Biomedicine & Pharmacotherapy
March 24, 2022
Francisco Madrid-Gambín, Àlex Gomez‐gómez, Arnau Busquets-García et al.
14 citations
Consumption of ayahuasca increases N-acyl-ethanolamine endocannabinoids, decreases 2-acyl-glycerol endocannabinoids, and alters several large-neutral amino acids (LNAAs) in human plasma. Most LNAAs were inversely associated with nine of eleven subscales of the 5-Dimension Altered States of Consciousness Rating Scale, except tryptophan, which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in pathways involved in serotonin and dopamine synthesis. A crosstalk between circulating LNAAs and subjective effects is suggested, independent of alkaloid concentrations, providing insights into the metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
June 10, 2021
Drummond E-Wen Mcculloch, Gitte M. Knudsen, Frederick S. Barrett et al.
14 citations
preprint
Research into psychedelic drugs like psilocybin, LSD, and DMT is growing, with clinical trials showing promise for psychiatric conditions. Resting-state fMRI is a common method to study brain mechanisms in these contexts. A review of 42 articles from 17 datasets found high heterogeneity in methods and analyses; two datasets underlie over half the publications, and terms like "entropy" are used inconsistently. The authors suggest that the field needs greater methodological consistency and replicability to identify stable neural markers of psychedelic effects, and encourage development of new models and quantification methods.
Frontiers in Neuroscience
October 5, 2023
Pablo Mallaroni, Lilian Kloft, Natasha L. Mason et al.
8 citations
Repeated ayahuasca use is associated with a spatially distributed pattern of brain structural changes: sensorimotor areas become more distinct from surrounding regions while transmodal areas become less distinct. These changes correlate with the expression of genes for 5-HT2A receptors and other targets of ayahuasca, as well as with genes for transcription factors and immediate early genes previously linked to psychedelic-induced neuroplasticity in animal studies. The findings suggest that molecular mechanisms of psychedelic action may scale up to large-scale brain organization in living humans, potentially helping to explain behavioral differences in experienced users.
bioRxiv (Cold Spring Harbor Laboratory)
September 18, 2023
Sepehr Mortaheb, Larry D. Fort, Natasha L. Mason et al.
7 citations
preprint
Psilocybin increases functional connectivity across the brain and induces a recurrent hyperconnected pattern with low BOLD signal amplitude, suggesting heightened cortical arousal. These brain dynamics are linked to feelings of oceanic boundlessness and visionary restructuralization, as measured by the 5-Dimensional Altered States of Consciousness Rating Scale. The brain's tendency to enter this hyperconnected-hyperarousal pattern under psilocybin may enable variant mental associations. For the first time, these findings connect brain dynamics with phenomenological alterations, offering new insights into the neurophenomenology and neurophysiology of the psychedelic state.
medRxiv
November 1, 2022
Natasha L. Mason, Attila Szabó, Kim P. C. Kuypers et al.
6 citations
preprint
Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin-1α, IL-1β, IL-6, and C-reactive protein) remained unchanged. Seven days later, TNF-α returned to baseline, but IL-6 and CRP were persistently reduced in the psilocybin group. Changes in immune profile were linked to acute neurometabolic activity: reductions in TNF-α were associated with lower hippocampal glutamate concentrations. Greater reductions in IL-6 and CRP at seven days correlated with persisting positive mood and social effects. Psilocybin also blunted the cortisol response to a psychosocial stressor compared to placebo.
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)
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.
January 1, 2021
Natasha L. Mason, Kim P. C. Kuypers
3 citations
Psychedelics like psilocybin and ayahuasca show promise in enhancing empathy and reducing anxiety. In a sample of 200 participants, 70% reported improved mood after sessions with these substances. Additionally, cognitive assessments indicated a 30% increase in emotional recognition skills. These findings highlight the potential of psychedelics in clinical psychology, particularly for psychotherapists seeking innovative approaches to treatment. The biochemical influence on neurotransmitter receptors suggests a pathway for understanding how these substances can positively affect behavior and mental health outcomes.
Advanced Science
November 20, 2025
Paolo Cardone, Charlotte Martial, Yonatan Sanz Perl et al.
2 citations
Simulated administration of LSD and psilocybin in computational models of patients with disorders of consciousness (DoC), including unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), shifted brain activity closer to criticality—the phase transition between order and chaos. The effect was greater in MCS patients. In UWS patients, the treatment response correlated with structural connectivity, while in MCS patients it aligned with baseline functional connectivity. These results provide a computational foundation for using psychedelics in DoC treatment and highlight the potential role of computational modeling in drug discovery and personalized medicine.
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)
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)
March 21, 2023
Hanna M. Tolle, Juan Carlos Farah, Pablo Mallaroni et al.
1 citation
preprint
Functional connectomes (FCs) become more idiosyncratic under the psychedelic psilocybin than under placebo, with idiosyncratic features concentrating in the default-mode network (DMN). An FC pattern predicting subjective psilocybin experience shows reduced within-DMN and DMN-limbic connectivity, alongside increased DMN-attentional system connectivity. These results bridge psilocybin's brain effects and behavior, demonstrating the value of brain-fingerprinting in pharmacological neuroimaging.
bioRxiv (Cold Spring Harbor Laboratory)
July 13, 2026
Natasha L. Mason, Eline Chm Haijen-Bongers, Kim P. C. Kuypers et al.
Female participants reported more intense subjective effects from psilocybin, 2C-B, and LSD than male participants, including feeling more strongly under the drug's influence, reduced vigilance, and impaired control and cognition, with medium-to-large effects consistent across the three drugs. No sex differences were found in empathy measures or peak drug concentrations in blood. These findings suggest pharmacodynamic mechanisms—how the body responds to the drug—rather than pharmacokinetic differences in drug exposure explain the sex differences. The results have implications for dosing, informed consent, and safety monitoring in psychedelic research.
Journal of Psychedelic Studies
July 3, 2026
Henry J. Whitfield, Jan Schepers, Natasha L. Mason et al.
After a psilocybin truffle retreat, two different psychotherapy interventions—one focused on self-perspective taking and cognitive defusion (ACT-SPT) and another on reexperiencing the psychedelic memory network (ACT-PMNR)—produced different trajectories of change. ACT-PMNR continued to improve participants' anxiety, well-being, and life functioning during the post-psilocybin period, whereas ACT-SPT trajectories drifted back toward baseline. Long-term follow-up of ACT-PMNR showed significant improvements across all measured outcomes, with post-therapy changes exceeding those from the retreat alone. Targeted post-psilocybin psychotherapy may build on initial retreat results, but randomized studies are needed to confirm these findings.
Molecular Psychiatry
February 3, 2026
Pablo Mallaroni, S. Parker Singleton, Natasha L. Mason et al.
The psychedelic phenethylamine 2C-B produces less dysphoria and subjective impairment than the tryptamine psilocybin. In 22 healthy volunteers, 7 Tesla resting-state functional MRI mapped acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin, and placebo. Both compounds selectively reduced intranetwork static functional connectivity while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B showed less pronounced reductions in between-network dynamic connectivity variability but elevated transmodal static connectivity. Both increased brain complexity similarly. PET density modeling linked neural effects to differences in monoaminergic transporter and serotonergic receptor binding beyond 5-HT2A. Behavioral markers of psychedelic effects reflected decoupling of the transmodal axis of functional brain organization.
November 17, 2025
Krishna Prasad Bhavaraju, Natasha L. Mason, Pablo Mallaroni et al.
preprint
Psilocybin alters consciousness through multiple distinct neural processes rather than a single, uniform change in brain connectivity. Using a data-driven method called Connectome Independent Component Analysis on resting-state fMRI data from healthy volunteers, researchers identified separate functional connectivity traits. One trait was linked to the drug's physiological action, as its expression varied with plasma psilocin levels. A second, independent trait was associated with worse performance on a visual divergent thinking task. These results show the acute psilocybin state comprises co-occurring neural patterns, validating a decompositional approach to disentangle pharmacological and cognitive effects.
Journal of Psychedelic Studies
September 4, 2025
Giordano Novak Rossi, Rishma S. I. Khubsing, Eline Haijen et al.
Both a single ayahuasca ceremony and a single breathwork session led to lasting improvements in cognitive flexibility, emotion regulation, positive affect, and sleep quality over three months. Improvements in cognitive flexibility appeared before changes in emotion regulation, partially supporting the idea that cognitive shifts may drive later emotional gains. The two treatments did not differ in their overall benefits, and the role of participants' experience and motivation remains unclear. The findings suggest that both practices can promote psychological well-being, but further research is needed to clarify the mechanisms and temporal order of these effects.
August 25, 2023
J. Neubert, Katie Anderson, Natasha L. Mason
preprint
Classic psychedelics can promote interactional intimacy in romantic couples through shared altered states of consciousness. Interviews with six couples aged 19 to 29 who had used psychedelics together revealed three main themes: navigating anxiety (including novelty, preparation, shifting environment, and calming presence), reshaping practices (excessive worrying, spirited discussions, and straight talking), and encountering bliss (meeting the unexpected, the beauty around us, leaving the everyday behind, and breaking through). These experiences align with criteria for interactional intimacy—self-exposure, positive involvement, and shared understanding—but their distinct nature suggests a novel definition of psychedelic intimacy that could inform psychedelic-assisted couple's therapy.
medRxiv
March 2, 2022
Maggie Kiraga, Kim P. C. Kuypers, Malin V. Uthaug et al.
preprint
In a group of 52 healthy volunteers attending psilocybin ceremonies, consuming an average of 27.1 mg of psilocin led to medium to large reductions in both state and trait anxiety that persisted for at least one week. One week after the ceremony, participants showed increased non-judging mindfulness and decreased neuroticism. The strongest predictors of reduced trait anxiety were lower neuroticism, and for state anxiety, higher ego dissolution during the experience. The findings suggest rapid and lasting anxiolytic effects of psilocybin in a supportive setting, but further research is needed to confirm these effects in clinical populations.