Journal of Psychoactive Drugs
February 3, 2021
Bhanu Sharma, David W. Lawrence, Roland R. Griffiths et al.
37 citations
An analysis of the top-cited classic psychedelic publications found that recent highly cited work (published after 2010) focuses more on clinical trials and therapeutic applications, especially for affective and substance use disorders, while older highly cited work was dominated by basic science and preclinical studies. Psilocybin was the primary substance in recent top-cited articles, whereas LSD was more common in older ones. The recent cohort also had a much higher annual citation rate. The field is moving from foundational pharmacological understanding toward identifying clinical uses.
Neuroimage
January 29, 2021
Beatrice M. Jobst, Selen Atasoy, Adrián Ponce-Alvarez et al.
37 citations
After taking LSD, the brain's dynamics become less stable and more diverse in response to perturbations. Using a whole-brain computational model fitted to fMRI data from individuals under LSD or placebo, researchers simulated external disruptions to different brain regions. They measured recovery time with the Perturbational Integration Latency Index (PILI). Globally, LSD caused consistently higher PILI values, indicating a shift further from stable equilibrium. Locally, the largest differences appeared in the limbic, visual, and default mode networks. LSD also increased variability of PILI across brain regions, suggesting greater response diversity. These findings reveal brain-wide dynamical changes underlying the psychedelic state and suggest potential clinical applications for psychiatric disorders.
J Psychopharmacol
June 15, 2020
Anna Borissova, Bart Ferguson, Matthew B. Wall et al.
37 citations
MDMA did not increase prosocial behavior in a controlled laboratory setting, despite raising blood levels of the drug and self-reported feelings of closeness and euphoria. In a double-blind, placebo-controlled experiment with 20 healthy volunteers, MDMA (100 mg) failed to significantly change task-based measures of empathy, trust, or cooperative behavior compared to placebo. Bayesian analyses supported the conclusion that MDMA and placebo had equivalent effects on empathy and cooperation. The drug also did not alter mood three days after administration. These findings suggest that the acute prosocial effects of MDMA observed in naturalistic or therapeutic contexts may not replicate under controlled experimental conditions.
Journal of Affective Disorders
July 15, 2023
Matthew B. Wall, Cynthia Lam, Natalie Ertl et al.
36 citations
Psilocybin-assisted therapy for depression alters the brain's response to music, suggesting an elevated responsiveness to music after treatment that is related to subjective drug effects during dosing. Nineteen patients with treatment-resistant depression underwent two psilocybin dosing sessions. Brain scans before and after treatment showed increased activity in the superior temporal cortex when listening to music, and decreased activity in the medial frontal lobes during rest. These changes in music-related brain activity correlated with the intensity of subjective effects felt during the psilocybin sessions. The findings imply that psychedelic therapy may enhance emotional responsiveness to music, which could be relevant for treating depression.
Hypertension
March 8, 2021
Otto Simonsson, Peter S. Hendricks, Robin Carhart-Harris et al.
36 citations
Adults who had used a classic psychedelic at least once in their lifetime had 14% lower odds of hypertension in the past year, after adjusting for confounders. The association was strongest for tryptamine psychedelics (DMT, ayahuasca, psilocybin), which were linked to 20% lower odds of hypertension. No significant association was found for LSD or mescaline. The authors note these findings are correlational and call for randomized controlled trials to test causal effects.
Journal of Affective Disorders
March 1, 2025
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
35 citations
In treatment-resistant depression, a single dose of 25 mg of psilocybin produced stronger correlations between certain psychedelic experiences and depression improvement three weeks later than lower doses. The intensity of psychedelic effects was dose-related, but scores for different doses overlapped considerably. At the 25 mg dose, dimensions of oceanic boundlessness and visual restructuralization, along with emotional breakthrough, showed the strongest correlations with reduced depression scores. The study does not establish causation and requires replication. The overlap in experience intensity across doses suggests unblinding to dose is less likely. Correlations between psychedelic experience and outcome indicate specificity in psilocybin's mechanism of action.
J Palliat Med
April 13, 2021
Yvan Beaussant, James A. Tulsky, Benjamin Guérin et al.
34 citations
Researchers from palliative care, psychosocial oncology, spiritual care, oncology, and psychedelic-assisted therapies identified seven key opportunities for advancing research on psychedelic-assisted therapy for people with serious illness. Four opportunities relate to science and design: clarifying which conditions the therapy is indicated for, developing and refining therapeutic protocols, investigating how set and setting affect outcomes, and understanding mechanisms of action. Three opportunities concern institutional and societal drivers: education and certification for therapists, regulations and funding, and diversity and inclusion. Participants also noted epistemological limitations of the medical model for understanding psychedelics' therapeutic value.
Conscious Cogn
December 8, 2020
Camila Sanz, Carla Pallavicini, Facundo Carrillo et al.
34 citations
Language produced under the influence of LSD shows increased entropy and reduced semantic coherence, consistent with a state of heightened neural entropy. Non-semantic analysis of speech organization revealed increased verbosity and a reduced lexicon, changes more similar to manic psychoses than to schizophrenia, as confirmed by direct comparison with reference samples. Features related to language organization allowed machine learning classifiers to identify speech under LSD with accuracy comparable to that obtained by examining semantic content. These results provide a quantitative characterization of disorganized natural speech as a landmark feature of the psychedelic state.
Brain Communications
January 1, 2024
Jakub Vohryzek, Joana Cabral, Louis-David Lord et al.
33 citations
Psilocybin therapy for depression shows promise, but its causal mechanisms are unknown. By comparing brain dynamics in treatment responders (those with >50% symptom reduction) and non-responders before treatment, researchers used large-scale brain modeling to identify brain regions whose perturbation could shift a depressive brain state to a healthy one. The identified regions correlated with density maps of serotonin receptors 5-HT2a and 5-HT1a, where psilocin (psilocybin's active metabolite) acts as an agonist. These findings provide causal mechanistic evidence linking specific brain regions and serotonergic transmission to recovery from depression via psilocybin.
Sci Rep
July 26, 2023
Balázs Szigeti, David Nutt, Robin Carhart-Harris et al.
33 citations
Blinding in medical trials aims to evenly distribute expectancy effects between treatment groups, but it often fails. Using computational modeling, this work shows that weak blinding combined with positive treatment expectancy creates an 'activated expectancy bias' (AEB), which can inflate treatment effect estimates and produce false positive results. The authors introduce the Correct Guess Rate Curve (CGRC) to estimate outcomes of a perfectly blinded trial from imperfectly blinded data. Re-analyzing a self-blinding psychedelic microdose trial dataset, they find that observed placebo-microdose differences are susceptible to AEB and may be false positives, suggesting microdosing acts as an active placebo. The findings highlight the distinction between trials with a placebo control group and genuinely placebo-controlled trials.
Neuroscience & Biobehavioral Reviews
April 4, 2025
Claudio Agnorelli, Kate Godfrey, Gabriela Sawicka et al.
32 citations
Classic psychedelics (LSD, psilocybin, N,N-DMT) and non-classic psychedelics (ketamine, MDMA) enhance neuroplasticity—the nervous system's ability to adapt—through molecular, structural, and functional changes. Animal studies indicate these drugs induce meta-plasticity (heightened sensitivity to environmental stimuli) and hyper-plasticity (re-opening developmental windows for long-term structural changes), with implications for mood and behavior. Translating these findings to humans faces challenges due to limitations in current imaging techniques, but promising new directions include novel PET radioligands, non-invasive brain stimulation, and multimodal approaches. This review informs the development of targeted interventions for neuropsychiatric disorders.
J Affect Disord
February 27, 2024
Debora Copa, David Erritzøe, Bruna Giribaldi et al.
31 citations
Brain connectivity patterns measured before psilocybin treatment can predict how much depression symptoms will improve. In people with treatment-resistant depression given two doses of psilocybin (25 mg each, one week apart), baseline resting-state functional MRI scans showed that connectivity within visual, default mode, and executive networks predicted early symptom improvement, while salience network connectivity predicted who would respond up to 24 weeks later, with about 90% accuracy. Similar patterns appeared in a separate trial comparing psilocybin to escitalopram. Fronto-occipital and fronto-temporal connections predicted early and late symptom reduction, respectively. Small sample sizes and differences between datasets limit generalizability, and the lack of a placebo arm limits specificity.
Scientific Reports
August 22, 2023
Hannes Kettner, Stephen Ross, Richard J. Zeifman et al.
31 citations
Co-using a low dose of MDMA with psilocybin or LSD is associated with less intense challenging experiences—such as grief and fear—and increased feelings of self-compassion, love, and gratitude, compared to using psilocybin or LSD alone. In a survey of 698 people planning to use these substances, the 27 who also took a low dose of MDMA reported these benefits without a reduction in mystical-type experiences or compassion. Medium-to-high MDMA doses did not show the same effects. The findings suggest MDMA may buffer against some difficult aspects of psychedelic experiences, but the study's small, non-experimental convenience sample limits certainty.
bioRxiv (Cold Spring Harbor Laboratory)
May 17, 2021
S. Parker Singleton, Andrea I. Luppi, Robin Carhart-Harris et al.
30 citations
preprint
LSD and psilocybin reduce the amount of energy the brain needs to transition between different activity states, as measured by functional MRI. This flattening of the brain's control energy landscape allows for more frequent state transitions and more diverse (entropic) brain activity. The effects are linked to the spatial distribution of serotonin 2a receptors, the main target of these psychedelics. The findings suggest that these compounds make brain state transitions more facile and temporally diverse, offering a mechanistic explanation for the altered subjective experience induced by psychedelics.
J Psychopharmacol
January 27, 2024
Jessica Barbut Siva, Tommaso Barba, Hannes Kettner et al.
29 citations
A prospective survey study examined how serotonergic antidepressants affect the acute subjective experience of classic psychedelics and subsequent well-being and depressive symptoms. People taking antidepressants reported less intense mystical-type experiences and greater anxiety during psychedelic sessions compared to those not on antidepressants. Despite this blunting, both groups showed similar improvements in well-being and reductions in depressive symptoms after the session. The findings suggest that while antidepressants may dampen the acute psychedelic experience, they do not necessarily hinder long-term mental health benefits.
PLoS Computational Biology
February 1, 2023
Giulio Ruffini, Giada Damiani, Diego Lozano-Soldevilla et al.
28 citations
Brain dynamics under LSD become more disordered and complex, moving further from the critical point that characterizes healthy brain function. Using Ising spin models fitted to fMRI data from fifteen participants, the authors show that LSD reduces interhemispheric connectivity, especially between corresponding regions in opposite hemispheres. Ising temperatures were significantly higher under LSD than placebo, indicating a shift into a more disordered (paramagnetic) state. Algorithmic complexity of brain activity, measured by block decomposition, correlated with both Ising temperature and condition, supporting the entropic brain hypothesis that psychedelics increase neural disorder.
Network Neuroscience
January 1, 2022
Josephine Cruzat, Yonatan Sanz Perl, Anira Escrichs et al.
28 citations
Psychedelic drugs like LSD and psilocybin may treat neuropsychiatric disorders by dose-dependently altering the brain's functional hierarchy—the organization of neural activity across regions. Using a turbulence framework that measures local synchronization (vorticity) in both space and time, researchers found that both drugs produce consistent and distinct effects, particularly compressing the default mode network, a higher-level network. These findings support the hypothesis that psychedelics modulate the functional hierarchy and provide a quantitative comparison of how LSD and psilocybin change brain dynamics, with implications for therapeutic use.
Neuroimage
December 1, 2023
Stefano Delli Pizzi, Piero Chiacchiaretta, Carlo Sestieri et al.
27 citations
LSD selectively alters the functional connectivity between specific thalamic nuclei and sensory and associative cortical areas. Using structural and resting-state functional MRI in healthy volunteers under acute LSD administration, researchers found increased coupling of the ventral complex, pulvinar, and non-specific thalamic nuclei with somatosensory and auditory cortices, as well as with associative cortex regions rich in serotonin 2A receptors. At subcortical levels, LSD increased connectivity among these thalamic nuclei but decreased striatal-thalamic connectivity. These nucleus-specific changes help explain LSD's modulation of subcortical-cortical circuits and associated behavioral effects.
bioRxiv (Cold Spring Harbor Laboratory)
May 3, 2020
Manesh Girn, Leor Roseman, Boris C. Bernhardt et al.
27 citations
preprint
LSD and psilocybin flatten the brain's hierarchical organization, reducing the functional separation between sensory and higher-order cognitive networks. Using a non-linear dimensionality reduction technique on resting-state fMRI data, the authors found that both drugs compressed the principal gradient of cortical connectivity, which normally spans from unimodal (sensory) to transmodal (association) cortex. This flattening was driven by decreased differentiation at both ends of the hierarchy—default and frontoparietal networks at the upper end and somatomotor networks at the lower end—and was accompanied by increased crosstalk between unimodal and transmodal regions. Changes in the principal gradient under LSD tracked self-reported ego-dissolution. The findings support a mechanistic model of the psychedelic state and demonstrate that macroscale connectivity gradients are sensitive to serotonergic modulation.
Scientific Reports
January 29, 2025
Richard J. Zeifman, Meg J. Spriggs, Hannes Kettner et al.
26 citations
A preliminary test of the REBUS model found that a high dose of psilocybin (25 mg) reduced confidence in negative self-beliefs in 11 healthy individuals, both during the acute experience and four weeks later. Greater brain signal entropy and stronger subjective effects under psilocybin correlated with larger decreases in negative self-belief confidence. Decreases in negative self-belief confidence were linked to increases in well-being. The findings provide initial evidence that relaxing and revising negative self-beliefs may underlie psilocybin's positive psychological effects, with increased neuronal entropy as a possible mechanism. Replication in larger clinical samples is needed.
Journal of Psychopharmacology
March 22, 2024
Tommaso Barba, David Erritzøe, Meg J. Spriggs et al.
26 citations
In a clinical trial comparing psilocybin plus psychological support to escitalopram plus psychological support for major depressive disorder, patients who discontinued their SSRI or SNRI medication before receiving psilocybin showed a reduced treatment effect on all depression severity and well-being measures compared with those who were unmedicated at trial entry. Discontinuation did not affect the intensity of the acute psychedelic experience. The findings are exploratory and hypothesis-generating, not confirmatory, and the study did not test SSRI/SNRI continuation. A controlled trial comparing discontinuation versus continuation before psilocybin is needed.
International Journal of Mental Health and Addiction
March 7, 2024
Brandon Weiss, Leor Roseman, Bruna Giribaldi et al.
26 citations
Acute psychological experiences, particularly mystical experience and ego dissolution, partially account for how psilocybin therapy improves depression compared to escitalopram. In a phase 2 trial of patients with moderate-to-severe major depressive disorder, mystical experience and ego dissolution uniquely mediated the effect of treatment on depressive response. Higher levels of mystical experience, emotional breakthrough, and intense music-listening responses were also linked to greater antidepressant improvement. These findings suggest that acute psychological experiences play a causal mechanistic role in psilocybin therapy for depression.
bioRxiv (Cold Spring Harbor Laboratory)
August 10, 2020
Andrea I. Luppi, Jakub Vohryzek, Morten L. Kringelbach et al.
26 citations
preprint
Consciousness arises from how the brain's structural wiring shapes its dynamic activity. By decomposing resting-state fMRI data into harmonic modes of the human structural connectome, a generalizable signature of lost consciousness emerges—whether from anesthesia or brain injury—while a reversed signature characterizes psychedelic states induced by LSD or ketamine, reflecting decoupling of function from structure. This connectome harmonic approach discriminates between behaviorally indistinguishable brain-injured patients and tracks covert consciousness, linking neurobiology to conscious experience.
Brain
January 1, 2024
Andrea I. Luppi, Manesh Girn, Fernando E. Rosas et al.
25 citations
Serotonin 2A receptor (5-HT2AR) signaling drives both the evolutionary expansion and ongoing modulation of the human cerebral cortex's most complex cognitive centers. The cortex is organized along a gradient from simple sensory processing to high-level integration, with the transmodal cortex at the apex—a region disproportionately enlarged in humans and rich in 5-HT2AR expression. During early brain development, 5-HT2AR signaling on neural progenitor cells stimulates their proliferation, contributing to cortical expansion. In the adult brain, 5-HT2AR agonism promotes neuroplasticity, learning, and cognitive flexibility with therapeutic potential. The receptor thus plays a dual role in enabling cortical growth and sophisticated functioning.
bioRxiv (Cold Spring Harbor Laboratory)
May 8, 2020
Andrea Alamia, Christopher Timmermann, Rufin Vanrullen et al.
25 citations
preprint
The psychedelic drug DMT rapidly induces an immersive conscious state with vivid visual imagery. EEG recordings showed that DMT alters cortical traveling waves: the typical alpha-band backward wave of eyes-closed rest decreased, while a forward wave similar to that seen during visual stimulation increased. This supports a model where psychedelics reduce the precision-weighting of prior expectations, shifting the balance from top-down to bottom-up information flow. The findings suggest that backward traveling waves are correlates of precision weighting and that reduced backward and increased forward waves are a mechanistic principle of psychedelic-induced altered states.