Proceedings of the National Academy of Sciences of the United States of America
March 28, 2023
Christopher Timmermann, Leor Roseman, Sharad Haridas et al.
217 citations
Intravenous DMT, a potent psychedelic and serotonin 2A receptor agonist, profoundly alters brain function in healthy volunteers. In a placebo-controlled study with 20 participants, multimodal neuroimaging (EEG-fMRI) showed that DMT robustly increases global functional connectivity, disrupts and desegregates brain networks, and compresses the principal cortical gradient. These changes overlapped with brain regions rich in serotonin 2A receptors and associated with human-specific psychological functions. EEG and fMRI measures correlated, linking neurophysiological changes to network-level effects. The findings indicate DMT predominantly acts on the brain's transmodal association cortex, the evolutionarily recent area tied to advanced cognition and high 5-HT2A receptor density.
Scientific reports
November 23, 2021
Christopher Timmermann, Hannes Kettner, Chris Letheby et al.
208 citations
People who use psychedelic drugs often shift away from materialist views of reality and consciousness toward panpsychism and fatalism, with most changes lasting at least six months. In a large prospective online survey, these belief shifts correlated with greater past psychedelic use and improved mental health. Emotional synchrony with others during the experience mediated the changes, and baseline impressionability moderated them. An independent clinical trial confirmed the direction of belief change, suggesting psychedelics may causally influence metaphysical beliefs away from hard materialism, though contextual independence remains uncertain.
NeuroImage
February 15, 2021
Andrea I Luppi, Robin L Carhart-Harris, Leor Roseman et al.
186 citations
LSD alters brain network dynamics non-uniformly over time, making globally segregated connectivity states more complex and weakening the link between functional and anatomical connectivity. The drug reduces functional connectivity in the anterior medial prefrontal cortex specifically during states of high segregation. Ego dissolution was predicted by increased small-world organization during a state of high global integration. These temporally-specific effects reveal a more nuanced picture of psychedelic-induced changes in brain connectivity and complexity than previously reported.
International journal of environmental research and public health
December 16, 2019
Hannes Kettner, Sam Gandy, Eline C H M Haijen et al.
159 citations
People who use psychedelics report a stronger sense of connection to nature, and this increase lasts for at least two years. In a prospective online study, individuals planning to use a psychedelic completed questionnaires before and after their experience. Nature relatedness was significantly higher at 2 weeks, 4 weeks, and 2 years after the experience. The increase was linked to greater psychological well-being and depended on how strongly participants felt ego-dissolution and how much they perceived their natural surroundings during the acute psychedelic state. The findings suggest a causal, context-dependent effect of psychedelic use on nature relatedness, with implications for mental health treatments and planetary health.
Nature communications
October 3, 2022
S Parker Singleton, Andrea I Luppi, Robin L Carhart-Harris et al.
156 citations
Psychedelics like LSD and psilocybin temporarily alter subjective experience by acting on serotonin 2a (5-HT2a) receptors, increasing the diversity (entropy) of brain activity. This increase may arise from a flattening of the brain's control energy landscape. Using fMRI data, the authors show that these compounds reduce the control energy needed for transitions between brain states compared to placebo. Across individuals, lower control energy correlates with more frequent state transitions and higher entropy. Incorporating PET data on 5-HT2a receptor distribution under non-drug conditions, the analysis links these receptors to reduced control energy. The findings demonstrate that receptor-informed network control theory can model how neuropharmacological manipulation affects brain dynamics.
Therapeutic advances in psychopharmacology
February 1, 2015
Hannah Steeds, Robin L Carhart-Harris, James M Stone
132 citations
Schizophrenia involves positive, negative, and cognitive symptoms, and about one-third of patients do not respond to existing medications. This review evaluates how drugs acting on dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic, and kappa opioid systems model aspects of schizophrenia in animals and humans. Understanding interactions between these neurotransmitter systems and their links to symptoms is crucial for forming a coherent hypothesis of schizophrenia's pathogenesis and developing new therapies.
Journal of Psychopharmacology
January 1, 2016
Jana Speth, Clemens Speth, Mendel Kaelen et al.
119 citations
A single dose of LSD (75 μg) reduced how often people spontaneously thought about the past, while thoughts about the present or future remained unchanged. In a placebo-controlled crossover study with 20 healthy volunteers, fewer references to past mental spaces appeared in reports collected about 2.5 hours after intravenous administration. This reduction correlated with the drug's subjective intensity and with decreased resting-state functional connectivity within the default-mode network, a brain system involved in autobiographical memory and rumination. The findings suggest LSD may reduce past-focused thinking, which could be relevant for treating conditions like depression where excessive reflection on the past is common.
Communications biology
January 28, 2023
Andrea I Luppi, Jakub Vohryzek, Morten L Kringelbach et al.
98 citations
Consciousness depends on how tightly brain function follows the brain's physical wiring. Using MRI scans, researchers measured structure-function coupling across spatial scales in people who were unconscious from anesthesia or brain injury and in people under psychedelics (LSD or ketamine). During loss of consciousness, function more closely tracked the brain's structural connections, a signature that could distinguish behaviorally similar brain-injured patients and detect covert consciousness. In contrast, psychedelics decoupled function from structure, and this decoupling correlated with physiological and subjective scores. The findings suggest that connectome harmonic decomposition reveals how neuromodulation and network architecture jointly shape consciousness.
ACS chemical neuroscience
February 7, 2024
Pedro A M Mediano, Fernando E Rosas, Christopher Timmermann et al.
60 citations
LSD increases brain entropy (neural signal diversity) across all conditions, but the effect is strongest when eyes are closed. Brain entropy changes correlate with subjective psychedelic experience ratings, except when viewing a video, possibly because external stimuli compete with LSD-induced imagery. This shows context modulates neural dynamics during psychedelic experiences, highlighting the importance of environment in psychedelic psychotherapy.
Journal of affective disorders
August 1, 2023
Richard J Zeifman, Anne C Wagner, Candice M Monson et al.
56 citations
In a double-blind randomized controlled trial comparing psilocybin therapy (two 25 mg sessions plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among 59 individuals with major depressive disorder, reductions in experiential avoidance mediated improvements in well-being, depression severity, suicidal ideation, and trait anxiety only in the psilocybin group. Exploratory analyses indicated that these improvements (except for suicidal ideation) occurred serially through increased connectedness. Experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance. The findings support reduced experiential avoidance as a mechanism underlying psilocybin therapy's positive outcomes.
Psychological medicine
October 1, 2023
Jonathan W Kanen, Qiang Luo, Mojtaba Rostami Kandroodi et al.
44 citations
LSD increases the rate at which people learn from both rewards and punishments during a probabilistic reversal learning task, suggesting a state of heightened learning plasticity. Healthy volunteers given intravenous LSD or placebo completed a task where they had to learn which of three stimuli was most often rewarded, with the reward contingencies later reversing. Computational modeling of reinforcement learning showed that LSD primarily enhanced the reward learning rate and also elevated the punishment learning rate, while decreasing stimulus stickiness (a measure of choice repetition), indicating increased exploration. These effects point to a potential mechanism by which LSD could help revise maladaptive associations in clinical treatment.
Journal of psychopharmacology (Oxford, England)
January 1, 2024
Lisa X Luan, Emma Eckernäs, Michael Ashton et al.
41 citations
A novel method of administering the psychedelic DMT via a bolus injection followed by a constant-rate infusion safely extends the experience to 30 minutes in a stable and tolerable fashion. In eleven healthy volunteers, subjective effects plateaued into a steady state while plasma DMT concentrations continued to rise, indicating acute psychological tolerance. Anxiety ratings remained low and heart rate habituated within 15 minutes, demonstrating psychological and physiological safety. This continuous intravenous administration method lays groundwork for further basic and clinical research into DMT's potential for treating mental health conditions and studying consciousness.
Psychological medicine
January 1, 2024
Brandon Weiss, Induni Ginige, Lu Shannon et al.
38 citations
In a trial comparing psilocybin therapy with the antidepressant escitalopram for moderate-to-severe major depressive disorder, both treatments led to personality changes in a direction consistent with improved mental health. Psilocybin was linked to decreases in neuroticism, introversion, disagreeableness, and impulsivity, and increases in absorption, conscientiousness, and openness at six weeks, with some changes lasting six months. Escitalopram was linked to decreases in neuroticism, disagreeableness, and impulsivity, and increases in openness at six weeks, with neuroticism remaining decreased at six months. No significant differences between the two treatments were observed, except that patients' pre-trial positive expectations for escitalopram moderated personality changes after that treatment, but not after psilocybin.
Scientific Reports
February 7, 2024
Christopher Timmermann, Richard J Zeifman, David Erritzoe et al.
37 citations
Intravenous DMT, a fast-acting psychedelic, improved depression scores in healthy volunteers one to two weeks after administration. In a placebo-controlled comparison (13 participants) and a prospective dataset (17 participants), depression severity decreased significantly. Reductions in trait neuroticism appeared only in the placebo-controlled sample. Changes in depression and anxiety correlated with the intensity of acute peak experiences, suggesting that DMT may reduce depressive symptoms by inducing such experiences. The short half-life and flexible dosing of intravenous DMT make it a practical candidate for psychedelic medicine, though further research in clinical samples is needed.
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.
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.
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.
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
April 25, 2023
Brandon Weiss, David Erritzoe, Bruna Giribaldi et al.
24 citations
A reanalysis of data from a trial comparing psilocybin therapy (PT) to escitalopram (ET) for major depressive disorder found that 14 of 16 outcome measures favored PT, but the QIDS-SR-16 did not. The QIDS-SR-16 showed higher variance, imprecision from compound items and sum-scoring, vague response options, and lack of focus on a core depression factor. When the trial data were examined at item, facet, and factor levels, results suggested PT was superior in reducing depressed mood, anhedonia, a core depression factor, and specific symptoms like sexual dysfunction. This raises concerns about relying on individual scales that miss depression's multidimensional structure.
NeuroImage
November 1, 2022
Hardik Rajpal, Pedro A M Mediano, Fernando E Rosas et al.
23 citations
Schizophrenia and drug-induced states from LSD and ketamine both increase neural signal diversity, but they differ in brain connectivity: schizophrenia shows increased information flow from front to back of the brain, while the drugs reduce it. These differences can be modeled by altering Bayesian inference in a predictive processing framework: drug effects correspond to reduced precision of prior beliefs, whereas schizophrenia involves increased precision of sensory information. The findings clarify similarities and differences between these altered states, with implications for understanding consciousness and developing mental health treatments.
Neuroscience of consciousness
January 1, 2025
Christopher Timmermann, James W Sanders, David Reydellet et al.
19 citations
The psychedelic 5-MeO-DMT can, in its most extreme cases, produce a complete absence of self-experience and other perceptual content while preserving a quality of aroused, waking awareness. In an exploratory observational study in naturalistic ceremonial settings, micro-phenomenological interviews, questionnaires, and EEG recordings revealed a dynamic progression of effects, including variable disruptions of bodily and narrative self, reduced phenomenal distinctions, and visual imagery. EEG showed global alpha and posterior beta power reductions, suggesting inhibition of top-down brain models. The findings indicate 5-MeO-DMT's potential as a pharmacological model for deconstructed consciousness, though retrospective questionnaires have limitations.
Biological psychiatry. Cognitive neuroscience and neuroimaging
July 1, 2023
Stefano Delli Pizzi, Piero Chiacchiaretta, Carlo Sestieri et al.
18 citations
LSD alters brain functional connectivity and local signal amplitude in opposite directions depending on the type of serotonin receptor involved. In healthy volunteers, LSD increased activity and connectivity in cortical regions of the default mode and attention networks, which have high densities of 5-HT2A receptors; these changes correlated with visual hallucinations. Conversely, LSD decreased activity and connectivity in limbic areas rich in 5-HT1A receptors. The spatial patterns of these functional changes overlapped with the distribution of the two serotonin receptor subtypes, suggesting distinct receptor-mediated mechanisms underlie LSD's reorganization of brain networks.
American Journal of Psychiatry
May 7, 2025
Matthew B Wall, Lysia Demetriou, Bruna Giribaldi et al.
16 citations
Psilocybin therapy greatly improved depressive symptoms but had only a small effect on how the brain responds to emotional stimuli. This contrasts with SSRIs, which often reduce emotional responsiveness alongside their antidepressant action. The findings suggest that psychedelic therapy may work through different neural mechanisms than conventional antidepressants.
Journal of psychopharmacology (Oxford, England)
October 1, 2024
Valerie Bonnelle, Amanda Feilding, Fernando E Rosas et al.
16 citations
The joint influence of the sympathetic and parasympathetic nervous systems over cardiac activity, known as sympathovagal coactivation, is positively related to ratings of spiritual experience and insightfulness during the DMT-induced peak experience, and also to improved well-being two weeks later. The balance between the two autonomic branches before DMT injection predicted insightfulness scores and subsequent coactivation. These findings demonstrate the autonomic nervous system's involvement in psychedelic-induced peak experiences.
Journal of Psychopharmacology
November 14, 2022
Meg J Spriggs, Bruna Giribaldi, Taylor Lyons et al.
15 citations
A fixed 25 mg dose of psilocybin produces similar acute psychedelic effects and improvements in well-being regardless of body mass index (BMI). Pooling data from three therapeutic studies, results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes, or emotional breakthroughs. There was weak evidence that lower BMI participants reported greater 'dread of ego dissolution,' but BMI did not meaningfully add to predictions beyond age, sex, and study. Mystical-type experiences and emotional breakthroughs strongly predicted well-being improvements, but BMI did not. These findings suggest body weight-adjusted dosing may be unnecessary, supporting fixed dosing to reduce practical and financial burdens on psychedelic therapy scalability.