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 N. 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 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.
Psychopharmacology
April 29, 2026
Anne-Fiona Griesfeller, Lotte Kooman, Lilian Kloft-Heller et al.
A scoping review of 53 sources found no coherent explanation for how psychedelics might recover repressed memories, nor consistent evidence that they do so reliably. Most publications focused on LSD, but few defined what they meant by repressed memory. Proposed mechanisms—psychoanalytical reductions of defensive memory blockades and neurobiological alterations of executive control—lacked empirical support. The review concludes that future work should provide clear definitions, test effects across multiple psychedelic substances, use placebo-controlled designs, and account for the potential occurrence of false memories.
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.
July 3, 2025
Natasha L. Mason, Pablo-Alexandre Mallaroni, Attila Szabo et al.
preprint
The long-term antidepressant effects of classic psychedelics may arise from changes in behavioral processes (decreased rumination, enhanced cognitive flexibility), central processes (downregulation of the hippocampal-prefrontal cortex axis, normalization of glutamate concentrations, increased neuroplasticity), and peripheral processes (downregulation of inflammatory markers). These interconnected changes collectively trigger a sustained therapeutic response, with the glutamatergic system serving as the main interface orchestrating them. The proposed Syner-G model emphasizes glutamatergic-dependent signaling as the primary unifying and synergizing interface between these processes. Future research avenues are suggested to advance understanding of psychedelic mechanisms and neuropsychiatric disease.
International review of neurobiology
January 1, 2025
Iva Totomanova, Eline Haijen, Petra P M Hurks et al.
Small doses of LSD and psilocybin produce subtle acute effects on neural connectivity, brain electrophysiology, blood pressure, sleep duration, pain perception, temporal processing, and mood, and reduce symptoms of depression and obsessive-compulsive behavior in patient samples. Extra-pharmacological factors such as baseline subjective state, expectations, and individual differences in drug metabolism influence treatment outcomes. Controlled microdosing studies suggest potential therapeutic applications, but large-scale clinical trials are still needed.
Neuroscience and Biobehavioral Reviews
July 1, 2022
Drummond E-Wen Mcculloch, Gitte Moos Knudsen, Frederick Streeter Barrett et al.
A large group of psychedelic imaging researchers reviewed 42 articles from 17 unique studies that used resting-state functional magnetic resonance imaging (rs-fMRI) to examine psychedelic effects. They found that nearly all studies varied in data processing and analysis methods, two datasets underpin over half of the published literature, and key outcome terms are used ambiguously. The authors recommend guidelines to improve consistency and replicability in future research, arguing that the field must balance novel methods with standardized approaches to reliably understand the neural mechanisms of psychedelics.
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.
Nature reviews. Neuroscience
July 1, 2021
Johannes G. Ramaekers, Natasha L. Mason, Lilian Kloft et al.
Acute cannabis intoxication can impair neurocognitive function, potentially leading to human error, injury, and psychological distress. However, the impairing effect varies among individuals and may not occur in all users. The neurocognitive response is driven by changes in mesocorticolimbic and salience network activity and can be exacerbated or mitigated by biological and pharmacological factors, product formulations, and frequency of use, and it can differ between recreational and therapeutic use. These determinants should be considered when defining cannabis impairment in legal contexts, prescribing cannabis therapeutically, and informing the public about safe and responsible use.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
December 1, 2019
Natasha L. Mason, Eef L. Theunissen, Nadia R. P. W. Hutten et al.
THC increases striatal glutamate concentrations and reduces functional connectivity between the nucleus accumbens and cortical areas, indicating increased dopaminergic activity. These changes were dose dependent, occurring in the full dose group where THC serum concentrations exceeded 2 ng/ml at T-max. Average glutamate changes correlated strongly with functional connectivity alterations. THC-induced changes in functional connectivity correlated with feelings of subjective high and decreased performance on an attention task. The findings suggest THC elicits subjective and cognitive alterations via increased striatal dopaminergic activity and loss of corticostriatal connectivity, associated with increased striatal glutamate.