bioRxiv (Cold Spring Harbor Laboratory)
September 1, 2019
Joanes Grandjean, David Buehlmann, Michaela Buerge et al.
5 citations
preprint
Psilocybin, a serotonin 2A receptor agonist, alters functional connectivity in the brain's default-mode network, which is involved in self-reference and disrupted in depression. In lightly-anesthetized mice, resting-state fMRI showed psilocybin reduced connectivity within the ventral striatum. Using gene expression maps and viral tracer projections, two distinct effects emerged: psilocybin increased connectivity between serotonin-associated networks and parts of the mouse default-mode network, thalamus, and midbrain, while decreasing connectivity within dopamine-associated striatal networks. These findings suggest that interactions between serotonin- and dopamine-regulated neural networks contribute to psilocybin's neural and psychological effects, and show how molecular and structural connectivity data can clarify pharmaco-fMRI results.
bioRxiv (Cold Spring Harbor Laboratory)
January 31, 2018
Ana Cecília de Menezes Galvão, Raíssa Nóbrega de Almeida, Erick Allan Dos Santos Silva et al.
5 citations
preprint
In treatment-resistant depression, a single dose of ayahuasca normalizes the blunted awakening salivary cortisol response that is characteristic of the disorder. Patients with major depression showed hypocortisolemia and a diminished cortisol awakening response compared with healthy controls at baseline. During the dosing session, both patients and controls who ingested ayahuasca had a large increase in salivary cortisol relative to placebo groups. Forty-eight hours after ayahuasca, the awakening cortisol response in treated patients became similar to that of controls, an effect not seen with placebo. No changes in plasma cortisol occurred 48 hours after either ayahuasca or placebo. The modulation of salivary cortisol may contribute to ayahuasca's rapid antidepressant effects.
bioRxiv (Cold Spring Harbor Laboratory)
March 11, 2025
Chenchen Song, Tinya Chang, Tobias Buchborn et al.
4 citations
preprint
A single dose of the psychedelic psilocybin lastingly improves social behavior in a mouse model of autism (Cntnap2-knockout mice). This effect is blocked by inhibiting DNA methyltransferase I, suggesting an epigenetic mechanism involving DNA methylation underlies psilocybin's long-term influence on social function.
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2024
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
4 citations
preprint
Psilocybin induces fast and sustained improvements in mental well-being, yet its long-term mechanisms are not fully understood. Four weeks after a full dose, fronto-striatal-thalamic (FST) circuitry—involved in goal-directed behavior and motivation—shows increased dynamic activity and flexibility in healthy volunteers. Computational modeling indicates that reduced structural constraints on functional dynamics cause this increased flexibility. Long-term changes include increased bottom-up and reduced top-down information flow, mediated by serotonergic (5-HT2A) and dopaminergic (D2) receptor systems. This functional re-organization of FST circuits may represent a common mechanism underlying clinical improvements across neuropsychiatric disorders such as substance abuse, major depression, and anorexia.
bioRxiv (Cold Spring Harbor Laboratory)
October 21, 2024
Sixtine Fleury, Katherine M. Nautiyal
4 citations
preprint
Psilocybin's persisting clinical effects are commonly attributed to activation of the serotonin 2A receptor, but its active metabolite binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). In mice, 5-HT1BR expression influenced brain-wide activity after psilocybin administration, measured by differences in c-Fos patterns across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. 5-HT1BR mediated some acute and persisting behavioral effects: mice lacking 5-HT1BRs showed attenuated hypolocomotion to psilocybin, and both transgenic and pharmacological loss-of-function models indicated 5-HT1B involvement in decreased anhedonia and reduced anxiety-like behavior. The research implicates 5-HT1BR as a mediator of psilocybin's behavioral and neural effects in mice.
bioRxiv (Cold Spring Harbor Laboratory)
April 15, 2024
Arthur Juliani, Veronica Chelu, Laura Graesser et al.
4 citations
preprint
Serotonergic psychedelics show promise for treating mood and anxiety disorders, but their therapeutic mechanism remains debated. A popular theory holds that strong 5-HT2a receptor activation disrupts cortical dynamics, loosening rigid, maladaptive beliefs and making them open to revision. This work extends that perspective by developing a simple energy-based model of cortical dynamics rooted in predictive processing and neuromodulation. The model simulates hypothetical computational mechanisms for both 5-HT2a and 5-HT1a agonism, and its results account for several existing empirical observations about psychedelics' effects on cognition and affect. The model provides a theoretically grounded hypothesis for the clinical success of LSD, psilocybin, and DMT, and identifies biased 5-HT1a agonist psychedelics like 5-MeO-DMT as potentially fruitful for developing more effective and tolerable psychotherapeutic agents.
bioRxiv (Cold Spring Harbor Laboratory)
November 2, 2023
Jordan Taylor Jacobs, Alan Rockefeller, Harte Singer et al.
4 citations
preprint
*Psilocybe zapotecorum*, a mushroom with historical indigenous use, contains a potent psilocybin concentration of 17.9 mg/g, ranging from 10.6-25.7 mg/g across seven samples. Its full genome, revealing the psilocybin gene cluster, offers new biological insights. Combining Fungal Biology and Applications with Chemical synthesis and alkaloids, the work profiles its complex tryptamine chemistry, including psilocin and baeocystin. A total tryptamine concentration reached 22.5 mg/g. These findings advance Psychedelics and Drug Studies by illuminating the diversity of naturally occurring psilocybin sources.
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2022
Tim Hirschfeld, Johanna Prugger, Tomislav Majić et al.
4 citations
preprint
Lysergic acid diethylamide (LSD) produces a sigmoid-like increase in altered states of consciousness, with effects plateauing around 100 micrograms. The strongest changes involve perception and illusory imagination, followed by positively experienced ego-dissolution, while anxiety and dread of ego dissolution show only small effects. Considerable variability in responses highlights the importance of non-pharmacological factors. These dose-response relationships can serve as references for future research on LSD.
bioRxiv (Cold Spring Harbor Laboratory)
October 11, 2022
Pablo Mallaroni, Natasha L. Mason, Lilian Kloft et al.
4 citations
preprint
Brain functional connectomes are unique and reliable identifiers of individuals, but it was unknown whether these 'fingerprints' persist during altered states of consciousness. Ayahuasca, a serotonergic psychedelic, disrupts functional connectivity. In a within-subject study using 7T fMRI, 21 members of the Santo Daime church were scanned after collective ayahuasca intake. Connectome fingerprinting revealed a shared functional space and a spatiotemporal reallocation of key edges. Differences in higher-order functional connectivity motifs predicted perceptual drug effects, showing that individualized connectivity markers can trace a subject's functional connectome across altered states.
bioRxiv (Cold Spring Harbor Laboratory)
December 19, 2019
J.M. Barnby, Vaughan Bell, Quinton Deeley et al.
4 citations
preprint
Dopamine transmission influences social attributions related to paranoia, but not the salience of paranormal or other beliefs. In a double-blind, placebo-controlled experiment, 27 healthy men received either L-DOPA (150 mg), haloperidol (3 mg), or placebo across three sessions. Haloperidol reduced attributions of harmful intent in a Dictator Game, while L-DOPA reduced such attributions only in fair conditions. Haloperidol unexpectedly increased attributions of self-interest for opponents' decisions. No changes occurred in belief salience for politics, religion, science, morality, or the paranormal. These results suggest dopamine selectively affects social inferences linked to paranoia, independent of mood or skepticism.
bioRxiv (Cold Spring Harbor Laboratory)
January 25, 2018
Flávia Santos Da Silva, Erick Allan Dos Santos Silva, Geovan Menezes de Sousa et al.
4 citations
preprint
In a juvenile model of depression using common marmosets, a single dose of ayahuasca reversed depressive-like symptoms within 24 hours, including recovery of cortisol levels, reduced stereotypic scratching in males, increased feeding, and restored body weight in both sexes. The effects lasted 14 days. The study suggests ayahuasca produces faster and more durable antidepressant effects than the tricyclic antidepressant nortriptyline, supporting its potential as a treatment for early-age depression.
bioRxiv (Cold Spring Harbor Laboratory)
Ruby M. Potash, Sean D. Van Mil, Mar Estarellas et al.
4 citations
preprint
During a deep meditative state called jhana, the brain's non-oscillatory, nonlinear neural activity—rather than oscillatory synchrony—best distinguishes the state from ordinary waking consciousness. In a single highly experienced meditator (over 20,000 hours of practice) studied across 29 sessions, EEG recordings showed that combining subjective ratings of attention with a nonlinear connectivity metric improved the ability to decode the meditative state compared to using neural measures alone. Deeper jhana states were marked by a balance between feedback and feedforward neural processes, indicating an equalization of internally and externally directed information processing. These findings suggest that refined conscious states involve distinct large-scale neural dynamics not captured by traditional oscillatory measures.
bioRxiv (Cold Spring Harbor Laboratory)
July 31, 2025
Rick Zirkel, Matthew Isaacson, Clara Liao et al.
3 citations
preprint
Psilocybin prolongs increases in visual stimulus-evoked capillary blood flow in the mouse visual cortex without altering stimulus-evoked neural activity. This effect was reduced by pretreatment with a 5-HT2A receptor antagonist. Multi-modal widefield imaging confirmed extended vascular responses in surface vessels with no observed effect on population neural response. Computational simulations showed that prolonged neurovascular coupling responses can produce spurious increases in BOLD-based measures of functional connectivity. These findings demonstrate that psilocybin broadens neurovascular responses in the brain, highlighting the need to account for these effects when interpreting human neuroimaging data of psychedelic drug action.
bioRxiv (Cold Spring Harbor Laboratory)
April 14, 2025
Leonardo Novelli, Devon Stoliker, Tamrin Barta et al.
3 citations
preprint
PsiConnect is a large-scale neuroimaging study that examined brain activity in 62 participants before and after a 19 mg dose of psilocybin using functional, structural, and diffusion-weighted MRI combined with EEG. The design included resting-state scans and three naturalistic conditions: guided meditation, music listening, and movie watching. Half of the participants completed an 8-week meditation training program, allowing exploration of interactions among meditation, psilocybin, and brain function. Multi-echo fMRI improved signal-to-noise ratio and reduced artifacts. Behavioral and self-report measures captured acute and longitudinal effects, with follow-ups extending to one year. The data is curated according to open science principles.
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 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.