bioRxiv (Cold Spring Harbor Laboratory)
February 6, 2025
Bryce Axe, Ashwath Maheswari, Reagan Walhof et al.
3 citations
preprint
Repetitive mild head injuries from sports, accidents, or military service cause lasting cognitive, motor, and behavioral problems and raise the risk of dementia, Parkinson's disease, and chronic traumatic encephalopathy, yet no approved treatment exists. Testing the psychedelic psilocybin in adult female rats with mild repetitive head injury, the authors report that psilocybin reduces vasogenic edema, restores normal vascular reactivity and functional connectivity, reduces buildup of phosphorylated tau, increases levels of brain-derived neurotrophic factor and its receptor TrkB, and modulates lipid signaling molecules. These findings suggest psilocybin may have healing effects on head injury-related brain damage.
bioRxiv (Cold Spring Harbor Laboratory)
January 4, 2025
Clara Liao, Ethan O'Farrell, Yaman Qalieh et al.
3 citations
preprint
A single dose of psilocybin triggers time-dependent and cell-type-specific changes in gene expression in the medial frontal cortex of mice. Excitatory neurons showed altered genes involved in synaptic plasticity, while GABAergic neurons showed changes in genes related to mitochondrial function and metabolism. These transcriptional responses occurred in an early phase at 1-2 hours and a late phase at 72 hours after administration. Ketamine produced similar transcriptional changes. These findings suggest that psilocybin's long-term neural and behavioral effects may stem from lasting alterations in gene expression.
bioRxiv (Cold Spring Harbor Laboratory)
October 26, 2024
Saampras Ganesan, Nicholas T. van Dam, Sunjeev K. Kamboj et al.
3 citations
preprint
Personalized high-precision neurofeedback (NF) can help novice meditators better disengage from mental activity during meditation, improving emotional well-being and mindful awareness. In a single-blind, controlled study, 40 novices received two days of meditation training with feedback from either their own or a matched participant's posterior cingulate cortex (PCC) activity, measured using 7 Tesla fMRI. The experimental group showed stronger functional decoupling of PCC from dorsolateral prefrontal cortex, indicating improved control over disengagement. This led to greater improvements in emotional well-being and mindful awareness during a week of real-world self-guided meditation, supporting the utility of NF-guided meditation training.
bioRxiv (Cold Spring Harbor Laboratory)
August 19, 2024
Naji Alnagger, Paolo Cardone, Charlotte Martial et al.
3 citations
preprint
Disorders of consciousness, such as unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), have few treatments. Using whole-brain computational models built from individual patients' fMRI and diffusion-weighted imaging data, this virtual clinical trial simulated the effects of LSD and psilocybin. The psychedelics shifted the brains of patients with disorders of consciousness closer to a critical dynamical state, with a larger effect in MCS patients. In UWS patients, the treatment response depended on structural connectivity, whereas in MCS patients it aligned with baseline functional connectivity. These results provide a computational foundation for considering psychedelics in treating disorders of consciousness and highlight the role of computational modeling in drug discovery and personalized medicine.
bioRxiv (Cold Spring Harbor Laboratory)
June 13, 2024
Christopher R. Nicholas, Matthew I. Banks, Richard C Lennertz et al.
3 citations
preprint
Co-administering the amnestic benzodiazepine midazolam with psilocybin in 8 healthy participants partially impaired memory for the psychedelic experience while still allowing a conscious experience to occur. The degree of memory impairment was inversely associated with salience, insight, and well-being induced by psilocybin. These results suggest that memory of the acute psychedelic experience contributes to therapeutically relevant behavioral effects. Because midazolam blocks memory by blocking cortical neural plasticity, it may also help evaluate how the pro-neuroplastic properties of psychedelics contribute to their therapeutic activity.
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)
May 30, 2025
Michael Y. Wang, M. Prabhavi N. Perera, Paul B. Fitzgerald et al.
2 citations
preprint
Attrition rates for mindfulness-based interventions (MBIs) for chronic pain average 30.1%, but vary widely depending on program structure. Stricter completion thresholds are linked to higher dropout: requiring at least six sessions to count as a completer yields a 49.7% attrition rate, versus 18% when only three sessions are required. Online delivery shows higher attrition (51.0%) than in-person delivery (25.6%), and individual formats have higher attrition than group formats. These findings suggest that modifying program structure—such as lowering session requirements, offering in-person sessions, and using group formats—could reduce participant withdrawal.
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)
February 13, 2024
Julio Rodriguez-Larios, Kian Foong Wong, Julian Lim
2 citations
preprint
Mindfulness training did not reduce lapses of attention or their associated theta brain oscillations during meditation, but it did slow alpha oscillations in frontal electrodes, a pattern previously seen in highly experienced meditators and thought to reflect decreased arousal. The study recorded EEG from 41 participants before and after 8 weeks of mindfulness training or a waitlist, interrupting them during meditation to report focus and drowsiness. Self-reported lapses of attention were linked to increased theta oscillations that were slower and more widespread than those during focused states. These findings clarify the neural correlates of mindfulness meditation and may inform neuromodulation protocols.