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.
JAMA Psychiatry
March 25, 2026
Wiesław Jerzy Cubała, Malek Bajbouj, Michael Bauer et al.
3 citations
A single day of treatment with an inhaled synthetic formulation of mebufotenin (GH001) significantly reduced depression symptoms in adults with treatment-resistant depression compared to placebo. In a randomized, double-blind trial of 81 patients, those receiving up to three escalating doses of GH001 showed an average 15.5-point greater improvement on the Montgomery-Åsberg Depression Rating Scale by day 8 than those on placebo. Remission rates were 57.5% for GH001 and 0% for placebo. No severe or serious adverse events occurred. The findings suggest GH001 may be a rapid-acting, well-tolerated treatment option for treatment-resistant depression.
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.
Drug and Alcohol Dependence
August 11, 2023
Teuntje A. D. Pelgrim, Johannes G. Ramaekers, Matthew B. Wall et al.
3 citations
THC, the main psychoactive component of cannabis, reduces functional connectivity in the salience network—a brain system involved in processing awareness and salient information—specifically weakening connections from the right insula to the left insula and anterior cingulate cortex. A trend toward decreased connectivity was also observed in the hippocampus-midbrain-striatum network, which may relate to acute psychotic-like effects. The COMT Val158Met genotype modulated subjective responses: individuals with the Met/Met genotype experienced the strongest dysphoric reactions and showed reduced connectivity in the hippocampus-midbrain-striatum network after THC. These findings suggest that prefrontal dopamine levels influence the acute effects of cannabis.
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.
Journal of Drug Issues
February 24, 2024
Frederick Vinckenbosch, Eef L. Theunissen, Agnieszka Stelling et al.
2 citations
A survey of 511 nitrous oxide users in the Netherlands found that most inhale the gas from party balloons filled with 4–14 liters, using a repetitive rebreathing technique for about 12 cycles with or without short breaks. 10.3% of respondents reported having inhaled N2O while driving, and many drove within an hour of inhalation. The findings establish a representative dosing method and a relevant timeframe for future research on the drug's psychomotor effects, which may inform policy and enforcement regarding N2O-related road traffic accidents.
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.
Molecular Psychiatry
April 8, 2026
Johannes G. Ramaekers, Kim P. C. Kuypers, Franz X. Vollenweider
1 citation
MDMA, originally developed for military purposes and later used recreationally, is now being tested in clinical trials for PTSD. A narrative review of placebo-controlled single-dose studies in healthy volunteers found that 75-125 mg of MDMA acutely enhances mood, empathy, trust, and arousal while transiently impairing memory encoding through increased serotonin signaling. Motor coordination and cognitive flexibility decline modestly, but inhibitory control and executive function remain largely intact. Post-acutely, fatigue and low mood may occur. These effects may support trauma processing by facilitating fear extinction and disrupting negative memory reconsolidation, though they also complicate trial design by compromising blinding and inflating expectancy.
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.
Journal of Psychedelic Studies
September 8, 2025
Malin Vedøy Uthaug, Giancarlo Allocca, Martha Havenith et al.
1 citation
The paper introduces the concept of 'bodyset'—the state of the body, including both body and brain—as a vital element in preparing for psychedelic experiences, expanding the traditional 'set and setting' framework. Through a literature review, it argues that the body likely matters for wellbeing, peak performance, and peak experiences. Comprehensive multidisciplinary research, especially on biomarkers, is needed to clarify the role of bodyset in psychedelic experiences and therapy outcomes. The authors suggest that considering physical state alongside psychological and environmental factors may enhance understanding of psychedelic effects and inform other treatments like breathwork.
Neuropsychopharmacology
April 22, 2025
Johannes G. Ramaekers
1 citation
No Summary
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.
European Neuropsychopharmacology
October 1, 2016
Kim P. C. Kuypers, Jordi Riba, Mario de la Fuente Revenga et al.
1 citation
Psychedelics show promise in addressing infertility linked to obesity and insulin resistance. In a study of 150 women with polycystic ovary syndrome, 65% experienced improved ovulation rates after psychedelic therapy, alongside significant reductions in hyperinsulinemia and beneficial changes in adipokine levels. These findings suggest that psychedelics may influence neurotransmitter receptors, potentially aiding the endocrine system's regulation of hormones related to reproductive health. The implications extend to internal medicine and biophysics, highlighting a novel intersection between mental health and metabolic disorders.
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
June 26, 2026
Malin V. Uthaug, Jack G. Allocca, Martha 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.
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.
Br J Pain
September 4, 2025
Mauro Cavarra, Nadia R. P. W. Hutten, Jan Schepers et al.
A single 15 μg dose of lysergic acid diethylamide (LSD) did not significantly alter pain perception in healthy volunteers compared to placebo in a randomized controlled trial. The study used a double-blind design to test whether a microdose of LSD would produce analgesic effects, but found no meaningful difference between the LSD and placebo conditions on measures of pain tolerance or threshold.
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.