not produce direct analgesic effects in mice, despite suggestions from clinical and preclinical data that it might help chronic pain. Across multiple pain assays and models of acute and chronic inflammatory, neuropathic, and musculoskeletal pain, no dose of psilocybin was analgesic. The finding indicates that any therapeutic benefits for chronic pain syndromes are unlikely to come from direct pain relief.
bioRxiv (Cold Spring Harbor Laboratory)
April 14, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
2 citations
preprint
Chronic administration of low-dose LSD in mice does not produce the cardiovascular damage seen with serotonin, a known cardiotoxin. Serotonin caused significant ventricular thickening after 4 and 8 weeks, while LSD at two sub-hallucinogenic doses showed no such changes. Although LSD activates 5-HT 2B receptors—the same receptors linked to heart disease from chronic activation—the activation is substantial but short-lived compared to the cardiotoxin d-fenfluramine. Affinity and potency of LSD, psilocybin, and norfenfluramine at mouse and human 5-HT 2B receptors were similar. These findings indicate no evidence of cardiovascular risk from prolonged low-dose LSD in mice.
bioRxiv (Cold Spring Harbor Laboratory)
January 8, 2025
Delong Zhou, Heike Schuler, Vedrana Cvetkovska et al.
2 citations
preprint
A single dose of psilocybin increases synaptic transmission in the medial prefrontal cortex of mice. Single-cell RNA sequencing reveals that, 24 hours after administration, plasticity-related gene expression rises in excitatory neurons, with particularly robust changes in a deep-layer neuron type called L5/6 NP. This cell-type specificity aligns with 5-HT 2C receptor expression patterns, not 5-HT 2A. Multivariate analyses show that psilocybin-induced gene expression in L5/6 NP neurons predicts 5-HT 2C transcript levels. Blocking 5-HT 2C receptors with an antagonist attenuates the sustained effect on synaptic transmission, identifying 5-HT 2C signaling and L5/6 NP neurons as key mediators of psilocybin's lasting neuroplastic effects.
bioRxiv (Cold Spring Harbor Laboratory)
December 22, 2024
Rubén García‐cabrerizo, Itziar Beruete-Fresnillo, M. Julia García‐fuster
2 citations
preprint
Adolescent depression is a major public health problem, but treatment options are limited, partly because antidepressants work differently depending on age and sex. In adolescent rats, a single oral dose of psilocybin produced rapid antidepressant-like effects within 30 minutes in both males and females, shown by less immobility and more escape behavior in the forced swim test. After 7 days of daily dosing, males maintained these effects for at least 15 days at both doses tested. Females showed dose-dependent effects that lasted only up to 8 days at the highest dose. These findings suggest psilocybin may offer fast and lasting antidepressant action during adolescence, a period of high depression vulnerability and poor response to conventional treatments, and highlight the need to tailor therapies to biological sex.
bioRxiv (Cold Spring Harbor Laboratory)
December 7, 2024
Alexander J. Bradshaw, Cathy Sharp, B. van der Merwe et al.
2 citations
preprint
The closest wild relative of the widely cultivated magic mushroom Psilocybe cubensis has been discovered in sub-Saharan Africa and named Psilocybe ochraceocentrata. DNA analysis of type specimens and multi-locus phylogenetic and molecular clock dating show the two species last shared a common ancestor about 1.5 million years ago (range 710,000 to 2.55 million years ago), long before cattle domestication or modern humans appeared. This refutes the long-held hypothesis that P. cubensis was introduced to the Americas via cattle brought from Africa around 1500 CE. Both species grow on herbivore dung, which likely pre-adapted P. cubensis to specialize on domesticated cattle dung. Ecological niche modeling indicates the species have been present across Africa, Asia, and the Americas over the last 3 million years.
bioRxiv (Cold Spring Harbor Laboratory)
October 22, 2024
Pablo Mallaroni, S. Parker Singleton, Natasha L. Mason et al.
2 citations
preprint
A double-blind, placebo-controlled crossover study with 22 healthy volunteers compared the acute brain effects of the psychedelic phenethylamine 2C-B (20 mg) and the tryptamine psilocybin (15 mg) using 7T resting-state functional MRI. Both compounds reduced connectivity within brain networks and broadly increased connections between networks and between subcortical and cortical regions. Compared to psilocybin, 2C-B caused less reduction in between-network connectivity but increased connectivity in transmodal regions. Both drugs similarly increased brain complexity. The neural effects aligned with differences in monoaminergic and serotonergic receptor binding beyond 5-HT2A, suggesting 2C-B's distinct pharmacology shapes its functional brain dynamics.
bioRxiv (Cold Spring Harbor Laboratory)
July 6, 2024
Chloe L. West, Georgia Bastos, Annabel Duran et al.
2 citations
preprint
Serotonergic psychedelics like psilocybin may treat psychiatric disorders by loosening ingrained beliefs, shifting brain processing from top-down to bottom-up. People who recently used 5-HT2A-agonist psychedelics showed slower eye movements and stronger sensory prediction errors during visual tasks. Those using 5-MeO-DMT, which targets 5-HT1A receptors, showed altered eye movements but unchanged deviance detection. In mice, the 5-HT2A-agonist DOI altered deviance detection in primary visual cortex and weakened top-down feedback from higher cortical area ACa. These effects persisted beyond the acute drug period, supporting predictive processing theories of psychedelic action.
bioRxiv (Cold Spring Harbor Laboratory)
June 25, 2024
Milan van Maldegem, Jakub Vohryzek, Selen Atasoy et al.
2 citations
preprint
Ketamine, a dissociative anesthetic, produces different brain dynamics at anesthetic versus sub-anesthetic doses. Using connectome harmonic decomposition (CHD) to analyze resting-state fMRI data from volunteers during ketamine-induced unresponsiveness, the study found increased prevalence of localized harmonics, similar to patterns seen in psychedelic states induced by LSD or psilocybin. This contrasts with traditional GABAergic sedation (e.g., propofol), where global harmonics increase with higher doses. The results indicate that ketamine-induced unresponsiveness does not necessarily suppress conscious experience and influences connectome harmonics oppositely to GABAergic hypnotics. CHD may track alterations in conscious awareness rather than behavioral responsiveness.
bioRxiv (Cold Spring Harbor Laboratory)
May 17, 2024
Elizabeth L. Fisher, Ryan Smith, Andrew W. Corcoran et al.
2 citations
preprint
Rats treated with psilocybin achieved more rewards in a decision-making task, driven by increased task engagement, altered forgetting rates, and reduced loss aversion. Computational modeling of the rats' behavior revealed that psilocybin may induce an optimism bias through changes in how beliefs are updated. This finding has potential relevance for clinical populations characterized by a lack of optimism, such as those with depression.
bioRxiv (Cold Spring Harbor Laboratory)
October 9, 2023
Marina D. Luccioni, Jules T. Wyman, Edgard O. Espinoza et al.
2 citations
preprint
The Sonoran Desert Toad is the only animal known to secrete the psychedelic compound 5-MeO-DMT as a chemical defense, but whether it produces this compound itself or acquires it from its diet was unclear. Analyzing toxin gland secretions and stomach contents from wild toads and other amphibians in and around Tucson, Arizona, showed that all Sonoran Desert Toads had high concentrations of 5-MeO-DMT, while other toad species did not. The diet of the Sonoran Desert Toad was similar to that of other amphibians, suggesting no special dietary source. Slight differences in diet between toads from native and urban habitats were observed. These findings indicate that diet is not directly linked to 5-MeO-DMT production, supporting the idea that the toads either synthesize the compound themselves or rely on a microbial partner.
bioRxiv (Cold Spring Harbor Laboratory)
October 7, 2023
Kenneth Shinozuka, Katarina Jerotic, Pedro A. M. Mediano et al.
2 citations
preprint
Serotonergic psychedelics such as LSD, psilocybin, and DMT alter consciousness and show therapeutic potential for depression and addiction, but their mechanisms remain unclear. A systematic review and meta-analysis across three levels—phenomenology, neuroimaging, and pharmacology—reveals that medium and high doses of LSD produce significantly stronger visionary restructuring than psilocybin. Neuroimaging shows psychedelics generally strengthen connectivity between brain networks while weakening connectivity within networks. Pharmacologically, LSD triggers more inositol phosphate formation at the 5-HT2A receptor than DMT or psilocin, but no significant differences emerged in receptor selectivity among the drugs. The findings highlight high heterogeneity and risk of bias, underscoring the need for standardized methods.
bioRxiv (Cold Spring Harbor Laboratory)
February 16, 2023
Pablo Mallaroni, Natasha L. Mason, Johannes T. Reckweg et al.
2 citations
preprint
2C-B, a hallucinogenic phenethylamine derived from mescaline, produces subjective psychedelic effects that are shorter in duration and milder than those of psilocybin. In a double-blind, placebo-controlled study with 22 healthy participants experienced with psychedelics, 2C-B (20 mg) induced alterations of waking consciousness of a psychedelic nature, but dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution were largest under psilocybin (15 mg). Both compounds caused equivalent psychomotor slowing and spatial memory impairments compared to placebo, and neither produced empathogenic effects on the Multifaceted Empathy Test. 2C-B also induced transient pressor effects similar to psilocybin, with self-reported effects largely resolving within 6 hours. These findings support categorizing 2C-B as a subjectively 'lighter' psychedelic.
bioRxiv (Cold Spring Harbor Laboratory)
April 29, 2022
Devin P. Effinger, Sema G. Quadir, M. C. Ramage et al.
2 citations
preprint
A single dose of psilocin, the active metabolite of psilocybin, produces sex-specific, time-dependent, and lasting changes in central amygdala (CeA) activity and reactivity to an aversive air-puff stimulus in mice. Psilocin acutely increased CeA activity in both sexes and increased stimulus-specific CeA reactivity in females but not males. In males, psilocin caused time-dependent decreases in reactivity from 2 to 28 days after administration, while females showed no such decrease. Behavioral threat responses also changed in a sex-dependent manner, with no effects on exploratory behavior or locomotion. These findings suggest enduring, sex-specific alterations in CeA function underlie psilocin's therapeutic effects in affective disorders.
bioRxiv (Cold Spring Harbor Laboratory)
March 2, 2022
Andrew Gaddis, Daniel E. Lidstone, Mary Beth Nebel et al.
2 citations
preprint
Psilocybin, a classic psychedelic, alters perception and cognition by affecting connectivity between the thalamus and cortex. Using a novel analysis of resting-state fMRI data, this study found that psilocybin changes the functional organization within specific thalamic nuclei—primarily the mediodorsal and pulvinar nuclei—and alters their connections with visual and default mode networks. These changes correlated with subjective drug effects. When the thalamus was treated as a single unit, a numerical but not statistically significant increase in thalamocortical connectivity was observed, suggesting that psilocybin causes widespread modest increases offset by strong focal decreases in relevant nuclei.
bioRxiv (Cold Spring Harbor Laboratory)
June 23, 2021
Aurora Savino, Charles D. Nichols
2 citations
preprint
Psychedelic drugs are being studied as potential treatments for psychiatric conditions like mood and substance use disorders. The 5-HT2A receptor is their main molecular target, and early research indicated effects on neuroplasticity gene expression. By analyzing RNA-seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), researchers found that psychedelics rewire gene co-expression networks, making them less centralized but more complex, with an overall increase in signaling entropy—a feature of highly plastic systems. This molecular signaling entropy mirrors increased brain entropy observed in human neuroimaging studies, suggesting a shared underlying mechanism. Network topology analysis also identified potential transcriptional regulators and implicated different cell types in psychedelic activity.
bioRxiv (Cold Spring Harbor Laboratory)
February 2, 2021
E. Amit Romach, M. Nachliely, Olivia Moran et al.
2 citations
preprint
Psychedelics such as LSD and psilocybin, increasingly used by cancer patients to relieve anxiety and depression, may interfere with immune-based cancer treatments like immune checkpoint inhibitors. Preclinical data suggest that consuming psychedelics during such therapy could negatively impact tumor growth and diminish the therapeutic benefits of immune checkpoint inhibitors. The authors call for further research to validate these findings, given the rising use of cannabinoids and psychedelics among cancer patients receiving immune-based treatments.