Neuropsychopharmacology
January 26, 2019
M. Madsen, Patrick M. Fisher, Daniel Burmester et al.
505 citations
Psilocybin, the main psychedelic component of magic mushrooms, produces its effects by activating serotonin 2A receptors in the brain. In eight healthy volunteers who received a single oral dose of psilocybin (3–30 mg), PET scans showed dose-related occupancy of these receptors up to 72%. Plasma levels of psilocin, the active metabolite, and receptor occupancy both closely matched subjective ratings of psychedelic intensity, supporting that stimulation of serotonin 2A receptors is a key determinant of the psychedelic experience. Although psilocin levels in the blood varied over time, they were strongly linked to the intensity of the experience, which is important for designing clinical studies.
Proceedings of the National Academy of Sciences
April 13, 2020
Morten L. Kringelbach, Josephine Cruzat, Joana Cabral et al.
326 citations
By combining multimodal neuroimaging data, a framework was developed that demonstrates the fundamental principles of bidirectional coupling between neuronal and neurotransmitter dynamical systems. The work causally explains the functional effects of stimulating specific serotoninergic receptors (5-HT2AR) with psilocybin in healthy humans. This could lead to a better understanding of why psilocybin shows promise as a therapeutic intervention for neuropsychiatric disorders such as depression, anxiety, and addiction.
Curr Biol
September 27, 2018
Gustavo Deco, Josephine Cruzat, Joana Cabral et al.
246 citations
A whole-brain model integrating anatomical, functional, and neurotransmitter data explains how serotonin 2A receptor stimulation with LSD alters brain dynamics. The model combines diffusion MRI, functional MRI, and PET scans of serotonin 2A receptor density to simulate resting-state activity and music listening effects. It shows that LSD's effects arise from non-linear interactions between anatomical connectivity, the brainwide distribution of 5-HT2A receptors, and neuromodulation of neuronal gain. Accounting for neuromodulatory activity in brain models can yield insights into brain function and aid drug discovery for neuropsychiatric disorders.
International Journal of Molecular Sciences
January 15, 2021
Nakul Ravi Raval, Annette Johansen, Lene Lundgaard Donovan et al.
191 citations
A single psychedelic dose of psilocybin increases synaptic density and temporarily reduces serotonin 2A receptor density in the pig brain. One day after injection, hippocampal synaptic vesicle protein 2A (SV2A) density was 4.42% higher, while hippocampal and prefrontal cortex 5-HT2AR density dropped by 15.21% to 50.19%. Seven days later, SV2A density remained significantly higher in the hippocampus (+9.24%) and prefrontal cortex (+6.10%), but 5-HT2AR density had returned to baseline. These persistent synaptic changes and acute receptor down-regulation may underlie psilocybin’s antidepressant effects.
European Neuropsychopharmacology
March 4, 2020
M. Madsen, Patrick M. Fisher, Dea Siggaard Stenbæk et al.
189 citations
A single dose of the serotonin 2A receptor agonist psilocybin can produce lasting beneficial effects on mood and personality, and potentially on mindfulness, but the underlying mechanisms are unclear. In ten healthy, psychedelic-naïve volunteers, psilocybin (0.2-0.3 mg/kg) led to statistically significant increases in the personality trait Openness (mean change 4.2) and in mindfulness (mean change 0.5) at three months. Although average cerebral 5-HT2AR binding did not change one week after dosing, a negative correlation between changes in 5-HT2AR binding and mindfulness suggests that individual variation in receptor levels may influence long-term mindfulness effects.
Journal of Cerebral Blood Flow & Metabolism
April 30, 2014
Anders Ettrup, Sofi Da Cunha‐bang, Brenda Mcmahon et al.
106 citations
A new radioactive tracer, [11C]Cimbi-36, was tested in 29 healthy volunteers for brain imaging using PET scans. This tracer binds to serotonin 2A receptors, which are involved in mood and perception, and is an agonist, meaning it activates the receptor rather than blocking it. High uptake in the brain matched known locations of these receptors. A two-tissue compartment model using arterial blood samples gave the most accurate measurements. In five subjects given a blocker drug (ketanserin), tracer binding decreased in cortical areas but not in the cerebellum, confirming the tracer's specificity and that the cerebellum can serve as a reference region. This is the first agonist PET radioligand to successfully image these receptors in humans.
Frontiers in Pharmacology
March 9, 2022
Drummond E-Wen Mcculloch, Maria Zofia Grzywacz, Martin Bruun Madsen et al.
91 citations
Psilocybin, a psychedelic drug, can produce lasting positive psychological changes in healthy people. In 28 healthy volunteers who received 35 medium-high doses, the intensity of the acute mystical experience, measured by the Mystical Experience Questionnaire, predicted positive persisting effects three months later. Specifically, the subscales for positive mood and mysticality were linked to later benefits, while transcendence of time/space and ineffability were not. Qualitative reports described themes of connection with the Universe, familial love, and profound beauty. The type of acute experience appears important for predicting enduring positive outcomes.
Archives of General Psychiatry
June 6, 2011
David Erritzøe, Vibe G. Frøkjær, Klaus K. Holst et al.
86 citations
MDMA use, but not hallucinogen use, is linked to changes in the brain's presynaptic serotonin system. Because hallucinogens primarily act on serotonin 2A receptors, the negative association between MDMA use and serotonin transporter (SERT) binding is likely due to MDMA's direct presynaptic effect rather than its serotonin 2A agonistic actions. Cross-sectional data suggest that subcortical, but not cortical, SERT binding may recover after several months of MDMA abstinence.
J Neurosci
November 1, 2022
Steven F. Grieco, Eero Castrén, Gitte M. Knudsen et al.
83 citations
Psychedelic drugs are being reexamined as treatments for brain disorders, with hundreds of clinical trials underway by 2022. Emerging evidence suggests these drugs may produce lasting therapeutic effects by inducing structural and functional neural plasticity. The work reviews basic and clinical research on mechanisms, including receptor binding, gene expression, dendritic changes, and effects on microcircuitry and brain-wide circuits. It also outlines unmet clinical needs and unanswered neuroscience questions for future study.
Journal of Psychopharmacology
October 8, 2020
Dea Siggaard Stenbæk, M. Madsen, Brice Ozenne et al.
81 citations
People with higher levels of serotonin 2A receptor (5-HT2AR) binding in the neocortex before taking psilocybin experienced shorter peak psychedelic intensity and a longer time to return to normal consciousness. Higher pre-drug 5-HT2AR binding also predicted lower scores on a measure of mystical-type experiences. The findings reinforce that individual differences in brain 5-HT2AR levels shape the temporal and subjective features of the psilocybin experience.
Journal of Psychopharmacology
June 30, 2021
Drummond E-Wen Mcculloch, Martin Bruun Madsen, Dea Siggaard Stenbæk et al.
79 citations
A single dose of psilocybin in 10 healthy volunteers who had never used psychedelics produced a significant decrease in resting-state functional connectivity within the executive control network (ECN) one week later, an effect that was no longer present at three months. No other changes in brain connectivity were observed at either time point. Exploratory analyses suggested that the decreased ECN connectivity at one week predicted increased mindfulness at three months. The findings point to modulation of the ECN during the psychedelic 'afterglow' period as a possible neural pathway for lasting positive effects on well-being, though the neural basis of personality changes seen at three months remains unknown.
Neuropsychopharmacology
June 21, 2022
Gitte M. Knudsen
56 citations
A single dose of serotonergic classical psychedelics like LSD, psilocybin, or DMT can produce long-lasting effects on personality, such as increased openness, and reduce depressive symptoms. This review synthesizes behavioral, biochemical, neuroimaging, and electrophysiological evidence suggesting that these enduring effects are rooted in neural plasticity. The authors highlight that while the acute emotional effects of these compounds are well understood, the mechanisms behind their sustained benefits remain understudied, and they propose future research directions to clarify how a single psychedelic dose can lead to prolonged therapeutic changes in the brain and mind.
BMC Public Health
December 1, 2015
Christian Jensen, Jon Lansner, Anders Petersen et al.
53 citations
A nine-week meditation-based program called 'Open and Calm' (OC), which trains relaxed, receptive attention and non-intervening witnessing, reduced perceived stress, depressive symptoms, and sleep disturbances while improving quality of life and mental health compared to treatment as usual. Improvements were sustained three months later and were unrelated to age, gender, education, or whether the program was done individually or in a group. The dropout rate was only 6%. The program shows promise for public mental health promotion and reducing stress-related illness.
Journal of Nuclear Medicine
October 18, 2010
Anders Ettrup, Mikael Palner, Nic Gillings et al.
50 citations
A radiolabeled agonist tracer, (11)C-CIMBI-5, was developed for PET imaging of the serotonin 2A (5-HT2A) receptor in the brain. In vitro assays showed CIMBI-5 is a high-affinity agonist at the 5-HT2A receptor. Ex vivo rat studies demonstrated a specific binding ratio of 0.77 ± 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, indicating selective binding. PET studies in pigs revealed a cortical binding potential of 0.46 ± 0.12 and a target-to-background ratio similar to the antagonist tracer (18)F-altanserin. Ketanserin treatment reduced cortical binding to cerebellar levels, confirming selective in vivo binding. (11)C-CIMBI-5 is a promising tool for investigating 5-HT2A agonist binding in the living human brain.
Translational Psychiatry
August 11, 2022
Nicole Fadahunsi, Jens Lund, Alberte Wollesen Breum et al.
47 citations
A single dose of psilocybin substantially alters the prefrontal cortex transcriptome in mice but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Sub-chronic microdosing also has no metabolic effects, does not augment GLP-1-induced weight loss, and does not enhance diet-induced weight loss. A single high dose reduces sucrose preference but fails to counter binge-like eating behavior. These preclinical data discourage clinical investigation, though nuances in psychedelic drug action may require human evaluation.
European Neuropsychopharmacology
December 4, 2020
Lene Lundgaard Donovan, Jens Vilstrup Johansen, Nídia Fernandez Ros et al.
45 citations
A single dose of psilocybin given to awake female pigs caused behavioral changes—headshakes, scratching, and rubbing—lasting about 20 minutes. The dose produced a 67% occupancy of cerebral 5-HT2A receptors and plasma psilocin levels comparable to those in humans during an intense psychedelic experience. One day after injection, 19 genes in the prefrontal cortex were differentially expressed; after one week, only 3 genes were. Gene set enrichment analysis showed multiple immunological pathways were regulated one week after exposure. The authors suggest that any effects on gene expression are very modest, providing a framework for future research into the lasting molecular mechanisms of a single psilocybin dose.
NeuroImage
October 27, 2022
Anders Lykkebo-Valløe, Brice Ozenne, Sophia Armand et al.
44 citations
Psilocybin's acute perceptual psychedelic effects may arise from drug-level decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. The authors apply and argue for a modified approach to modeling eigenvectors from LEiDA that more fully acknowledges their underlying structure. These findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.
Chemical Research in Toxicology
December 16, 2015
Sebastian Leth‐Petersen, Charlotte Gabel‐Jensen, Nic Gillings et al.
43 citations
The metabolism of the potent psychedelic compound 25B-NBOMe, an illicit drug linked to several fatalities, was studied in pigs and humans. The primary metabolic pathway is 5'-demethylation, followed by conjugation to glucuronic acid. These findings were confirmed by carbon-11 labeling of 25B-NBOMe in three different positions and in vivo evaluation in both species.
Human Psychopharmacology Clinical and Experimental
June 14, 2012
Cecilie Löe Licht, M.v. Christoffersen, Mads Okholm et al.
40 citations
Among 98 Danish users of MDMA (Ecstasy) and hallucinogens, simultaneous use of multiple psychoactive substances was common. Participants had tried an average of 12.6 substances in their lifetime. MDMA was frequently combined with amphetamines (69%), hallucinogens (56%), and cocaine (47%). Alcohol and cannabis were used before, during, and after MDMA, LSD, and psilocybin, while amphetamines were typically taken before these drugs. Users preferred specific combinations to enhance or counteract effects. At their last recalled use, MDMA was taken with an average of 2.1 other substances in 32 different combinations.
Frontiers in Psychology
October 5, 2022
Anna Søndergaard, Brice Ozenne, Sophia Armand et al.
35 citations
People who took psilocybin showed significantly higher trait mindfulness three months later, and the size of this increase was linked to how intense their mystical-type experience was during the drug session. Higher trait mindfulness before taking psilocybin was associated with lower serotonin 2A receptor binding in the right amygdala, a brain region involved in emotional processing. These findings suggest that the acute, mystical quality of the psilocybin experience may help shift awareness in ways that support mindful living, and that pre-existing mindfulness relates to specific brain receptor patterns.
Headache The Journal of Head and Face Pain
January 1, 2024
Anja Sofie Petersen, Inger Marie Sørensen, Harald Schiønning et al.
29 citations
In a small open-label trial, ten people with chronic cluster headache received three doses of psilocybin (0.14 mg/kg) over three weeks. Attack frequency dropped by an average of 31% from the four-week baseline to the four-week follow-up, and one patient had 21 weeks of complete remission. Changes in hypothalamic–diencephalic functional connectivity correlated negatively with the reduction in attack frequency, suggesting this neural pathway may be involved in the treatment response. The treatment was well tolerated. The results indicate psilocybin may have prophylactic potential for chronic cluster headache, though larger controlled studies are needed.
The Lancet
February 11, 2023
Florence Butlen‐ducuing, Drummond E-Wen Mcculloch, Marion Haberkamp et al.
28 citations
No Summary
bioRxiv (Cold Spring Harbor Laboratory)
February 5, 2021
M. Madsen, Dea Siggaard Stenbæk, Albin Arvidsson et al.
27 citations
preprint
Psilocybin, a psychedelic drug, produces its effects through its active metabolite psilocin, which activates serotonin 2A receptors in the brain. In fifteen healthy individuals given a moderate oral dose (0.2–0.3 mg/kg), higher plasma psilocin levels and stronger subjective drug intensity correlated with reduced integrity and segregation of brain networks, particularly the default mode network, and with increased connectivity between networks such as the executive control and dorsal attention networks. These changes in functional brain architecture tracked the time course and magnitude of the psychedelic experience, linking network desegregation to altered consciousness.
Neuropsychopharmacology
March 8, 2019
M. Madsen, Patrick M. Fisher, Daniel Burmester et al.
21 citations
correction
No Summary
medRxiv
July 3, 2023
Drummond E-Wen Mcculloch, Anders S. Olsen, Brice Ozenne et al.
20 citations
preprint
Psychedelics like psilocybin are thought to increase brain entropy, but previous findings have not been replicated. In 28 healthy participants with 121 fMRI scans taken before and after psilocybin, brain entropy was measured alongside plasma psilocin levels, serotonin 2A receptor occupancy, and subjective drug intensity. Shannon entropy of path-length and instantaneous correlation distributions showed significant positive associations with drug effects, while sample entropy showed divergent associations depending on time-scale. However, 8 of 13 entropy metrics showed no significant effects, and the metrics correlated poorly with each other. The results suggest a nuanced acute effect of psilocybin on brain entropy and highlight specific metrics that may mediate clinical effects.