Research Square
September 20, 2022
Jakub Vohryzek, Joana Cabral, Louis-David Lord et al.
10 citations
Psilocybin therapy for depression shows promise, but how it works is unclear. By comparing responders (those with >50% reduction in symptoms) to non-responders after 10mg and 25mg doses, whole-brain modeling identified specific brain regions whose dynamics shift from a depressive to a healthy state. These regions overlap with maps of serotonin 5-HT2A and 5-HT1A receptors, which psilocin—the active metabolite of psilocybin—activates. The findings provide causal evidence linking serotonergic transmission and recovery from depression via psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
July 25, 2018
Louis-David Lord, Paul Expert, Selen Atasoy et al.
10 citations
preprint
Brain activity can be viewed as exploring a landscape of different activity patterns over time, shifting between stable states of functional connectivity that support various mental processes. In a study using fMRI data from healthy participants given intravenous psilocybin (the active compound in magic mushrooms), researchers analyzed how this dynamical landscape changes during the psychedelic state. They found that a connectivity state linked to the fronto-parietal control system became strongly destabilized, while transitions toward a globally synchronized state increased. These changes suggest the psychedelic state biases the brain toward global integration at the cost of local network segregation, offering a mechanistic perspective on the subjective psychedelic experience and potential guidance for pharmacological interventions in neuropsychiatric disorders.
Drug Science Policy and Law
September 1, 2025
David Nutt, David Erritzøe, Anne Katrin Schlag et al.
9 citations
The field of psychedelic research lacks standardized terminology for clinical development, dosing, safety monitoring, and regulatory classification. A comprehensive framework is proposed that classifies psychedelics by pharmacology (serotonergic, glutamatergic, kappaergic, GABAergic, and atypical), introduces dose-dependent categories (microdose, minidose, mididose, macrodose), and standardizes terms like “short-acting” with specific pharmacokinetic parameters. Safety considerations include cardiovascular and psychological effects, with risk mitigation protocols for higher-risk compounds like ibogaine. A three-phase treatment model—preparation, dosing, and integration—is recommended as a minimum standard. The lack of comparative research on psychotherapy modalities is identified as a critical gap.
Imaging Neurosci (Camb)
January 3, 2025
Kenneth Shinozuka, Prejaas K.b. Tewarie, Andrea I. Luppi et al.
9 citations
LSD weakens the brain's usual hierarchy of information flow by making neural communication more balanced between sending and receiving signals. Using magnetoencephalography (MEG) data from 16 healthy adults given 75 micrograms of LSD intravenously, researchers measured directed functional connectivity under four conditions (eyes-closed with or without music, eyes-open with or without video). Across the whole brain, LSD reduced the asymmetry of directed connectivity over time. Machine learning classifiers distinguished LSD from placebo more accurately using hierarchy metrics than traditional connectivity measures. These results indicate that LSD flattens the brain's hierarchical information processing by increasing the balance between senders and receivers of neural signals.
PsyArXiv
April 13, 2023
Lisa Xiaolu Luan, Emma Eckernäs, Michael Ashton et al.
9 citations
preprint
A within-subjects, placebo-controlled study tested a novel method of administering N,N-Dimethyltryptamine (DMT) by combining a bolus injection with a constant-rate infusion to extend the experience to 30 minutes. The method effectively maintained stable and tolerable subjective effects over the infusion period. Anxiety ratings remained low, and heart rate habituated within 15 minutes, indicating psychological and physiological safety. Plasma DMT concentrations increased consistently starting ten minutes into administration, while psychological effects plateaued, suggesting acute psychological tolerance to DMT. These findings demonstrate the safety and effectiveness of continuous intravenous DMT administration for basic and clinical research.
Drug Science Policy and Law
January 1, 2022
Plinio Ferreira, Adam Winstock, Anne Katrin Schlag et al.
9 citations
Nitrous oxide (laughing gas) and alkyl nitrites (poppers) rank among the least harmful recreational drugs when assessed on 16 criteria including dependence, injury, and economic cost. An expert panel using Multi-Criteria Decision Analysis scored nitrous oxide at 6 and poppers at 5 on a 0–100 overall harm scale, placing them just above magic mushrooms (psilocybin). Nitrous oxide scored higher for dependence, environmental damage, mental impairment, and family adversities; poppers scored higher for injury, drug-related damage, economic cost, and mortality. The findings aim to inform UK policy decisions, as nitrous oxide possession is not currently controlled under the Misuse of Drugs Act.
Psychopharmacology
May 1, 2018
Mendel Kaelen, Bruna Giribaldi, Jordan Raine et al.
9 citations
correction
Music plays a central role in psychedelic therapy by helping to guide and support the therapeutic process. The article synthesizes evidence that music can influence emotional states, facilitate psychological insights, and enhance the overall therapeutic outcome when combined with psychedelic substances. The authors argue that music acts as a "hidden therapist" by directing the trajectory of the psychedelic experience, promoting emotional release, and supporting the integration of the experience afterward. This suggests that careful selection and use of music is crucial for optimizing the therapeutic benefits of psychedelic therapy.
Nature Medicine
April 1, 2026
Manesh Girn, Manoj K. Doss, Leor Roseman et al.
8 citations
Psychedelic drugs are being studied again for their therapeutic potential, but how they change brain function is not well understood. By combining 11 brain-scanning datasets from five different psychedelics (psilocybin, LSD, mescaline, DMT, and ayahuasca) across three continents, researchers found a common pattern: increased communication between brain networks that handle high-level thinking (default, frontoparietal, and limbic) and those that handle sensory input (visual and somatomotor). Key deep-brain regions (thalamus, caudate, putamen) and the cerebellum also changed how they connect with sensorimotor networks. Contrary to some earlier studies, reductions in within-network connectivity were weak to moderate and varied by drug. These findings help resolve previous inconsistencies and provide a comprehensive map of how psychedelics alter large-scale brain organization.
bioRxiv (Cold Spring Harbor Laboratory)
February 15, 2022
Matthew B. Wall, Cynthia Lam, Natalie Ertl et al.
8 citations
preprint
Psychedelic-assisted psychotherapy with psilocybin, which often incorporates music, may enhance the brain's response to emotional stimuli. In nineteen patients with treatment-resistant depression, functional MRI scans taken before and after two psilocybin dosing sessions showed that music listening, compared to resting-state, triggered greater brain activity in the bilateral superior temporal cortex after treatment. The right ventral occipital lobe showed increased activity during the resting-state scan post-treatment. Activity in music-related brain regions correlated with the intensity of subjective effects experienced during dosing. These results suggest psilocybin therapy specifically elevates responsiveness to music, linked to the drug's subjective effects.
bioRxiv
August 21, 2023
Jakub Vohryzek, Joana Cabral, Christopher Timmermann et al.
7 citations
preprint
The brain's activity constantly reorganizes across space and time. A new framework called Harmonic Decomposition of Spacetime (HADES) was developed to track how spatial activity patterns (harmonic modes) change over time. As a proof-of-principle, HADES was applied to brain recordings from healthy participants under the psychedelic DMT and in a normal state. DMT significantly decreased contributions from most low-frequency harmonic modes. After normalizing by condition, a specific decrease appeared in the second functional harmonic, which represents the brain's hierarchy from unimodal to transmodal regions, supporting the hypothesis that psychedelics alter this functional hierarchy. Dynamic measures of fractional occupancy, lifetime, and latent space precisely described changes in the spacetime hierarchical organization of brain activity during the psychedelic state.
medRxiv
June 3, 2023
Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi et al.
7 citations
preprint
Psilocybin therapy for major depressive disorder may work through a different brain mechanism than the SSRI escitalopram. In a trial comparing two groups—one receiving two 25 mg psilocybin doses plus daily placebo, the other receiving daily escitalopram plus two inactive 1 mg psilocybin doses—brain responses to emotional faces were measured with fMRI before and after six weeks of treatment. The escitalopram group showed significantly reduced brain activity in response to fear, happy, and neutral faces, including a specific reduction in amygdala response to fear faces. The psilocybin group showed no such reduction and even a slight increase in brain responsiveness, despite large improvements in depressive symptoms. Reduced emotional responsiveness may be a biomarker of SSRIs' antidepressant action not shared by psilocybin therapy.
Elife
November 9, 2020
Andrea Alamia, Christopher Timmermann, David Nutt et al.
7 citations
correction
No Summary
Neuropharmacology
August 23, 2018
David J Heal, Jack E Henningfield, Bruno G. Frenguelli et al.
7 citations
Psychedelic compounds can temporarily alter brain connectivity, potentially re-opening periods of heightened plasticity that allow rigid neural patterns to be reshaped. This process may facilitate cognitive shifts, including new perspectives and changes in emotional processing, which could underlie therapeutic breakthroughs for various mental health conditions. The text suggests that by disrupting entrenched brain networks, psychedelics enable a reconfiguration of neural pathways, offering a mechanism for lasting improvements in mental well-being.
Frontiers in Psychology
June 6, 2025
William Roseby, Hannes Kettner, Leor Roseman et al.
6 citations
Psychedelics like psilocybin strongly increase the sense that life has meaning, based on three different studies: a clinical trial for depression, a healthy volunteer study, and naturalistic retreats. The 'presence of meaning' rose substantially after a psychedelic experience, while the 'search for meaning' dropped only slightly. These meaning enhancements were moderately linked to improvements in mental health, such as greater wellbeing and reduced depression. Mystical, ego dissolution, and emotional breakthrough experiences were associated with increased meaning, though the strength varied by context. The evidence converges to show a robust, lasting positive effect of psychedelics on meaning in life, with context influencing outcomes.
Communications Biology
March 11, 2025
Juan Ignacio Piccinini, Yonatan Sanz Perl, Carla Pallavicini et al.
6 citations
The transition into a psychedelic brain state is often overlooked in favor of static descriptions of acute effects. Using a time-dependent whole-brain model and fMRI data from 15 volunteers given intravenous DMT, the work shows that a transient of heightened reactivity in fronto-parietal regions and visual cortices correlates with serotonin 5HT2a receptor density. Simulated perturbations suggest that minimal disturbances can achieve maximal effects during this brief period, and the temporal evolution of these features aligns with pharmacokinetics. These findings indicate a mechanism for how short psychedelic episodes may exert a lasting influence over time.
Nat Med
June 1, 2021
David Nutt, Harriet de Wit
6 citations
The text is a brief, playful title that reinterprets the abbreviation MDMA, suggesting a connection to medical doctors (MD) rather than providing substantive content. It does not present a finding, argument, or data.
CNS Spectrums
January 30, 2025
Steve O'Brien, David Nutt
5 citations
MDMA-assisted therapy (MDMA-AT) for PTSD and other behavioral disorders has a controversial history, moving from research to recreational use and back to medicine. Pivotal trials have been conducted, but recent setbacks have hindered clinical application. The chapter argues that MDMA-AT still holds potential to transform psychiatry, though its future is uncertain due to ongoing debates over ethics, methodology, and political influence.
Cambridge University Press eBooks
January 1, 2025
Steve O’Brien, David Nutt
5 citations
MDMA-assisted therapy (MDMA-AT) for PTSD and other behavioral disorders has a complex history, moving from research to recreational use and back to medicine. The chapter argues that despite recent setbacks for its clinical application, MDMA-AT holds potential for transforming psychiatry. It covers pivotal trials and the challenges researchers face, while noting an uncertain future amid ongoing debates over ethics, methodology, and political influence.
bioRxiv (Cold Spring Harbor Laboratory)
April 28, 2024
Kenneth Shinozuka, Prejaas K.b. Tewarie, Andrea I. Luppi et al.
5 citations
preprint
LSD weakens the brain's directed connectivity hierarchy by increasing the balance between senders and receivers of neural signals. This finding supports the REBUS theory, which proposes that psychedelics flatten the hierarchy of information flow in the brain. Analyzing magnetoencephalography data from 16 healthy participants given 75 micrograms of intravenous LSD, the study found that LSD diminishes the asymmetry of directed connectivity averaged over time. Machine learning classifiers distinguished LSD from placebo more accurately when trained on hierarchy metrics than on traditional functional connectivity measures.
bioRxiv
March 20, 2024
Valerie Bonnelle, Amanda Feilding, Fernando E. Rosas et al.
5 citations
preprint
Intense positive emotional experiences induced by psychedelics, known as 'peak experiences', are strong predictors of positive outcomes in psychedelic-assisted therapy. This study investigated how the autonomic nervous system (ANS) relates to such experiences. Analyzing electrocardiogram data from 17 participants who received DMT or placebo, researchers found that coactivation of the sympathetic and parasympathetic branches of the ANS during the DMT experience was strongly correlated with ratings of 'Spiritual Experience' and 'Insightfulness', and also linked to improved wellbeing two weeks later. Additionally, the balance between these branches before DMT injection predicted 'Insightfulness' scores. These findings demonstrate the ANS's involvement in psychedelic-induced peak experiences and suggest potential for biofeedback tools to enhance therapy.
Biochemistry
February 7, 2024
Vito F. Palmisano, Claudio Agnorelli, Andrea Fagiolini et al.
5 citations
Classic psychedelics, which resemble serotonin, act on 5-HT2A receptors inside neurons. This computational study used molecular dynamics simulations to examine how 12 tryptamines cross cell membranes. Dimethylation of the amine group and a methoxy group at position 5 increased permeability. Positional substitutions on the indole ring also influenced permeation, while protonation raised the energy barrier at the bilayer center, making molecules highly impermeable. These simulation-based trends can guide future drug design for psychedelics with improved activity.
Lancet
March 12, 2016
Polly Taylor, David Nutt, Val Curran et al.
5 citations
No Summary
Nat Med
February 16, 2026
David Erritzøe, Tommaso Barba, Tiffanie Benway et al.
4 citations
A single 21.5-mg intravenous dose of the psychedelic DMT, given with psychotherapeutic support, produced a rapid and significant reduction in depressive symptoms in adults with moderate-to-severe major depressive disorder. In a double-blind, placebo-controlled trial with 34 participants, those receiving DMT showed a greater decrease in depression scores at two weeks compared to placebo. Antidepressant effects persisted up to three months in an open-label phase. Adverse events were mostly mild to moderate, and no serious adverse events occurred.
Molecular Psychiatry
April 26, 2025
Rebecca Harding, Neomi Singer, Talma Hendler et al.
4 citations
Psilocybin therapy reduces anhedonia more than the SSRI escitalopram in major depressive disorder, yet escitalopram dampens emotional responses to musical surprises while psilocybin therapy preserves them. Escitalopram increases brain activity in memory and emotion regions during musical surprises, whereas psilocybin therapy decreases activity in the ventromedial prefrontal cortex and angular gyrus and increases sensory region activation. These contrasting neural and behavioral effects suggest fundamentally different treatment mechanisms: psilocybin may maintain subjective responses by reducing the salience of prediction errors or strengthening hedonic expectations, while escitalopram may weaken hedonic priors.
Human Brain Mapping
April 1, 2025
Clayton R. Coleman, Kenneth Shinozuka, Robert Tromm et al.
4 citations
LSD alters consciousness by changing connectivity between the dorsolateral prefrontal cortex (DLPFC), thalamus, and visual areas. In healthy participants, stronger functional connectivity between the left and right DLPFC, thalamus, and fusiform face area correlated with greater ego dissolution. Emotional arousal was linked to increased connectivity between the right DLPFC, intraparietal sulcus, and salience network. A confirmatory reverse analysis supported these findings. Magnetoencephalography data showed that LSD increased theta-band information flow from the thalamus to the DLPFC, supporting the idea that disrupted thalamic gating underlies ego dissolution. The results clarify the DLPFC's role in LSD-induced altered states.