bioRxiv (Cold Spring Harbor Laboratory)
November 3, 2022
Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al.
5 citations
preprint
The short-acting psychedelic 5-MeO-DMT increases head-twitch response in mice in a dose-dependent manner, with a shorter duration than psilocybin. It strongly suppresses social ultrasonic vocalizations during mating behavior and produces long-lasting increases in dendritic spine density in the medial frontal cortex by elevating the rate of spine formation, but unlike psilocybin, it does not affect spine size. These findings reveal behavioral and neural effects of 5-MeO-DMT and highlight both similarities and differences with psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
July 23, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
5 citations
preprint
Psilocybin and the serotonin precursor 5-HTP both cause a characteristic head twitch response in mice, a behavior linked to the human psychedelic experience. The head twitch response depends primarily on the 5-HT2A receptor, as blocking this receptor with volanserin reduced the response. Activating the 5-HT1A receptor also reduced head twitching. In contrast, blocking the 5-HT2C receptor had a bimodal effect, enhancing the response at lower doses but reducing it at higher doses. Blocking the trace amine associated receptor 1 (TAAR1) reduced head twitching caused by 5-HTP but not by psilocybin, indicating a differential role for this receptor. These findings identify multiple receptors that could be targeted to modulate the effects of psychedelic compounds in therapeutic settings.
bioRxiv (Cold Spring Harbor Laboratory)
July 13, 2022
Andrea I. Luppi, Justine Y. Hansen, R. Adapa et al.
5 citations
preprint
Psychoactive drugs reshape brain function by engaging multiple neurotransmitter systems simultaneously. By mapping the distribution of 19 neurotransmitter receptors and transporters (via PET) and the connectivity changes caused by 10 drugs (anesthetics, psychedelics, and stimulants), the study shows that drug effects are organized along hierarchical gradients of brain structure and function. Additionally, brain regions susceptible to drug-induced changes are also vulnerable to structural alterations from brain disorders. These findings reveal systematic links between molecular neurochemistry and large-scale functional reorganization.
bioRxiv (Cold Spring Harbor Laboratory)
June 29, 2020
Joaquín González, Matías Cavelli, Santiago Castro‐zaballa et al.
5 citations
preprint
Ibogaine, a psychedelic alkaloid with anti-addictive properties, produces a waking state that shares brain-wave traits with REM sleep. In rats, ibogaine increased gamma oscillation power in the brain but made those oscillations less coherent and less complex than normal waking levels. This pattern mirrors REM sleep features within the gamma frequency band, providing biological evidence for the long-standing hypothesis that ibogaine induces a dream-like state while awake—a phenomenon called oneirogenesis. The findings offer an empirical basis for understanding how ibogaine's unique subjective effects may contribute to its anti-addictive potential.
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)
November 21, 2020
Matthew B. Wall, Tom P. Freeman, Chandni Hindocha et al.
4 citations
preprint
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are two major cannabis constituents with contrasting actions: THC is psychoactive and addiction-promoting, while CBD may have opposite effects. In two placebo-controlled, double-blind studies, inhaled THC (8 mg) strongly disrupted functional connectivity in associative and sensorimotor striatal networks, and this disruption was selectively alleviated in the limbic striatum when co-administered with CBD (10 mg). Oral CBD (600 mg) alone increased connectivity in the associative network but caused minor decreases in limbic and sensorimotor networks. The insula emerged as a key region affected by cannabinoid-induced connectivity changes, with implications for cannabis-related disorders and cannabinoid therapeutics.
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)
July 19, 2019
Natasha L. Mason, Eef L. Theunissen, Nadia R. P. W. Hutten et al.
4 citations
preprint
Regular cannabis users develop tolerance to the drug's impairing and rewarding effects, but the underlying brain changes are unclear. In a double-blind, randomized, placebo-controlled crossover study, 12 occasional and 12 chronic cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, then underwent ultra-high field fMRI and magnetic resonance spectroscopy. In occasional users, cannabis caused decreased functional connectivity and increased striatal glutamate concentrations in reward circuitry, linked to greater subjective high and worse sustained attention. These changes were absent in chronic users, suggesting reduced responsiveness of reward circuitry to cannabis intoxication and a pharmacodynamic mechanism for tolerance development.
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.