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.
Frontiers in Psychiatry
May 19, 2022
Eef L. Theunissen, Kim P. C. Kuypers, Natasha L. Mason et al.
7 citations
At equal levels of subjective intoxication, natural cannabis (THC) and the synthetic cannabinoid JWH-018 both impair psychomotor function, divided attention, and impulse control to a similar degree. Both drugs also produce psychotomimetic effects, but JWH-018 causes considerably more pronounced dissociative effects than THC. The study matched participants from two placebo-controlled experiments by their subjective high to compare the drugs' neurocognitive and psychotomimetic profiles, concluding that psychotropic dose equivalence offers a uniform method for comparing CB1 receptor agonists.
medRxiv
November 1, 2022
Natasha L. Mason, Attila Szabo, 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.
Frontiers in Psychiatry
April 14, 2022
Johannes G. Ramaekers, Eef L. Theunissen, Peter van Ruitenbeek et al.
6 citations
Comparing brain function between chronic cannabis users and non-users may be confounded by factors like polydrug use, alcohol, withdrawal, or lifestyle. A proposed methodology uses acute Δ9-tetrahydrocannabinol (THC) dosing studies to directly assess neuroadaptations in chronic users. This approach quantifies neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge and stratifies users from occasional to dependent. It enables evaluation of THC-induced neuroadaptive and neurocognitive changes across cannabis use history, informing neurobiological models of reward-driven, compulsive cannabis use.
Human Psychopharmacology Clinical and Experimental
October 25, 2018
Patrick C. Dolder, Elizabeth B. de Sousa Fernandes Perna, Natasha L. Mason et al.
6 citations
4-Fluoroamphetamine (4-FA), a novel psychoactive substance with effects between MDMA and amphetamine, reduced cognitive empathy while leaving emotional empathy unaffected in healthy poly-drug users. Plasma oxytocin levels increased one hour after a 100 mg dose compared with placebo, but this hormonal change was unrelated to the behavioral effects on empathy. The findings indicate that 4-FA affects empathy differently from MDMA and amphetamine, and confirm that drug-induced changes in peripheral oxytocin are not associated with empathy.
Journal of psychopharmacology (Oxford, England)
April 1, 2025
Manoj K. Doss, Lilian Kloft, Natasha L. Mason et al.
5 citations
In experienced users, ayahuasca acutely enhances recollection-based memory—the ability to recall specific details—without increasing false memories or affecting familiarity-based memory, a feeling of knowing. In an observational study of 24 Santo Daime members who had consumed ayahuasca over 500 times on average, participants completed a false memory task before and after taking a self-selected church dose. After ayahuasca, hit rates, memory accuracy, and recollection improved, while familiarity and false memory remained unchanged. The authors suggest that β-carboline activity in the brew may account for this recollection enhancement, which contrasts with past psychedelic research showing impaired recollection. Practice effects could not be ruled out, but multiple measures of false memory and metamemory did not improve across sessions.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Francisco Madrid-Gambin, Noemí Haro, Natasha L. Mason et al.
4 citations
The metabolome—the collection of small molecules in blood—differs between occasional and chronic cannabis users both when sober and after acute THC intoxication. Fourteen metabolites, mainly involved in endocannabinoid and amino acid metabolism, distinguished the two groups with 80% accuracy. During intoxication, occasional users showed attentional impairment and elevated subjective high, accompanied by increases in organic acids, β-hydroxybutyrate, and ceramides; chronic users did not show these changes. The findings demonstrate that metabolomic profiling can identify metabolic alterations specific to the neurocognitive state of cannabis intoxication and to cannabis use frequency.
Psychopharmacology
April 30, 2025
Johannes G. Ramaekers, Johannes T. Reckweg, Natasha L. Mason et al.
4 citations
Low to moderate doses of 3-methylmethcathinone (3-MMC) produce prolonged, dose-related analgesic effects in healthy volunteers. In a cross-over, placebo-controlled study with 14 participants, doses of 25, 50, and 100 mg elevated pressure pain threshold and reduced subjective painfulness and unpleasantness in both pressure pain threshold and cold pressor test paradigms. The analgesic effects were most prominent after 50 and 100 mg and persisted for up to 5 hours after dosing. 3-MMC also produced dose-related mood improvements at 1 hour but not at 5 hours. The findings suggest that doses low enough to avoid challenging subjective experiences and associated with a benign side effect profile may be sufficient for analgesia.
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)
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)
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.
Frontiers in Psychology
January 1, 2025
Johannes T. Reckweg, Natasha L. Mason, Eef L. Theunissen et al.
2 citations
A three-item Peak Experience Scale (PES) was developed to quickly gauge the intensity of the psychoactive experience with the psychedelic 5-MeO-DMT and to guide dosing. Data came from three studies involving 84 healthy volunteers and patients with treatment-resistant depression who inhaled a 5-MeO-DMT formulation at doses of 0 (placebo), 2, 6, 12, or 18 mg, or an incremental individualized dosing regimen. PES ratings increased significantly with dose, peaking after the individualized regimen. The scale showed strong internal consistency and high correlation with other psychedelic assessment tools like the Mystical Experience Questionnaire and Ego Dissolution Inventory, but not with the Challenging Experience Questionnaire. The PES is an effective, simple tool for rapidly assessing psychedelic experience strength and may help guide dosing of rapid-acting psychedelics.
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.
Biological Psychiatry
October 21, 2025
Katharina S Lege, Pablo Mallaroni, Sepehr Mortaheb et al.
1 citation
Acute cannabis intoxication alters brain network dynamics, reducing the occurrence of a hyperconnected brain state in both occasional and chronic users. Chronic users show persisting neuroadaptations, including decreased brain network segregation, independent of intoxication. Attentional performance is most impaired in occasional users, suggesting tolerance develops in chronic users. Both acute and persistent effects on brain dynamics correlate with spatial CB1 receptor density. The findings indicate that cannabis-induced cognitive impairment depends on individual neuroadaptations and receptor density, relevant for therapeutic, legal, and societal contexts.
medRxiv
November 20, 2024
Jan Ramaekers, Johannes T. Reckweg, Natasha L. Mason et al.
1 citation
preprint
In the first human study of 3-methylmethcathinone (3-MMC), a synthetic cathinone designer drug, 14 participants received escalating doses of 25, 50, and 100 mg in a placebo-controlled crossover trial. The drug caused dose-dependent increases in heart rate and blood pressure that were not clinically significant, along with subjective feelings of being high. 3-MMC also enhanced performance across several neurocognitive domains, including processing speed, cognitive flexibility, psychomotor function, attention, and memory, without affecting impulse control. Participants reported mild dissociative and psychedelic effects, decreased appetite, and transient increases in drug liking and wanting. The cardiovascular and psychostimulant profile resembles amphetamine-related compounds. Low to moderate doses were well tolerated and safe, with potential health risks likely only at high or excessive doses.
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.
Journal of Psychedelic Studies
June 26, 2026
Malin V. Uthaug, Jack G. Allocca, Martha N. Havenith et al.
A new construct called Pivotal Physical States (PiPS) is proposed as the bodily counterpart to Pivotal Mental States (PiMS). PiMS theory holds that psychedelics and stressors like fasting and hypoxia can trigger transformative mental states via serotonin receptor activation, enhancing cognitive flexibility and learning. The paper argues that these same stressors also induce profound bodily changes through the peripheral serotonin system and other somatic mechanisms, creating 'pivotal states' spanning the mind–body continuum. This dual action may enable psychological and physiological recalibration in positive or negative directions depending on moderators. The authors call for empirical validation of PiPS to guide integrated research and therapeutic applications.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
June 1, 2026
Francisco Madrid-Gambin, Pablo Mallaroni, Noemí Haro et al.
The psychedelic state induced by ayahuasca arises from coordinated, system-level interactions between peripheral metabolism and brain network dynamics, rather than isolated neurochemical events. In 20 experienced ceremonial users, the subjective dimensions of oceanic boundlessness, visionary restructuralization, and auditory alterations covaried with circulating DMT and β-carbolines, shifts in lipid, amino acid, and energy metabolism, and reconfiguration of dorsal attention and default mode network connectivity. Shared features across these experiences were most strongly linked to endocannabinoid-related N-acylethanolamines, acylglycerols, and ceramides, extending beyond canonical serotonergic models to downstream lipid-signaling and metabolic processes. The findings offer translational insight into metabolic pathways that may modulate brain function and subjective response.
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.